Heavy Cannabis Research Articles

Cannabis use and anticipatory pleasure as reported by subjects with early psychosis and community controls

BackgroundThere is evidence of decreased pleasure and deficits in the anticipation of reward in both psychotic illness and drug addiction. Individuals with low anticipatory pleasure may preferentially engage in behaviours associated with immediate reward such as cannabis use. MethodNinety-one psychosis patients and 91 controls without history of psychosis were administered the Temporal Experience of Pleasure Scale (TEPS), a self report which measures anticipatory and consummatory pleasure. Cannabis use diagnosis was assessed using the Structured Clinical Interview for DSM IV (SCID). Subjects reported the frequency of cannabis consumption and time since last use. ResultsPatients did not show a significant deficit in anticipatory or consummatory pleasure compared to controls; however, patients with an active cannabis-use disorder tended to have lower consummatory pleasure than controls with active cannabis disorder (p<.05). Patients who continued to use cannabis during treatment of their first episode of psychosis reported significantly lower anticipatory pleasure compared to those who had a lifetime cannabis diagnosis but were able to maintain abstinence (F(1,60)=5.6, p=.021). Frequency of cannabis use was negatively correlated to anticipatory and consummatory pleasure (Pearson R=−.46, −.48 respectively) in 37 patients currently using cannabis but not in 46 cannabis-using controls (partial R=−.04, −.07 respectively). ConclusionAnticipatory pleasure may not be decreased in early psychosis patients. Lower hedonic response may be associated with persistent, heavy cannabis use in patients in the early phase of psychotic disorders.

Assessing Topographical Orientation Skills in Cannabis Users

The long-term effects of cannabis on human cognition are still unclear, but, considering that cannabis is a widely used substance and, overall, its potential use in therapeutic interventions, it is important to evaluate them. We hypothesize that the discrepancies among studies could be attributed to the specific cognitive function investigated and that skills subserved by the hippocampus, such as the spatial orientation abilities and, specifically, the ability to form and use cognitive maps, should be more compromised than others. Indeed it has been showed that cannabis users have a reduced hippocampus and that the hippocampus is the brain region in which cannabis has the greatest effect since it contains the highest concentration of cannabinoid receptors. To test this hypothesis we asked 15 heavy cannabis users and 19 nonusers to perform a virtual navigational test, the CMT, that assesses the ability to form and use cognitive maps. We found that using cannabis has no effect on these hippocampus-dependent orientation skills. We discuss the implications of our findings and how they relate to evidence reported in the literature that the intervention of functional reorganization mechanisms in cannabis user allows them to cope with the cognitive demands of navigational tasks.

Examining the effects of former cannabis use on cerebellum-dependent eyeblink conditioning in humans

Previous work in humans has shown that chronic cannabis users exhibit disruptions in classical eyeblink conditioning (EBC), a form of associative learning that is known to be dependent on the cerebellum. Based upon previous work in animals, it was hypothesized that these learning deficits were related to cannabinoid receptor (CB1R) downregulation. However, it remains unclear whether there is a recovery of cerebellum-dependent learning after the cessation of cannabis use. Therefore, former cannabis users (n=10), current cannabis users (n=10), and cannabis-naïve controls (n=10), all free of DSM-IV Axis-I or -II disorders, were evaluated. A standard delay EBC procedure was utilized in which paired presentations of a conditioned stimulus (CS; e.g., tone) and a co-terminating unconditioned stimulus (US; e.g., ocular airpuff) were administered, thus eliciting a conditioned eyeblink response (CR). The primary dependent measures were percentage of CRs and CR latency across conditioning blocks. Similar to prior studies, current cannabis users exhibited marked impairments in both the acquisition and timing of CRs compared to controls. Although former cannabis users showed intact CR acquisition compared to controls, they exhibited significantly impaired (shorter) CR latencies. In both cannabis groups, UR amplitude did not differ from controls, indicating normal US processing. These data suggest that a recovery of function has occurred for the learning of the CS-US association, while the accurate timing of the CR shows lasting impairments. Taken together, these results suggest that heavy cannabis use can disrupt timing-related synaptic plasticity within the cerebellum, even after the cessation of cannabis use.

