Summary Over the last decade fentanyls, methamphetamine and benzodiazepines have proliferated in US illicit drug markets. These synthetic drugs, increasingly in combinations, are implicated in the ongoing rise in overdose fatalities. Although drug overdoses commonly involve more than one substance, polydrug use has long been understudied. Now, the replacement of heroin with novel synthetics such as fentanyls, the resurgence of methamphetamine, and the proliferation of counterfeit pills, have created a situation of new complexity and unknown risks with an urgent need for knowledge. People who use drugs are creating new patterns and modes of polydrug use, for which their motives and influences are yet to be understood. Some polydrug use may be unintentional due to contamination or counterfeit products. For example, the contamination or co-use of methamphetamine with fentanyls may explain the recent rise in stimulant-related mortality. Examination of the use of the once rare but resurgently popular methamphetamine and heroin cocktail, aka `goofball', now remodeled with fentanyl, may give clues to the salience and rationale of polysynthetics in drug use repertoires as well as their adverse outcomes. Aim 1 (Ethnography): To elucidate the effects of synthetic drug supply changes (primarily fentanyls and methamphetamine) on people who use drugs in combination and to understand their preferences for and responses and adaptations to these changes. Aim 2 (Epidemiology): To examine the shift towards polysynthetic drug use through studies of local and national drug supply and health outcome databases and to determine a) the roles of unintentional co-use from cross-contamination and counterfeit pharmaceuticals, intentional co-use and drug price/purity/potency in patterns of synthetic polydrug use and b) the morbidity and mortality outcomes of these use patterns. Aim 3 (Modeling): To forecast overdose mortality based on evolving risk and protective factors from synthetic drug combinations. We will use mechanistic (agent-based modeling) and statistical predictive modeling tools, accounting for the effects of different modes of administration (smoking vs injecting), adaptation (eg tester shots) and interventions (eg naloxone). The Synthetics in Combination (SYNC) study will integrate micro-to-macro-level anthropological, economic, epidemiological and modeling approaches to gain insight into polydrug use on the ground, to measure and predict both adverse effects and model methods of mitigating harm. Achieving its objectives will advance understanding of drug epidemics and morbidities, help tailor public health interventions and provide community level tools for better monitoring and allocation of scarce resources.