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Rationale Compromised cognitive control in cannabis use–tempting situations is thought to play a key role in the development of cannabis use disorders. However, little is known about how exposure to cannabis cues and contexts may influence cognitive control and the underlying neural mechanisms in cannabis users. Objectives Working memory (WM) is an attention reliant executive function central to cognitive control. In this study, we investigated how distracting cannabis words affected WM load–dependent performance and related brain activity in near-daily cannabis users (N = 36) relative to controls (N = 33). Methods Brain activity was recorded during a novel N-back flanker WM task with neutral and cannabis flankers added as task-irrelevant distractors. Results On a behavioural level, WM performance did not differ between groups, and the presence of cannabis flankers did not affect performance. However, in cannabis users compared to controls, the presence of cannabis flankers reduced WM load–related activity in multiple regions, including the insula, thalamus, superior parietal lobe and supramarginal gyrus. Conclusions The group specificity of these effects suggest that cannabis users might differ from controls in the way they process cannabis-related cues and that cannabis cue exposure could interfere with other cognitive processes under cognitively demanding circumstances. Future studies should focus on the role of context in cognitive control–related processes like WM and attention to further elucidate potential cognitive impairments in heavy cannabis users and how these relate to loss of control over drug seeking itself.

Background and aims: Lockdown measures aimed at limiting the number of infections and deaths from the coronavirus disease 2019 (COVID-19) have introduced substantial psychosocial stressors in everyday life. We aimed to investigate the influence of the Dutch lockdown on cannabis use and cannabis use disorder (CUD) and investigate relations with change in mental wellbeing and experienced psychosocial stressors during the lockdown.Design: Explorative longitudinal baseline-, pre- and during lockdown survey study.Setting: The Netherlands, online between January 2019 and May 2020.Participants: Community sample of 120 monthly to daily cannabis users and reference group of 63 non-using controls.Measurements: Change in cannabis use and CUD symptom severity from baseline to pre-lockdown to post-lockdown. Change in cannabis use motives, mental health, quality of social relationships and job status from pre-lockdown to post-lockdown.Findings: In cannabis users, lockdown related to increased cannabis use (B = 1.92, 95% CI 0.23-3.61, p = 0.027), but not CUD symptom severity. Cannabis users experienced 30% job loss and increased loneliness (p < 0.001, BF10 > 100), while contact with partners (p = 0.005, BF10 = 8.21) and families improved (p < 0.001, BF10 = 19.73), with no differences between cannabis users and control. Generally, mental health problems (all p s > 0.277, all BF10 < 0.139) did not change but individual differences were significant and severity of cannabis use pre-lockdown, COVID-19 related worries, change in anxiety, expansion motives, social motives and family contact all uniquely related to variance in change in cannabis use or CUD.Conclusions: While cannabis use among daily cannabis users in The Netherlands increased at the group level during the period of COVID-19 lockdown, the effect of the first months of lockdown on cannabis use disorder severity and mental wellbeing varied significantly among individual daily cannabis users.

The aim of this review is to discuss the most recent evidence for the short-term and long-term effects of cannabis on cognition. The evidence that cannabis intoxication is associated with short-term impairment across several basal cognitive domains, including learning and (episodic) memory, attentional control, and motor inhibition is increasing. However, evidence regarding the effects of long-term heavy cannabis use on cognition remains equivocal. Cannabis research suffers from difficulties in measuring cannabis exposure history, poor control over potential subacute effects, and heterogeneity in cognitive measures and sample composition. Multidisciplinary collaborations and investment in studies that help overcome these difficulties should be prioritized.

AIMS: To summarize and evaluate our knowledge of the relationship between heavy cannabis use, cannabis use disorder (CUD) and the brain.METHODS: Narrative review of relevant literature identified through existing systematic reviews, meta-analyses and a PubMed search. Epidemiology, clinical representations, potential causal mechanisms, assessments, treatment and prognosis are discussed.RESULTS: Although causality is unclear, heavy and dependent cannabis use is consistently associated with a high prevalence of comorbid psychiatric disorders and learning and memory impairments that seem to recover after a period of abstinence. Evidence regarding other cognitive domains and neurological consequences, including cerebrovascular events, is limited and inconsistent. Abstinence after treatment is only achieved in a minority of cases; treatment targeted at reduction in use appears have some success. Potential moderators of the impact of CUD on the brain include age of onset, heaviness of use, CUD severity, the ratio of ∆9-tetrahydrocannabinol to cannabidiol and severity of comorbid disorders.CONCLUSIONS: Current evidence of long-term effects of daily cannabis use and cannabis use disorder on brain-related outcomes is suggestive rather than conclusive, but use is associated with psychiatric morbidity and with cognitive impairments that recover after a period of abstinence.

