PROJECT ABSTRACT This overdose epidemic in the United States (US) is evolving, and adequate understanding of the behavioral patterns of polysubstance use is critical. Polysubstance use occurs frequently with both prescription and recreational psychoactive drugs. However, patterns of current polysubstance use have not been evaluated in the general population. Delineating the nature of the behavior can help shift focus beyond opioids for combating this epidemic. This research will utilize an existing nationally representative drug survey (~60,000 respondents per year) and conduct a new follow-up polysubstance survey surrounding personal experiences in life relevant to drug use. The overall objective of this research will be to better understand today’s polysubstance use behaviors among the general population. We will do this in three ways. First, present-day behavioral patterns of polysubstance users in the general population will be characterized using latent class analysis to define unique behavioral risk profiles and quantity their prevalence. Second, critical time points in drug behavior progression will be explored. Among current drug users completing the follow-up survey, a latent profile analysis to characterize the trajectories, or profiles, which characterize drug use will be evaluated. Finally, this research will integrate upstream factors such as interpersonal, community, and societal level factors measured on the follow-up survey. This research will be the first to quantify the prevalence of these factors and incorporate them into a predictive model to classify polysubstance use based on a person’s life experiences and not their drug use directly. Finding meaningful and impactful points of intervention is key to effectively reducing the health risks associated with polysubstance use in the future. This approach addresses the evolving drug overdose epidemic by quantifying the complexities of substance use disorders among the general population, delineating the profiles of changing risk across the life span to find opportunities for intervention, and evaluating the predictive value of upstream factors for classifying polysubstance use. The information gleaned from this project can be leveraged -for real-world interventions.