Cannabis Dopamine Research

Distinct endocannabinoids specifically signal to astrocytes or neurons in the adult mouse hippocampus.

Noriega-Prieto, Jose Antonio · 2026

In the hippocampus, 2-AG activates CB1 receptors on neurons to depress synaptic transmission, while anandamide activates CB1 receptors on astrocytes to potentiate adjacent synapses.

The neuropsychopharmacology of cannabis: A review of human imaging studies.

Bloomfield, Michael A P · 2019

Cannabis and THC acutely affect executive, emotional, reward, and memory processing through direct CB1 effects and indirect effects on glutamate, GABA, and dopamine systems.

Deficits in striatal dopamine release in cannabis dependence.

van de Giessen, E · 2017

Eleven severely cannabis-dependent participants (free of all comorbidities, including nicotine use) and 12 healthy controls underwent PET brain scans before and after amphetamine challenge to measure dopamine release. Cannabis-dependent participants had significantly lower dopamine release in the striatum (p = 0.002, effect size 1.48), including the associative striatum (ES = 1.39), sensorimotor striatum (ES = 1.41), and the pallidus (ES = 1.16).

Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control.

Bhattacharyya, S · 2014

In a double-blind study, healthy occasional cannabis users received either THC or placebo and performed a response inhibition task during brain imaging.

Cannabinoids: reward, dependence, and underlying neurochemical mechanisms--a review of recent preclinical data.

Tanda, Gianluigi · 2003

Strong and persistent THC self-administration was demonstrated in squirrel monkeys at doses matching those humans self-administer when smoking marijuana, providing the first reliable direct measure of THC's reinforcing effects.

Effects of acute alcohol administration on endocannabinoids and relation to subjective effects.

Petrie, Gavin N · 2026

Acute alcohol consumption decreased 2-AG concentrations compared to placebo.

Dopamine, γ-aminobutyric acid, and glutamate balance in the nucleus accumbens shell: Differential effects of cannabinoid 1 receptor agonists Δ9-Tetrahydrocannabinol, AM11101, and AM8936.

Smith, Evan C · 2026

Low-dose THC increased dopamine and GABA in the nucleus accumbens shell, while high-dose THC decreased dopamine.

Corticosterone stimulates synthesis of 2-arachidonoylglycerol via putative membrane-bound glucocorticoid receptors and inhibits GABA release via CB1 cannabinoid receptors in the ventrolateral periaqueductal gray.

Coutens, Basile · 2025

In the ventrolateral periaqueductal gray (vlPAG), corticosterone activates putative membrane-bound glucocorticoid receptors, which stimulate 2-AG synthesis.

Cannabinoid CB1 receptor in dopaminergic circuit from ventral tegmental area to nucleus accumbens links trait anxiety with reward learning.

Cui, Chi · 2025

High trait anxiety mice exhibited increased reward learning.

D1-like dopamine receptors in the dentate gyrus mediate cannabidiol's facilitation of extinction and prevention of reinstatement in methamphetamine-induced conditioned place preference.

Danesh, Elaheh · 2025

CBD enhanced extinction of meth-conditioned place preference and prevented reinstatement.

Changes in peripheral endocannabinoid levels in substance use disorders: a review of clinical evidence.

Elliott, Georgia O · 2025

Across substance use disorders, anandamide (AEA) concentrations were usually elevated, while 2-AG was measured less often and showed mixed results.

Long-lasting behavioral, molecular and functional connectivity alterations after chronic THC exposure during adolescence in mice.

Gómez-Acero, Laura · 2025

Adolescent THC exposure impaired social interaction and increased vulnerability to sensorimotor gating deficiencies (similar to those in heavy cannabis users).

Integrating endocannabinoid signaling, CCK interneurons, and hippocampal circuit dynamics in behaving animals.

Malhotra, Shreya · 2025

New biosensors and imaging tools can now track endocannabinoid signaling at individual synapses in behaving animals.

Altered neurobehavioral reward response predicts psychotic-like experiences in youth exposed to cannabis prenatally.

Amir, Carolyn M · 2024

Prenatal cannabis exposure (PCE) was longitudinally associated with psychotic-like experiences in youth.

The Effects of Acute Cannabis With and Without Cannabidiol on Neural Reward Anticipation in Adults and Adolescents.

Skumlien, Martine · 2023

Adults showed reduced ventral striatum activation during reward anticipation after THC, while adolescents did not.

Cannabinoids, reward processing, and psychosis.

Gunasekera, Brandon · 2022

THC modulated activity in the striatum, midbrain, insula, and anterior cingulate during reward processing, with some effects correlating with the severity of THC-induced psychotic symptoms.

Multimodal MRI data fusion reveals distinct structural, functional and neurochemical correlates of heavy cannabis use.

Hirjak, Dusan · 2022

Two transmodal components significantly differed between heavy cannabis users and controls.