Orbitofrontal Volumes in Early Adolescence Predict Initiation of Cannabis Use: A 4-Year Longitudinal and Prospective Study

There is growing evidence that long-term, heavy cannabis use is associated with alterations in regional brain volumes. Although these changes are frequently attributed to the neurotoxic effects of cannabis, it is possible that some abnormalities might predate use and represent markers of vulnerability. To date, no studies have examined whether structural brain abnormalities are present before the onset of cannabis use. This study aims to determine whether adolescents who have initiated cannabis use early (i.e., before age 17 years) show premorbid structural abnormalities in the amygdala, hippocampus, orbitofrontal cortex, and anterior cingulate cortex. Participants (n = 121) were recruited from primary schools in Melbourne, Australia, as part of a larger study examining adolescent emotional development. Participants underwent structural magnetic resonance imaging at age 12 years and were assessed for cannabis use 4 years later, at age 16 years. At the follow-up assessment, 28 participants had commenced using cannabis (16 female subjects [57%]), and 93 had not (43 female subjects [46%]). Smaller orbitofrontal cortex volumes at age 12 years predicted initiation of cannabis use by age 16 years. The volumes of other regions (amygdala, hippocampus, and anterior cingulate cortex) did not predict later cannabis use. These findings suggest that structural abnormalities in the orbitofrontal cortex might contribute to risk for cannabis exposure. Although the results have important implications for understanding neurobiological predictors of cannabis use, further research is needed to understand their relationship with heavier patterns of use in adulthood as well as later abuse of other substances.

Neurophysiological functioning of occasional and heavy cannabis users during THC intoxication

RationaleExperienced cannabis users demonstrate tolerance to some of the impairing acute effects of cannabis.ObjectivesThe present study investigates whether event-related potentials (ERPs) differ between occasional and heavy cannabis users after acute Δ9-tetrahydrocannabinol (THC) administration, as a result of tolerance.MethodsTwelve occasional and 12 heavy cannabis users participated in a double-blind, placebo-controlled, crossover study. On two separate days, they smoked a joint containing 0 or 500 μg/kg body weight THC. ERPs were measured while subjects performed a divided attention task (DAT) and stop signal task (SST).ResultsIn the DAT, THC significantly decreased P100 amplitude in occasional but not in heavy cannabis users. P300 amplitude in the DAT was significantly decreased by THC in both groups. The N200 peak in the SST was not affected by treatment in neither of the groups. Performance in the SST was impaired in both groups after THC treatment, whereas performance in the DAT was impaired by THC only in the occasional users group.ConclusionsThe present study confirms that heavy cannabis users develop tolerance to some of the impairing behavioral effects of cannabis. This tolerance was also evident in the underlying ERPs, suggesting that tolerance demonstrated on performance level is not (completely) due to behavioral compensation.

Erratum

AddictionVolume 106, Issue 11 p. 2053-2053 Free Access Erratum This article corrects the following: Reaching out towards cannabis: approach-bias in heavy cannabis users predicts changes in cannabis use Janna Cousijn, Anna E. Goudriaan, Reinout W. Wiers, Volume 106Issue 9Addiction pages: 1667-1674 First Published online: August 5, 2011 First published: 06 October 2011 https://doi.org/10.1111/j.1360-0443.2011.03677.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Reaching out towards cannabis: approach-bias in heavy cannabis users predicts changes in cannabis use Janna Cousijn, Anna E. Goudriaan & Reinout W. Wiers In the footnote to table 2 in this paper 1 an abbreviation was given in full incorrectly. AAT should have read Approach Avoidance Task. The publisher apologises for this error. Reference 1 Cousijn J., Goudriaan A. E., Wiers R. W. Reaching out towards cannabis: approach-bias in heavy cannabis users predicts changes in cannabis use. Addiction 2011; 106: 1667– 74. Wiley Online LibraryPubMedWeb of Science®Google Scholar Volume106, Issue11November 2011Pages 2053-2053 ReferencesRelatedInformation

Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls

Cannabis abuse is related to impairments in a broad range of cognitive functions. However, studies on cannabis abuse in relation to brain structure are sparse and results are inconsistent, probably due to differences in imaging methodology, severity of cannabis abuse, and use of other substances. The goal of the current MRI study was to investigate brain morphology related to current and lifetime severity of cannabis use and dependence in heavy cannabis users without intensive use of other illicit drugs. Voxel-based morphometry was used to assess differences in regional grey and white matter volume between 33 heavy cannabis users and 42 matched controls. Within heavy cannabis users, grey and white matter volume was correlated with measures of cannabis use and dependence. Analyses were focused a priori on the orbitofrontal cortex, anterior cingulate cortex, striatum, amygdala, hippocampus, and cerebellum, regions implicated in substance dependence and/or with high cannabinoid receptor-1 concentrations. Regional grey matter volume in the anterior cerebellum was larger in heavy cannabis users. Within the group of heavy cannabis users, grey matter volume in the amygdala and hippocampus correlated negatively with the amount of cannabis use or dependence. No associations were found between white matter volume and measures of cannabis use or dependence. These findings indicate that associations between heavy cannabis use and altered brain structure are complex. Differential patterns of structural changes for various cannabis use levels imply that alterations in brain structure are associated with specific characteristics of cannabis use and dependence.

Characterizing smoking topography of cannabis in heavy users

Little is known about the smoking topography characteristics of heavy cannabis users. Such measures may be able to predict cannabis use-related outcomes and could be used to validate self-reported measures of cannabis use. The current study was conducted to measure cannabis smoking topography characteristics during periods of ad libitum use and to correlate topography assessments with measures of self-reported cannabis use, withdrawal and craving during abstinence, and cognitive task performance. Participants (N = 20) completed an inpatient study in which they alternated between periods of ad libitum cannabis use and abstinence. Measures of self-reported cannabis use, smoking topography, craving, withdrawal, and sleep measures were collected. Participants smoked with greater intensity (e.g., greater volume, longer duration) on initial cigarette puffs with a steady decline on subsequent puffs. Smoking characteristics were significantly correlated with severity of withdrawal, notably sleep quality and architecture, and craving during abstinence, suggesting dose-related effects of cannabis use on these outcomes. Smoking characteristics generally were not significantly associated with cognitive performance. Smoking topography measures were significantly correlated with self-reported measures of cannabis use, indicating validity of these assessments, but topography measures were more sensitive than self-report in predicting cannabis-related outcomes. A dose-effect relationship between cannabis consumption and outcomes believed to be clinically important was observed. With additional research, smoking topography assessments may become a useful clinical tool.

Reaching out towards cannabis: approach‐bias in heavy cannabis users predicts changes in cannabis use

AimsRepeated drug exposure can lead to an approach-bias, i.e. the relatively automatically triggered tendencies to approach rather that avoid drug-related stimuli. Our main aim was to study this approach-bias in heavy cannabis users with the newly developed cannabis Approach Avoidance Task (cannabis-AAT) and to investigate the predictive relationship between an approach-bias for cannabis-related materials and levels of cannabis use, craving, and the course of cannabis use.Design, settings and participantsCross-sectional assessment and six-month follow-up in 32 heavy cannabis users and 39 non-using controls.MeasurementsApproach and avoidance action-tendencies towards cannabis and neutral images were assessed with the cannabis AAT. During the AAT, participants pulled or pushed a joystick in response to image orientation. To generate additional sense of approach or avoidance, pulling the joystick increased picture size while pushing decreased it. Craving was measured pre- and post-test with the multi-factorial Marijuana Craving Questionnaire (MCQ). Cannabis use frequencies and levels of dependence were measured at baseline and after a six-month follow-up.FindingsHeavy cannabis users demonstrated an approach-bias for cannabis images, as compared to controls. The approach-bias predicted changes in cannabis use at six-month follow-up. The pre-test MCQ emotionality and expectancy factor were associated negatively with the approach-bias. No effects were found on levels of cannabis dependence.ConclusionsHeavy cannabis users with a strong approach-bias for cannabis are more likely to increase their cannabis use. This approach-bias could be used as a predictor of the course of cannabis use to identify individuals at risk from increasing cannabis use.