Objectives: Posttraumatic stress disorder (PTSD) is a potentially debilitating mental health problem. There has been a recent surge of interest regarding the use of cannabinoids in the treatment of PTSD. We therefore sought to systematically review and assess the quality of the clinical evidence of the effectiveness of cannabinoids for the treatment of PTSD. Method: We included all studies published until December 2018 where a patient has had PTSD diagnosed and had been prescribed or were using a cannabinoid for the purpose of reducing PTSD symptoms. Our primary outcome measure was the reduction in PTSD symptoms using a validated instrument. In the absence of randomized controlled trials, we included the next best available levels of evidence including observational and retrospective studies and case reports. We assessed risk of bias and quality using validated tools appropriate for the study design. Results: We included 10 studies in this review, of which only one study was a pilot randomized, double-blind, placebo-controlled, crossover clinical trial. Every identified study had medium to high risk of bias and was of low quality. We found that cannabinoids may decrease PTSD symptomology, in particular sleep disturbances and nightmares. Conclusions: Most studies to date are small and of low quality, with significant limitations to the study designs precluding any clinical recommendations about its use in routine clinical practice. Evidence that cannabinoids may help reduce global PTSD symptoms, sleep disturbances, and nightmares indicates that future well-controlled, randomized, double-blind clinical trials are highly warranted. PROSPERO registration number: 121646.

Objectives: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. Methods: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD−, n = 20) and controls ( n = 37). Results: Compared to CD− and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. Conclusion: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

Despite the significant societal and personal burden of cannabis use, the impact of long-term use and Cannabis Use Disorder (CUD) on white matter microstructure is still unclear. Previous studies show inconsistent findings, in part due to heterogeneity in methodology, variable severity of cannabis use, and potential confounding effects of other mental health issues and substance use. The goal of this diffusion tensor imaging (DTI) study was to compare whole-brain white matter microstructure between 39 near daily cannabis users and 28 controls closely matched on age, sex, alcohol use, cigarette use and mental health. Within the group of cannabis users, associations between white matter microstructure and recent cannabis use, dependence severity, and age of onset and duration of weekly use were investigated. White matter microstructure did not differ between cannabis users and controls and did not covary with recent cannabis use, dependence severity, or duration of use. Earlier onset of weekly cannabis use was related to lower fractional anisotropy (FA) in various sections of the right inferior longitudinal fasciculus and uncinate fasciculus. These findings suggest that long-term near-daily cannabis use does not necessarily affect white matter microstructure, but vulnerability may be higher during adolescence. These findings underscore the importance of sample composition and warrant further studies that investigate the moderating role of age of onset in the impact of cannabis on the brain.

Males and females show different patterns of cannabis use and related psychosocial outcomes. However, the neuroanatomical substrates underlying such differences are poorly understood. The aim of this study was to map sex differences in the neurobiology (as indexed by brain volumes) of dependent and recreational cannabis use. We compared the volume of a priori regions of interest (i.e., amygdala, hippocampus, nucleus accumbens, insula, orbitofrontal cortex (OFC), anterior cingulate cortex and cerebellum) between 129 regular cannabis users (of whom 70 were recreational users and 59 cannabis dependent) and 114 controls recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age, IQ, and alcohol and tobacco use. Dependent cannabis users, particularly females, had (marginally significant) smaller volumes of the lateral OFC and cerebellar white matter than recreational users and controls. In dependent (but not recreational) cannabis users, there was a significant association between female sex and smaller volumes of the cerebellar white matter and OFC. Volume of the OFC was also predicted by monthly standard drinks. No significant effects emerged the other brain regions of interest. Our findings warrant future multimodal studies that examine if sex and cannabis dependence are specific key drivers of neurobiological alterations in cannabis users. This, in turn, could help to identify neural pathways specifically involved in vulnerable cannabis users (e.g., females with cannabis dependence) and inform individually tailored neurobiological targets for treatment.

