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Purpose of Review This narrative review provides an update of our knowledge on the relation between heavy cannabis use and cannabis use disorder (CUD) and the brain based on (f)MRI studies conducted in the past 5 years. Recent Findings Heavy cannabis use and CUD are associated with structural brain changes—particularly volume—as well as altered resting-state functional connectivity (RSFC) in several networks and regions. Task-based fMRI studies reveal altered activity and connectivity in cannabis users compared to controls, but consistency of the results is domain dependent. Heaviness of use, CUD status, age, sex, and tobacco co-use are important potential moderators of the effects of cannabis on the brain. Summary Heavy cannabis use and CUD are associated with differences in brain structure and function, but causality remains unclear, and long-term effects following abstinence require further investigation. Considering moderators of the effects of cannabis on the brain is crucial to further assess individual differences in the impact of cannabis use.

BACKGROUND: Prevalence of nitrous oxide (N 2 O) use appears to be increasing in numerous countries worldwide, and excessive use has been associated with physical and mental problems. Because there currently is no consensus whether N 2 O has addictive potential, we aimed to evaluate the evidence for the presence and prevalence of DSM-5 substance use disorder (SUD) symptoms in N 2 O users. ANALYSIS: A literature search was conducted to assess the evidence for the presence of any of the 11 DSM-5 SUD symptoms in N 2 O users and the prevalence experiencing those symptoms. A substantial part of the studied N 2 O users use more than intended (i.e. 46% to 98%) and spend a substantial amount of time using N 2 O. At least some of the studied N 2 O users experience interpersonal problems (i.e. 13% to 80%) and use N 2 O in risky situations, such as driving under the influence. Evidence for the other criteria is either insufficient or inconclusive. CONCLUSIONS: The literature base for the presence and prevalence of DSM-5 substance use disorder (SUD) symptoms in nitrous oxide (N 2 O) users is limited and largely consists of qualitative studies and case studies, but it provides consistent evidence for the presence of at least four SUD criteria in heavy N 2 O users. N 2 O could well be addictive and should be treated as a potentially addictive substance until systematic assessments can provide evidence-based guidance to users, healthcare professionals and legislators.

Considerable differences in the types of cannabis products, methods of use, social norms and cultures and legal climates surrounding use exist among regions, resulting in distinct cannabis use contexts. Research examining and accounting for these contextual differences is crucial to further understanding cannabis use and cannabis use disorder, and for developing and refining context sensitive strategies for prevention, treatment and harm reduction.

Social attunement (SA)-the tendency to harmonize behavior with the social environment-has been proposed to drive the escalation of alcohol use in adolescence, while reducing use in adulthood. Little is known about how heightened social sensitivity in adolescence may interact with neural alcohol cue reactivity-a marker of alcohol use disorder-and its relationship to alcohol use severity over time. The aims of this study were to test whether (1) adolescents and adults differ in social alcohol cue reactivity in the nucleus accumbens, anterior cingulate cortex, and right medial prefrontal cortex (mPFC), and (2) age moderates the relationship between social alcohol cue reactivity and social attunement, measures of drinking at baseline, and changes in drinking over time. A sample of male adolescents (16-18 years) and adults (29-35 years) completed an fMRI social alcohol cue-exposure task at baseline and an online follow-up two to three years later. No main effects of age or drinking measures were observed in social alcohol cue reactivity. However, age significantly moderated associations of social alcohol cue reactivity in the mPFC and additional regions from exploratory whole-brain analyses with SA, with a positive association in adolescents and negative association in adults. Significant age interactions emerged only for SA in predicting drinking over time. Adolescents with higher SA scores escalated drinking, while adults with higher SA scores reduced drinking. These findings warrant further research on SA as a risk and protective factor and suggest that social processes influence cue reactivity differentially in male adolescents and adults.

Cannabis legislation and attitudes towards use are changing. Given that evidence from cultural neuroscience research suggests that culture influences the neurobiological mechanisms underlying behaviour, it is of great importance to understand how cannabis legislation and attitudes might affect the brain processes underlying cannabis use disorder. Brain activity of 100 dependent cannabis users and 84 controls was recorded during an N-back working memory (WM) task in participants from the Netherlands (NL; users = 60, controls = 52) and Texas, USA (TX; users = 40, controls = 32). Participants completed a cannabis culture questionnaire as a measure of perceived benefits (positive) and perceived harms (negative) of cannabis from their personal, friends-family's and country-state's perspectives. Amount of cannabis use (grams/week), DSM-5 CUD symptoms and cannabis use-related problems were assessed. Cannabis users self-reported more positive and less negative (personal and friends-family) cannabis attitudes than controls, with this effect being significantly larger in the TX cannabis users. No site difference in country-state attitudes was observed. TX cannabis users, compared with NL cannabis users, and those cannabis users perceiving more positive country-state attitudes showed a more positive association between grams/week and WM-related activity in the superior parietal lobe. NL cannabis users, compared with TX cannabis users, and those cannabis users with less positive personal attitudes showed a more positive association between grams/week and WM-load-related activity in the temporal pole. Both site and cultural attitudes moderated the association of quantity of cannabis use with WM- and WM-load-related activity. Importantly, differences in legislation did not align with perceived cannabis attitudes and appear to be differentially associated with cannabis use-related brain activity.

