Prenatal Cannabis Exposure Shaping Altered Brain Connectivity: Neural Correlates of Cognitive and Mental Health...

Emerging evidence from both human and preclinical research indicates that cannabis use during pregnancy can influence offspring neurodevelopmental outcomes. Δ⁹-Tetrahydrocannabinol (THC), the psychoactive compound in cannabis, permeates the placental barrier and modulates the endocannabinoid system, a critical regulator of neurodevelopmental processes. Although converging findings suggest that prenatal cannabis exposure (PCE) is associated with adverse cognitive and mental health outcomes in offspring, the neurobiological mechanisms underlying these associations-particularly in terms of large-scale functional brain network organization-remain poorly understood. In this large-scale cross-sectional study, we leveraged baseline data from the ongoing longitudinal Adolescent Brain Cognitive Development (ABCD) Study, which enrolled 11,875 children across 22 research sites. We examined the effects of PCE, occurring both before and after maternal awareness of pregnancy, on offspring psychopathology and cognitive performance. Resting-state functional MRI data were analyzed using the NeuroMark framework, enabling the identification of individualized intrinsic connectivity networks (ICNs) and estimation of functional network connectivity (FNC) among them. Associations between prenatal exposure, behavioral outcomes, and functional connectivity were assessed using linear mixed-effects models, controlling for a comprehensive set of familial, pregnancy-related, and child-specific covariates. Among 10,836 children (female/male = 5,194/5,642; mean age = 9.96 ± 0.62 years), 754 (6.96%) were prenatally exposed to cannabis. Compared with non-exposed peers, exposed children exhibited higher levels of psychopathology and poorer cognitive performance, except composite fluid cognition (Cohen's d = - 0.1393 ~ 0.2451, false discovery rate [FDR]-corrected p < .05), consistent with prior reports linking PCE to adverse developmental outcomes. Importantly, prenatal exposure was associated with alterations in FNC that significantly overlapped with neurofunctional correlates of both mental health symptoms (positive correlations between t-statistics, r= 0.0641 ~ 0.5993, FDR-corrected p < .05) and cognitive performance (negative correlations, r = - 0.5438 ~ - 0.6665, FDR-corrected p < .05). These findings provide novel evidence that PCE is associated with altered large-scale brain network connectivity, which in turn relates to both cognitive and mental health outcomes in late childhood. The overlapping neurofunctional correlates of exposure and behavioral outcomes suggest that THC's interaction with the endocannabinoid system may disrupt the maturation of functional brain networks, providing a potential mechanistic link between prenatal exposure and neurodevelopmental vulnerability.