Cue reactivity is an important biomarker of cannabis use disorder (CUD). Despite high rates of cigarette and cannabis co‐use, its role in cannabis cue reactivity remains unclear. Using a visual functional magnetic resonance imaging cue reactivity paradigm, we investigated interactive effects of cannabis and cigarette use on cannabis cue relative to cigarette and neutral cue reactivity in a priori regions of interest—the amygdala, striatum, anterior cingulate cortex (ACC), ventral tegmental area (VTA), and orbitofrontal cortex—and a whole‐brain analysis. In our sample of cannabis users and controls closely matched on cigarette use, significant interactions between cannabis and cigarette use status emerged in the amygdala, striatum, ACC, frontal pole, and inferior frontal gyrus. Cannabis‐only users showed heightened cue reactivity in the amygdala compared with nonusing controls. Co‐users did not show heightened cue reactivity compared with cigarette smoking controls, although cue‐induced VTA activity was positively correlated with grams per week of cannabis. Cigarette smoking controls showed unexpectedly heightened cue reactivity compared to co‐users and nonsmoking controls. These findings and the high prevalence of cannabis and cigarette co‐use underscore the importance of considering cigarette smoking status when investigating the role of cue reactivity in heavy cannabis use., Heightened neural cue reactivity is considered a biomarker of substance use disorders. Cigarette co‐use is common among heavy cannabis users and it matters when investigating cannabis cue reactivity. Across several regions of interest, cannabis only users demonstrated significantly elevated heightened cue reactivity compared to non‐cigarette smoking controls, while cannabis and cigarette co‐users did not. Cigarette smokers in the control group showed unexpectedly heightened levels of cannabis cue reactivity compared to non‐smoking controls and heavy cannabis users.

The impact of cannabis on the adolescent compared to adult brain is of interest to researchers and society alike. From a theoretical perspective, adolescence represents a period of both risk and resilience to the harms of cannabis use and cannabis use disorders. The aim of this systematic review is to provide a critical examination of the moderating role of age on the relationship between cannabis use and cognition. To this end, we reviewed human and animal studies that formally tested whether age, adolescent or adult, changes the relationship between cannabis exposure and cognitive outcomes. While the results of this review do not offer a conclusive answer on the role of age, the novel review question, along with the inclusion of both human and animal work, has allowed for the formation of new hypotheses to be addressed in future work. First, general executive functioning seems to be more impaired in adolescent frequent cannabis users compared to adult frequent cannabis users. Second, age-effects may be most prominent among very heavy and dependent users. Third, craving and inhibitory control may not decrease as much post-intoxication in adolescents compared to adults. Lastly, adolescents’ vulnerability to reduced learning following cannabis use may not persist after sustained abstinence. If these hypotheses prove correct, it could lead to important developments in policy and prevention efforts. Electronic supplementary material The online version of this article (10.1007/s00406-019-00981-7) contains supplementary material, which is available to authorized users.

Contains fulltext : 208275.pdf (Publisher’s version ) (Closed access) Motivational processes like attentional bias and craving have been related to substance use. However, results are inconclusive. The present cross-sectional study was designed to replicate and extend previous research by investigating the relationships between attentional bias, craving, cognitive control and (severity of) cannabis use in a sample of inpatient adolescents and young adults (aged 18–30) diagnosed with CUD according to DSM-5. Contrary to expectations, our sample did not show attentional bias for cannabis words, neither did attentional bias correlate with craving, cognitive control or (severity of) cannabis use. In line with our hypotheses, however, increased session-induced craving was correlated to more daily cannabis use and reduced cognitive control. Furthermore, participants who displayed reduced cognitive control used more cannabis per day. A bootstrapped hierarchical regression model showed that, contrary to expectations, cognitive control did not modulate the relationships between attentional bias, craving and cannabis use. This study highlights the unique role of craving in relation to cannabis use and extends previous findings that cognitive control appears to have no moderating role regarding cannabis use disorder. Based on our results, it might well be that the underlying mechanisms of cannabis use disorder differ from those in other substance use disorders. 6 p.

This is a summary and critical review of the National Academies of Sciences, Engineering and Medicine (NASEM) report of the health effects of cannabis. The report stated that effects of cannabis are understudied, and research findings are mixed. It concluded that the under‐developed evidence base poses a public health risk and rightly addressed complexities of cannabis research that need to be resolved collaboratively. We support NASEM's urgent call for research, but add that the mixed evidence base cannot be attributed solely to research limitations. Rather, we propose a need to acknowledge the heterogeneity in the effects of cannabis to advance the field.

Rationale: Cannabis (CB) use and dependence are associated with regionally specific alterations to brain circuitry and substantial psychosocial impairment.Objectives: The objective of this study was to investigate the association between CB use and dependence, and the volumes of brain regions critically involved in goal-directed learning and behaviour—the orbitofrontal cortex (OFC) and caudate.Methods: In the largest multi-site structural imaging study of CB users vs healthy controls (HC), 140 CB users and 121 HC were recruited from four research sites. Group differences in OFC and caudate volumes were investigated between HC and CB users and between 70 dependent (CB-dep) and 50 non-dependent (CB-nondep) users. The relationship between quantity of CB use and age of onset of use and caudate and OFC volumes was explored.Results: CB users (consisting of CB-dep and CB-nondep) did not significantly differ from HC in OFC or caudate volume. CB-dep compared to CB-nondep users exhibited significantly smaller volume in the medial and the lateral OFC. Lateral OFC volume was particularly smaller in CB-dep females, and reduced volume in the CB-dep group was associated with higher monthly cannabis dosage.Conclusions: Smaller medial OFC volume may be driven by CB dependence-related mechanisms, while smaller lateral OFC volume may be due to ongoing exposure to cannabinoid compounds. The results highlight a distinction between cannabis use and dependence and warrant examination of gender-specific effects in studies of CB dependence.