Cannabis use selectively modulates circulating biomarkers in the blood of schizophrenia patients.

Ibarra-Lecue, Inés · 2022

Platelet serotonin 2A receptors, active Akt protein, anandamide, other lipid mediators, and pro-inflammatory IL-6 were all significantly increased in schizophrenia patients.

Changes in striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence in male and female mice.

Kesner, Andrew J · 2022

THC withdrawal produced altered striatal dopamine release, sleep disturbances that mimic clinical observations (disrupted sleep architecture), and affect-related behavioral changes.

A Cannabinoid Hypothesis of Schizophrenia: Pathways to Psychosis.

Little, Rachel · 2022

The review describes several putative pathways from cannabis to psychosis, integrating evidence about the endocannabinoid system, THC's effects on dopamine and glutamate signaling, and the connection between cannabis use and first-episode psychosis..

Cannabis exposure during adolescence: A uniquely sensitive period for neurobiological effects.

Peters, K Z · 2022

The endocannabinoid system changes during adolescence affect how it modulates developing dopamine circuits.

Neural responses to reward anticipation and feedback in adult and adolescent cannabis users and controls.

Skumlien, Martine · 2022

Cannabis users and controls had similar neural responses during reward anticipation and in reward-related brain regions during feedback.

Do the effects of cannabis on the hippocampus and striatum increase risk for psychosis?

Daniju, Y · 2020

Using the MAM rodent model as a framework, the review found clear evidence that cannabis/cannabinoids affect hippocampal and medial temporal lobe function and structure.

Contribution of Dopamine Transporter Gene Methylation Status to Cannabis Dependency.

Grzywacz, Anna · 2020

No overall difference in DAT1 gene promoter methylation was found between groups.

Interactions Between Alcohol and the Endocannabinoid System.

Kunos, George · 2020

The review consolidates 20 years of evidence showing that alcohol increases endocannabinoid signaling, which mediates both its rewarding/addictive neural effects and its toxic effects in the liver (fatty liver disease).

Does cannabis use predict psychometric schizotypy via aberrant salience?

O'Tuathaigh, Colm M P · 2020

Among 910 students, frequent cannabis use predicted higher scores on positive and disorganized schizotypy subscales.

Cannabis use influence on peripheral brain-derived neurotrophic factor levels in antipsychotic-naïve first-episode psychosis.

Toll, A · 2020

Among 70 drug-naive first-episode psychosis patients and 57 healthy volunteers, cannabis use was associated with reduced BDNF levels only in the psychosis group.

Endocannabinoid System and Alcohol Abuse Disorders.

Basavarajappa, Balapal S · 2019

Alcohol alters endocannabinoid levels and CB1 receptor expression in brain addiction circuits.

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders.

Basavarajappa, Balapal S · 2019

The ECS plays a major role in the motivation to abuse alcohol, with chronic alcohol consumption modulating endocannabinoids and CB1 receptor expression in brain addiction circuits.

Acute effects of ∆9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype.

Bossong, Matthijs G · 2019

THC increased perfusion in bilateral insula, medial superior frontal cortex, and left orbital frontal gyrus.

Modulatory effects of cannabinoids on brain neurotransmission.

Cohen, Koby · 2019

CB1 and CB2 receptors interact with six major neurotransmitter systems: dopamine, serotonin, noradrenaline, GABA, glutamate, and opioids.

Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity.

Mason, Natasha L · 2019

THC increased striatal glutamate concentrations and reduced functional connectivity (FC) between the nucleus accumbens and cortical areas, indicating increased dopamine activity.

Highs and lows of cannabinoid-dopamine interactions: effects of genetic variability and pharmacological modulation of catechol-O-methyl transferase on the acute response to delta-9-tetrahydrocannabinol in humans.

Ranganathan, Mohini · 2019

Val/Val individuals showed the greatest THC-induced working memory and attention deficits.

Adolescent Synthetic Cannabinoid Exposure Produces Enduring Changes in Dopamine Neuron Activity in a Rodent Model of Schizophrenia Susceptibility.

Aguilar, David D · 2018

Researchers used a novel rodent model where about 40% of rats carry genetic susceptibility to a schizophrenia-like phenotype.

Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion.

Freeman, Tom P · 2018

Researchers gave 16 cannabis users three different treatments across separate sessions: cannabis with CBD, cannabis without CBD, and placebo, then measured brain responses to music using fMRI. Cannabis without CBD dampened the brain's response to music in several key regions: bilateral auditory cortex, right hippocampus, right amygdala, and right ventral striatum (a core reward region).

Chronic Δ9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability.

