Long-term Cannabis Use Research Articles

Long-term use of cannabidiol-enriched medical cannabis in a prospective cohort of children with drug-resistant developmental and epileptic encephalopathy

ObjectiveWe report our findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD)-enriched medical cannabis as add-on therapy in children with drug-resistant epileptic encephalopathies (DEEs) after a median follow-up of 20 months. MethodsA prospective cohort study was conducted to assess effectiveness, safety, and tolerability of CBD-enriched medical cannabis oil added to standard antiseizure medications in children with drug-resistant DEE seen at a single center. ResultsBetween October 2018 and March 2020, 59 patients were enrolled. Mean age at enrollment was 10.5 years (range, 2–17 years). Median treatment duration was 20 months (range, 12–32). Median age at first seizure was 8 months (range, 1 day – 10 years). At the end of follow-up, 78% of the children had a ≥ 50% decrease in seizure frequency and 47.5% had a > 75% decrease. Seven patients (11.9%) were seizure free. The number of seizures was reduced from a median of 305/month to 90/month, amounting to a mean reduction of 57% and a median reduction of 71% (p < 0.0001). Adverse effects were mostly mild or moderate. CBD was discontinued in 17 patients (28.8%) due to lack of response to treatment, increased seizure frequency, intolerance to the drug, or poor compliance. ConclusionIn children with drug-resistant DEEs, long-term treatment of CBD-enriched medical cannabis as an adjuvant therapy to antiseizure therapy was found to be safe, well tolerated, and effective. Sustained reductions in seizure frequency and improvement of aspects of daily living were observed compared to our preliminary findings.

Long-term cannabis use and cognition

Long-term cannabis use and cognition

Executive function performance in long-term cannabis use

Executive function performance in long-term cannabis use

Medical Cannabis Use and Pain: An Experience Sampling Study.

Background: Little research has tested associations of pain and MC use after long-term treatment and through methods that have external validity outside experimental settings. The study examined associations of pain, associated painful experiences, and long-term medical cannabis (MC) use in chronic pain (CP) patients using a naturalistic daily diary study that provided novel and externally valid data.Methods: Data were obtained from 78 MC users with CP three times daily over a 10-day period (nobservations = 1,688). Mixed-effects models were used to test the associations between MC use and momentary experiences of pain, affect, and fatigue.Results: Within persons, elevated experiences of pain intensity were associated with greater intention to use MC within the next hour. No evidence was found that the time lapse since last MC use was associated with pain levels, negative affect, or fatigue.Conclusions: The results imply that after long-term use, CP patients intend to use MC in response to pain experiences. Yet, they may not actually achieve the pain relief. More research is needed to examine whether continued MC use despite lack of pain relief is related to relief of other symptoms (e.g., dependence, withdrawal) or positive benefits (e.g., general sense of well-being) or tolerance.

Long-Term Frequent Cannabis Use and Related Serum Cannabinoid Levels Are Not Associated with Kidney Dysfunction.

Introduction: Human studies about the impact of cannabis use on both healthy kidneys as well as kidney function in patients with kidney disease are lacking. To shed more light on this understudied topic, we reevaluated a previous clinical study. The sample of this study was exclusively suited for investigating effects of recreational long-term cannabis use on humans under real-life conditions. Methods: This special sample had sought and was undergoing inpatient detox-treatment. It was characterized by a lone and considerable cannabis-dependence without any other relevant active comorbidity (except of a concurrent nicotine-dependence). In the present post hoc analysis, we are focused on this sample's routine laboratory tests at admission, including the glomerular filtration rate (GFR), which is the key routine parameter for kidney function assessment. Next, we investigated the association between participants' GFR and their cannabis-related data, including serum cannabinoid levels (Δ-9-tetrahydrocannabinol and main metabolites 11-Hydroxy-Δ-9-tetrahydrocannabinol and 11-Nor-9-carboxy-Δ-9-tetrahydrocannabinol). Results: In the whole sample (N=42; 9 females; mean 28.7 years old), we found five persons (12%; 95% confidence interval [2.1-21.7%]) with a mild kidney dysfunction (GFR; 86-75 mL/min). These persons (two females), however, had reported a stronger nicotine misuse. Furthermore, we found no significant association between the study-populations' GFR and reported cannabis burden (median daily use 2.5 g for 36 months, moderate general symptom-load). Most remarkably, the GFR was also not significantly correlated with the serum cannabinoid-levels. Conclusion: Chronic recreational cannabis-use (including its related discomfort) did not affect the kidney function of our almost selectively "cannabis-burdened" population in a relevant manner.