Item does not contain fulltext Cannabis exerts its psychoactive effect through cannabinoid receptors that are widely distributed across the cortical surface of the human brain. It is suggested that cannabis use may contribute to structural alterations across the cortical surface. In a large, multisite dataset of 120 controls and 141 cannabis users, we examined whether differences in key characteristics of the cortical surface - including cortical thickness, surface area, and gyrification index were related to cannabis use characteristics, including (i) cannabis use vs. non-use, (ii) cannabis dependence vs. non-dependence vs. non-use, and (iii) early adolescent vs. late adolescent onset of cannabis use vs. non-use. Our results revealed that cortical morphology was not associated with cannabis use, dependence, or onset age. The lack of effect of regular cannabis use, including problematic use, on cortical structure in our study is contrary to previous evidence of cortical morphological alterations (particularly in relation to cannabis dependence and cannabis onset age) in cannabis users. Careful reevaluation of the evidence on cannabis-related harm will be necessary to address concerns surrounding the long-term effects of cannabis use and inform policies in a changing cannabis regulation climate.

Cannabis use disorders (CUDs) affect 13.1 million individuals worldwide. Brain morphology specific to CUDs may mediate the adverse behavioral outcomes of CUDs. We reviewed findings from 20 human neuroimaging studies on grey and white matter morphology in cannabis users that specifically included CUD assessments. There is evidence for CUD-specific morphological abnormalities within the striatum, medial temporal lobe, prefrontal cortex, cerebellum, and corpus callosum. Factors that may aggravate morphological abnormalities associated with CUDs include earlier onset age, higher lifetime exposure, and CUD-associated problems, while abstinence may result in (partial) recovery. These observations suggest that the neural substrates of compulsive cannabis use (e.g., striatum) may be distinct from those linked to cannabinoid exposure (e.g., hippocampus). The lack of studies examining individuals with a diagnosed CUD prevents drawing strong conclusions on CUD-specific morphological abnormalities. Comparing cannabis users with and without CUD is essential to delineate the neurobiology and inform new treatment strategies.

Cannabis use is highly prevalent and often considered to be relatively harmless. Nonetheless, a subset of regular cannabis users may develop dependence, experiencing poorer quality of life and greater mental health problems relative to non-dependent users. The neuroanatomy characterizing cannabis use versus dependence is poorly understood. We aimed to delineate the contributing role of cannabis use and dependence on morphology of the hippocampus, one of the most consistently altered brain regions in cannabis users, in a large multi-site dataset aggregated across four research sites. We compared hippocampal volume and vertex-level hippocampal shape differences (1) between 121 non-using controls and 140 cannabis users; (2) between 106 controls, 50 non-dependent users and 70 dependent users; and (3) between a subset of 41 controls, 41 non-dependent users and 41 dependent users, matched on sample characteristics and cannabis use pattern (onset age and dosage). Cannabis users did not differ from controls in hippocampal volume or shape. However, cannabis-dependent users had significantly smaller right and left hippocampi relative to controls and non-dependent users, irrespective of cannabis dosage. Shape analysis indicated localized deflations in the superior-medial body of the hippocampus. Our findings support neuroscientific theories postulating dependence-specific neuroadaptations in cannabis users. Future efforts should uncover the neurobiological risk and liabilities separating dependent and non-dependent use of cannabis.

A milestone in cannabis research is the establishment of a clinically relevant cannabis withdrawal syndrome, yet little is known about the underlying mechanisms. We investigated the predictive role of mental health and cognitive factors in withdrawal severity during an active attempt to cut down, relative to uninterrupted cannabis use. Ninety heavy cannabis users were randomly assigned to an experimental or control group. The experimental group was asked to cut down substance use for 1 week. Past week substance use, substance use-related problems, depressive symptoms, cravings, and cognitive control were assessed at baseline. Past week substance use and withdrawal severity were assessed at follow-up. The experimental group reduced their cannabis use more and experienced more withdrawal than the control group. Hierarchical regression analysis per predictor indicated that cannabis use-related problems, depressive symptoms, and cannabis craving, but not cognitive control, predicted stronger withdrawal. Craving uniquely predicted withdrawal in the experimental group. A combined hierarchical regression indicated that only depressive symptoms and cannabis use-related problems uniquely predicted withdrawal across groups. These results suggest that depressive symptoms and cannabis use-related problems are generally indicative of cannabis withdrawal severity, whereas craving specifically predicts cannabis withdrawal during an active attempt to cut-down cannabis use.

