PROJECT SUMMARY/ABSTRACT The overdose epidemic continues unabated in the United States. Changes to the drug supply and increases in stimulant-involved overdose deaths have shifted what was an opioid overdose epidemic to a polysubstance overdose epidemic. Over half of overdose deaths nationally now involve multiple substances, leading some researchers to identify the current polysubstance era as the epidemic’s “fourth wave.” Increases in polysubstance use (PSU) and PSU overdose pose a host of challenges for practitioners and researchers to address. Knowing whether and to what extent emerging harm reduction interventions can reduce PSU-involved overdose risk is critical for public health authorities and service providers. Overdose prevention centers (OPCs), community- based facilities at which individuals consume pre-obtained controlled substances under the supervision of trained staff who can intervene in event of an overdose, are one such intervention. Over 200 OPCs operate globally, but the first two publicly recognized OPCs in the United States opened in New York City in 2021. OPCs in other countries are associated with reduced fatal and non-fatal overdose risk and reduced emergency service utilization. However, prior research has not assessed the impact of OPC use on overdose risk among PSU- involved populations. In addition, concurrent mental health disorders remain a critical yet underexplored risk factor for PSU overdose and other harms, yet studies to date have not assessed the association between OPC use and mental health outcomes, despite estimates suggesting a high untreated mental health burden among OPC clients. As such, the objective of this K01 proposal is to address these critical research gaps to: (1) identify heterogeneous impacts of OPC use on non-fatal and fatal overdose risk among individuals engaging in PSU; (2) estimate the impact of OPC use on treated psychiatric events among clients with PSU; and (3) assess the needs of harm reduction providers to integrate mental health services into existing syringe service and OPC delivery models, with a particular focus on the needs of PSU-involved populations. The research plan is bolstered by an exceptional mentorship team and training plan. The proposed project builds on the candidate’s background in substance use epidemiology and data science and provides new training in several areas: (1) novel statistical methods for the identification of heterogeneous treatment effects of OPC use on overdose risk among PSU- involved individuals; (2) psychiatric epidemiology and the complex relationship between mental health, substance use disorders, and PSU; and (3) implementation science to conceptualize and evaluate novel integrated behavioral health care models for PSU-involved populations. The combined research and training plan will enable the candidate to transition into an independent researcher of policy-relevant social and behavioral factors that shape overdose risk. This research aligns with CDC’s Overdose Prevention Research Priorities to identify PSU overdose risk and protective factors across multiple levels of the social ecology.

PROJECT NARRATIVE Polysubstance use (PSU) and concomitant overdose are substantial public health issues, with over half of overdose deaths nationally involving multiple substances. The proposed research aims to address two key facets of overdose prevention centers (OPCs), a novel harm reduction intervention, as they relate to overdose risk and mental health in PSU-involved populations: (1) the capacity for OPCs to reduce overdose mortality and morbidity for this high-risk population and (2) the potential role of OPCs as a venue to address mental health needs of PSU-involved populations. This K01 will uncover evidence to support the optimization of an emerging public health intervention as it scales nationally in the context of an ongoing polysubstance overdose epidemic and support a new investigator in developing an independent research career dedicated to building equitable and integrated access to substance use and mental health services to prevent overdose.