Associations between classic psychedelics and nicotine dependence in a nationally representative sample

Opioid use disorder (OUD) remains a major public health problem in the United States, with large increases in opioid-related mortality over recent decades and current treatments (methadone, buprenorphine) having limitations. Interest has grown in classic psychedelics (for example psilocybin, LSD, peyote, mescaline) as potential therapeutic agents or protective factors for substance use disorders, supported by preliminary clinical and naturalistic studies that suggest reductions in craving and substance use following psychedelic experiences. This study by Jones and colleagues set out to replicate and extend prior population-level findings linking lifetime use of classic psychedelics to reduced odds of OUD. Using recent nationally representative data, the investigators tested whether lifetime use (yes/no) of four commonly reported classic psychedelics (psilocybin, peyote, mescaline, LSD) was associated with past-year OUD, and whether any observed associations held across individual DSM-IV criteria for opioid dependence and abuse. The authors emphasise the need to examine individual compounds rather than treating classic psychedelics as a single homogeneous group.

The analysis used pooled data from the National Survey on Drug Use and Health (NSDUH) covering 2015–2019. The analytic sample comprised all surveyed adults aged 18 years or older (unweighted N = 214,505). The NSDUH is a nationally representative household survey; it does not sample currently homeless people, active-duty military personnel, or incarcerated individuals. The study relied on publicly available, self-reported survey data and was exempt from IRB review. The primary exposure variables were lifetime (ever) use, coded yes/no, of four classic psychedelics: psilocybin, peyote, mescaline, and LSD. Covariates entered a priori included demographic factors (sex, age, race/ethnicity, educational attainment, marital status, annual household income), self-reported engagement in risky behaviour, and lifetime use of several other substances (MDMA/ecstasy, PCP, inhalants, cocaine, tranquilizers, stimulants, sedatives, and marijuana). The principal outcome was past-year opioid use disorder, defined by meeting criteria for past-year opioid dependence or abuse (DSM-IV). For sensitivity analyses, each of the 11 DSM-IV diagnostic criteria for opioid dependence/abuse were treated as separate dependent variables. The authors used survey-weighted multivariable logistic regression (Survey package in R) to account for the complex survey design; adjusted odds ratios (aORs) from these models quantify associations between lifetime psychedelic use and outcomes, controlling for the covariates listed. Where a classic psychedelic showed an association with lowered odds of OUD, the investigators ran sensitivity analyses across the 11 DSM-IV items. A post-hoc set of chi-squared tests 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).

Descriptive comparisons indicated that participants with past-year OUD differed demographically from those without OUD: they were more likely to be single, have lower formal education, be younger, male, white, have lower household income, and report more frequent engagement in risky behaviour. In the main survey-weighted multivariable model, lifetime psilocybin use was the only classic psychedelic associated with lower odds of past-year OUD (adjusted odds ratio aOR: 0.70; 95% CI 0.60–0.83), corresponding to a 30% reduction in odds. The other substances examined (peyote, mescaline, LSD) showed no association with lowered odds of OUD and in some cases were associated with increased odds or null findings. Sensitivity analyses examining the 11 DSM-IV criteria showed that lifetime psilocybin use was significantly associated with reduced odds for seven of the 11 criteria, with aORs in the reported range 0.66–0.83. Two additional criteria showed marginal associations in the direction of lowered odds (aOR range 0.75–0.80; p < 0.10). The post-hoc chi-squared tests found that psilocybin users who had versus had not misused opioids differed significantly across all demographic variables assessed (marital status, education level, age, sex, race/ethnicity, and annual household income).

Jones and colleagues interpret their findings as a replication and refinement of earlier population-level work: lifetime use of classic psychedelics appears associated with reduced odds of opioid use disorder, but this association in the current dataset is specific to psilocybin rather than to other classic psychedelics. The magnitude of the psilocybin–OUD association (about 30% lower odds) is comparable to that reported in earlier NSDUH-based analyses, lending support to the robustness of the relationship in cross-sectional, nationally representative samples. The authors note that the association with psilocybin was not limited to a narrow subset of diagnostic features but extended across multiple DSM-IV criteria, suggesting a broad pattern of lower likelihood of opioid-related problems. Several potential mechanisms are proposed by the authors. Pharmacological explanations centre on psilocybin’s action as a serotonin (5-HT2A) agonist, which might modulate pathways involved in craving and reward; the role of mystical-type or spiritually salient subjective experiences induced by psilocybin is also discussed as a possible mediator, based on correlations observed in prior clinical work. The investigators additionally acknowledge that pre-drug differences or other third-variable factors—such as personality, baseline spirituality, or unmeasured demographic characteristics—could account for or partly mediate the observed association. Their post-hoc demographic comparisons between psilocybin users who had or had not misused opioids underscore the potential for such confounding. The authors explicitly acknowledge key limitations: the cross-sectional design precludes causal inference; all measures are self-reported, introducing risk of under-reporting; the NSDUH omits certain populations (homeless, incarcerated, active-duty military), which may bias estimates; and the exposure measures capture only lifetime use without information on recency, frequency, dose, or context. Given these constraints, Jones and colleagues call for clinical trials and longitudinal studies to test causality and to investigate mediators, and they recommend follow-up work to better account for demographic and other confounding factors.

The study replicates earlier population-level evidence linking classic psychedelic use to reduced odds of opioid use disorder, but refines that finding by showing the association in this dataset was specific to psilocybin rather than LSD or the phenethylamine-class psychedelics (mescaline, peyote). The authors conclude that clinical trials and longitudinal research are required to determine causality and to identify mediators, and that further work could provide foundational evidence to inform ethical and safe clinical investigations of psilocybin’s potential in treating OUD.