Background: Cannabis exposure, particularly heavy cannabis use, has been associated with neuroanatomical alterations in regions rich with cannabinoid receptors such as the hippocampus in some but not in other (mainly cross-sectional) studies. However, it remains unclear whether continued heavy cannabis use alters hippocampal volume, and whether an earlier age of onset and/or a higher dosage exacerbate these changes. Methods: Twenty heavy cannabis users (mean age 21 years, range 18–24 years) and 23 matched non-cannabis using healthy controls were submitted to a comprehensive psychological assessment and magnetic resonance imaging scan at baseline and at follow-up (average of 39 months post-baseline; standard deviation=2.4). Cannabis users started smoking around 16 years and smoked on average five days per week. A novel aspect of the current study is that hippocampal volume estimates were obtained from manual tracing the hippocampus on T1-weighted anatomical magnetic resonance imaging scans, using a previously validated protocol. Results: Compared to controls, cannabis users did not show hippocampal volume alterations at either baseline or follow-up. Hippocampal volumes increased over time in both cannabis users and controls, following similar trajectories of increase. Cannabis dose and age of onset of cannabis use did not affect hippocampal volumes. Conclusions: Continued heavy cannabis use did not affect hippocampal neuroanatomical changes in early adulthood. This contrasts with prior evidence on alterations in this region in samples of older adult cannabis users. In young adults using cannabis at this level, cannabis use may not be heavy enough to affect hippocampal neuroanatomy.

Item does not contain fulltext Orbitofrontal cortex (OFC) sulcogyral patterns are stable morphological variations established early in life. They consist of three distinct pattern types, with Type III in particular being associated with poor regulatory control (e.g., high sensation seeking and negative emotionality, low constraint), which may confer risk for earlier onset of cannabis (CB) use and greater use in later life. The OFC sulcogyral pattern may therefore be a stable trait marker in understanding individual differences in substance-use vulnerability and associated affective disturbances in users. In a large multisite cross-sectional study, we compared OFC pattern type distribution between 128 healthy controls (HC) and 146 CB users. Within users (n=140), we explored the association between OFC pattern type and CB use level, and subsequently if level of CB use informed by OFC pattern type may mediate disturbances in affective tone, as indexed by depressive symptoms. While OFC pattern distribution did not distinguish between HC and CB groups, it informed greater lifetime use within users. Specifically, CB users with pattern Type III in the right OFC tended to use more CB over their lifetime, than did CB users with pattern Type I or II. Greater lifetime CB use was subsequently associated with higher depressive symptoms, such that it mediated an indirect association between right OFC pattern Type III and higher depressive symptoms. The present study provides evidence for neurobiological differences, specifically sulcogyral pattern of the OFC, to modulate level of CB use, which may subsequently influence the expression of depressive symptoms.

One of the characteristics of people suffering from addictive behaviors is the tendency to be distracted by drug cues. This attentional bias for drug cues is thought to lead to increased craving and drug use, and may draw individuals into a vicious cycle of drug addiction. In the current study we developed a Dutch version of the cannabis Stroop task and measured attentional bias for cannabis words in a group of heavy cannabis users and matched controls. The classical Stroop task was used as a global measure of cognitive control and we examined the relationship between cognitive control, cannabis-related problems, cannabis craving and cannabis attentional bias. Using our version of the cannabis Stroop task, a group of heavy cannabis users showed attentional bias to cannabis words, whereas a control group of non-users did not. Furthermore, within the group of cannabis users, those who were clinically recognized as dependent showed a stronger attentional bias than the heavy, non-dependent users. Cannabis users who displayed reduced cognitive control (as measured with the classical Stroop task) showed increased session-induced craving. Contrary to expectations, however, cognitive control did not appear to modulate the relationship between attentional bias to cannabis words (cannabis Stroop task) and cannabis dependence. This study confirmed the relationship between cannabis dependence and attentional bias and extends this by highlighting a moderating role for cognitive control, which may make some more vulnerable to craving.