John, William S · 2018

Six adult male rhesus monkeys were tested on cognitive tasks using touchscreen tests (CANTAB) before and during 12 weeks of daily THC (1.0-2.0 mg/kg). Acute THC impaired cognitive performance in a task-specific manner and reduced food-motivated responding and body temperature. During chronic treatment, THC produced persistent residual impairment only to working memory, measured 22 hours after each dose.

Fronto-striatal effective connectivity of working memory in adults with cannabis use disorder.

Ma, Liangsuo · 2018

Researchers compared brain connectivity between 23 adults with cannabis use disorder and 23 demographically matched controls during a working memory (N-back) task. Compared to controls, CUD participants showed reduced modulatory connectivity from the right dorsolateral prefrontal cortex (R-DLPFC) to the left caudate during working memory. However, CUD participants showed increased connectivity in three other prefrontal-striatal pathways: left DLPFC to left caudate, right DLPFC to right caudate, and right ventrolateral PFC to left caudate. The authors interpreted this as a compensatory pattern: the CUD brain may recruit additional prefrontal-striatal connections to maintain working memory performance when the primary pathway is impaired..

Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: A randomized fMRI study.

Machielsen, Marise W J · 2018

Thirty-eight patients with schizophrenia (30 with cannabis use disorder, 8 without) and 20 healthy controls were included.

Subcortical Local Functional Hyperconnectivity in Cannabis Dependence.

Manza, Peter · 2018

Researchers examined resting-state brain connectivity in subcortical regions using data from 441 young adults in the Human Connectome Project. Thirty cannabis-dependent subjects were compared to 30 controls matched on age, sex, education, BMI, anxiety, depression, and alcohol/tobacco use. Cannabis-dependent individuals showed markedly increased local functional connectivity in several subcortical regions: ventral striatum (where the nucleus accumbens is located), midbrain (where dopamine-producing neurons reside), brainstem, and lateral thalamus. These hyperconnectivity effects occurred without significant differences in subcortical brain volumes. The effects were most pronounced in individuals who began cannabis use earliest in life and who reported high levels of negative emotionality. The researchers interpreted these findings as reflecting changes in dopaminergic circuits implicated in both psychosis and habit formation/reward processing..

Roles for the endocannabinoid system in ethanol-motivated behavior.

Henderson-Redmond, Angela N · 2016

This review synthesized evidence showing that the endocannabinoid system plays a central role in alcohol-motivated behavior.

Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes.

Ramaekers, J G · 2016

Researchers gave 122 regular drug users acute doses of cannabis, cocaine, and placebo and measured cognitive impulsivity and brain connectivity.

Adolescent Δ(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats.

Scherma, Maria · 2016

Adolescent rats received increasing doses of THC for 11 consecutive days during the equivalent of human adolescence.

Analysis of tolerance and behavioral/physical dependence during chronic CB1 agonist treatment: effects of CB1 agonists, antagonists, and noncannabinoid drugs.

Desai, Rajeev I · 2013

Squirrel monkeys chronically treated with the potent CB1 agonist AM411 developed enormous tolerance to cannabinoid agonists, with up to 250-fold rightward shifts in potency.

Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring.

DiNieri, Jennifer A · 2011

This study combined human fetal tissue analysis with a rat model to investigate how prenatal cannabis exposure affects the developing brain's reward system. In human fetal subjects, prenatal cannabis exposure specifically decreased dopamine D2 receptor (DRD2) gene expression in the nucleus accumbens, the brain's key reward region.

Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment.

Morris, Claudia V · 2011

The review examined molecular mechanisms through which prenatal cannabis and cigarette exposure disrupted brain development. Prenatal cannabis exposure specifically altered dopamine D2 receptor gene expression in the fetal brain's reward center (nucleus accumbens), potentially through epigenetic mechanisms including DNA methylation and histone modification.

Endogenous cannabinoid and opioid systems and their role in nicotine addiction.

Maldonado, Rafael · 2010

The review detailed how the endogenous cannabinoid and opioid systems interact with dopamine-driven reward pathways that underlie nicotine addiction.

Cannabis abuse and addiction: a contemporary literature review.

Iyalomhe, G B S · 2009

This review synthesized recent developments in understanding cannabis abuse and addiction, with particular focus on neurobiological mechanisms. Recent advances identified dopamine and serotonin (5-HT) as key neuronal substrates responsible for the rewarding effects of cannabis and the addictive process.

Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons.

Pistis, Marco · 2004

After just 3 days of cannabinoid treatment followed by a 2-week washout, adolescent-treated rats showed long-lasting changes in how their dopamine neurons responded to other drugs.

The effects of cannabinoids on the brain.

Ameri, A · 1999

This extensive review covered the full spectrum of cannabis effects on the brain, from molecular mechanisms to behavioral consequences. A striking finding was that recent research had revealed THC-induced cell death in the hippocampus, with neuron shrinkage and DNA fragmentation, effects the review stated had been "underestimated for a long time." Cognitive deficits, particularly in concentration and memory, appeared to persist after withdrawal. At the receptor level, the review detailed how CB1 receptors mediate THC's effects through G proteins, inhibiting calcium channels and stimulating potassium channels.