Effects of smoking cannabis on lung function

Although cannabis (or marijuana) is the world’s most widely-used illicit drug, there has been surprisingly little research into its effects on respiratory health. Part of the problem is the inherent difficulty of studying the long-term effects of an illegal habit. It has often been assumed that smoking cannabis will have similar long-term effects to smoking tobacco. Several recent observational studies suggest that this is not the case and that cannabis has quite different effects on the lung function. There are consistent findings that smoking cannabis is associated with large airway inflammation, symptoms of bronchitis, increased airway resistance and lung hyperinflation. The evidence that smoking cannabis leads to features of chronic obstructive pulmonary disease, such as airflow obstruction and emphysema is not convincing. However, there are numerous case reports of bullous emphysema among cannabis smokers. These findings have not been confirmed in systematic analytical studies and probably represent uncommon adverse effects in very heavy cannabis smokers. There is now additional controversial evidence that cannabis is at least an occasional cause of respiratory malignancies, but again the evidence is inconclusive.

Short term memory impairment and Schizophrenia-like symptoms are associated with cannabinoids in head hairs in chronic heavy cannabis users

Short term memory impairment and Schizophrenia-like symptoms are associated with cannabinoids in head hairs in chronic heavy cannabis users

Adolescent exposure to cannabis as a risk factor for psychiatric disorders

Adolescence represents a critical period for brain development and the endocannabinoid system plays a crucial role in the regulation of neuronal refinement during this period. Cannabis is the most consumed drug among adolescent people and its heavy use may affect maturational refinement by disrupting the regulatory role of the endocannabinoid system. In animals, adolescent cannabinoid exposure has been reported to cause long-term impairment in specific components of learning and memory and to differentially affect emotional reactivity with milder effects on anxiety behaviour and more pronounced effects on depression-like behaviour. Moreover, adolescent exposure to cannabinoids might represent a risk factor for developing psychotic-like symptoms at adulthood. Also epidemiological studies suggest that heavy adolescent cannabis use may increase the risk of cognitive abnormalities, psychotic illness, mood disorders and other illicit substance use later in life. In conclusion, the available data point to the hypothesis that heavy cannabis use in adolescence could increase the risk of developing psychiatric disorders, especially in people who already have a vulnerability to develop a psychiatric syndrome. Only few papers have investigated the neurobiological substrates of this vulnerability, thus further studies are needed to clarify the molecular mechanisms underlying the effect of cannabis on the adolescent brain.

Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats

Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or “ecstasy”) also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ9-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2×10mg/kg×4h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA.

Childhood sexual abuse and psychosis: data from a cross-sectional national psychiatric survey in England

A number of studies in a range of samples attest a link between childhood sexual abuse and psychosis. To use data from a large representative general population sample (Adult Psychiatric Morbidity Survey 2007) to test hypotheses that childhood sexual abuse is linked to psychosis, and that the relationship is consistent with mediation by revictimisation experiences, heavy cannabis use, anxiety and depression. The prevalence of psychosis was established operationally in a representative cross-sectional survey of the adult household population of England (n = 7353). Using computer-assisted self-interview, a history of various forms of sexual abuse was established, along with the date of first abuse. Sexual abuse before the age of 16 was strongly associated with psychosis, particularly if it involved non-consensual sexual intercourse (odds ratio (OR) = 10.14, 95% CI 4.8-21.3, population attributable risk fraction 14%). There was evidence of partial mediation by anxiety and depression, but not by heavy cannabis use nor revictimisation in adulthood. The association between childhood sexual abuse and psychosis was large, and may be causal. These results have important implications for the nature and aetiology of psychosis, for its treatment and for primary prevention.