Deficient executive functions play an important role in the development of addiction. Working-memory may therefore be a powerful predictor of the course of drug use, but chronic substance use may also impair working-memory. The aim of this 3-year longitudinal neuro-imaging study was to investigate the relationship between substance use (e.g. alcohol, cannabis, nicotine, illegal psychotropic drugs) and working-memory network function over time in heavy cannabis users and controls. Forty-nine participants performed an n-back working-memory task at baseline and at 3-year follow-up. At follow-up, there were 22 current heavy cannabis users, 4 abstinent heavy cannabis users and 23 non-cannabis-using controls. Tensor-independent component analysis (Tensor-ICA) was used to investigate individual differences in working-memory network functionality over time. Within the group of cannabis users, cannabis-related problems remained stable, whereas alcohol-related problems, nicotine dependence and illegal psychotropic substance use increased over time. At both measurements, behavioral performance and network functionality during the n-back task did not differ between heavy cannabis users and controls. Although n-back accuracy improved, working-memory network function remained stable over time. Within the group of cannabis users, working-memory network functionality was not associated with substance use. These results suggest that sustained moderate to heavy levels of cannabis, nicotine, alcohol and illegal psychotropic substance use do not change working-memory network functionality. Moreover, baseline network functionality did not predict cannabis use and related problems three years later, warranting longitudinal studies in more chronic or dependent cannabis users.

Theoretical models of addiction suggest that a substance use disorder represents an imbalance between hypersensitive motivational processes and deficient regulatory executive functions. Working-memory (a central executive function) may be a powerful predictor of the course of drug use and drug-related problems. Goal of the current functional magnetic resonance imaging study was to assess the predictive power of working-memory network function for future cannabis use and cannabis-related problem severity in heavy cannabis users. Tensor independent component analysis was used to investigate differences in working-memory network function between 32 heavy cannabis users and 41 nonusing controls during an N-back working-memory task. In addition, associations were examined between working-memory network function and cannabis use and problem severity at baseline and at 6-month follow-up. Behavioral performance and working-memory network function did not significantly differ between heavy cannabis users and controls. However, among heavy cannabis users, individual differences in working-memory network response had an independent effect on change in weekly cannabis use 6 months later (ΔR(2) = 0.11, P = 0.006, f(2) = 0.37) beyond baseline cannabis use (ΔR(2) = 0.41) and a behavioral measure of approach bias (ΔR(2) = 0.18): a stronger network response during the N-back task was related to an increase in weekly cannabis use. These findings imply that heavy cannabis users requiring greater effort to accurately complete an N-back working-memory task have a higher probability of escalating cannabis use. Working-memory network function may be a biomarker for the prediction of course and treatment outcome in cannabis users.

RATIONALE: Experimental laboratory studies suggest that the approach bias (relatively fast approach responses) toward substance-related materials plays an important role in problematic substance use. How this bias is moderated by intention to use versus recent use remains unknown. Moreover, the relationship between approach bias and other motivational processes (satiation and craving) and executive functioning remains unclear.OBJECTIVES: The aim of this study was to investigate the cannabis approach bias before and after cannabis use in real-life setting (Amsterdam coffee shops) and to assess the relationship between approach bias, craving, satiation, cannabis use, and response inhibition.METHODS: Cannabis, tobacco, and neutral approach and avoidance action tendencies were measured with the Approach Avoidance Task and compared between 42 heavy cannabis users with the intention to use and 45 heavy cannabis users shortly after cannabis use. The classical Stroop was used to measure response inhibition. Multiple regression analyses were conducted to investigate relationships between approach bias, satiation, craving, cannabis use, and response inhibition.RESULTS: In contrast to the hypotheses, heavy cannabis users with the intention to use did not show a cannabis approach bias, whereas intoxicated cannabis users did show an approach bias regardless of image category. This could be attributed to a general slowing of avoidance action tendencies. Moreover, craving was negatively associated with the approach bias, and no relationships were observed between the cannabis approach bias, satiation, prior cannabis use, and response inhibition.CONCLUSION: Cannabis intoxication in a real-life setting inhibited general avoidance. Expression of the cannabis approach bias appeared not to be modulated by satiation or response inhibition.

Background: Cannabis use typically commences during adolescence, a period during which the brain undergoes profound remodeling in areas that are high in cannabinoid receptors and that mediate cognitive control and emotion regulation. It is therefore important to determine the impact of adolescent cannabis use on brain function.Objective: We investigate the impact of adolescent cannabis use on brain function by reviewing the functional magnetic resonance imaging studies in adolescent samples.Method: We systematically reviewed the literature and identified 13 functional neuroimaging studies in adolescent cannabis users (aged 13 to 18 years) performing working memory, inhibition and reward processing tasks.Results: The majority of the studies found altered brain function, but intact behavioural task performance in adolescent cannabis users versus controls. The most consistently reported differences were in the frontal-parietal network, which mediates cognitive control. Heavier use was associated with abnormal brain function in most samples. A minority of studies controlled for the influence of confounders that can also undermine brain function, such as tobacco and alcohol use, psychopathology symptoms, family history of psychiatric disorders and substance use.Conclusion: Emerging evidence shows abnormal frontal-parietal network activity in adolescent cannabis users, particularly in heavier users. Brain functional alterations may reflect a compensatory neural mechanism that enables normal behavioural performance. It remains unclear if cannabis exposure drives these alterations, as substance use and mental health confounders have not been systematically examined.

