Overdose mortality rates for opioids or stimulants are higher in males than females, controlling for rates of drug misuse: State-level data

IMPORTANCE: Drug overdoses from opioids like fentanyl and heroin and stimulant drugs such as methamphetamine and cocaine are a major cause of mortality in the United States, with potential sex differences across the lifespan. OBJECTIVE: To determine overdose mortality for specific drug categories across the lifespan of males and females, using a nationally representative state-level sample. DESIGN: State-level analyses of nationally representative epidemiological data on overdose mortality for specific drug categories, across 10-year age bins (age range: 15–74). SETTING: Population-based study of Multiple Cause of Death 2020–2021 data from the Centers of Disease Control and Prevention (CDC WONDER platform). PARTICIPANTS: Decedents in the United States in 2020–2021 MAIN OUTCOME MEASURES: The main outcome measure was sex-specific rates of overdose death (per 100,000) for: synthetic opioids excluding methadone (ICD-10 code: T40.4; predominantly fentanyl), heroin (T40.1), psychostimulants with potential for misuse, excluding cocaine (T43.6, predominantly methamphetamine; labeled “psychostimulants” hereafter), and cocaine (T40.5). Multiple regression analyses were used to control for ethnic-cultural background, household net worth, and sex-specific rate of misuse of the relevant substances (from the National Survey on Drug Use and Health, 2018–2019). RESULTS: For each of the drug categories assessed, males had greater overall overdose mortality than females, after controlling for rates of drug misuse. The mean male/female sex ratio of mortality rate for the separate drug categories was relatively stable across jurisdictions: synthetic opioids (2.5 [95%CI, 2.4–2.7]), heroin, (2.9 [95%CI, 2.7–3.1], psychostimulants (2.4 [95%CI, 2.3–2.5]), and cocaine (2.8 [95%CI, 2.6–2.9]). With data stratified in 10-year age bins, the sex difference generally survived adjustment for state-level ethnic-cultural and economic variables, and for sex-specific misuse of each drug type (especially for bins in the 25–64 age range). For synthetic opioids, the sex difference survived adjustment across the lifespan (i.e., 10-year age bins ranging from 15–74), including adolescence, adulthood and late adulthood. CONCLUSIONS AND RELEVANCE: The robustly greater overdose mortality in males versus females for synthetic opioids (predominantly fentanyl), heroin, and stimulant drugs including methamphetamine and cocaine indicate that males who misuse these drugs are significantly more vulnerable to overdose deaths. These results call for research into diverse biological, behavioral, and social factors that underlie sex differences in human vulnerability to drug overdose.