Changes in the proportion of fatal overdoses by substance type in the US, 1999–2021

<i>Background:</i> Recent studies have quantified the rate of fatal overdoses that involve opioids, stimulants, and other drugs, but the proportion of overdose deaths attributable to these substances - after accounting for polysubstance use - has not been determined.<i>Objective:</i> We aim to generate the first estimates of the share of overdose deaths by substance type from 1999 to 2021.<i>Methods:</i> By analyzing the National Vital Statistics System's mortality files, we calculated the percent of overdose deaths (<i>n</i> = 1,043,852, 30% female) by substance type in the US for the years 1999 to 2021. We offer and rely on two novel methods: the single-substance method and the apportioned-substance method.<i>Results:</i> In 2021, opioids accounted for 56% (apportioned-substance) to 64% (single-substance) of overdose deaths and stimulants accounted for 30% (single-substance) to 34% (apportioned-substance), which means that opioids and stimulants accounted for 89% to 94% of overdose deaths. From 1999 to 2021, fentanyl became an increasing share of opioid deaths (from 12%-14% to 78%-87%; <i>p</i> < .01) and methamphetamine became an increasing share of stimulant deaths (from 11%-12% to 60%-70%; <i>p</i> < .01).<i>Conclusion:</i> Opioid deaths and stimulant deaths comprised at least 89% of overdose deaths, and methamphetamine and fentanyl represented rising proportions of fatal overdoses. To prevent drug deaths, resources should be directed primarily to therapies and interventions for opioids and stimulants.