Neurobiology of marijuana abuse.

Abood, M E · 1992

This review highlighted a puzzling disconnect in cannabis research.

Modulatory function of cannabidiol on the extinction and reinstatement of methamphetamine-seeking behavior through the D2-like dopamine receptors in the dentate gyrus.

Azizbeigi, Ronak · 2026

CBD facilitated extinction and suppressed reinstatement of methamphetamine conditioned place preference, effects that were blocked by the D2 receptor antagonist Sulpiride in the dentate gyrus, suggesting CBD works partly through indirect dopamine modulation..

Perinatal exposure to delta-9-tetrahydrocannabinol (THC) alters goal-directed behavior and dopamine functioning in wistar rats.

Carbajal, Monica S · 2026

Perinatal THC exposure (5 mg/kg/day from pre-breeding to PND 14) decreased motivation on high-effort operant tasks in both sexes, with males showing fewer reinforcers earned; dopamine response to cocaine was attenuated in the nucleus accumbens without baseline DA changes..

Illuminating chromaffin granules: compartmentalization of endocannabinoids in bovine adrenal glands supports role in hormone modulation.

Roukens, Jaap-Jan · 2026

N-acylethanolamines including anandamide predominated in the adrenal cortex while 2-AG was concentrated in the medulla.

THC induced similar physiological effects on HIV transgenic rats and their controls without affecting HIV-induced deficits in effortful motivation.

Vemuri, Sunitha · 2026

THC at 3 mg/kg reduced pain sensitivity, body temperature, and locomotor activity across all genotypes, with some sex-dependent effects.

Prenatal Delta-9-Tetrahydrocannabinol Exposure Induces Transcriptional Alterations in Dopaminergic System with Associated Electrophysiological Dysregulation in the Prefrontal Cortex of Adolescent Rats.

Di Bartolomeo, Martina · 2025

Prenatal cannabis exposure increased mRNA levels of dopamine D1 and D2 receptors in the prefrontal cortex, with a particularly strong effect on D2 in males.

Cannabinoid Ligand-Mediated Glycogen Depletion in Astrocytes Is Associated With Increased Intracellular Calcium, Energy Metabolism, and Membrane Dynamics.

Fink, Katja · 2025

CB1-selective agonist ACEA triggered rapid, transient calcium elevations in rat astrocytes, while CB2-biased ligands AM1241 and Gp1a produced sustained metabolic effects including prolonged increases in intracellular glucose and lactate.

Value signals guiding choices for cannabis versus non-drug rewards in people who use cannabis near-daily.

Lawn, Will · 2025

Subjective value signals for cannabis appeared in vmPFC, ventral striatum, and dorsal PCC as expected.

Preventive beneficial effects of cannabidiol in a reserpine-induced progressive model of parkinsonism.

Lima, Alvaro C · 2025

In mice given low-dose reserpine to progressively develop Parkinson-like symptoms, CBD (0.5 mg/kg) delayed the appearance of catalepsy and abnormal mouth movements.

Personality-based intergenerational effects of prenatal THC exposure in an inherited mouse model of social dominance and submissiveness.

Mari, Mohamed · 2025

In selectively bred dominant mice, prenatal THC exposure reduced body weight and increased anxiety-like behaviors.

Astroglial CB1 Reveal Sex-Specific Synaptic Effects of Amphetamine.

Mariani, Yamuna · 2025

Amphetamine impaired astroglial CB1 receptor-dependent synaptic plasticity in the nucleus accumbens of male mice but not females.

Cannabis Use is Related to Anhedonia in Adolescents With Diverse Mood and Anxiety Symptoms.

Nguyen, Tram N B · 2025

Adolescents who used cannabis endorsed worse anticipatory anhedonia (difficulty looking forward to pleasurable experiences) compared to those who never used or tried cannabis only once.

Cannabidiol mechanism of action on modulating extinction and reinstatement of methamphetamine-seeking behavior: Targeting D2-like dopamine receptors in the hippocampus.

Omidiani, Seyed Erfan · 2025

A D2-like receptor antagonist (Sulpiride) at 1 and 4 micrograms significantly attenuated CBD's acceleration of methamphetamine conditioned place preference extinction (p<0.01, p<0.05).

Biochemical Role of the Endocannabinoid System in the Pathophysiology of Attention Deficit Hyperactivity Disorder: A Narrative Review and Future Directions.

Özmeral Erarkadaş, Kübra · 2025

Eleven preclinical and 2 clinical studies showed alterations in endocannabinoid system components linked to ADHD-related behaviors.

Coadministration antagonist dopamine receptor D4 with CB2 receptor agonist decreases binge-like intake of palatable food in mice.

