Cannabis Dependence is Associated with Reduced Hippocampal Subregion Volumes Independently of Sex: Findings from an ENIGMA Addiction Working Group Multi-Country Study.

Background: Males and females who consume cannabis can experience different mental health and cognitive problems. Neuroscientific theories of addiction postulate that dependence is underscored by neuroadaptations, but do not account for the contribution of distinct sexes. Further, there is little evidence for sex differences in the neurobiology of cannabis dependence as most neuroimaging studies have been conducted in largely male samples in which cannabis dependence, as opposed to use, is often not ascertained. Methods: We examined subregional hippocampus and amygdala volumetry in a sample of 206 people recruited from the ENIGMA Addiction Working Group. They included 59 people with cannabis dependence (17 females), 49 cannabis users without cannabis dependence (20 females), and 98 controls (33 females). Results: We found no group-by-sex effect on subregional volumetry. The left hippocampal cornu ammonis subfield 1 (CA1) volumes were lower in dependent cannabis users compared with non-dependent cannabis users (p<0.001, d=0.32) and with controls (p=0.022, d=0.18). Further, the left cornu ammonis subfield 3 (CA3) and left dentate gyrus volumes were lower in dependent versus non-dependent cannabis users but not versus controls (p=0.002, d=0.37, and p=0.002, d=0.31, respectively). All models controlled for age, intelligence quotient (IQ), alcohol and tobacco use, and intracranial volume. Amygdala volumetry was not affected by group or group-by-sex, but was smaller in females than males. Conclusions: Our findings suggest that the relationship between cannabis dependence and subregional volumetry was not moderated by sex. Specifically, dependent (rather than non-dependent) cannabis use may be associated with alterations in selected hippocampus subfields high in cannabinoid type 1 (CB1) receptors and implicated in addictive behavior. As these data are cross-sectional, it is plausible that differences predate cannabis dependence onset and contribute to the initiation of cannabis dependence. Longitudinal neuroimaging work is required to examine the time-course of the onset of subregional hippocampal alterations in cannabis dependence, and their progression as cannabis dependence exacerbates or recovers over time.

Daily Cannabidiol Administration for 10 Weeks Modulates Hippocampal and Amygdalar Resting-State Functional Connectivity in Cannabis Users: A Functional Magnetic Resonance Imaging Open-Label Clinical Trial.

Introduction: Cannabis use is associated with brain functional changes in regions implicated in prominent neuroscientific theories of addiction. Emerging evidence suggests that cannabidiol (CBD) is neuroprotective and may reverse structural brain changes associated with prolonged heavy cannabis use. In this study, we examine how an ∼10-week exposure of CBD in cannabis users affected resting-state functional connectivity in brain regions functionally altered by cannabis use. Materials and Methods: Eighteen people who use cannabis took part in a ∼10 weeks open-label pragmatic trial of self-administered daily 200 mg CBD in capsules. They were not required to change their cannabis exposure patterns. Participants were assessed at baseline and post-CBD exposure with structural magnetic resonance imaging (MRI) and a functional MRI resting-state task (eyes closed). Seed-based connectivity analyses were run to examine changes in the functional connectivity of a priori regions-the hippocampus and the amygdala. We explored if connectivity changes were associated with cannabinoid exposure (i.e., cumulative cannabis dosage over trial, and plasma CBD concentrations and Δ9-tetrahydrocannabinol (THC) plasma metabolites postexposure), and mental health (i.e., severity of anxiety, depression, and positive psychotic symptom scores), accounting for cigarette exposure in the past month, alcohol standard drinks in the past month and cumulative CBD dose during the trial. Results: Functional connectivity significantly decreased pre-to-post the CBD trial between the anterior hippocampus and precentral gyrus, with a strong effect size (d=1.73). Functional connectivity increased between the amygdala and the lingual gyrus pre-to-post the CBD trial, with a strong effect size (d=1.19). There were no correlations with cannabinoids or mental health symptom scores. Discussion: Prolonged CBD exposure may restore/reduce functional connectivity differences reported in cannabis users. These new findings warrant replication in a larger sample, using robust methodologies-double-blind and placebo-controlled-and in the most vulnerable people who use cannabis, including those with more severe forms of Cannabis Use Disorder and experiencing worse mental health outcomes (e.g., psychosis, depression).

