Associations between classic psychedelics and opioid use disorder in a nationally-representative U.S. adult sample

Opioid use disorder (OUD) is described as a major public health crisis in the United States, with rapidly rising overdose deaths and substantial morbidity. Existing pharmacological treatments (methadone, buprenorphine) can be effective but present problems such as ongoing dependence, motivating interest in alternative or adjunctive interventions. Classic psychedelics — including LSD, psilocybin, peyote and mescaline — have re-emerged in research on addiction, with preliminary clinical and naturalistic studies suggesting potential benefit for various substance use disorders. Jones and colleagues situate the present analysis within this limited literature and the specific question of whether lifetime use of classic psychedelics is associated with lower odds of OUD in a nationally representative sample. They aim to replicate and extend findings reported by Pisano et al., using more recent National Survey on Drug Use and Health (NSDUH) data (2015–2019) and examining associations for individual classic psychedelic compounds rather than treating them as a single class. The authors emphasise the need to identify whether associations are compound-specific and to assess relationships across individual diagnostic criteria for opioid dependence and abuse.

Data came from the 2015–2019 waves of the National Survey on Drug Use and Health (NSDUH), a nationally representative annual survey of civilians aged 12+; this analysis included all adults aged ≥18 years, producing an unweighted sample of N = 214,505. Populations not covered by the NSDUH (people experiencing homelessness not in shelters, active-duty military, and currently incarcerated individuals) are noted as excluded. The study was exempt from institutional review due to use of publicly available de-identified data. The primary exposure variables were self-reported lifetime use (yes/no) of four commonly reported classic psychedelics in the NSDUH: psilocybin, peyote, mescaline and LSD. The primary outcome was past-year diagnosis of OUD, defined as meeting criteria for opioid dependence or abuse in the past year; the 11 DSM‑IV diagnostic criteria for opioid dependence and abuse were used as individual dependent variables in sensitivity analyses. For clarity, DSM‑IV criteria refer to the specific behavioural and physiological symptoms used to define abuse and dependence in that diagnostic system. Covariates entered a priori into models included sex, age, race/ethnicity, educational attainment, self-reported engagement in risky behaviour, annual household income, marital status, and lifetime use of other substances (MDMA/ecstasy, PCP, inhalants, cocaine, tranquilizers, stimulants, sedatives, and marijuana). The analytic approach mirrored Pisano et al.: survey-weighted multivariable logistic regression models were estimated using the 'Survey' package in R to account for the NSDUH complex sampling design and weights. Adjusted odds ratios (aORs) are reported for associations; an aOR is an odds ratio from a multivariable model that accounts for the listed covariates. For any psychedelic associated with reduced odds of OUD, the researchers ran sensitivity analyses examining associations between that substance and each of the 11 DSM‑IV criteria for opioid dependence and abuse. In addition, post-hoc chi-squared analyses compared demographic characteristics of psilocybin users who had versus had not ever misused opioids (i.e. tried heroin or used prescription pain relievers to get high) to explore potential demographic confounding. The extracted text does not provide further model diagnostics or details on handling of missing data.

Demographic contrasts indicated that participants with past-year OUD were more likely to be single, have lower formal education, be younger, male, white, have lower household income, and report greater engagement in risky behaviour; these group differences are reported as descriptive findings in a referenced Table. The extracted text does not present the detailed sample counts for each subgroup. In multivariable survey-weighted logistic regression testing lifetime use of the four classic psychedelics against past-year OUD, lifetime psilocybin use was associated with lowered odds of OUD (adjusted odds ratio [aOR] 0.70; 95% confidence interval [CI] 0.60–0.83), equivalent to a roughly 30% reduction in odds. No other classic psychedelics examined (peyote, mescaline, LSD) showed a similar protective association; the text states they either had no association or were associated with increased odds, but does not provide effect estimates for those compounds in the extracted material. Sensitivity analyses focusing on psilocybin showed it was associated with reduced odds for seven of the 11 DSM‑IV criteria for opioid dependence and abuse, with aORs in the range 0.66–0.83. Two additional criteria showed marginal associations (aORs 0.75–0.80) at p < 0.10. The extracted text does not list which specific criteria were significant versus marginal. Post-hoc chi-squared analyses indicated that psilocybin users who had ever misused opioids differed significantly from psilocybin users who had not on all assessed demographics: marital status, education level, age, sex, race/ethnicity and yearly household income. The extracted text does not report chi-squared statistics or subgroup sample sizes in detail.

Jones and colleagues interpret their findings as a replication and refinement of prior work: psilocybin, but not other classic psychedelics examined, was associated with lower odds of past-year OUD in a large nationally representative sample, and the magnitude of association (about 30% reduction in odds) is similar to that reported by Pisano et al. They note that the reduced odds associated with psilocybin were evident across multiple diagnostic criteria, suggesting the association is not limited to a single facet of opioid-related problems. The authors emphasise that results are cross-sectional and correlational, and therefore causality cannot be inferred. They identify several possible mechanisms that might underlie the observed association: pharmacological effects of psilocybin as a 5-HT2A (serotonin) agonist with potential downstream effects on craving and reward circuitry; the occurrence of mystical-type or spiritually meaningful experiences during psilocybin sessions that have been linked to recovery in other addiction studies; and pre-existing third-variable differences in people who use psychedelics (for example personality or demographic traits) that could both predispose to psychedelic use and reduce risk of OUD. The researchers draw attention to their post-hoc finding that psilocybin users who had versus had not misused opioids differ significantly on multiple demographics, noting that although these demographics were controlled for, unmeasured confounding remains a concern. Key limitations acknowledged include reliance on self-report (raising the possibility of under-reporting), exclusion by the NSDUH of certain high-risk populations (homeless, incarcerated, active-duty military), lack of information on recency or frequency of psychedelic use (the NSDUH assesses lifetime use only), and residual confounding due to variables not captured in the dataset. The authors conclude by calling for longitudinal studies and clinical trials to test causality and to investigate mediators and moderators of the association, including more granular demographic analyses to clarify why psilocybin—but not other classic psychedelics—showed a protective association.

The study replicates prior NSDUH-based findings linking lifetime psychedelic use to lowered odds of opioid use disorder but specifies that this association is present for psilocybin only, not for LSD, mescaline or peyote. The authors recommend future clinical trials and longitudinal research to determine causality and to explore mediating mechanisms; they frame the present findings as an incremental step toward understanding factors that may prevent or alleviate OUD.