Psilocybin was the sole classic psychedelic substance associated with lowered odds of past year OUD in a large, nationally-representative sample of the U.S. population. These findings accord with other population-based survey research indicating that classic psychedelics share differing relationships to mental health outcomes in naturalistic contexts16,17,18,19. Additionally, the magnitude of the association between psilocybin use and OUD (30% reduction in odds) is comparable to that initially reported by Pisano et al. using NSDUH data from 2008 to 2013—allowing us to report that Pisano et al.’s findings replicate in a different (more recent) nationally-representative sample. The association between lifetime use of psilocybin and OUD was not driven by a few particular criteria for OUD; rather, lifetime psilocybin use was significantly associated with reduced odds of seven out of 11 DSM-IV criteria for opioid dependence and abuse.
These results are cross-sectional and correlational and so cannot be used to make causal inferences. However, this study offers an important contribution to the research literature by demonstrating the replication of Pisano et al.’s original finding that lifetime use of psychedelics conferred lowered odds of opioid dependence and abuse. As clinically minded researchers pursue trials aimed at demonstrating the therapeutic efficacy of psilocybin-based treatments for opioid addiction, our study provides a foundation for this line of inquiry with preliminary evidence from a naturalistic context. Furthermore, our findings suggest it is worth investigating the protective effects of psilocybin for all related diagnostic criteria for OUD, including overuse and tolerance, opioid-related emotional distress, and opioid-related social and work problems.
Limitations
These results should be interpreted in the context of several important limitations. Above all, given that our results are based on cross-sectional data, they cannot be used to draw causal conclusions. Casual investigations (e.g., clinical trials) are needed to better understand the nature of the association between psilocybin use and lowered odds of OUD. Additionally, all of the questions we drew from the NSDUH are based on self-report. As a result, for questions on both psychedelic use and OUD, under-reporting might be a confound in our analyses and conclusions.
Next, although we controlled for many demographic covariates, there are many we likely could not control for due to the limitations of the NSDUH dataset. For instance, the NSDUH does not assess information about homelessness status nor collect information from individuals who are currently incarcerated or serving as active-duty military members. Not accounting for demographic factors such as these may lead to an overestimation of the strength of the association between psilocybin use and lowered odds of OUD. Future research should attempt to control for these factors to maximize the integrity of any observed relationships between psilocybin use and OUD.
Finally, items assessing psychedelic use asked about “lifetime” use, but not recency or frequency, precluding examination of these features of psychedelic use. However, given that psilocybin has been shown to elicit lasting reductions in substance dependence after just two to three administrations, causal interpretations of our findings remain plausible even in light of this limitation22.
Potential mediators
A number of potential mediators might underlie the current study’s findings. First, as mentioned in Pisano et al., the effects of psilocybin on the serotonin system might mediate its protective association with OUD. Classic psychedelic compounds, including psilocybin, act primarily as serotonin (5-HT 2A ) agonists, meaning that they bind to a receptor site typically targeted by serotonin23. Abnormal serotonin neurotransmission is linked to many aspects of addiction, such as craving and heightened responses to drug cues24,25,26. Furthermore, there is suggestive evidence that serotonin agonists may support the treatment of opioid addiction as they may indirectly inhibit the release of dopamine27, a key neurotransmitter that is implicated in the maladaptive reward system changes associated with opioid addiction28. At present, pharmacological explanations of our findings remain purely speculative. Future research on the pharmacology of psilocybin can potentially shed further light on the link between this compound and lowered odds of OUD.
Second, the mystical-type experiences induced by psilocybin represent another key mechanism that might explain that protective associations between psilocybin and OUD. There is suggestive evidence of this mediation effect within clinical explorations of psychedelics for the treatment of addiction. In Johnson et al.'s open-label trial of psilocybin for nicotine dependence, improvement was correlated with measures of mystical experience and spiritual significance of psilocybin sessions29. More broadly, spiritual experience and belief have been linked to positive substance abuse recovery outcomes30,31,32. Further inquiry into the role of mystical-type experiences in promoting recovery from addiction can help to elucidate the nature of the observed link between psilocybin use and reduced odds of OUD.
Lastly, third-variable pre-drug factors may plausibly underlie the protective associations observed within our study as well. Prior research has demonstrated there are pre-drug differences associated with psychedelic users (e.g. greater extroversion, higher levels of spirituality) that may simultaneously confer lowered odds of adverse mental health outcomes such as OUD33,34,35,36,37.
Additionally, demographic differences associated with psilocybin use and OUD may contribute to our observed associations. Our post-hoc analyses revealed significant demographic differences between psilocybin users who have versus have not misused opioids on all of the demographic dimensions we assessed (marital status, education level, age, sex, race/ethnicity, and yearly household income). Although we accounted for these demographic variables in our analyses, as previously stated, there are possibly additional demographic factors that we could not control for that mediate our findings. Future research should more closely investigate how demographic differences impact the associations between psilocybin use and lowered odds of OUD. These investigations may have the additional benefit of identifying protective factors associated with the alleviation of OUD. Lastly, if these inquires reveal demographic differences associated with the use of specific psychedelic compounds (i.e. differing populations that use psilocybin versus peyote), these inquiries may also clarify why psilocybin—and no other classic psychedelic substance—conferred lowered odds of OUD.