Developmental variation in basal ganglia tissue iron, neurocognitive functioning, and impulsivity is associated with substance use trajectories in youth

Neurodevelopmental models implicate dopaminergic and neurocognitive maturation in adolescent risk-taking, yet their joint contribution to substance use trajectories in humans remains unclear. We examined basal ganglia tissue iron, a marker of dopamine-related neurobiology, alongside impulsivity and inhibitory control in relation to longitudinal substance use patterns in the NCANDA-A cohort (N = 802; ages 12-30; 6,078 visits). Growth Mixture Models identified four trajectories: no/low use (30% of participants), youth peak (26%), adolescent increasing (17%), and adult increasing (26%). Substance use, inhibitory control, and tissue iron increased with age, while impulsivity declined. Greater substance use was associated with heightened impulsivity, low inhibitory control, and low tissue iron, prominently in early adolescence among youth peak patterns. Trajectories were further distinguished by divergent maturation of impulsivity and tissue iron. Results suggest that developmental variation in tissue iron and neurocognition contribute to youth substance use, highlighting adolescence as a sensitive window for risk stratification and prevention.