Behavioural and brain volumetric changes associated with problematic substance use through the lifespan

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Abstract
Addiction stands as a critical public health concern, contributing substantially to morbidity, mortality and societal burden worldwide. It can be conceptualized along a developmental continuum, from risky substance use in adolescence to compulsive use and addiction in adulthood, yet the neural changes underlying this continuum remain poorly understood. Here we show age-specific brain structural trajectories along this continuum by harmonizing multimodal data across large population cohorts spanning adolescence to late adulthood. We identified three life stages with distinct patterns of problematic substance use (PSU). Before age 25, PSU was associated with neurodevelopmental differences, alongside greater impulsivity and rule-breaking, suggesting a key window for early prevention. Between ages 25 and 45, PSU was linked to structural differences in brain regions linked to craving and reward processing, supporting early detection and intervention during the reinforcement and maintenance of substance use. After age 45, PSU-related brain differences may reflect cumulative effects of prolonged substance exposure, emphasizing broader health monitoring. These stage-specific patterns also differed by sex, particularly earlier in life. Together, our findings map structural brain changes across the addiction continuum and provide a lifespan framework for stage-specific prevention, intervention and health monitoring.

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