Using cannabis is perceived by many as relatively harmless, but the adverse effects of problematic cannabis use are significant. Thirteen million individuals globally have Cannabis Use Disorders (CUDs; UNODC, 2015), with relapse rates comparable to those of other substance use disorders (~52–70%; Budney et al., 1999; Chauchard et al., 2013). Contrasting non-problematic recreational cannabis use, severe forms of CUD involve compulsive use despite significant harms to mental health; high stress levels (craving, withdrawal); cognitive deficits; academic and work absenteeism; and significant risky behaviors, such as driving and operating machinery while intoxicated. Worryingly, the concentration of Δ9-tetrahydrocannabinol, the compound driving the addiction liability of cannabis, has risen in cannabis products over the past decade (UNODC, 2015).

Cannabis is the most frequently used illicit drug worldwide, but little is known about the mechanisms underlying continued cannabis use. Cue-reactivity (the physical, psychological, behavioural and neural reaction to substance-related cues) might be related to continued cannabis use. In this 3-year prospective neuroimaging study we investigated whether cannabis cue-induced brain activity predicted continued cannabis use and associated problem severity 3 years later. In addition, baseline brain activations were compared between dependent and non-dependent cannabis users at follow-up. Analyses were focussed on brain areas known to be important in cannabis cue-reactivity: anterior cingulate cortex, orbitofrontal cortex, ventral tegmental area, amygdala and striatum. At baseline, 31 treatment-naive frequent cannabis users performed a cue-reactivity functional magnetic resonance imaging task. Of these participants, 23 completed the 3-year follow-up. None of the cue-induced region of interest activations predicted the amount of cannabis use at follow-up. However, cue-induced activation in the left striatum (putamen) significantly and independently predicted problem severity at follow-up ( p < 0.001) as assessed with the Cannabis Use Disorder Identification Test. Also, clinically dependent cannabis users at follow-up showed higher baseline activation at trend level in the left striatum compared with non-dependent users. This indicates that neural cue-reactivity in the dorsal striatum is an independent predictor of cannabis use-related problems. Given the relatively small sample size, these results are preliminary and should be replicated in larger samples of cannabis users.

Cannabis use disorders (CUDs) affect 13.1. million individuals worldwide and represent the most vulnerable portion of regular cannabis users. Neuroanatomical alterations in the brain may mediate the adverse outcomes of CUDs. We reviewed findings from 16 structural neuroimaging studies of gray matter morphology in CUDs. As of this writing the research shows preliminary evidence for CUD-specific alterations within the striatum, medial temporal lobe, prefrontal cortex, and cerebellum. Age of onset, gender, cumulative cannabis consumption, abstinence, and CUD-associated problems may be important moderators in the association between CUDs and brain morphology. The paucity of neuroimaging studies investigating brain morphology in CUDs, however, prevents strong conclusions being drawn about CUD-specific brain morphology. Studying the commonalities and differences between cannabis users with and without a CUD will be an important next step to understand the neurobiological mechanisms underlying CUDs and to develop new treatment strategies.

Decision-making deficits are thought to play an important role in the development and persistence of substance use disorders. Individual differences in decision-making abilities and their underlying neurocircuitry may, therefore, constitute an important predictor for the course of substance use and the development of substance use disorders. Here, we investigate the predictive value of decision making and neural mechanisms underlying decision making for future cannabis use and problem severity in a sample of heavy cannabis users. Brain activity during a monetary decision-making task (Iowa gambling task) was compared between 32 heavy cannabis users and 41 matched non-using controls using functional magnetic resonance imaging. In addition, within the group of heavy cannabis users, associations were examined between task-related brain activations, cannabis use and cannabis use-related problems at baseline, and change in cannabis use and problem severity after a 6-month follow-up. Despite normal task performance, heavy cannabis users compared with controls showed higher activation during wins in core areas associated with decision making. Moreover, within the group of heavy cannabis users, win-related activity and activity anticipating loss outcomes in areas generally involved in executive functions predicted change in cannabis use after 6 months. These findings are consistent with previous studies and point to abnormal processing of motivational information in heavy cannabis users. A new finding is that individuals who are biased toward immediate rewards have a higher probability of increasing drug use, highlighting the importance of the relative balance between motivational processes and regulatory executive processes in the development of substance use disorders.

