Frontostriatal interactions and socioenvironmental associations with alcohol and cannabis onset in the Adolescent Brain Cognitive Development Study.

Thiessen K.; Breslin F.; Kerr K.; Schütz C. · medRxiv : the preprint server for health sciences · 2026

**Background & Methods** This longitudinal prospective study utilized data from the Adolescent Brain Cognitive Development (ABCD) Study, which follows over 10,000 youth. Researchers employed family-clustered time-varying Cox proportional hazard models to examine interactions between brain imaging markers (right Inferior Frontal Gyrus inhibitory control and bilateral nucleus accumbens reward response) and socioenvironmental factors (early life adversity and peer substance use) as predictors of alcohol and cannabis onset. **Key Findings** - A significant crossover interaction was identified between left nucleus accumbens activity and right Inferior Frontal Gyrus activity: left NAc activity showed a slight positive association with first full alcoholic drink when right IFG activity was higher, but a negative association when right IFG activity was lower. - Peer alcohol and cannabis use emerged as the strongest predictors of substance onset for both substances, substantially outweighing neurobiological factors. - Early life adversity was associated only with cannabis onset (not alcohol onset), and alcohol onset was more common in females, suggesting substance-specific and sex-specific risk profiles. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This preprint study has notable strengths, including a large prospective longitudinal cohort, objective neuroimaging biomarkers, and prospective modeling that allows examination of temporal precedence. However, limitations include: (1) it is a preprint not yet peer-reviewed; (2) the modest effect sizes of neurobiological interactions relative to socioenvironmental factors suggest limited clinical utility for brain-based prediction; (3) causality cannot be definitively established for socioenvironmental associations; (4) generalizability may be limited by ABCD cohort demographics; and (5) reverse causality remains a concern despite longitudinal design—neurobiological differences identified may still partially reflect early substance exposure rather than pure predisposition. The authors appropriately acknowledge that peer-focused prevention strategies may be more impactful than neurobiologically-targeted interventions based on these findings.

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