Lifetime Psychedelic Use and Opioid Use Disorder Severity: Substance-Use Pattern Specific and Mental Health-Dependent Associations in a National Survey

Background and Aims The ongoing opioid epidemic remains a major public health crisis in the United States, with over 100,000 opioid-related deaths annually. Mental health disorders are strongly associated with opioid use disorder (OUD), compounding risks of misuse and overdose. Emerging evidence indicates that psychedelics may be associated with reduced risk of OUD. This study aimed to estimate the associations between lifetime psychedelic use and OUD severity, accounting for mental health impairment, and to test whether these associations vary by mental health status. Design Cross-sectional analysis of the 2023 National Survey on Drug Use and Health using structural equation modeling with multiple-group moderation. Reporting follows STROBE guidelines for observational studies. Setting United States, nationally representative community survey. Participants 45,133 adults aged ≥18 years (55% female; mean age = 35.6 years, SD = 13.7). Measurements The primary dependent variable was OUD severity (no disorder, mild, moderate, severe). Independent variables were two psychedelic factors: mescaline/peyote (Psychedelic_F1) and LSD, psilocybin, MDMA, DMT (Psychedelic_F2). Mental health impairment was modeled as a latent construct (psychological distress, functional impairment, major depression) and also used to define high vs. low impairment groups. Covariates were age, sex, and household income. Findings Psychedelic_F1 was associated with lower OUD severity (β = -0.34, p =.001, 95%CI [-0.550, -0.153]), while the Psychedelic_F2 was associated with higher severity (β = 0.60, p