Rodríguez-Serrano, Luis Miguel · 2025

In mice given 1-hour access to palatable food, a dopamine D4 receptor antagonist (L-745870) reduced binge-like intake.

Lower striatal dopamine D2 receptor availability in individuals who test positive for quantitated urine metabolites of tobacco and/or marijuana smoke.

Yoder, Karmen K · 2025

Individuals positive for urine metabolites of tobacco and/or cannabis had an average 13.1% lower D2 receptor availability across all striatal subregions compared to negative individuals, with the most significant differences in reward-related brain areas..

Unveiling the link between chronic pain and misuse of opioids and cannabis.

Dagher, Merel · 2024

Over 50 million Americans live with chronic pain, and many don't receive adequate treatment.

Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia.

Martínez-Rivera, Arlene · 2024

Pharmacologically boosting 2-AG levels via MAGL inhibition attenuated opioid reward in both conditioned place preference and self-administration paradigms without affecting opioid analgesia.

Oral pre- and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice.

Peterson, Colleen S · 2024

Male offspring had decreased GABAergic input, depolarized resting membrane potential, and increased spontaneous firing of VTA dopamine neurons.

Sex-specific maladaptive responses to acute stress upon in utero THC exposure are mediated by dopamine.

Valeria, Serra · 2024

Only male offspring prenatally exposed to THC showed a compromised balance of stress hormone receptors (mineralocorticoid and glucocorticoid) in the ventral tegmental area, alongside stress-induced disruption of sensorimotor gating (PPI).

Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.

Paredes-Ruiz, Karen Jaqueline · 2023

JZL184 attenuated 3-NP-induced mitochondrial dysfunction and lipid peroxidation.

Therapeutic potential of PIMSR, a novel CB1 receptor neutral antagonist, for cocaine use disorder: evidence from preclinical research.

Galaj, Ewa · 2022

PIMSR dose-dependently inhibited cocaine self-administration, shifted the dose-response curve downward, decreased motivation to seek cocaine, and reduced cue-induced reinstatement.

Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.

Sarikahya, Mohammed H · 2022

Prenatal THC exposure induced lasting behavioral and neuronal changes in male and female rat offspring resembling neuropsychiatric conditions, with profound disruption of fatty acid pathways in the developing brain..

THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior.

Dahlén, Amelia · 2021

THC caused dose-dependent behavioral stereotypy (repetitive circular swimming) in adult zebrafish.

l-Theanine Prevents Long-Term Affective and Cognitive Side Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry.

De Felice, Marta · 2021

L-theanine pretreatment before adolescent THC exposure prevented long-term dysregulation of dopamine activity in both the prefrontal cortex and ventral tegmental area, blocked downregulation of GSK-3 and Akt signaling (biomarkers linked to psychiatric risk), and prevented the development of affective and cognitive abnormalities in adulthood..

Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats.

Di Bartolomeo, Martina · 2021

Perinatal THC exposure increased both Cnr1 (CB1) and Drd2 (D2 receptor) mRNA levels in the adult rat prefrontal cortex, with reduced DNA methylation at the Drd2 regulatory region.

Endocannabinoid modulation of dopamine release during reward seeking, interval timing, and avoidance.

Everett, Thomas J · 2021

This review detailed how the endocannabinoid 2-AG acts as a gatekeeper for dopamine signaling across three distinct behaviors.

Endocannabinoid and dopaminergic system: the pas de deux underlying human motivation and behaviors.

Laksmidewi, A A A Putri · 2021

This review framed the endocannabinoid-dopamine interaction through Maslow's hierarchy of needs — an unusual but clarifying lens.

Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies.

McElroy, Dan L · 2021

GAT211 dose-dependently reduced locomotor activity, prevented MK-801-induced hyperlocomotion (a model of psychosis), and limited dopamine D2 receptor-mediated ERK phosphorylation in neuronal cells.

A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking and Addiction.

Peters, Kate Z · 2021

This Cold Spring Harbor review laid out the definitive case for how cannabis engages the brain's addiction circuitry.

Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure.

Sagheddu, Claudia · 2021

Pre-pubertal male rats exposed prenatally to THC showed reduced population activity of VTA dopamine neurons but more tonically active neurons, enhanced sensitivity to D2 receptor activation by apomorphine, and stress-induced disruption of sensorimotor gating (PPI).

Female but not male rats show biphasic effects of low doses of Δ9-tetrahydrocannabinol on anxiety: can cannabidiol interfere with these effects?

Salviato, Beatriz Zanutto · 2021

This study revealed a striking sex difference that most cannabis research has missed by testing only males.

Sex, species and age: Effects of rodent demographics on the pharmacology of ∆9-tetrahydrocanabinol.

