Leveraging pooled medical examiner records to surveil complex and emerging patterns of polysubstance use in the United States

•In a sample representing 18% of the US population, most (63%) drug-related deaths involved two or more substances.•More (85%) drug-related deaths involving pharmaceuticals had polysubstance involvement, compared to deaths involving illicit drugs (63%).•Polysubstance drug-related deaths were most common among women, in very rural and very urban settings, and among American Indian and Alaska Native and White individuals. The United States (US) is an extreme global outlier for drug-related death rates. However, data describing drug-related deaths are generally available only on an 8–13-month lag. Furthermore, granular details about substance-involvement are often not available, which particularly stymies efforts to track fatal polysubstance and novel psychoactive substance use. Detailed medical examiner records provide a powerful source of information for drug-related death surveillance, but have been underutilized. We pooled medical examiner data from five US states and 14 counties that together comprise 18% of the US population to examine demographic, geographic, and drug-specific trends in polysubstance drug-related deaths. We employed mixed effects logistic regression to identify demographic factors associated with polysubstance rather than single substance drug-related deaths. We assessed the correlations between drug classes and described geographic variation in the prevalence of specific drugs and the presence of novel and emerging psychoactive substances. Our sample included 73,077 drug-related deaths from 2012 through early 2022. Nearly two-thirds of drug-related deaths were polysubstance-involved, with the number and percentage growing annually. High percentages of polysubstance drug-related deaths were observed in both urban and rural jurisdictions. After adjusting for year and jurisdiction, female, American Indian and Alaska Native, and White individuals had the most elevated odds of polysubstance drug-related deaths. Drug-related deaths involving benzodiazepines or opioids, whether pharmaceutical or illicit, and pharmaceutical drugs were most likely to have polysubstance involvement, while methamphetamine-involved deaths were least likely to involve multiple substances. Strong correlations were observed between prescription opioids and prescription benzodiazepines, fentanyl and xylazine, and designer benzodiazepines and novel synthetic opioids. Analysis of detailed medical examiner records reveals the breadth and complexity of polysubstance drug