Question Are there differences in the temporal pattern, presentation, or outcomes for drug-specific etiology of out-of-hospital cardiac arrest (OHCA) due to overdose (OD)? Findings In a population-based cohort study of 6790 adult patients with emergency medical services–treated OHCA from a US metropolitan system, the incidence of OD-OHCA more than doubled from January 1, 2015, to December 31, 2021, compared with the incidence of non-OD OHCA (ie, no significant change); OHCA due to combined opioid-stimulant etiology experienced the lowest survival among drug-specific profiles. Meaning The combination of increasing incidence and lower survival among OHCA secondary to combined opioid-stimulant substance use frames an urgent need for prevention and resuscitation strategies in this population. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2811464 Yogeswaran V , Drucker C , Kume K, et al. Presentation and Outcomes of Ad...