2000 / Review / Strong evidenceThe landmark IOM report found therapeutic promise for cannabinoids in pain, nausea, and appetite, recommended against smoking in favor of an inhaler, called for research investment, and found limited gateway and addiction risks.
2001 / Longitudinal Cohort / Moderate evidenceOver 15 years, cannabis abusers were four times more likely to develop depression including suicidal thoughts. Depression at baseline did not predict future cannabis abuse, arguing against self-medication.
2001 / Review / Preliminary evidenceIn one of the only controlled studies of suicidal substance abusers, fluoxetine reduced depression, suicidal ideation, alcohol, and marijuana use, with benefits lasting one year.
2001 / Randomized Controlled Trial / Moderate evidenceTHCV-COOH, a urinary metabolite unique to natural marijuana, reliably distinguished marijuana use from prescription Marinol use in a controlled crossover study.
2001 / Review / Moderate evidenceThe endocannabinoid system is disrupted in Huntington's, Parkinson's, schizophrenia, and tremor, offering both pathological insights and therapeutic targets including agonists, antagonists, and endocannabinoid modulators.
2001 / Review / Preliminary evidenceAustralian editorial arguing for prosecution exemptions for patients using cannabis medicinally, noting that while cannabinoid drugs were not registered, patient need warranted a compassionate policy response.
2001 / Review / Preliminary evidenceConference report showing whole cannabis extracts outperformed single cannabinoids for spasticity in animal models, while UK clinical trials for pain and multiple sclerosis were underway.
2001 / Review / Moderate evidenceComprehensive review finding solid evidence for cannabinoids in nausea and appetite, emerging evidence for pain and spasticity, and weak evidence for glaucoma and asthma, while advocating for non-smoked delivery methods.
2001 / Review / Moderate evidenceA review by THC discoverer Raphael Mechoulam tracing cannabinoids from ancient use to modern clinical applications in nausea, appetite, multiple sclerosis, arthritis, and neuroprotection.
2001 / Randomized Controlled Trial / Moderate evidenceA small randomized trial found that single-dose THC (5-10 mg) for Tourette syndrome did not impair cognition across multiple domains, unlike findings from recreational cannabis use studies.
2001 / Animal Study / Preliminary evidenceChronic THC treatment in rats did not produce tolerance to memory impairment or hippocampal acetylcholine reduction, with both effects mediated by CB1 receptors but operating on different timescales.
2001 / Pilot Study / Preliminary evidenceA synthetic cannabinoid eye drop reduced eye pressure by up to 31% in 8 glaucoma patients who had not responded to conventional treatments, working through CB1 receptors in the eye.
2001 / Systematic Review / Strong evidenceSystematic review of 30 trials finding cannabinoids outperformed conventional antiemetics for chemotherapy nausea (NNT 6) and vomiting (NNT 8), but with notable side effects including dizziness and dysphoria.
2001 / Review / Preliminary evidenceReview of European workplace drug testing finding it far less standardized than US programs, with cannabis as the most frequently detected substance and significant gaps in quality control.
2002 / Observational / Moderate evidenceEconometric study using cigarette prices as a natural experiment found evidence that smoking leads to cannabis use, but weak evidence that cannabis use leads to harder drugs, challenging gateway theory.
2002 / Longitudinal Cohort / Moderate evidencePopulation-based study of 232 first schizophrenia episodes finding double the rate of substance abuse compared to controls, with cannabis used by 88% of drug abusers and drug use often preceding illness onset.
2002 / Animal Study / Preliminary evidenceAnimal study showing a compound from passionflower reduced THC tolerance, dependence, and withdrawal symptoms in mice, suggesting potential for cannabis withdrawal treatment.
2002 / Longitudinal Cohort / Strong evidenceA 21-year study of 1,265 New Zealand children found cannabis use linked to crime, depression, suicidal behavior, and other drug use, with younger users (14-15) affected more than older users (20-21).
2002 / Observational / Preliminary evidenceA California compassionate access program found that all 9 glaucoma patients given THC or marijuana discontinued within 9 months due to tolerance and side effects, despite initial pressure reduction.
2002 / Cross Sectional / Moderate evidenceTwin study of 3,360 male pairs finding that the genetic link between depression and cannabis/alcohol dependence was largely explained by shared genetic risk for antisocial personality disorder.
2002 / Review / Moderate evidenceComprehensive review mapping how cannabinoids affect different brain regions: memory in the hippocampus, movement and reward in the basal ganglia, appetite in the hypothalamus, with neuroprotective properties.
2002 / Review / Moderate evidenceReview finding cannabis increases heart rate with rapid tolerance development, poses minimal risk for young healthy users but significant risks for people with existing cardiovascular disease.
2002 / Cross Sectional / Moderate evidenceA nationally representative US twin study found cannabis use in the past year was at least 60% heritable, with identical twins much more similar than fraternal twins or siblings.
2002 / Randomized Controlled Trial / Moderate evidenceRandomized trial in 16 MS patients found neither oral THC nor cannabis extract reduced spasticity, and both worsened patients' overall impression compared to placebo.
2002 / Review / Moderate evidenceReview finding that blocking or removing CB1 receptors enhanced memory performance, suggesting the endocannabinoid system normally constrains memory formation, while also modulating opioid dependence.