The individuality of shape asymmetries of the human cerebral cortex.

Asymmetries of the cerebral cortex are found across diverse phyla and are particularly pronounced in humans, with important implications for brain function and disease. However, many prior studies have confounded asymmetries due to size with those due to shape. Here, we introduce a novel approach to characterize asymmetries of the whole cortical shape, independent of size, across different spatial frequencies using magnetic resonance imaging data in three independent datasets. We find that cortical shape asymmetry is highly individualized and robust, akin to a cortical fingerprint, and identifies individuals more accurately than size-based descriptors, such as cortical thickness and surface area, or measures of inter-regional functional coupling of brain activity. Individual identifiability is optimal at coarse spatial scales (~37 mm wavelength), and shape asymmetries show scale-specific associations with sex and cognition, but not handedness. While unihemispheric cortical shape shows significant heritability at coarse scales (~65 mm wavelength), shape asymmetries are determined primarily by subject-specific environmental effects. Thus, coarse-scale shape asymmetries are highly personalized, sexually dimorphic, linked to individual differences in cognition, and are primarily driven by stochastic environmental influences.

Cannabis, Cannabinoids, and Brain Morphology: A Review of the Evidence.

Cannabis and cannabinoid-based products are increasingly being accepted and commodified globally. Yet there is currently limited understanding of the effect of the varied cannabinoid compounds on the brain. Exogenous cannabinoids interact with the endogenous cannabinoid system that underpins vital functions in the brain and body, and they are thought to perturb key brain and cognitive function. However, much neuroimaging research has been confined to observational studies of cannabis users, without examining the specific role of the various cannabinoids (Δ9-tetrahydrocannabinol, cannabidiol, etc.). This review summarizes the brain structural imaging evidence to date associated with cannabis use, its major cannabinoids (e.g., Δ9-tetrahydrocannabinol, cannabidiol), and synthetic cannabinoid products that have emerged as recreational drugs. In doing so, we seek to highlight some of the key issues to consider in understanding cannabinoid-related brain effects, emphasizing the dual neurotoxic and neuroprotective role of cannabinoids, and the need to consider the distinct role of the varied cannabinoids in establishing their effect on the brain.

Reward-related attentional capture and cognitive inflexibility interact to determine greater severity of compulsivity-related problems.

BACKGROUND AND OBJECTIVES: Neurocognitive processes are key drivers of addictive and compulsive disorders. The current study examined whether reward-related attentional capture and cognitive inflexibility are associated with impulsive and/or compulsive personality traits, and whether these cognitive characteristics interact to predict greater compulsivity-related problems across obsessive-compulsive and drinking behaviors. METHODS: One-hundred and seventy-three participants (mean age = 34.5 years, S.D = 8.4, 42% female) completed an online visual search task to measure reward-related attentional capture and its persistence following reversal of stimulus-reward contingencies. Participants also completed questionnaires to assess trait impulsivity, compulsivity, alcohol use, and obsessive-compulsive behaviors. RESULTS: Greater reward-related attentional capture was associated with trait compulsivity, over and above all impulsivity dimensions, while greater cognitive inflexibility was associated with higher negative urgency (distress-elicited impulsivity). Reward-related attentional capture and cognitive inflexibility interacted to predict greater compulsivity-related problems among participants who reported obsessive-compulsive behaviors in the past month (n = 57) as well as current drinkers (n = 88). Follow-up analyses showed that, for OCD behaviors, this interaction was driven by an association between higher reward-related attentional capture and more problematic behaviors among cognitively inflexible participants only. For drinking, the same pattern was seen, albeit at trend level. LIMITATIONS: This study includes a non-clinical, online sample and is cross-sectional, thus its findings need to be interpreted with these limitations in mind. CONCLUSIONS: Reward-related attentional capture and cognitive flexibility are related to trait compulsivity and impulsivity (negative urgency) respectively, and interact to determine more problematic behaviors.