Adolescent administration of Δ9-THC decreases the expression and function of muscarinic-1 receptors in prelimbic prefrontal cortical neurons of adult male mice.

Long-term cannabis use during adolescence has deleterious effects in brain that are largely ascribed to the activation of cannabinoid-1 receptors (CB1Rs) by delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive compound in marijuana. Systemic administration of ∆9-THC inhibits acetylcholine release in the prelimbic-prefrontal cortex (PL-PFC). In turn, PL-PFC acetylcholine plays a role in executive activities regulated by CB1R-targeting endocannabinoids, which are generated by cholinergic stimulation of muscarinic-1 receptors (M1Rs). However, the long-term effects of chronic administration of increasing doses of ∆9-THC in adolescent males on the distribution and function of M1 and/or CB1 receptors in the PL-PFC remains unresolved. We used C57BL\\6J male mice pre-treated with vehicle or escalating daily doses of ∆9-THC to begin filling this gap. Electron microscopic immunolabeling showed M1R-immunogold particles on plasma membranes and in association with cytoplasmic membranes in varying sized dendrites and dendritic spines. These dendritic profiles received synaptic inputs from unlabeled, CB1R- and/or M1R-labeled axon terminals in the PL-PFC of both treatment groups. However, there was a size-dependent decrease in total (plasmalemmal and cytoplasmic) M1R gold particles in small dendrites within the PL-PFC of mice receiving ∆9-THC. Whole cell current-clamp recording in PL-PFC slice preparations further revealed that adolescent pretreatment with ∆9-THC attenuates the hyperpolarization and increases the firing rate produced by local muscarinic stimulation. Repeated administration of ∆9-THC during adolescence also reduced spontaneous alternations in a Y-maze paradigm designed for measures of PFC-dependent memory function in adult mice. Our results provide new information implicating M1Rs in cortical dysfunctions resulting from adolescent abuse of marijuana.

Cannabis Use and Risk of Schizophrenia: A Literature Review

Background and Objective: Cannabis remains the most widely used illicit drug worldwide. The similarity in the chemical structure of tetrahydrocannabinol to the brain chemical anandamide allows the body to recognize it and alter normal brain functioning. The objective of this review article is to summarize the evidence for the association between cannabis and schizophrenia. Methods: A literature search was conducted using the PubMed database and other sources. The keywords used were “cannabis” and “psychosis” and “schizophrenia.” Fifty-two articles relevant to our topic have been selected for this review. Results: Evidence from observational epidemiological studies has shown a positive association between regular cannabis use and schizophrenia risk. Meta-analyses and Mendelian randomization studies support the evidence from observational study designs. Discussion and Conclusions: The association between cannabis and schizophrenia is biologically plausible. Moreover, there has been emerging evidence of genes interacting with cannabis use to confer a higher risk for schizophrenia. There are enough reason and sufficient epidemiological evidence to warn people about the risk of developing schizophrenia with cannabis use. Scientific Significance: The increasing legalization of cannabis for recreational use is of significant concern. Long-term cannabis use might predispose people to increased risk of developing schizophrenia. Health professionals have a major role to play by taking maximum advantage of social and psychological interventions to educate people about the potential danger associated with cannabis and avoid its use.

Not Just a Pot: Visual Episodic Memory in Cannabis Users and Polydrug Cannabis Users: ROC and ERP Preliminary Investigation.

Background While research has consistently identified an association between long-term cannabis use and memory impairments, few studies have examined this relationship in a polydrug context (i.e., when combining cannabis with other substances).Aims: In this preliminary study, we used event-related potentials to examine the recognition process in a visual episodic memory task in cannabis users (CU) and cannabis polydrug users (PU). We hypothesized that CU and PU will have both–behavioral and psychophysiological–indicators of memory processes affected, compared to matched non-using controls with the PU expressing more severe changes.Methods 29 non-using controls (CG), 24 CU and 27 PU were enrolled into the study. All participants completed a visual learning recognition task while brain electrical activity was recorded. Event-related potentials were calculated for familiar (old) and new images from a signal recorded during a subsequent recognition test. We used receiver operating characteristic curves for behavioral data analysis.Results The groups did not differ in memory performance based on receiver operating characteristic method in accuracy and discriminability indicators nor mean reaction times for old/new images. The frontal old/new effect expected from prior research was observed for all participants, while a parietal old/new effect was not observed. While, the significant differences in the late parietal component (LPC) amplitude was observed between CG and PU but not between CG and CU nor CU and PU. Linear regression analysis was used to examine the mean amplitude of the LPC component as a predictor of memory performance accuracy indicator. LPC amplitude predicts recognition accuracy only in the CG.Conclusion The results showed alterations in recognition memory processing in CU and PU groups compared to CG, which were not manifested on the behavioral level, and were the most prominent in cannabis polydrug users. We interpret it as a manifestation of the cumulative effect of multiple drug usage in the PU group.