BACKGROUND: While cannabis use in women is increasing worldwide, research into gender differences in cannabis use disorder (CUD) symptomology is lacking. In response to limited effectiveness of addiction treatment, research focus has been shifting from clinical diagnoses towards interactions between symptoms, as patterns of symptoms and their interactions could be crucial in understanding etiological mechanisms in addiction. The aim of this study was to evaluate the CUD symptom network and assess whether there are gender differences therein.METHODS: A total of 1257 Dutch individuals reporting weekly cannabis use, including 745 men and 512 women, completed online questionnaires assessing DSM-5 CUD symptoms and additional items on plans to quit or reduce use, cigarette use, and the presence of psychological diagnoses. Gender differences were assessed for all variables and an Ising model estimation method was used to estimate CUD symptom networks in men and women using network comparison tests to assess differences.RESULTS: There were gender differences in the prevalence of 6 of the 11 symptoms, but symptom networks did not differ between men and women. Cigarette use appeared to only be connected to the network through withdrawal, indicating a potential role of cigarette smoking in enhancing cannabis withdrawal symptoms. Furthermore, there were gender differences in the network associations of mood and anxiety disorders with CUD symptoms.CONCLUSION: The association between smoking and withdrawal as well as gender differences in the role of comorbidities in the CUD network highlight the value of using network models to understand CUD and how symptom interactions might affect treatment.

Social attunement (SA)-the tendency to harmonize behavior with the social environment-has been proposed to drive the escalation of alcohol use in adolescence, while reducing use in adulthood. Little is known about how heightened social sensitivity in adolescence may interact with neural alcohol cue reactivity-a marker of alcohol use disorder-and its relationship to alcohol use severity over time. The aims of this study were to test whether (1) adolescents and adults differ in social alcohol cue reactivity in the nucleus accumbens, anterior cingulate cortex, and right medial prefrontal cortex (mPFC), and (2) age moderates the relationship between social alcohol cue reactivity and social attunement, measures of drinking at baseline, and changes in drinking over time. A sample of male adolescents (16-18 years) and adults (29-35 years) completed an fMRI social alcohol cue-exposure task at baseline and an online follow-up two to three years later. No main effects of age or drinking measures were observed in social alcohol cue reactivity. However, age significantly moderated associations of social alcohol cue reactivity in the mPFC and additional regions from exploratory whole-brain analyses with SA, with a positive association in adolescents and negative association in adults. Significant age interactions emerged only for SA in predicting drinking over time. Adolescents with higher SA scores escalated drinking, while adults with higher SA scores reduced drinking. These findings warrant further research on SA as a risk and protective factor and suggest that social processes influence cue reactivity differentially in male adolescents and adults.

The social plasticity hypothesis proposes that social attunement, i.e., the adaptation to and harmonization with one's environment, plays a crucial role in the risk for developing alcohol use disorders (AUDs) during adolescence, whereas in adulthood it paradoxically may make individuals more sensitive to the social pull to reduce drinking. This study aimed to develop a valid measure of social attunement: the social attunement questionnaire (SAQ). A total of 26-items were developed and the questionnaire was completed by 576 Dutch mid to late adolescents and adults over three rounds of online data collection. Using exploratory factor analysis in part of the sample (N = 373), the final questionnaire was reduced to two subscales with a total of 11 items. This structure was confirmed using confirmatory factor analysis in the second part of the sample (N = 203). Results showed that the SAQ has acceptable internal consistency, good measurement invariance to gender, and subscales assessing both cognitive as well as behavioural components of social attunement. In line with expectations on alcohol use settings, SAQ scores were not associated directly with alcohol use, but they were predictive of alcohol use when taking into account the interaction between perceived peer drinking and age. The SAQ appears suitable for the assessment of social attunement in (young) adult men and women, particularly assessing the role of social attunement in alcohol use settings. Further research is needed to confirm the utility of the SAQ in older adults and a broader variety of social settings.

Although cannabis use patterns differ between men and women, studies on sex differences on the effects of cannabis on the brain and cognitive control are largely lacking. Working memory (WM) is a component of cognitive control believed to be involved in the development and maintenance of addiction. In this study, we evaluated the association between cannabis use and WM (load) related brain activity in a large sample, enabling us to assess sex effects in this association. The brain activity of 104 frequent cannabis users (63% men) and 85 controls (53% men) was recorded during an N-back WM task. Behavioral results showed a significant interaction between WM load and group for both accuracy and reaction time, with cannabis users showing a relatively larger decrease in performance with increasing WM load. Cannabis users compared to controls showed a relatively smaller reduction in WM (load) related activity in the precuneus and posterior cingulate cortex at higher WM load. This WM (load) related activity was not associated with performance nor cannabis use and related problems. An exploratory analysis showed higher WM-related activity in the superior frontal gyrus in men compared to women. While cannabis users showed higher WM (load) related activity in central nodes of the default mode network, this was not directly attributable to group specific worsening of performance under higher cognitive load. Further research is necessary to assess whether observed group differences increase with higher cognitive load, how group differences relate to measures of cannabis use, and how sex affects these group differences.

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, on-line 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- to post-lockdown. Change in cannabis use motives, mental health, quality of social relationships and job status from pre- to post-lockdown. Findings: In cannabis users, lockdown related to increased cannabis use [B = 1.96, 95% confidence interval (CI) = 0.26–3.66, P = 0.024], but not CUD symptom severity. Cannabis users experienced 30% job loss and increased loneliness [P < 0.001, Bayes factor (BF) 10 > 100], while contact with partners (P = 0.005, BF 10= 8.21) and families improved (P < 0.001, BF 10 = 19.73), with no differences between cannabis users and control. Generally, mental health problems (all Ps > 0.277, all BF 10 < 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 wellbein

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.

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.

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.

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.