Drug consumption trends in the United States have substantially changed in recent years, triggering a surge in overdose deaths. Efforts to address the crisis at the local level are oftentimes focused on meeting the needs of persons in the most advanced stages of substance use disorder (SUD), in part because this group is most visible at acute care, public health, and social service sites and corresponding data systems. Intervening at an earlier stage of use represents an opportunity to prevent drug use from progressing to polysubstance use, injection drug use (IDU), SUD, overdose, and other severe health outcomes. However, the precursors to drug use initiation and the patterns of consumption that follow are poorly characterized and the factors associated with progression to severe outcomes are largely unknown. Illicitly manufactured fentanyl (IMF) and concurrent use of opioids and stimulants are now at the core of America’s overdose crisis, responsible for much of the recent increase in overdose deaths. Specific consumption behaviors and corresponding rationale associated with IMF and co- occurring use of methamphetamine and opioids are not well-characterized and may directly correlate with overdose risk. We propose to conduct an exploratory sequential mixed methods evaluation of drug use behaviors, patterns, trajectories, and risk factors in a sample of King County, WA residents who initiated use within the past three years of a high-risk drug class (includes illicitly manufactured fentanyl, heroin, methamphetamine, cocaine, crack, and prescription opioids or benzodiazepines used for a non-prescribed or euphoric purpose). Our study will: (1) evaluate how and why polysubstance patterns emerge and evolve through one- on-one semi-structured in-depth interviews, (2) describe polydrug use trajectories following initiation of a high-risk drug class; and (3) quantitatively assess factors associated with consumption of IMF and the concurrent use of opioids and methamphetamine through a case- control study. The quantitative and qualitative results from our study will inform development of novel early intervention strategies and development of methods to reach a currently hidden population with overdose prevention programs and related evaluations.