Protocol to study neurobiological pathways to adverse patterns of substance use in adolescents with anxiety.

Anxiety is among the most common clinical challenges in adolescence and serves as both a potential precursor and exacerbator of substance use disorder (SUD) during a developmental period when substance initiation is prevalent. Yet outcomes are markedly heterogenous: some studies suggest multifinality in adverse patterns of substance use (APSU) - defined as developmentally atypical trajectories of substance involvement, distinct from but predictive of later SUD-among individuals with anxiety. The sources of variability remain unclear; thus, symptom detection alone provides limited insight into the underlying pathophysiology, predictability, progression, and preventability of anxiety-linked trajectories to APSU. This paper describes an ongoing 5-year study (National Institute on Drug Abuse-R01) that longitudinally examines maturational change in neural connectivity and stress physiology, in combination with risk and resiliency factors, to characterize pathways through which anxiety symptoms may lead to APSU in adolescents. Such longitudinal studies that track the evolution of predictors, mechanisms, and outcomes hold promise for informing the development of precision-based preventive and treatment interventions, with potential to enhance effectiveness and reach a broader population of youth.