Using 2017 NSDUH data (n=56,276), the authors found past naturalistic use of peyote/mescaline was associated with lower odds of past-year substance dependence or abuse (adjusted OR 0.68, p<0.001), whereas past LSD and psilocybin use were associated with increased odds; none of the classic psychedelics were linked to nicotine dependence. The paper notes it is unclear whether these differences reflect pharmacological properties or the cultural/ceremonial contexts of peyote/mescaline use.
Objective
Classic psychedelics (LSD, psilocybin, and peyote/mescaline) have been used to support addiction treatment in a variety of contexts ranging from ceremonial use to clinical trials. The aim of this study was to test the hypothesis that past naturalistic use of classic psychedelics would be associated with decreased prevalence of substance use disorder, when controlling for known confounders.
Methods
This cross-sectional study used 2017 NSDUH survey data to evaluate the association between past use of the classic psychedelics LSD, psilocybin and peyote/mescaline and past year substance dependence or abuse. We calculated adjusted odds ratios by multivariate logistic regression, controlling for a range of sociodemographic variables, use of non-psychedelic illicit drugs and mental health related variables.
Results
A total of 56,276 participants were included in this study. Past use of LSD and psilocybin were associated with increased odds of substance dependence or abuse compared to those who had never used psychedelics before, and this was more likely for those who had used LSD more recently. However, prior use of peyote or mescaline was associated with lower odds of past year substance dependence or abuse compared to people who had never used psychedelics before (aOR = 0.68, p < 0.001). Past use of classic psychedelics was not associated with nicotine dependence.
Conclusion
Past use of peyote/mescaline was associated with decreased odds of substance use disorder compared to people who had never used psychedelics before, while past use of LSD or psilocybin was not. It remains unclear whether this difference is due to pharmacological differences between these compounds or simply due to the context in which peyote/mescaline are traditionally taken. Future research should investigate why naturalistic use of different psychedelics is associated with different substance use disorder effects.
Papers cited by this study that are also in Blossom
Krebs, T. S., Johansen, P. Ø. · Journal of Psychopharmacology (2012)
Bogenschutz, M. P., Johnson, M. W. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2016)
DiVito, A. J., Leger, R. F. · Molecular Biology Reports (2020)
Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)
Alcohol and drug addiction impose a large and growing public‑health burden, and existing treatments for substance use disorders (SUD) have limited effectiveness for many patients. Earlier clinical and epidemiological research, including mid‑20th century LSD trials and more recent studies of psychedelic‑assisted psychotherapy, has suggested that classic psychedelics (principally LSD, psilocybin and mescaline) can produce enduring improvements in mood, anxiety and addictive behaviours. Proposed mechanisms include serotonin 5‑HT2A receptor agonism that increases glutamatergic transmission and neuroplasticity, psychological effects of mystical or peak experiences, and modulation of impulsivity; contemporary frameworks also emphasise the importance of context or "set and setting" in shaping outcomes, and point to longstanding ceremonial use of substances such as peyote in communal healing rituals. Amit and colleagues framed this work around a gap in population‑level evidence: while some large naturalistic studies report positive mental‑health associations for psychedelic use, there are few large, representative analyses that compare different classic psychedelics individually against a broad SUD outcome. The study therefore aimed to test whether lifetime naturalistic exposure to classic psychedelics (examined both as a class and separately as LSD, psilocybin and peyote/mescaline) was associated with lower prevalence of past‑year substance dependence or abuse after adjustment for sociodemographic, psychiatric and other drug‑use confounders, with nicotine dependence included as a secondary outcome.
