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

Introduction: Adolescent-onset cannabis use is rising in the era of marijuana legalization. Recent imaging studies have identified neuroanatomical differences between adult cannabis users and controls that are more prominent in early-onset users. Other studies point to sex-dependent effects of cannabis. Methods: A systematic review following PRISMA guidelines and subsequent effect-size seed-based d mapping (SDM) meta-analyses were conducted to investigate relationships between age (across the 12-to-21-year-old developmental window), sex, and gray matter volume (GMV) differences between cannabis using (CU) and typically developing (TD) youth. Results: Our search identified 1,326 citations, 24 of which were included in a qualitative analysis. A total of 6 whole-brain voxel-based morphometry (VBM) studies comparing regional GMV between 357 CU [mean (SD) age = 16.68 (1.28); 71% male] and 404 TD [mean (SD) age = 16.77 (1.36); 63% male] youth were included in the SDM-meta-analysis. Meta-analysis of whole-brain VBM studies identified no regions showing significant GMV difference between CU and TD youth. Meta-regressions showed divergent effects of age and sex on cortical GMV differences in CU vs. TD youth. Age effects were seen in the superior temporal gyrus (STG), with older-aged CU youth showing decreased and younger-aged CU youth showing increased STG GMV compared to age-matched TD youth. Parallel findings in the STG were also observed in relation to duration of CU (years) in supplemental meta-regressions. Regarding sex effects, a higher proportion of females in studies was associated with increased GMV in the middle occipital gyrus in CU vs. TD youth. Conclusions: These findings suggest that GMV differences between CU and TD youth, if present, are subtle, and may vary as a function of age, cumulative cannabis exposure, and sex in young people. Whether age- and sex-related GMV differences are attributable to common predispositional factors, cannabis-induced neuroadaptive changes, or both warrant further investigation.