Prevalence of cannabinoid hyperemesis syndrome and its financial burden on the health care industry

Cannabis is the most commonly consumed recreational drug in the world. As more states legalize cannabis use in some form, the incidence of cannabinoid hyperemesis syndrome (CHS) is expected to rise. CHS is a constellation of symptoms including severe cyclical nausea and vomiting and epigastric or periumbilical abdominal pain as a result of long-term cannabis use. Recognizing the diagnosis and educating patients on the benefits of cessation is essential, as these patients often undergo extensive and repeated evaluations in the clinic, emergency department, and inpatient setting that could be avoided with extensive history taking and early recognition of the syndrome. In this study, we compared costs incurred by patients in various settings to determine if there is a difference between patients with and without CHS. Although there were not statistically significant cost differences between groups for all cost categories, it is clear that patients with CHS consume considerably more health care dollars than patients who deny cannabis use, and obtaining a detailed social history is imperative to prevent unnecessary workups and increased financial burden on the health care industry.

The Role of Cannabidiol in Neurological Disorders.

Cannabis has been used for both recreational and medicinal purposes for more than 4 millennia. Cannabis has been studied in various medical disorders including neurological disorders. There are well-known risks of long-term use of cannabis, including low motivation, lowered cognitive capabilities, and diminished IQ and brain mass. Cannabinoids are compounds in cannabis that are known to have therapeutic potential. The most abundant chemicals in cannabinoids are delta-9-tetrahydrocannabinol and cannabidiol. Delta-9-tetrahydrocannabinol has psychotropic effects that limits its use as a pharmacotherapeutic agent. Cannabidiol is a nonpsychotropic chemical and therefore has become a compound of interest for clinical researchers to study its therapeutic potential. This article reviews the efficacy and safety of cannabidiol in various neurological disorders in humans.

Sensory gating in tobacco-naïve cannabis users is unaffected by acute nicotine administration.

Long-term cannabis use has been associated with the appearance of psychotic symptoms and schizophrenia-like cognitive impairments; however these studies may be confounded by concomitant use of tobacco by cannabis users. We aimed to determine if previously observed cannabis-associated deficits in sensory gating would be seen in cannabis users with no history of tobacco use, as evidenced by changes in the P50, N100, and P200 event-related potentials. A secondary objective of this study was to examine the effects of acute nicotine administration on cannabis users with no tobacco use history. Three components (P50, N100, P200) of the mid-latency auditory-evoked response (MLAER) were elicited by a paired-stimulus paradigm in 43 healthy, non-tobacco smoking male volunteers between the ages of 18-30. Cannabis users (CU, n = 20) were administered nicotine (6 mg) and placebo gum within a randomized, double-blind design. Non-cannabis users (NU, n = 23) did not receive nicotine. Between-group sensory gating effects were only observed for the N100, with CUs exhibiting a smaller N100 to S1 of the paired stimulus paradigm, in addition to reduced dN100 (indicating poorer gating). Results revealed no significant sensory gating differences with acute administration of nicotine compared to placebo cannabis conditions. These findings suggest a relationship between gating impairment and cannabis use; however, acute nicotine administration nicotine does not appear to impact sensory gating function.

The predictive value of neurobiological measures for recidivism in delinquent male young adults.

