Project Summary Polydrug use (PDU) is increasingly implicated as a crucial factor underlying the U.S. overdose crisis, responsible for the deaths of over 100,000 Americans in the past year alone. Overdose is still highly associated with opioid use, but also overwhelmingly occurs in the context of combinations of drugs - notably stimulants and synthetic opioids. In 2019, the Northeast had the highest proportion of overdose deaths involving synthetic opioids and the largest absolute increase in stimulant-involved overdose deaths, and the Maryland overdose rate was among the highest in the country. The overdose prevention infrastructure has not yet been optimized to address PDU and the heterogeneity of associated experiences. With a multi-level perspective informed by life course and social network theories, we propose a multi-phase mixed methods study to examine patterns, trajectories, and risk and protective factors for PDU and overdose among people with various patterns of stimulant and opioid use. We will use behavioral data from the AIDS Linked to the IntraVenous Experience (ALIVE) study to identify PDU patterns and trajectories, mixed methods data from the 2019 Statewide Ethnographic Assessment of Drug Use and Services (SEADS) project to identify descriptive PDU trajectories and contextualize periods of drug use transition and stability, and complementary qualitative life course data collection (n=100) to explore recent changes and life course events aligned with different types of PDU, which will in turn inform statistical models of risk and protective factors for PDU types and overdose. Results from this study will allow program planners to estimate range and scale of heterogeneity among PDU and begin to disentangle intervention needs of unique sub-groups of PDU. This project will result in specific recommendations for tailored overdose risk reduction approaches and supportive resources for the heterogeneous needs of PDU and key turning points of PDU trajectories. We will translate our findings and conduct broad dissemination, working with local stakeholders, partner organizations, and governmental agencies to inform overdose and treatment programs in real time and across all three project years.