Cannabis Affects Cerebellar Volume and Sleep Differently in Men and Women

Abstract

Background: There are known sex differences in behavioral and clinical outcomes associated with drugs of abuse, including cannabis. However, little is known about how chronic cannabis use and sex interact to affect brain structure, particularly in regions with high cannabinoid receptor expression, such as the cerebellum, amygdala, and hippocampus. Based on behavioral data suggesting that females may be particularly vulnerable to the effects of chronic cannabis use, we hypothesized lower volumes in these regions in female cannabis users. We also hypothesized poorer sleep quality among female cannabis users, given recent findings highlighting the importance of sleep for many outcomes related to cannabis use disorder.Methods: Using data from the Human Connectome Project, we examined 170 chronic cannabis users (>100 lifetime uses and/or a lifetime diagnosis of cannabis dependence) and 170 controls that we attempted to match on age, sex, BMI, race, tobacco use, and alcohol use. We performed group-by-sex ANOVAs, testing for an interaction in subcortical volumes, and in self-reported sleep quality (Pittsburgh Sleep Questionnaire Inventory).Results: After controlling for total intracranial volume and past/current tobacco usage, we found that cannabis users relative to controls had smaller cerebellum volume and poorer sleep quality, and these effects were driven by the female cannabis users (i.e., a group-by-sex interaction). Among cannabis users, there was an age of first use-by-sex interaction in sleep quality, such that females with earlier age of first cannabis use tended to have more self-reported sleep issues, whereas this trend was not present among male cannabis users. The amygdala volume was smaller in cannabis users than in non-users but the group by sex interaction was not significant.Conclusions: These data corroborate prior findings that females may be more sensitive to the neural and behavioral effects of chronic cannabis use than males. Further work is needed to determine if reduced cerebellar and amygdala volumes contribute to sleep impairments in cannabis users.

Age- and Sex-Related Cortical Gray Matter Volume Differences in Adolescent Cannabis Users: A Systematic Review and Meta-Analysis of Voxel-Based Morphometry Studies

“…This suggests that sex may moderate the relationship between cannabis exposure and occipital morphology during adolescence. Our results regarding sex-related GMV effects are consistent with prior studies in CU adolescents and adults that have shown differences in GMV, cortical thickness, and gyrification in women that are directionally opposition from those found in men ( 26 , 34 , 35 , 59 , 60 ). A number of possible factors could explain this result.…”

Chronic exposure to inhaled vaporized cannabis high in Δ9-THC alters brain structure in adult female mice

“…Female mice did show an increase in cerebellum volume, albeit limited to only the deep cerebellar nuclei and the 10th cerebellar lobule. This is in contrast to the reported decrease in the volume of the cerebellar cortex in women with a history of cannabis use ( McPherson et al, 2021 ). However, clinical studies composed primarily of men report an increase in cerebellar volume and gray matter density with chronic cannabis use ( Cousijn et al, 2012 ; Battistella et al, 2014 ; Moreno-Rius, 2019 ; Wang et al, 2021b ).…”

Sex Differences in Substance Use Disorders: A Neurobiological Perspective

“…The prevalence of cannabis use and CbUD is higher in males than females ( 27 ), however during periods of abstinence, females are reported to experience stronger cannabis withdrawal symptoms when compared to males ( 28 ). A MRI study in CbUD reported that, similar to AUD, amygdala volume was smaller in individuals who use cannabis, yet was not mediated by sex ( 29 ). Among other brain volumes examined, smaller cerebellar volume was reported in those who use cannabis compared to controls and this effect was greater in females ( 30 ).…”