BackgroundNeurobiological measures have been associated with delinquent behaviour, but little is known about the predictive power of these measures for criminal recidivism and whether they have incremental value over and above demographic and behavioural measures. This study examined whether selected measures of autonomic functioning, functional neuroimaging and electroencephalography predict overall and serious recidivism in a sample of 127 delinquent young adults.MethodsWe assessed demographics; education and intelligence; previous delinquency and drug use; behavioural traits, including aggression and psychopathy; and neurobiological measures, including heart rate, heart rate variability, functional brain activity during an inhibition task and 2 electroencephalographic measures of error-processing. We tested longitudinal associations with recidivism using Cox proportional hazard models and predictive power using C-indexes.ResultsPast offences, long-term cannabis use and reactive aggression were strongly associated with recidivism, as were resting heart rate and error-processing. In the predictive model, demographics, past delinquency, drug use and behavioural traits had moderate predictive power for overall and for serious recidivism (C-index over 30 months [fraction of pairs in the data, where the higher observed survival time was correctly predicted]: C30 = 0.68 and 0.75, respectively). Neurobiological measures significantly improved predictive power (C30 = 0.72 for overall recidivism and C30 = 0.80 for serious recidivism).LimitationsFindings cannot be generalized to females, and follow-up was limited to 4 years.ConclusionDemographic and behavioural characteristics longitudinally predicted recidivism in delinquent male young adults, and neurobiological measures improved the models. This led to good predictive function, particularly for serious recidivism. Importantly, the most feasible measures (autonomic functioning and electroencephalography) proved to be useful neurobiological predictors.

Structural variations in the sulco-gyral pattern of the orbitofrontal cortex

BackgroundThe orbitofrontal cortex (OFC) is composed of sulci and gyri, which form patterns that are variations of an H-shape. Three pattern types are described with the Type III pattern associated with schizophrenia and increased risk of long-term cannabis use. No studies from Africa have described the prevalence of pattern types of the OFC. The aim of the study was to determine the sulcal and gyral patterns of the OFC in a South African sample, and whether there are any significant differences in these patterns between hemispheres and sex. MethodsA cross-sectional study of 43 embalmed adult brains was undertaken. The patterns of the sulci and gyri of the OFC were investigated, and the prevalence of each pattern type determined. Differences in the prevalence between hemispheres and sex were analyzed with Chi-square tests. ResultsType I was present in 27 hemispheres (31%), Type II in 28 (33%) and Type III in 31 (36%), with no significant differences observed between hemispheres and sex for any of the pattern types. ConclusionThe Type III pattern was found to be the most prevalent in this study. The Type III pattern may result from abnormal folding of the gyrus associated with premature birth. An increased expression of Type III has been observed in patients with an increased risk of developing schizophrenia and substance abuse disorders. Further studies are needed to investigate these associations and whether Type III can be considered as a biomarker for psychiatric disorders.

Cannabis use is not associated with increased balance disturbances in HIV-infected individuals

BackgroundThe association between long-term cannabis use and balance disturbances has not been investigated in people living with HIV (PWH). We hypothesized that long-term cannabis use in PWH might be associated with more deleterious effects on balance than in HIV seronegative individuals due to potential neurotoxic interactions between HIV and cannabis.MethodsThree thousand six-hundred and forty-eight participants with and without HIV completed an interviewer-administered timeline follow-back assessment to assess lifetime days and quantity of cannabis use and other cannabis use characteristics. A structured clinical interview was used to collect any history of balance disturbance. Comparisons between HIV+ vs the HIV− groups and moderate-severe vs. no or minimal imbalance in participant characteristics (demographics, cannabis use, medication currently used, and neurological disease) were performed using Student t tests for continuous variables and Fisher’s exact test for binary and categorical variables. Multivariate logistic regression was applied to determine the interaction effect of total quantity of cannabis use with HIV status on balance disturbance. Age, gender, cDSPN symptoms, gait ataxia, opioid medications, and sedatives were included as covariates in the adjusted model after variable selection. The effect sizes are presented as Cohen’s d or odds ratios.ResultsOn average, participants were 45.4 years old (SD = 11 years), primarily male (77.7%), and non-Hispanic white (48.1%). A majority of participants were HIV+ (79.1%). Four hundred thirty (11.9%) of the participants reported balance disturbances within the past 10 years. PWH were more likely to have balance disturbances than demographically matched HIV-uninfected participants (odds ratio [OR] 2.66, 95% CI 1.91–3.7). Participants with moderate-severe balance disturbances did not differ from those with no or minimal imbalance in the proportion who had ever used cannabis (73.8% vs. 74.4%; p = 0.8) (OR 1.03, 95% CI 0.80–1.32) neither did they have a higher total amount of cannabis use (4871 vs. 4648; p = 0.3) (Cohen’s d 0.11, 95% CI 0.01–0.14). In the HIV− population, those with balance disturbances reported more total amount of cannabis use as compared to those with normal balance (11316 vs 4154; p = 0.007). In the HIV+ population on the other hand, there was no significant association (4379 vs 4773; p = 0.6).ConclusionsWe found unexpectedly that while long-term cannabis use in HIV− individuals was associated with more severe balance disturbances, there were no associations in HIV+ individuals. This suggests that cannabis use in HIV is safe with respect to balance disturbances. Given that HIV is related to persistent inflammation despite virologic suppression on antiretroviral therapy, future mechanistic studies are needed to determine whether HIV-associated inflammation contributes to the higher prevalence of balance disturbance in HIV+ individuals and whether cannabinoids have anti-inflammatory effects that mitigate HIV-associated balance disturbance.