Cue-reactivity reflects enhanced motivational processing underlying continued substance use and relapse in substance use disorders. Substance use disorders are associated with greater cue-reactivity in orbitofrontal cortex, anterior cingulate cortex, striatum, ventral tegmental area and amygdala. Here we examine whether this also holds for frequent cannabis users. Using functional magnetic resonance imaging (fMRI), neural responses to neutral and cannabis-related cues were compared between frequent cannabis users (n = 31), sporadic cannabis users (n = 20) and cannabis-naive controls (n = 21). In addition, fMRI findings were correlated with the level of cannabis use, problem severity and craving. In frequent users compared with sporadic users and controls, cannabis images engendered higher activation than control images in the ventral tegmental area. Activation of the orbitofrontal cortex, anterior cingulate cortex and striatum was only higher in a subgroup of frequent users with high compared with low-problem severity. Activity in the right putamen and right dorsolateral prefrontal cortex correlated negatively with subjective craving in frequent users. Activity was not correlated with level of cannabis use. These findings indicate that cannabis cues activate areas associated with addiction pathology in frequent cannabis users compared with sporadic users and controls. However, among frequent users, cue-reactivity seems to be primarily associated with problem severity, not with amount of cannabis use. These findings imply neural cue-reactivity as a tool in assessing problem severity of cannabis use.

Aims Repeated drug exposure can lead to an approach-bias, i.e. the relatively automatically triggered tendencies to approachratherthatavoiddrug-relatedstimuli.Ourmainaimwastostudythisapproach-biasinheavycannabisusers 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 participants Cross-sectional assessment and six-month follow-up in 32 heavy cannabis users and 39 non-using controls. Measurements Approach 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. Findings Heavy 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 foundonlevelsof cannabisdependence.Conclusions Heavycannabisuserswithastrongapproach-biasforcannabis aremorelikelytoincreasetheircannabisuse.Thisapproach-biascouldbeusedasapredictorof thecourseof cannabis use to identify individuals at risk from increasing cannabis use.

Although the general public perceives cannabis as one of the less harmful illicit drugs, the past decades saw a surge in treatment demands for CUDs (UNODC, 2014). Cannabis nowadays is the primary illicit drug of concern in drug treatment services across North America, Oceania and Africa (UNODC, 2014). The low perceived harms of cannabis use are reflected in the small number of studies investigating the neurocognitive processes underlying CUDs [e.g., only 3 published functional Magnetic Resonance Imaging (fMRI) studies in individuals with a diagnosed CUD compared to controls, contrasting more than 1000 studies in individuals with an Alcohol Use Disorder]. Most studies on the mechanisms underlying cannabis abuse, including my own, investigated heterogeneous groups of chronic or heavy cannabis users with various levels of cannabis use related problems, not groups with diagnosed CUDs. Even though a substantial part of regular cannabis users will not experience any clear negative social and health consequences of cannabis, this does not imply that CUDs are less severe than other Substance Use Disorders (SUDs). The mental health issues associated with CUDs are substantial and often include comorbid psychiatric disorders including depression and anxiety (Stinson et al., 2006). Moreover, CUDs are difficult to treat and long-term abstinence is achieved by fewer than 20% (Danovitch and Gorelick, 2012). This urgently calls for a better understanding of CUDs. It is therefore time to reach out to those coping with CUDs by studying the mechanisms underneath. The goal of this opinion article is twofold: First, I want to address the strong need for neurocognitive studies in CUDs. Second, I propose that studying neurocognitive commonalities and differences between CUDs and comorbid disorders like depression and anxiety has great potential to unravel the mechanisms underlying CUDs and to eventually reveal new treatment targets.

Cognitive biases, including implicit memory associations are thought to play an important role in the development of addictive behaviors. The aim of the present study was to investigate implicit affective memory associations in heavy cannabis users. Implicit positive-arousal, sedation, and negative associations towards cannabis were measured with three Single Category Implicit Association Tests (SC-IAT’s) and compared between 59 heavy cannabis users and 89 controls. Moreover, we investigated the relationship between these implicit affective associations and explicit expectancies, subjective craving, cannabis use, and cannabis related problems. Results show that heavy cannabis users had stronger implicit positive-arousal associations but weaker implicit negative associations towards cannabis compared to controls. Moreover, heavy cannabis users had stronger sedation but weaker negative explicit expectancies towards cannabis compared to controls. Within heavy cannabis users, more cannabis use was associated with stronger implicit negative associations whereas more cannabis use related problems was associated with stronger explicit negative expectancies, decreasing the overall difference on negative associations between cannabis users and controls. No other associations were observed between implicit associations, explicit expectancies, measures of cannabis use, cannabis use related problems, or subjective craving. These findings indicate that, in contrast to other substances of abuse like alcohol and tobacco, the relationship between implicit associations and cannabis use appears to be weak in heavy cannabis users.

A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.

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. (C) 2011 Elsevier Inc. All rights reserved