2002 / Randomized Controlled Trial / Moderate evidenceFirst RCT showing THC significantly reduces tics and OCD symptoms in Tourette syndrome, with effects linked to the 11-OH-THC metabolite rather than THC itself.
2002 / Review / Moderate evidenceReview of 9 clinical trials and animal research finding cannabinoids reduced spasticity, pain, tremor, and bladder symptoms in MS, with elevated endocannabinoid levels in spastic conditions.
2002 / Animal Study / Preliminary evidenceElectrophysiology study showing cannabinoids strongly inhibited excitatory inputs to the brain's reward center through CB1 receptors, independent of dopamine and opioid systems.
2002 / Observational / Preliminary evidenceStudy discovering endocannabinoids in human reproductive fluids and cannabinoid receptors on sperm, finding that cannabinoid compounds and THC impaired sperm capacitation and fertilizing potential.
2002 / Review / Moderate evidenceReview finding cannabinoids can reduce MS spasticity and pain but questioning their superiority over existing treatments, with too few controlled trials for definitive conclusions.
2002 / Review / Moderate evidenceReview finding that smoking cessation did not increase relapse to other substances and continued smoking actually worsened marijuana treatment outcomes, supporting integrated treatment.
2003 / Review / Moderate evidenceGW Pharmaceuticals developed Sativex and other cannabis medicines, with phase III trials showing significant neuropathic pain reduction in MS, leading to licensing with Bayer AG.
2003 / Review / Moderate evidenceLancet Neurology review arguing that cannabinoid therapeutic potential extends beyond MS symptoms to neuroprotection, and that the field was only beginning to appreciate the possibilities.
2003 / Observational / Preliminary evidenceStopping heavy cannabis use was linked to withdrawal that began within 1–3 days, peaked in Days 2–6, and typically resolved by two weeks.
2003 / Review / Moderate evidenceComprehensive review cataloging cannabinoid therapeutic potential across MS, Parkinson's, neuroprotection, pain, and appetite, highlighting non-psychoactive cannabinoids as potentially offering benefits without psychoactivity.
2003 / Review / Moderate evidenceReview documenting that cannabis and other drugs of abuse suppress immune function through receptor-mediated mechanisms, increasing infection susceptibility, with implications for HIV/AIDS.
2003 / Review / Moderate evidenceReview comparing cardiovascular effects of five substance classes, finding cannabis posed fewer heart risks than opiates, amphetamines, or alcohol, though cognitive effects were noted.
2003 / Review / Strong evidenceComprehensive pharmacokinetics review: inhaled THC peaks in minutes and lasts 2-3 hours; oral THC takes 30-90 minutes and lasts 4-12 hours, with therapeutic applications across pain, nausea, and neuroprotection.
2003 / Review / Moderate evidenceNature Reviews Cancer paper documenting that cannabinoids inhibited tumor growth in lab and animal studies while being well tolerated, raising the question of anticancer therapeutic potential.
2003 / Review / Moderate evidencePolicy review finding THC moderately effective for nausea, appetite, and pain, comparing medical cannabis approaches across US, UK, Australia, and Canada.
2003 / Review / Strong evidenceMajor Brain journal review finding cannabis cognitive impairments appear reversible with little evidence of brain pathology, and limited evidence for causal psychiatric illness links.
2003 / Cross Sectional / Preliminary evidenceBrain wave study showing chronic cannabis users processed auditory attention differently, with reduced P3 responses to targets and greater effects in early-onset users, undetected by standard tests.
2003 / Randomized Controlled Trial / Strong evidenceFirst long-term controlled trial showing THC (up to 10 mg/day) significantly reduced Tourette syndrome tics over 6 weeks in 24 patients with no serious adverse effects.
2003 / / evidenceIn anesthetized rats, activating CB1 receptors in the brainstem's ventrolateral medulla increased blood pressure and sympathetic nerve activity while eliminating phrenic nerve discharge. This revealed a novel cannabinoid-cardiorespiratory link.
2003 / Cross Sectional / Moderate evidenceSurvey of 420 MS patients finding 96% aware of cannabis therapeutic potential, 16% using it medicinally with reported improvements in anxiety, spasticity, and chronic pain.
2003 / Animal Study / Moderate evidenceAnimal study showing CB1 receptor knockout mice suffered worse neurodegeneration in MS model, while CB1 activation provided neuroprotection, suggesting cannabis could slow MS disease progression.
2003 / Cross Sectional / Preliminary evidenceStudy finding cannabis users showed reduced depth inversion illusion scores, a pattern shared with schizophrenia patients, undetected by standard cognitive tests, suggesting subtle visual processing changes.
2003 / Review / Strong evidenceComprehensive review documenting reliable THC self-administration in monkeys and major cannabinoid-opioid-dopamine interactions underlying reward and dependence.
2003 / Review / Preliminary evidenceReview proposing cannabis may be a gateway to tobacco rather than the reverse, with university student research suggesting cigarette initiation often followed marijuana use.
2003 / Randomized Controlled Trial / Moderate evidenceControlled trial showing sublingual cannabis extracts (THC and CBD) significantly improved pain and bladder symptoms in 24 patients with treatment-resistant neurological conditions.