PROJECT SUMMARY/ABSTRACT Stimulant-involved fatal overdoses have increased rapidly since 2014; deaths involving psychostimulants, primarily methamphetamine, have quadrupled, while fatal overdoses involving cocaine have tripled. Black, Latino, and Native American people are increasingly using stimulants and dying from overdoses, though low- income White men remain the largest group of people who use stimulants (PWUS) and die of overdose. The proposed research targets RFA-CE-21-002 Objective 2: ?[to] assess risk and protective factors for illicit stimulant use, use disorder, and overdose that can contribute to the development or adaptation of intervention strategies.? Our goal is to identify intervention strategies that could be developed or adapted to reduce stimulant use (SU) and improve SU health outcomes (SU disorder, recovery, and overdoses). We will conduct our research in two states with distinct SU crises: Massachusetts (MA), where cocaine and fentanyl overdoses are rising, including among Black and Latino individuals, and South Dakota (SD), where rapid increases in methamphetamine use and overdose have disproportionately affected Native Americans. Our team of addiction and systems science experts will assess how multi-level risk and protective factors for SU and SU health outcomes interact dynamically, with a focus on disparities related to social determinants of health, in MA and SD (Aim 1). We will conduct a living systematic review of multi-level factors influencing SU and SU health outcomes and of multi-level intervention strategies that could synergistically reduce SU and improve SU health outcomes (Aim 1.1). We will also engage community partners across MA and SD at multiple levels of the system underlying stimulant use (PWUS, providers, and policymakers) in semi-structured qualitative interviews to develop a unified causal loop diagram (CLD) that depicts how risk and protective factors interact dynamically (Aim 1.2). Next, we will identify intervention strategies to reduce SU and improve SU health outcomes, including generalizable strategies for all populations and adapted strategies to reduce health disparities in underrepresented populations (Aim 2). We will develop a system dynamics simulation model, using the CLD and the living systematic review, to explain SU and SU health outcome trends in MA and SD (Aim 2.1). We will then utilize the model to explore and identify intervention strategies that have the greatest potential to reduce SU and improve SU health outcomes in MA and SD, while also generating insight that is applicable nationally (Aim 2.2). The proposed research will address the public health problems of SU, SU disorder, and overdose through the identification of efficacious and equitable intervention strategies. Our engagement with community partners using a systems modeling approach will allow us to provide immediately translatable insight to policymakers in MA and SD. In the long term, our findings will inform intervention strategies for reducing SU and improving SU health outcomes for all PWUS as well as underrepresented populations, and across rural and urban areas.