Sex and dependence related neuroanatomical differences in regular cannabis users: findings from the ENIGMA Addiction Working Group

Maria Gloria Rossetti,Albert Batalla,Marcella Bellani,Yann Chye,Praveetha Patalay,Robert Hester,Chao Suo,Hugh Garavan,Nadia Solowij,Nicholas B Allen,Valentina Lorenzetti,Murat Yücel,Rocio Martin-Santos,Paolo Brambilla,Paul M Thompson,Patricia Conrod,Scott Mackey,Anna E Goudriaan,Janna Cousijn

doi:10.1038/s41398-021-01382-y

Abstract

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.

Highlights

Cannabis is the most widely used illicit substance on the planet and is the first drug of concern in treatment services nearly worldwide[1]
We focused on a priori regions of interest (ROIs) that have been examined by at least three studies[9,24] and showed volumetric differences between cannabis users and controls i.e., amygdala, hippocampus, nucleus accumbens (NAcc), insula, OFC, ACC and the cerebellum[20,24,25,26,27,28]
Based on previous structural MRI studies, we expected that (i) cannabis users would show smaller volumes in some ROIs24–26,32 and larger volumes in other ROIs (i.e., NAcc, cerebellar grey matter)[20,27,28] and (ii) there would be group-by-sex interactions within the OFC and the amygdala[15,17].We explored whether sex differences would emerge in other a-priori ROIs where these effects have not been examined so far[18,19,20]

Summary

Introduction

Cannabis is the most widely used illicit substance on the planet and is the first drug of concern in treatment services nearly worldwide[1]. Sex differences are apparent in many aspects of cannabis use and dependence. A recent mega-analysis reported no significant volume differences between cannabis users and controls in these regions[12]. The literature to date[9,12] has failed to account for putative moderators of volume alterations in cannabis users such as cannabis dependence status, which neuroscientific theories of addiction ascribe to profound neuroadaptations[13], and confounders associated with cannabis use including tobacco and alcohol exposure. The role of sex differences in volume alterations in cannabis users has been under-investigated[14]

Objectives

Methods

Results

Discussion

Conclusion