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

Abstract

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.

Keywords: adolescence; age; brain structural alterations; cannabis use and dependence; development; sex; voxel-based morphometry.

Figure 1

Flowchart outlining selection procedure of studies of GMV differences.

Figure 2

Meta-regression results showing associations between age at scan with gray matter differences between cannabis using and typically developing youth. Age-related meta-regression results. (A) Meta-regression results (CU > TD youth) showing associations between Age at Scan and gray matter differences between CU and TD youth shown in red. All results thresholded at p < 0.005. (B) Associations between age and gray matter differences in the left superior temporal cortex (85 voxels, SDM-Z = −3.168) (shown in red). Effect sizes (SDM-estimates) used to create the meta-regression plots were extracted from the peak of maximum slope significance. The meta-regression SDM-estimate value is derived from the proportion of studies that reported gray matter changes near the voxel so it is expected that some values are at 0 or near +/– 1. Each included study is represented as a numbered dot, with the dot size reflecting relative total sample size of each specific study in comparison to the average total sample size of all six studies included in the regression. Study key: 1 = Gilman et al. (39); 2 = Thayer et al. (41); 3 = Weiland et al. (11); 4 = Orr et al. (12); 5 = Cousijn et al. (40); 6 = Jarvis et al. (42).

Figure 3

Meta-regression results showing associations between proportion of females in studies with gray matter differences between cannabis using and typically developing youth. Sex-related meta-regression results. (A) Meta-regression results (CU > TD youth) showing associations between proportion of females in studies and gray matter differences between CU and TD youth shown in green. All results thresholded at p < 0.005. (B) Associations between sex and gray matter differences in the right middle occipital gyrus (162 voxels, SDM-Z = 3.953) (shown in green). Effect sizes (SDM-estimates) used to create the meta-regression plots were extracted from the peak of maximum slope significance. The meta-regression SDM-estimate value is derived from the proportion of studies that reported gray matter changes near the voxel so it is expected that some values are at 0 or near +/– 1. Each included study is represented as a numbered dot, with the dot size reflecting relative total sample size of each specific study in comparison to the average total sample size of all six studies included in the regression. Study key: 1 = Gilman et al. (39); 2 = Thayer et al. (41); 3 = Weiland et al. (11); 4 = Orr et al. (12); 5 = Cousijn et al. (40); 6 = Jarvis et al. (42).