Prenatal exposure to tobacco and cannabis, early cannabis initiation, and daily dual use of combustible cigarettes and cannabis during young adulthood

IntroductionDaily combustible cigarette use is common among cannabis users, and dual use of cigarettes and cannabis is associated with detrimental outcomes. This study addresses gaps in the literature by examining data from the prenatal and adolescent phases of a prospective, longitudinal study to predict adult daily dual use. MethodsYoung adult offspring (M age = 22.8 years, 53% female) from a prenatal cohort reported on combustible cigarette and cannabis use (N = 500, 58% Black, 42% White). Pathways to daily dual use were modeled using variables from the gestational and adolescent phases of the study including prenatal tobacco, alcohol, and cannabis exposures; ages at initiation of cigarettes and cannabis; and adolescent learning/memory, impulsivity, and behavior problems. ResultsPrenatal cannabis and tobacco use were not directly linked to adult daily dual use of cannabis and tobacco. However, structural equation modeling revealed three significant indirect pathways from prenatal cigarette and cannabis exposures to adult daily dual use of cigarettes and cannabis via early cigarette initiation, early cannabis initiation, and adolescent behavior problems. ConclusionsThis study identified pathways from prenatal cannabis and tobacco exposure to adult daily dual use, in addition to clarifying adolescent outcomes that may be part of the pathways. In a climate of growing acceptance of cannabis use and increasing legalization of recreational use, these findings serve as a warning that early exposure to cannabis may have an important role in shaping long-term dual use of tobacco and cannabis.

Investigating cannabis use and associated symptoms among university students with and without a history of concussion

ABSTRACT Recently, there has been a growing interest in the use of cannabis after traumatic brain injury (TBI); however, little is known about the long-term effects of cannabis on milder injuries and post-concussive symptoms. Further, substance use often increases post-TBI and, thus, individuals who chronically use cannabis may unknowingly be exceeding safe or therapeutic doses. The current cross-sectional study explores the prevalence of cannabis use among university students with and without a history of concussion and examines the relationship between concussion and post-concussive symptoms as a function of cannabis use. Eighty-four undergraduates (n = 51 without a prior concussion; n = 33 with a prior concussion) completed a series of questionnaires, capturing their head injury history, current and past substance use, and post-concussive symptomatology. Results indicated that those with a history of concussion were more likely to use cannabis and had higher cannabis use severity scores compared to those without a previous concussion. Further, among cannabis users only, concussion severity demonstrated a significant positive association with post-concussive symptom (e.g., headaches, memory problems) severity (i.e., frequency, intensity, duration). Taken together, the long-term use of cannabis may be detrimental to individuals with a history of concussion, exacerbating, rather than mitigating, post-concussive symptoms.

Evidence That Cannabis Exposure, Abuse, and Dependence Are Related to Glutamate Metabolism and Glial Function in the Anterior Cingulate Cortex: A 1H-Magnetic Resonance Spectroscopy Study.

There is evidence that long-term cannabis use is associated with alterations to glutamate neurotransmission and glial function. In this study, 26 long-term cannabis users (males=65.4%) and 47 non-cannabis using healthy controls (males=44.6%) underwent proton magnetic resonance spectroscopy (1H-MRS) of the anterior cingulate cortex (ACC) in order to characterize neurometabolite alterations in cannabis users and to examine associations between neurometabolites, cannabis exposure, and cannabis use behaviors. Myo-inositol, a marker of glial function, and glutamate metabolites did not differ between healthy controls and cannabis users or cannabis users who met criteria for DSM5 cannabis use disorder (n=17). Lower myo-inositol, a putative marker of glial function, was related to greater problematic drug use (F1,22 = 11.95, p=.002; Cohen’s f=0.59, large effect; Drug Abuse Screening Test) and severity of cannabis dependence (F1,22 = 6.61, p=.17; Cohen’s f=0.44, large effect). Further, past-year cannabis exposure exerted different effects on glutamate and glutamate+glutamine in males and females (glutamate: F1,21 = 6.31, p=.02; glutamate+glutamine: F1,21 = 7.20, p=.014), such that greater past-year cannabis exposure was related to higher concentrations of glutamate metabolites in male cannabis users (glutamate: F1,14 = 25.94, p=.00016; Cohen’s f=1.32, large effect; glutamate+glutamine: F1,14 = 23.24, p=.00027, Cohen’s f=1.24, large effect) but not in female cannabis users (glutamate: F1,6 = 1.37, p=0.78; glutamate+glutamine: F1,6 = 0.001, p=.97). The present results extend existing evidence of altered glial function and glutamate metabolism with cannabis use by providing evidence linking problematic drug use behaviors with glial function as measured with myo-inositol and recent chronic cannabis exposure to alterations in glutamate metabolism. This provides novel directions for the interrogation of the impact of cannabis use on brain neurochemistry.