Wiley, Jenny L · 2021

11-OH-THC showed 7- to 31-fold greater potency than THC for catalepsy and hypothermia in mice and 7- to 9-fold greater potency in drug discrimination.

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.

Burgdorf, Caitlin E · 2020

Adolescent female FAAHC/A mice (but not males) showed enhanced mesolimbic dopamine circuitry from VTA to nucleus accumbens, altered CB1 receptor levels at inhibitory and excitatory terminals in the VTA, and increased THC conditioned place preference that persisted into adulthood..

Microstructure analysis of the effects of the cannabinoid agents HU-210 and rimonabant in rats licking for sucrose.

D'Aquila, Paolo S · 2020

HU-210 reduced licking by decreasing burst number and intra-burst lick rate (a motor competence index).

Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A and TRPV1 receptor mechanisms.

Galaj, Ewa · 2020

CBD (10-40 mg/kg) reduced cocaine self-administration, shifted the cocaine dose-response curve downward, and lowered break-points for cocaine seeking.

The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers.

Lawn, Will · 2020

In a double-blind, placebo-controlled crossover study, 23 healthy participants showed no differences in reward-related brain activity (measured by fMRI during a monetary incentive delay task) after 600mg CBD compared to placebo.

Differential effects of Δ9-tetrahydrocannabinol dosing on correlates of schizophrenia in the sub-chronic PCP rat model.

Seillier, Alexandre · 2020

In PCP-treated rats (schizophrenia model), only the lowest THC dose (0.1 mg/kg) reversed social interaction deficits and normalized elevated anandamide in the nucleus accumbens.

Pharmacological and Behavioral Effects of the Synthetic Cannabinoid AKB48 in Rats.

Bilel, Sabrine · 2019

AKB48 at low doses (0.25 mg/kg) preferentially stimulated dopamine release in the nucleus accumbens shell (reward center) and impaired visual reflexes at 0.3 mg/kg.

Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1-2 Phosphorylation.

Hudson, Roger · 2019

Intra-hippocampal THC increased VTA dopamine neuron firing and bursting, decreased GABA frequency, and amplified oscillatory activity via ERK1-2 phosphorylation.

Effects of chronic cannabinoid exposure during adolescence on reward preference and mPFC activation in adulthood.

Jacobs-Brichford, Eliza · 2019

Adult rats that received WIN 55,212-2 during adolescence (postnatal days 30-60) showed subtle changes in choice behavior and significantly reduced mPFC neural activity during lever presses and reward delivery in a probabilistic reward task, suggesting impaired excitatory-inhibitory balance from adolescent exposure..

Hemisphere-dependent endocannabinoid system activity in prefrontal cortex and hippocampus of the Flinders Sensitive Line rodent model of depression.

Kirkedal, C · 2019

2-AG was lower in the left hippocampus and left prefrontal cortex of depression-prone FSL rats compared to controls.

Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation.

Lecca, Salvatore · 2019

Rats exposed to maternal immune activation (MIA) had fewer active dopamine neurons, lower firing rates, and altered activity patterns.

Alcohol-induced conditioned place preference is modulated by CB2 cannabinoid receptors and modifies levels of endocannabinoids in the mesocorticolimbic system.

Martín-Sánchez, Ana · 2019

Alcohol-conditioned place preference was associated with decreased anandamide and other N-acylethanolamines in the medial prefrontal cortex and ventral midbrain.

Ventral hippocampal overexpression of Cannabinoid Receptor Interacting Protein 1 (CNRIP1) produces a schizophrenia-like phenotype in the rat.

Perez, Stephanie M · 2019

Viral-mediated overexpression of CNRIP1 in the ventral hippocampus caused impairments in latent inhibition and social interaction (behavioral correlates of schizophrenia) and increased dopamine neuron population activity in the ventral tegmental area, a putative marker of psychosis..

Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling.

Balla, Andrea · 2018

Previous CB1 receptor blockers like rimonabant were effective against obesity and nicotine addiction but were withdrawn because they caused depression and suicidal ideation.

The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users.

Batalla, Albert · 2018

Researchers examined hippocampal brain structure in 59 young men aged 18-30, including 30 chronic cannabis users who started regular use before age 16 and 29 controls.

Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.

Ibarra-Lecue, Inés · 2018

Researchers exposed mice to chronic THC during an early developmental window and then examined serotonin 2A receptor (5-HT2AR) function in the frontal cortex. Chronic THC shifted the receptor toward coupling with inhibitory G-proteins (Gαi1, Gαi3, Gαo, and Gαz) rather than the standard Gαq/11 pathway.

Pharmacological inhibition of 2-arachidonoilglycerol hydrolysis enhances memory consolidation in rats through CB2 receptor activation and mTOR signaling modulation.

Ratano, Patrizia · 2018

The MAGL inhibitor JZL184, which boosts 2-AG levels, enhanced memory consolidation when given right after training in a fear-based learning task.

