Prenatal cannabis exposure, the brain, and psychopathology during early adolescence

Abstract

Prenatal cannabis exposure (PCE) is associated with mental health problems in early adolescence, but the possible neurobiological mechanisms remain unknown. In a large longitudinal sample of adolescents (ages 9-12, n=9,322-10,186), we find that PCE is associated with localized differences in gray and white matter of the frontal and parietal cortices, their associated white matter tracts, and with striatal resting state connectivity, even after accounting for potential pregnancy, familial, and child confounds. Variability in forceps minor and pars triangularis diffusion metrics partially longitudinally mediate PCE-ADHD associations. PCE-related differences in brain development may confer vulnerability to worse mental health in early adolescence.

Fig. 1:. Association of PCE with brain metrics.

Plot shows the uncorrected P value (log scale; x axis) for the association between brain metrics and PCE from mixed-effect regressions. Each brain region is a separate point; each imaging modality is in a distinct color. The vertical dashed line is placed at P < 0.05 (two-sided) FDR-corrected (PFDR) for all 2,907 tests. Regions (n = 3) FDR significant for all tests are labeled; points with a dark black border are significant at PFDR < 0.05 for all comparisons within a given metric type (for example, corrected only for all comparisons of cortical thickness or only for all comparisons of fractional anisotropy of white matter tracts, and so on). Additional statistical information is provided in Supplementary Table 2. sMRI, structural MRI; fiber, white matter fiber tracts; WM, cortical white matter; GM, cortical and subcortical gray matter.

Fig. 2:. Significant associations of PCE with brain metrics, by exposure group.

Standardized regression β effect sizes and 95% confidence intervals (CIs) from mixed-effect regressions assessing the association of PCE before maternal knowledge of pregnancy or pre- and post-maternal knowledge of pregnancy compared with no exposure. a, Transverse diffusivity (DTI) of cortical gray matter. b, Mean diffusivity (DTI) of cortical gray matter. c, Hindered directional diffusion (RSI) of cortical white matter. d, Restricted directional diffusion (RSI) of cortical white matter. e, Restricted isotropic diffusion (RSI) of cortical white matter. f, Restricted total diffusion (RSI) of cortical white matter. g, Restricted directional diffusion (RSI) of white matter tracts. h, Restricted total diffusion (RSI) of white matter tracts. i, Average cortical-subcortical connectivity (rs-fMRI). Nonsignificant outcomes are not shown. *Significant after FDR correction for all 2,907 tests (two-sided; a, P = 1.65 × 10⁻⁵; h, P = 4.1 × 10⁻⁵; i, P = 5.1 × 10⁻⁵). The corresponding brain regions are shown on the right of each panel; each metric is shown in a different color. Additional statistical information is provided in Supplementary Table 3.

Fig. 3:. Association of brain metrics with psychopathology in early adolescence.

a, Standardized regression β effect sizes and 95% CIs from mixed-effect regressions assessing the association of significant (PFDR < 0.05) brain metrics with log-transformed psychopathology scales across the full sample (N = 10,584). b, Standardized mediation effect and 95% parametric CIs from longitudinal mediation analyses testing whether significant brain metrics mediate the association of PCE with psychopathology (N = 7,990). Analyses were run first collapsing across PCE groups (that is, any exposure), and post hoc analyses computed effects for each group separately. c, Mediation path diagrams for significant mediations (PFDR < 0.05) with regions that survived correction for all comparisons in primary analyses (Fig. 2; restricted total diffusion of the forceps minor and transverse diffusivity of the right pars triangularis gray matter). Values reflect standardized effects and 95% CIs. Additional statistical information is provided in Supplementary Table 4. c, total effect; c’, direct effect; DSM-5, Diagnostic and Statistical Manual of Mental Disorders 5th Edition ; Prob, problems.