This was a cross‑sectional analysis of the 2017 National Survey on Drug Use and Health (NSDUH), a nationally representative survey of the US civilian non‑institutionalised population aged 12 years and older. The analytic sample reported in the paper comprised 56,276 respondents. Primary exposure variables were lifetime use of classic psychedelics. The investigators created a combined variable coded positive if a respondent reported ever using LSD, psilocybin, peyote or mescaline, and they also analysed each substance individually; peyote and mescaline were combined into a single variable because mescaline is the active compound in peyote. The 2017 NSDUH uniquely included recency categories for LSD, so the authors used an additional predictor capturing how recently respondents had last used LSD (past 30 days, past 12 months but >30 days, more than 12 months prior). The primary outcome was past‑year illicit drug or alcohol dependence or abuse, reflecting the DSM‑IV constructs that approximate substance use disorder criteria; nicotine dependence (measured by the Nicotine Dependence Syndrome Scale, NDSS) was included as a secondary outcome because it captures craving. Control variables included past‑year mental‑illness severity and the demographic and behavioural covariates used in a prior NSDUH analysis (age, sex, race/ethnicity, education, household income, marital status, a self‑reported tendency to test oneself with risky behaviour, and lifetime non‑medical use of ten other drug categories such as cannabis, opiates, cocaine, stimulants, MDMA and inhalants). The survey lacked measures for some potentially important confounders (for example, set and setting, frequency and dose of psychedelic use, and lifetime exposure to an extremely stressful event), which were therefore not included. Statistical analyses used binary logistic regression to estimate unadjusted and adjusted odds ratios (OR, aOR). Models were run for the combined psychedelic exposure and separately for each compound, and analogous models were fitted with nicotine dependence as the dependent variable. A separate series of regressions used LSD recency as the predictor. Analyses were performed in SPSS v27. The authors stated that with n = 56,276 and 21 variables, power should be high; significance was set at p < 0.05 with a Bonferroni correction (p < 0.0167) applied when comparing individual psychedelics. All tests were two‑sided.
The sample included 56,276 respondents (27,037 males, 48%; 29,239 females, 52%). Lifetime exposure to any classic psychedelic was reported by 6,362 individuals (11.3%); lifetime prevalence was 8.3% for LSD, 8.2% for psilocybin and 2.3% for peyote/mescaline. Unadjusted analyses showed strong positive associations between lifetime psychedelic exposure and past‑year illicit drug or alcohol dependence or abuse: any classic psychedelic, OR = 6.03 (p < 0.001); LSD, OR = 5.73 (p < 0.001); psilocybin, OR = 6.02 (p < 0.001); peyote/mescaline, OR = 2.97 (p < 0.001). After adjusting for demographic, psychiatric and other drug‑use covariates, these associations were attenuated. For lifetime exposure to any classic psychedelic the adjusted odds ratio was aOR = 1.21 (p < 0.001). When analysed by compound, adjusted estimates differed markedly: LSD aOR = 1.41 (p = 0.024) and psilocybin aOR = 1.135 (p = 0.031), neither meeting the Bonferroni‑corrected threshold of p < 0.0167; by contrast, lifetime peyote/mescaline was associated with lower odds of past‑year illicit drug or alcohol dependence or abuse (aOR = 0.68, p < 0.001). For nicotine dependence the unadjusted associations were also positive (any psychedelic OR = 4.76, p < 0.001; LSD OR = 4.97; psilocybin OR = 4.42; peyote/mescaline OR = 3.67, all p < 0.001). These associations did not remain statistically significant after adjustment, although two adjusted estimates showed suggestive trends that did not survive the Bonferroni correction: LSD aOR = 1.17 (p = 0.0168) and peyote/mescaline aOR = 0.80 (p = 0.018). Analyses using LSD recency revealed that more recent LSD use was associated with markedly higher unadjusted odds of past‑year SUD: past 30 days OR = 18.34 (p < 0.001), past 12 months (but >30 days) OR = 15.65 (p < 0.001), and last use >12 months prior OR = 4.47 (p < 0.001). After adjustment, recency within the past year remained associated with greater odds of past‑year illicit drug or alcohol dependence or abuse (past 30 days aOR = 1.97, p < 0.001; past 12 months aOR = 2.17, p < 0.001), whereas the adjusted aOR for last LSD use >12 months prior was 0.94 and not significant. For nicotine dependence the unadjusted recency associations were elevated (for example, 4.35 times greater odds for past‑30‑day users), but adjusted results were mostly non‑significant; one small adjusted effect was reported for users who last used LSD more than a year prior (aOR = 1.14, p < 0.05). The authors emphasised that inclusion of control variables substantially attenuated the crude associations, and they reported that several covariates behaved as expected: older age and female sex were generally associated with lower odds of SUD, past‑year mental illness and penchant for risk‑taking were strong positive confounders, most other lifetime drug uses predicted higher odds of SUD (with a few exceptions), and socioeconomic variables (income and education) did not show clear directional trends in this analysis.