Neurocognitive functions of heavy cannabis using schizophrenia patients

This current study assessed neurocognitive functioning in a carefully selected sample of schizophrenia patients with and without heavy cannabis use and healthy controls. All subjects were negative for any other substance use. Schizophrenia subjects had impaired neurocognitive functions across a wide range of tasks compared to healthy controls. Cannabis using schizophrenia patients had focused impairments on tasks of attention, and the findings suggest an impulsive pattern of response among these patients.

Substance use by adolescents in special education and residential youth care institutions

This study examined substance use rates and related background factors among adolescents in special education (SE) and in residential youth care institutions (RYC). Information on substance use from 531 adolescents in RYC, 603 adolescents in SE for students with behavioral problems (SEB) and 1,905 adolescents in SE for students with learning disabilities (SEL) was compared with information from 7,041 adolescents who attended mainstream education. Results show that substance use rates are particularly high among adolescents in RYC and in SEB. For example, 22% of the 12–13 years old in RYC and 16% in SEB was a daily smoker compared with 1% of their counterparts in mainstream education. Background factors, including age, ethnic background and family situation, partly explained the differences in substance use between mainstream education on the one hand and SE and RYC on the other hand, but differences between the groups remained substantial and significant. Several interaction effects were found in the relation between SE/RYC and substance use that were all in line with the risk paradox: some subgroups that are normally at lower risk for problem behavior are at higher risk when they are subjected to high-risk indicators. The elevated risk of substance use among adolescents in RYC/SE was in some cases particularly marked for those who would normally be at lower risk for substance use (girls in SEB for heavy alcohol drinking and cannabis use, ethnic minority adolescents and adolescents with a stable family situation in RYC for respectively heavy weekly alcohol drinking and daily use of tobacco). Results of this study have important implications for health education and intervention programs for adolescents in RYC and SE.

News and Notes

News and Notes

MAKING SPACE FOR CANNABIS POLICY EXPERIMENTS

We thank Mark Kleiman for his considered and critical analysis of our book [1]. In the space of a brief reply we can address only some of the many interesting issues that he raised. We acknowledge that our book has not broken the cannabis policy stalemate. Our subtitle was, after all, moving beyond stalemate. Our aims were more realistic. We wanted to describe the important ways in which cannabis differs from other illicit drugs, namely: the greater extent of its global use, the modest adverse impacts it has on mortality and morbidity compared to the opioids and cocaine; and the selective and commonly discriminatory enforcement of criminal penalties against its use, even in countries such as the United States that are nominally tough on cannabis. We also wanted to summarize the international evidence on the mixed impacts of the limited policy reform options that are available to nation states under existing international drug control treaties. Secondly, we wanted to make the case for modifying the way that international control treaties govern cannabis to permit nation states to conduct and evaluate cannabis policy experiments that extend beyond minor variations in the severity of penalties for cannabis use. As Kleiman notes, such policy experiments could possibly include the regulation of a commercial cannabis market along the lines of current regulatory regimes for alcohol. We include this as one among a series of options without privileging it over the others. In choosing between these regimes, states will need to take into consideration many of the issues that Kleiman raised, namely, the potential irreversibility of such a policy; the likelihood that legal markets, lower price, implicit social approval and commercial promotion of the product could increase heavy cannabis use and cannabis-related harm; and uncertainty about the impact that increased cannabis use would have on alcohol-related harm. However, these states should not only look at the consequences of changing policy: they also need to examine the extensive adverse effects of current cannabis control regimes. We agree that there are policy options other than a legal cannabis market that deserve consideration as policy experiments. These include: the Spanish growers’ clubs; the Californian quasi-medical marijuana prescription regime; and state monopolies modelled on those adopted for alcohol in Scandinavia, Canada and many US states in the first part of the last century. All these are potentially interesting policy frameworks for cannabis, but there is necessarily very limited evidence on their impact because all are proscribed under current international treaties. Adequate evaluations will require serious trials and rigorous evaluations of these policy regimes. Our aim was to encourage the type of policy experiments and evaluations needed to better inform the development of cannabis policy. To that end we suggested how the international treaties could be liberalized to allow such experiments while allowing states to operate under the current treaty, if that is what they prefer. In our view, cannabis control systems that operate under the constraints of the current international regime fail to deliver good public policy and have an unfavourable balance of policy benefits and harms. There is a danger that the high standards that Mark Kleiman demands for evidence of the effectiveness of alternative cannabis policies will prevent the policy experimentation we advocate and so, by default, perpetuate the policy stalemate that we hoped to show a way beyond. None.