Caffeine and Cannabis Effects on Vital Neurotransmitters and Enzymes in the Brain Tissue of Juvenile Experimental Rats.

Owolabi, J O · 2017

Juvenile rats given cannabis, caffeine, or both for 21 days showed increased levels of GABA, glutamate, and dopamine across all treatment groups compared to controls. The metabolic enzyme G-6-PDH was elevated in all treated animals, but the combination of low-dose cannabis plus low-dose caffeine produced the most significant increase.

Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease.

Pasquarelli, Noemi · 2017

Researchers tested two strategies for boosting endocannabinoid levels in a chronic Parkinson's disease mouse model.

Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells.

Stanslowsky, Nancy · 2017

Researchers used human induced pluripotent stem cells (iPSCs) to grow neurons and studied how cannabinoids affected their development into dopamine-producing cells. At high concentrations (10 micromolar), both the endogenous cannabinoid anandamide (AEA) and THC significantly decreased neuronal functionality, indicated by reduced ion currents and synaptic activity.

Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway.

Todd, Stephanie M · 2017

Researchers examined whether CBD modulates THC's effects during repeated co-administration over 15 days in mice.

Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on "tetrad", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.

Canazza, Isabella · 2016

Researchers conducted the first comprehensive pharmacological characterization of AKB48 and its fluorinated derivative 5F-AKB48, two synthetic cannabinoids sold as "Spice" products. Both compounds showed nanomolar affinity for CB1 and CB2 receptors in binding experiments.

Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135.

De Luca, Maria Antonietta · 2016

Researchers characterized four third-generation synthetic cannabinoids (BB-22, 5F-PB-22, 5F-AKB-48, STS-135) and compared them to the earlier compound JWH-018. BB-22 and 5F-PB-22 had CB1 receptor binding affinities 30 and 26 times higher than JWH-018 respectively, with higher potency and efficacy as CB1 agonists.

Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice.

Ossato, Andrea · 2016

Researchers tested JWH-250 and JWH-073, two synthetic cannabinoids frequently found together in "herbal blend" products, in mice.

Strain dependence of adolescent Cannabis influence on heroin reward and mesolimbic dopamine transmission in adult Lewis and Fischer 344 rats.

Cadoni, Cristina · 2015

Researchers tested the "gateway hypothesis" by exposing adolescent rats of two genetically distinct strains (Lewis and Fischer 344) to THC and measuring heroin-related behaviors in adulthood.

Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release.

Lee, Sang-Hun · 2015

Using advanced electrophysiology and imaging in mouse hippocampus, researchers discovered that CB1 receptors at inhibitory synapses are constitutively active, meaning they continuously suppress GABA release even without being activated by endocannabinoids. The endocannabinoid 2-AG is continuously produced and further suppresses GABA release, but its effect is tightly controlled by the presynaptic enzyme MGL.

Interactions between ethanol and the endocannabinoid system at GABAergic synapses on basolateral amygdala principal neurons.

Talani, Giuseppe · 2015

Researchers examined how alcohol and the endocannabinoid system interact at inhibitory synapses in the basolateral amygdala (BLA), a brain region involved in processing emotional responses and drug dependence. Alcohol at intoxication-relevant concentrations increased the frequency of inhibitory signals, suggesting it acts directly on nerve terminals to boost GABA release.

Balanced modulation of striatal activation from D2 /D3 receptors in caudate and ventral striatum: Disruption in cannabis abusers.

Tomasi, Dardo · 2015

Researchers used both fMRI and PET imaging to examine how dopamine D2/D3 receptors in two parts of the striatum modulate brain activity during a reaction-time task. In healthy controls, dopamine receptors in the caudate (dorsal striatum) and ventral striatum showed a balanced push-pull pattern: caudate receptors inhibited ventral striatum activity while ventral striatum receptors facilitated it.

Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure.

Watson, Corey T · 2015

Researchers examined whether THC exposure during adolescence could produce epigenetic changes that pass to the next generation.

Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

Wiebelhaus, Jason M · 2015

Researchers tested how THC and drugs that increase natural brain cannabinoids affected the brain's reward system in mice using intracranial self-stimulation (ICSS), where animals press a lever to electrically stimulate the medial forebrain bundle. THC and JZL184 (a MAGL inhibitor that boosts 2-AG) both reduced operant responding for brain stimulation, food, and spontaneous movement.

The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study.

Bloomfield, Michael A P · 2014

Every participant scored above the clinical cutoff for apathy on the Apathy Evaluation Scale.

The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward.

Flores, África · 2014

Two complementary approaches pointed to the same result.

Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum.

Palomino, Ana · 2014

Acute cocaine exposure decreased DAGLa expression in the cerebellum, suggesting reduced production of the endocannabinoid 2-AG.

Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study.

van der Knaap, L J · 2014

In 463 adolescents (mean age 16), methylation of the membrane-bound COMT (MB-COMT) promoter was associated with non-daily smoking (OR=1.82, p=0.03), but not with daily smoking or alcohol use. A gene-epigenetic interaction was found for cannabis use: adolescents with the Met/Met genotype (associated with higher dopamine levels) and high MB-COMT promoter methylation were less likely to be high-frequency cannabis users compared to those with Val/Val or Val/Met genotypes.

Increased expression of cannabinoid receptor 1 in the nucleus accumbens core in a rat model with morphine withdrawal.

Yuan, Wei-Xin · 2013

Researchers examined CB1 cannabinoid receptor expression in the nucleus accumbens core (a key brain reward region) of rats during acute (1 day), latent (3 days), and chronic (3 weeks) morphine withdrawal.

Abnormal striatal circuitry and intensified novelty seeking among adolescents who abuse methamphetamine and cannabis.

Churchwell, John C · 2012

Researchers compared brain scans from three groups of adolescents: healthy controls (10), methamphetamine users (9), and combined methamphetamine plus cannabis users (8).

A brain on cannabinoids: the role of dopamine release in reward seeking.

Oleson, Erik B · 2012

In animal models, cannabinoids activate the mesolimbic dopamine system, the same reward circuit engaged by other drugs of abuse.

Cannabinoid receptor 1-expressing neurons in the nucleus accumbens.

Winters, Bradley D · 2012

Using genetically modified mice with fluorescent tagging of CB1-expressing neurons, researchers made several discoveries about these cells in the nucleus accumbens (NAc).

MDMA & cannabis: a mini-review of cognitive, behavioral, and neurobiological effects of co-consumption.

Schulz, Sybille · 2011

This review examined 23 articles on the combined effects of MDMA (ecstasy) and cannabis.

Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users.

Nestor, Liam · 2010

Fourteen chronic cannabis users and 14 non-using controls completed a monetary incentive delay task during fMRI brain scanning.

Altered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependence.

Spiga, Saturnino · 2010

Researchers examined brain structure changes during cannabinoid withdrawal in rats treated with two different cannabinoid agonists (THC and CP55940). During both spontaneous and precipitated withdrawal, dopamine-producing neurons in the ventral tegmental area (VTA) showed significant morphological shrinkage.

Substitution profile of Delta9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Delta9-tetrahydrocannabinol.

Lile, Joshua A · 2009

Eight healthy moderate cannabis users learned to distinguish 25 mg oral THC from placebo under double-blind conditions, achieving at least 80% accuracy over four consecutive sessions. Once trained, they were tested with multiple doses of THC, the sedative triazolam (a benzodiazepine), the opioid hydromorphone, and the stimulant methylphenidate (Ritalin). All tested drugs produced measurable subjective effects on self-report questionnaires.

Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1.

Martini, Lene · 2007

Agonist exposure led CB1 receptors to internalize, then get degraded rather than recycled back to the surface.

Neural substrates of faulty decision-making in abstinent marijuana users.

Bolla, Karen I · 2005

Researchers used PET imaging during the Iowa Gambling Task to study decision-making in 11 heavy marijuana users after 25 days of supervised abstinence at an NIH inpatient unit, compared to 11 non-drug users. The marijuana group showed greater activation in the left cerebellum and less activation in the right lateral orbitofrontal cortex and right dorsolateral prefrontal cortex compared to controls. When the marijuana group was split by usage level, heavy users (53-84 joints/week) showed less activation in the left medial orbitofrontal cortex and greater cerebellar activation than moderate users (8-35 joints/week).

Cannabinoids inhibit excitatory inputs to neurons in the shell of the nucleus accumbens: an in vivo electrophysiological study.

Pistis, Marco · 2002

Synthetic cannabinoids (WIN 55212,2 and HU-210) and THC all strongly inhibited the firing of neurons in the shell of the nucleus accumbens when those neurons were activated by inputs from the basolateral amygdala or medial prefrontal cortex.

Chronic (-)-delta9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats.

Gorriti, M A · 1999

Researchers investigated whether chronic cannabis exposure could sensitize the brain to psychosis-like effects, using amphetamine-induced behavior in rats as a model. Three patterns emerged across different exposure conditions.

Functional Adaptation in the Brain Habenulo-Mesencephalic Pathway During Cannabinoid Withdrawal.

Aroni, Sonia · 2024

THC withdrawal produced a marked decrease in VTA dopamine neuron firing and burst activity.

Dynamic overrepresentation of accumbal cues in food- and opioid-seeking rats after prenatal THC exposure.

Luján, Miguel Á · 2024

Prenatal THC exposure led to increased cue-evoked dopamine release and overrepresentation of effort-driven reward encoding patterns in the nucleus accumbens.