Amit and colleagues interpreted their findings as showing that crude population associations between lifetime psychedelic use and past‑year substance dependence or abuse are strongly confounded by sociodemographic, psychiatric and other drug‑use factors. Unadjusted models indicated substantially higher prevalence of SUD among psychedelic users, consistent with the common co‑occurrence of psychedelic and other substance use, but adjustment for covariates attenuated most associations. A key and novel observation was that associations differed by compound: lifetime peyote/mescaline use was associated with a lower adjusted odds of past‑year illicit drug or alcohol dependence or abuse (aOR = 0.68, p < 0.001), whereas adjusted associations for LSD and psilocybin were small and not statistically robust after multiplicity correction. The authors propose two non‑exclusive explanations. One is pharmacological: mescaline is a phenylalkylamine and may have different receptor selectivity (for example more selective 5‑HT2 receptor agonism) compared with indoleamines such as LSD and psilocybin, and differences at receptors such as 5‑HT2C might plausibly affect addictive processes. The other explanation emphasises set and setting: peyote/mescaline is often consumed in sacramental or communal contexts (for example within the Native American Church) that could provide therapeutic structure and social support absent from much naturalistic LSD or psilocybin use; the NSDUH lacks measures of context, frequency and dose, so this possibility could not be tested. The authors acknowledged several limitations. The primary SUD outcome derived from DSM‑IV dependence or abuse does not capture DSM‑5 criteria on craving, though the NDSS nicotine outcome did include craving; important potential confounders (set and setting, dose, frequency and lifetime exposure to severe stressors) were not available in the survey; and the cross‑sectional design precludes establishing temporality or causation. They noted that using lifetime psychedelic exposure and past‑year outcomes makes it likely that many exposures preceded outcomes but cannot substitute for prospective incidence data. The authors suggested future research directions: cohort studies to assess relative risk of developing SUD after psychedelic exposure, and controlled comparisons of LSD, psilocybin and mescaline within a unified set‑and‑setting protocol to help disentangle pharmacological from contextual effects. Overall, they emphasised that different classic psychedelics may have different associations with substance‑use outcomes and that further, more granular research is required to understand why.
The study tested the hypothesis that naturalistic lifetime use of classic psychedelics would be associated with lower likelihood of substance use disorder after adjustment for confounders. This pattern was not observed for LSD or psilocybin but was observed for peyote/mescaline, which was associated with reduced adjusted odds of past‑year illicit drug or alcohol dependence or abuse. Amit and colleagues conclude that naturalistic use of different psychedelic compounds may have different associations with SUD and recommend further comparative research that accounts for pharmacological differences and contextual factors.
Alcohol and drug addiction pose a major threat to public health. In 2010, illicit drug dependence accounted for 20 million disability adjusted life years. In 2015, alcohol and tobacco use cost the human population over a quarter billion disability adjusted life years and illicit drug use cost an additional tens of millions of disability adjusted life years. The public health burden of these diseases is likely to grow as the global prevalence of substance use disorders continues to rise. Substance use disorders (SUD) are complex conditions and treatment is not effective for many patients. Relapse rates for addictions are similar to those of chronic diseases like diabetes and asthma. Current treatment for SUD is multifaceted, with treatment outcomes dependent on the extent and nature of the patient's problems, appropriateness of treatment used to address those problems, and the quality of interaction between the patient and treatment providers. In the first wave of psychedelic research in the 1950's, LSD was investigated in the treatment of alcohol dependence. A recent meta-analysis of six randomized controlled trials from this period showed that a "single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse". In recent years there has been renewed interest in the use of classic psychedelics to aid in the treatment of SUD. Classic psychedelics are serotonin 2A (5-HT 2A ) receptor agonists, such as lysergic acid diethylamide (LSD), psilocybin and mescaline that induce hallucinogenic and mysticaltype experiences and have anti-depressive, anxiolytic, and antiaddictive effects. Though the exact anti-addictive mechanism of action is unknown, there is substantial evidence that drugs of abuse modulate serotonin transmission in the 5-HT raphe nuclei and their forebrain projections. Furthermore, 5-HT receptors seem to play a role in impulsivity, a behavioral characteristic that contributes to an individual's vulnerability to addiction. As such, effective pharmacological manipulation of the 5-HT system may be the mechanism which is contributing to successful recovery from the repeating cycle of addiction by alleviating some of the neurochemical abnormalities associated with drugs of abuse. The 5-HT 2A receptor agonism in frontal and limbic areas of the brain by classic psychedelics increase glutamatergic transmission and neuroplasticity, so much so that research has