Cerebellar white-matter changes in cannabis users with and without schizophrenia

The cerebellum is rich in cannabinoid receptors and implicated in the neuropathology of schizophrenia. Long-term cannabis use is associated with functional and structural brain changes similar to those evident in schizophrenia, yet its impact on cerebellar structure has not been determined. We examined cerebellar grey and white matter in cannabis users with and without schizophrenia. Seventeen patients with schizophrenia and 31 healthy controls were recruited; 48% of the healthy group and 47% of the patients were long-term heavy cannabis users (mean 19.7 and 17.9 years near daily use respectively). Cerebellar measures were extracted from structural 3-T magnetic resonance imaging (MRI) scans using semi-automated methods, and examined using analysis of covariance (ANCOVA) and correlational analyses. Cerebellar white-matter volume was reduced in cannabis users with and without schizophrenia compared to healthy non-users, by 29.7% and 23.9% respectively, and by 17.7% in patients without cannabis use. Healthy cannabis users did not differ in white-matter volume from either of the schizophrenia groups. There were no group differences in cerebellar grey matter or total volumes. Total cerebellar volume decreased as a function of duration of cannabis use in the healthy users. Psychotic symptoms and illness duration correlated with cerebellar measures differentially between patients with and without cannabis use. Long-term heavy cannabis use in healthy individuals is associated with smaller cerebellar white-matter volume similar to that observed in schizophrenia. Reduced volumes were even more pronounced in patients with schizophrenia who use cannabis. Cannabis use may alter the course of brain maturational processes associated with schizophrenia.

Cannabinoid receptor 1 gene polymorphisms and marijuana misuse interactions on white matter and cognitive deficits in schizophrenia

Marijuana exposure during the critical period of adolescent brain maturation may disrupt neuro-modulatory influences of endocannabinoids and increase schizophrenia susceptibility. Cannabinoid receptor 1 (CB1/ CNR1) is the principal brain receptor mediating marijuana effects. No study to-date has systematically investigated the impact of CNR1 on quantitative phenotypic features in schizophrenia and inter-relationships with marijuana misuse. We genotyped 235 schizophrenia patients using 12 tag single nucleotide polymorphisms (tSNPs) that account for most of CB1 coding region genetic variability. Patients underwent a high-resolution anatomic brain magnetic resonance scan and cognitive assessment. Almost a quarter of the sample met DSM marijuana abuse (14%) or dependence (8%) criteria. Effects of CNR1 tSNPs and marijuana abuse/dependence on brain volumes and neurocognition were assessed using ANCOVA, including co-morbid alcohol/non-marijuana illicit drug misuse as covariates. Significant main effects of CNR1 tSNPs (rs7766029, rs12720071, and rs9450898) were found in white matter (WM) volumes. Patients with marijuana abuse/dependence had smaller fronto-temporal WM volumes than patients without heavy marijuana use. More interestingly, there were significant rs12720071 genotype-by-marijuana use interaction effects on WM volumes and neurocognitive impairment; suggestive of gene–environment interactions for conferring phenotypic abnormalities in schizophrenia. In this comprehensive evaluation of genetic variants distributed across the CB1 locus, CNR1 genetic polymorphisms were associated with WM brain volume variation among schizophrenia patients. Our findings suggest that heavy cannabis use in the context of specific CNR1 genotypes may contribute to greater WM volume deficits and cognitive impairment, which could in turn increase schizophrenia risk.