Project Summary. Overdose deaths surpassed 100,000 in the United States in 2020. While opioid-related deaths largely attributable to fentanyl continue to rise, deaths involving stimulants, including cocaine, have increased by over 300% since 2013. A growing driver of the continued overdose crisis in the US is the role of concurrent use of multiple substances. Although there are pharmacological treatments to address opioid use disorder, few evidence-based options are available for addressing concurrent stimulant use among people using opioids. Understanding the dynamics of polysubstance use, particularly opioid and stimulant co-use, and the role of treatment with respect to the dynamics of co-use, is critical to inform ongoing overdose prevention. Yet, there are major gaps in our knowledge regarding the patterns and trajectories of opioid and stimulant co- use and their role in overdose. There is an urgent need to characterize the longitudinal nature of polysubstance use, treatment utilization, and overdose in community-based samples. The overarching objective of this proposal is to further our understanding of both long- and short-term patterns of opioid/stimulant use and examine the longitudinal relationship between co-use of opioids/stimulants and substance use treatment and non-fatal and fatal overdose over time, in order to inform treatment and overdose prevention services. We propose the following three specific aims: 1) To characterize long-term patterns of opioid and stimulant co-use and examine the relationship between trajectories of co-use, substance use treatment, overdose and mortality; 2) To examine real-time short-term patterns and transitions in and out of opioid and stimulant co-use and their association with substance use treatment and overdose; and 3) To assess opportunities and readiness for expanding and strengthening service capacity related to treatment and overdose among those with different patterns of opioid/stimulant use. To achieve these aims, we will leverage over 30 years of behavioral, laboratory and clinical data from among over 5,000 people who inject drugs within the AIDS Linked to the IntraVenous Experience (ALIVE) cohort to examine long-term trends and the social determinants of concurrent opioid/stimulant use. Supplemented with new recruitment of the Stimulant Opioid Non-Injection Cohort (SONIC), we will conduct new ecological momentary assessments in both samples to examine micro-patterns of use and employ state-of-the-art machine learning methods to identify patterns and their association with treatment and overdose over time in this community-based sample at high risk of overdose. Qualitative research with stakeholders and people with differing patterns of opioid/stimulant co-use will highlight gaps and challenges within the service system and identify specific implementation strategies to increase capacity to address heterogeneous concurrent opioid/stimulant use and related needs. The results of this study ...