shown that just one or two doses can have enduring positive outcomes for individuals with SUD. Classic psychedelics both enable reorganization of disordered neural pathways in the default mode network and attenuate maladaptive signaling in the mesolimbic reward circuitry that plays a central role in addiction. Persistent changes in substance use behavior seen after psychedelic experiences may be due to these neurological processes, but also seem to be mediated by psychological responses to the highly meaningful and mystical experience from psychedelics, similar to brain changes seen after traumatic events. Such profound mystical experiences are associated with sudden and lasting behavioral change, such as long-term abstinence from alcohol. Still, the plasticity-inducing effects of 5-HT 2A receptor agonism make the psychedelic experience especially sensitive to context. This context is commonly referred to as "set and setting". Set and setting theory proposes that psychedelics act as non-specific amplifiers of the contents of one's consciousness. Therefore, one's preparation, expectation, physical environment, and even cultural attitudes shape the effects of a psychedelic experience. Contemporary research has found that set and setting is so important for realizing therapeutic effect because psychedelics put the user in a state of enhanced suggestibility. In fact, in studies in which set and setting were neglected, therapeutic outcomes were less positive. It is for this reason that researchers believe that many indigenous groups have participated in sacramental ritual use of psychedelics for religious and pedagogical purposes since ancient times. Examples of such sacramental use include religious consumption of ayahuascaand the religious sacrament performed by the Native American Church (NAC) in which peyote is consumed as part of an all-night communal prayer and song ceremony for the purpose of healing physical or spiritual imbalances that an individual or the community may be experiencing. Similarly, ibogaine is often used in ceremonial contexts and in clinical research for addiction treatment. Use in these contexts has been associated with remission of psychopathologies such as depression, anxiety, and SUD. Current research continues to show the efficacy of treating various addictive disorders with psychedelic assisted psychotherapy in the clinical context. In addition to the extraordinary effects of psychedelic assisted psychotherapy seen in clinical trials, large population-based studies of naturalistic (i.e., non-laboratory) use of psychedelics have shown the power of these compounds to affect mood, behavior, and even increase openness. One of the largest population studies on psychedelic use sought to evaluate the effect of naturalistic use of psychedelics on mental health. The results of this study showed that use of psychedelics was not only not an independent risk factor for mental health problems, but that psychedelic use was indeed associated with a lower rate of mental health problems. Further epidemiological studies have suggested that naturalistic use of classic psychedelics is associated with positive mental health outcomes, including smoking cessationand decreased risk of opioid use disorder. These studies of naturalistic use of psychedelics are particularly important for our understanding of psychedelics because of the central role played by set and setting in mediating therapeutic effects and because naturalistic psychedelic use happens outside of controlled settings. While past epidemiological studies have shown significant association between past use of classic psychedelics and specific substance use disorders, there are no known large population-based studies which look at the association between naturalistic use of classic psychedelics categorically across several compounds and the broad category of substance use disorders. Therefore, the goal of this study is to validate the effect of naturalistic use of classic psychedelics seen in substance use disorders across classic psychedelic compounds. This large cross-sectional study compares the prevalence of substance use disorder among individuals who have and have not been exposed to the classic psychedelics LSD, psilocybin and peyote/mescaline as a class of substances and individually. Based on past research, we hypothesized that individuals exposed to any of these classic psychedelics would have lower rates of substance use disorder when controlling for demographic variables and for confounding by co-occurring mental illness.
This cross-sectional study used data from the 2017 National Survey on Drug Use and Health (NSDUH). The 2017 NSDUH survey provides estimates of substance use and mental health indicators from a representative sample of the US civilian non-institutionalized population. The data included individuals 12 years of age and older.
A new variable indicating lifetime use of classic psychedelics which was coded as "1" if the individual reported having ever used LSD, psilocybin, peyote, or mescaline. Each of the substances were also analyzed as individual substances and therefore each substance was represented with its own variable, except for peyote and mescaline which were collapsed into one variable since mescaline is the active compound in the peyote cactus.
Lysergic acid diethylamide was the only classic psychedelic in the 2017 survey that included questions on recency of use. This variable was included to investigate whether there were differences in substance dependence or abuse among individuals based on how long ago they had last used LSD in comparison to individuals who had never used LSD before.