Cannabis, More Than the Euphoria: Its Therapeutic Use in Drug-Resistant Epilepsy.

A significant number of epilepsy patients are refractory to conventional antiepileptic drugs. These patients experience considerable neurocognitive impairments that impact their quality of life and ability to function independently. This need for alternative treatment has generated increased interest in cannabis use as a therapeutic option in these patients. This review seeks to analyze data presented on the pharmacology, safety, and efficacy of cannabis use in patients with drug-resistant epilepsy (DRE) and to propose any future recommendations regarding its use. PubMed was used to retrieve all published studies and articles which evaluated the use of cannabis in epilepsy. The two foremost phytocannabinoids of cannabis showing anticonvulsant properties are tetrahydrocannabinol (THC) and cannabidiol (CBD). Due to the psychoactive properties of THC, most studies focused on CBD use in these patients. The use of CBD as an adjunct resulted in decreased seizure frequency, and secondary benefits observed included improvement in mood, alertness and sleep. Adverse events (AEs) reported were drowsiness, diarrhea, increased transaminases and worsening of seizures. It can safely be concluded that there is a significant benefit in DRE patients using CBD as adjunctive therapy. However, further controlled and adequately powered studies are needed to assess the pharmacokinetics and impact of the long-term use of cannabis.

Shifting the Paradigm on Cannabis Safety.

The global movement toward legalization of cannabis is resulting in an ever-increasing public perception that cannabis is safe. Cannabis is not the first drug to be available for nonmedical use, nor is it the first to have such an unfounded safety profile. The safety of long-term exposure to phytocannabinoids is misunderstood by, and under reported to, the general public. There is evidence to suggest that long-term use of recreational cannabis may be associated with an increased risk of undesirable side effects. This evidence warrants both appropriate caution from the general public and investment in further research by government and industry sectors that are profiting from the sale of these potent psychoactive agents. There is no doubt that these compounds have medical potential. However, in addition to the medical potential, we must also remain aware of the adverse health effects that are becoming synonymous with recreational cannabis use. This perspective highlights the privileged role that cannabis has as a perceived “safe drug” in society and summarizes some concerning side effects that are becoming associated with regular nonprescribed cannabis use.

Δ-Tetrahydrocannabinol Increases Dopamine D1-D2 Receptor Heteromer and Elicits Phenotypic Reprogramming in Adult Primate Striatal Neurons.

SummaryLong-term cannabis users manifest deficits in dopaminergic functions, reflecting Δ9-tetrahydrocannabinol (THC)-induced neuroadaptive dysfunctional dopamine signaling, similar to those observed upon dopamine D1-D2 heteromer activation. The molecular mechanisms remain largely unknown. We show evolutionary and regional differences in D1-D2 heteromer abundance in mammalian striatum. Importantly, chronic THC increased the number of D1-D2 heteromer-expressing neurons, and the number of heteromers within individual neurons in adult monkey striatum. The majority of these neurons displayed a phenotype co-expressing the characteristic markers of both striatonigral and striatopallidal neurons. Furthermore, THC increased D1-D2-linked calcium signaling markers (pCaMKIIα, pThr75-DARPP-32, BDNF/pTrkB) and inhibited cyclic AMP signaling (pThr34-DARPP-32, pERK1/2, pS845-GluA1, pGSK3). Cannabidiol attenuated most but not all of these THC-induced neuroadaptations. Targeted pathway analyses linked these changes to neurological and psychological disorders. These data underline the importance of the D1-D2 receptor heteromer in cannabis use-related disorders, with THC-induced changes likely responsible for the reported adverse effects observed in heavy long-term users.