PROJECT SUMMARY/ABSTRACT. While cannabis, nicotine, and alcohol remain the most widely endorsed substances during adolescence, mechanistic pathways by which the social determinants of health influence substance use outcomes among youth are unclear. Structural racism and discrimination results in poorer quality environments in many neighborhoods within the United States, with a greater disproportionate impact for marginalized populations. Neighborhood-level structural racism (NSR) is the totality of ways by which structural racism disproportionately disadvantages neighborhoods in areas of socioeconomic conditions, environmental health, and educational opportunities. NSR features, such as neighborhood inequities in access to healthy food, green space, housing, and poverty rates, comprise important social determinants of health that negatively affect neurocognitive skills as well as increase the risk for more negative consequences of substance use. This project will use a concurrent mixed method approach to investigate the impact of neighborhood-level structural racism on youth substance use and determine the extent this relationship is mediated by neurocognitive markers of decision-making and distress tolerance. We will use both qualitative and quantitative methods throughout the project to study NSR influences on SU in middle school youth (ages 12-14 years) in the R61 phase and in high school youth (14-17 years) in the R33 phase. We will leverage the availability of the Adolescent Brain Cognitive Development ® (ABCD) Study dataset (N = 11,880) to concurrently conduct quantitative analyses to test the neurocognitive pathways on the influence of NSR. Community engagement research approaches will be implemented throughout both the R61 and R33 phase and include oversight from a Community Advisory Board and a Youth Advisory Board. During the R61 phase, interviews with middle school Latino/a/x and Black youth (N = 30) will obtain youth perceived neighborhood- level risk factors for substance use. The quantitative studies will then investigate whether NSR impact youth cannabis, nicotine, and alcohol through neurocognitive pathways of decision-making and distress tolerance. Qualitative and quantitative findings from the R61 phase will be triangulated to inform the precision of the NSR for high school youth during the R33 phase. In addition, the R33 phase will use photovoice with high school youth (N=30), a photographic technique to identify and represent neighborhood features youth perceive contribute to engagement with substance use. Cohort effects will be tested by comparing findings from the high school cohort (R61) with the middle school cohort (R61). Findings from the project will be disseminated to community stakeholders and policy makers. In addition, findings may inform community-level interventions on the neighborhood features that pose risk to adverse substance use trajectories, as well as at the individual- level for neurocognitive intervention...