The DSM-4 had two diagnoses: substance dependence and substance abuse. In the DSM-5, these diagnoses were collapsed into one diagnosis-substance use disorder (mild to severe). Hence, the variable "past year illicit drug or alcohol dependence or abuse" was chosen as the primary outcome variable as it captures the central components to the diagnosis of substance use disorder (SUD).
This variable was added as a secondary dependent variable because, unlike past year illicit drug or alcohol dependence or abuse, this variable included information on substance cravings. While the DSM-5 diagnosis of SUD largely focuses on substance dependence and abuse criteria, it also includes criteria on substance cravings. The Nicotine Dependence Syndrome Scale (or NDSS) assesses dependence on nicotine and includes criteria on nicotine craving. As such, nicotine dependence based on NDSS score was included as an additional dependent variable to investigate whether past exposure to classic psychedelics was differentially associated with nicotine dependence.
This study investigated the presence of substance dependence or abuse among individuals who have and have not been exposed to classic psychedelics. Because SUD so often co-occurs with other mental illness,a categorical variable on presence and severity of past year mental illness was included as a control variable. In addition, Krebs and Johansen paper, which was a study using NSDUH data from previous years, compared various mental health outcomes among psychedelic users and non-users and included the following control variables which were also included in this study: age at interview, sex, race/ethnicity, education, household income, marital status, likes to test self with risky behavior, and lifetime non-medical use of each of ten types of drugs: cannabis (marijuana), opiates (heroin, opiate pain relievers), cocaine, tranquilizers/sedatives (benzodiazepines, barbiturates), stimulants (amphetamine, methamphetamine, methylphenidate), MDMA (ecstasy), inhaled anesthetics (nitrous oxide, ether), alkyl nitrites (poppers), other inhalants (solvents, volatile chemicals), and PCP (phencyclidine). The Krebs and Johansen studyalso included a control variable on lifetime exposure to an extremely stressful event. The 2017 NSDUH survey did not include any such variable and thus this control variable was not included in the study.
Regression analysis was done to find the ratio of the odds of having past year illicit drug or alcohol dependence or abuse among individuals who used classic psychedelics in their lifetime compared to those that had never used before. The binary logistic regression was first run to get the unadjusted odds ratio, and then another logistic regression was run which included control variables. The exposure variables (lifetime use of classic psychedelics) were then separated into three individual variables: lifetime use of LSD, lifetime use of psilocybin and lifetime use of peyote/mescaline and the same regression analysis was run, again using past year illicit drug or alcohol dependence or abuse as the dependent variable. Another set of logistic regressions was run using nicotine dependence as the dependent variable, first by using the variable lifetime use of classic psychedelics as one binary variable and then by differentiating between the three categories of classic psychedelics. These regressions were also run first without and then with the control variables mentioned above. Lastly, a series of logistic regressions was run using recency of LSD use as the predictor variable in place of lifetime exposure to classic psychedelics. No power analysis was performed because the sample size was n = 56,276 and there were 21 variables included in the analysis, suggesting that power would be well above 90% even for detecting a small effect size. All data analysis was done using SPSS version 27. Significance was set at the p < 0.05 level, adjusted using the Bonferroni correction when appropriate. The Bonferroni correction was applied for all regression analyses which differentiated between various psychedelics such that the adjusted significance level was considered at the p < 0.0167 level. All tests were two-sided.
