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

Background and AimsThe 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.DesignCross-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.SettingUnited States, nationally representative community survey.Participants45,133 adults aged ≥18 years (55% female; mean age = 35.6 years, SD = 13.7).MeasurementsThe 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 < .001, 95%CI [0.429, 0.759]). Mental health impairment was positively associated with OUD severity (β = 0.21, p < .001, 95%CI [0.184, 0.256]). Multiple-group SEM indicated moderation by mental health impairment (Δχ²(6) = 22.29, p = .001): Psychedelic_F1 was associated with lower OUD severity only in the high mental health impairment group (β = –0.15, p = .041, 95%CI [-0.299, -0.006]), whereas the association of Psychedelic_F2 with higher OUD severity was attenuated in high mental health impairment (β = 0.38, p < .001, 95%CI [0.274, 0.521] vs. β = 0.48, p = .004, 95%CI [0.164, 0.847]). ConclusionsIn the United States, two distinct psychedelic use patterns were identified. The factor capturing lifetime mescaline/peyote use was associated with lower OUD severity, while the factor including LSD, psilocybin, MDMA, and DMT use was associated with higher severity. These associations differed by level of mental health impairment, with more favorable associations with OUD severity most evident among individuals with greater mental health impairment. More research on the context and intention of psychedelic use in the general public is warranted.