Charting the fourth wave: Geographic, temporal, race/ethnicity and demographic trends in polysubstance fentanyl overdose deaths in the United States, 2010-2021.

AIMS: To characterize polysubstance death in the United States during the transition to the fourth wave of the drug overdose crisis. To characterize co-involved substances in fatal overdose involving synthetic opioids (mainly illicitly manufactured fentanyl analogues) by year, state, and intersectional sociodemographic groups.

DESIGN: Population-based study of national death records.

SETTING: United States.

PARTICIPANTS/CASES: All people who died from drug overdose in the United States between 2010 and 2021.

MEASUREMENTS: Percentage of all fatal overdose involving fentanyls, stimulants, and other drugs. Most commonly co-involved substances in fentanyl overdose by state and year. Percentage of fatal fentanyl overdose co-involving stimulants by state and year. Percentage of fatal fentanyl overdose co-involving stimulants by intersectional region, race/ethnicity, age, and sex.

FINDINGS: The percent of US overdose deaths involving both fentanyl and stimulants increased from 0.6% (n = 235) in 2010 to 32.3% (34 429) in 2021, with the sharpest rise starting in 2015. In 2010, fentanyl was most commonly found alongside prescription opioids, benzodiazepines, and alcohol. In the Northeast this shifted to heroin-fentanyl co-involvement in the mid-2010s, and nearly universally to cocaine-fentanyl co-involvement by 2021. Universally in the West, and in the majority of states in the South and Midwest, methamphetamine-fentanyl co-involvement predominated by 2021. The proportion of stimulant involvement in fentanyl-involved overdose deaths rose in virtually every state 2015-2021. Intersectional group analysis reveals particularly high rates for older Black and African American individuals living in the West.

CONCLUSIONS: By 2021 stimulants were the most common drug class found in fentanyl-involved overdoses in every state in the US. The rise of deaths involving cocaine and methamphetamine must be understood in the context of a drug market dominated by illicit fentanyls, which have made polysubstance use more sought-after and commonplace. The widespread concurrent use of fentanyl and stimulants, as well as other polysubstance formulations, presents novel health risks and public health challenges.