There were 56,276 individuals included in this study, 27,037 males (48%) and 29,239 females (52%). Lifetime exposure to at least one of the classic psychedelics was reported by 6,362 individuals (11.3%), 4,688 of those had been exposed to LSD at least once over the course of their lifetime (8.3%), 4,614 had been exposed to psilocybin (8.2%), and 1,285 had been exposed to either peyote or mescaline (2.3%). Further summary data can be found in Table. When analyzing these data to see how use of psychedelics was associated with SUD without taking into account control variables, we saw an unadjusted OR = 6.03 (p < 0.001), indicating that lifetime exposure to classic psychedelics was associated with six times greater odds of past year illicit drug or alcohol dependence or abuse. This OR was considerably attenuated after adjusting for the above-mentioned control variables (aOR = 1.21, p < 0.001). The unadjusted odds of past year drug or alcohol dependence or abuse among individuals exposed to LSD in their lifetimes was 5.73 (p < 0.001) times greater than among those who had never used LSD. When including control variables, however, we computed an aOR of 1.41 (p = 0.024). This result was not considered statistically significant considering the Bonferroni corrected significance level p < 0.0167. Similarly, the unadjusted OR = 6.02 (p < 0.001) for illicit drug or alcohol dependence or abuse among those with lifetime exposure to psilocybin substantially decreased when control variables were included in the model (aOR = 1.135, p = 0.031). While the unadjusted analysis for illicit drug or alcohol dependence or abuse among individuals who had been exposed to peyote or mescaline in their lifetime showed a positive association (OR = 2.97, p < 0.001), the adjusted model suggests that lifetime exposure to peyote or mescaline was significantly associated with lower odds of illicit drug or alcohol dependence or abuse in the past year (aOR = 0.68, p < 0.001). The results from these logistic regressions, including the attenuating affect of control variables are summarized in Table. When looking at nicotine dependence as the outcome variable, the odds ratio for individuals exposed to any psychedelic was 4.76, p < 0.001. When differentiating between psychedelics, OR LSD = 4.97, OR psilocybin = 4.42 and OR peyote/mescaline = 3.67 and all were significant at the p < 0.001 level. When including control variables, we found no significant association between nicotine dependence and exposure to psychedelics. However, aOR LSD = 1.17 (p = 0.0168) and aOR peyote/mescaline = 0.80 (p = 0.018) are suggestive of a trend that might be worth investigating in future studies, albeit not statistically significant when Bonferroni correction was applied. These results are summarized in Table. When differentiating the effect on substance use disorder by recency of LSD use, participants who were exposed to LSD within the past 30 days had 18.34 greater odds of past year illicit drug or alcohol dependence or abuse than those who had never used LSD, without controlling for other variables. Adjusting for control variables, aOR past 30 days = 1.972 for illicit drug or alcohol dependence or abuse. These same individuals had 4.35 times greater odds of nicotine dependence than people who had never used LSD, without controlling for other variables. All of these results were found at the p < 0.001 level. Similarly, for individuals who had used LSD more than a month prior but in the past year, the odds of past year SUD were 15.65 times greater than those who had never used LSD, without controlling for other variables. When adjusting for control variables, aOR = 2.17. This group (those who had used LSD within the past year but more than 30 days prior) had 3.57 times greater odds of nicotine dependence than those who had never use LSD before, without including control variables. All these results were significant at the p < 0.001 level. In the absence of control variables, individuals who had last used LSD 10.3389/fpsyt.2022.1066369 more than a year prior had 4.47 times greater odds of past year drug or alcohol dependence or abuse than those who had never used LSD before. This same group had 5.23 times greater odds of nicotine dependence without factoring in control variables. These were both found to be significant at the p < 0.001 level. whose last use of LSD was more than a year prior had just 1.14 times greater odds of nicotine dependence than those who had never used LSD before, p < 0.05. The adjusted odds ratio of drug or alcohol dependence for those who last used LSD more than a year prior was 0.94, though these results were not significant.
With the presence of control variables, LSD recency within the past year was significantly associated with greater odds of past year illicit drug or alcohol dependence or abuse (OR past 30 days = 1.97, p < 0.001; OR past 12 months = 2.17, p < 0.001). In addition, the odds of nicotine dependence were slightly greater among people who had used LSD more than a year prior to survey, compared to people who had never used LSD before (OR = 1.14, p < 0.05). No other associations were significant when controlling for other variables. These results are summarized in Table.
The purpose of this study was to investigate whether individuals who had used classic psychedelics in a naturalistic setting were less likely to have substance use disorder compared to those who had never used classic psychedelics. This study used a large sample of individuals who reported on their use of psychedelics, illicit drugs, alcohol, and nicotine, thereby illuminating several interesting facets of psychedelic use and its associated effects in a representative sample of the US population. Without adjusting for control variables, the part of the population that had used psychedelics in their lifetime were indeed significantly and dramatically more likely to have substance dependence or abuse in the past year. This makes sense when considering the growing prevalence of psychedelic use among users of other drugs. Though prior psychedelic use was found to be associated with greater prevalence of substance dependence or abuse in the past year, adjusted analysis revealed a meaningful decrease in this effect. Furthermore, while lifetime exposure to classic psychedelics in general was associated with a slightly increased likelihood of past year substance dependence or abuse, differentiating between psychedelic substances in the regression analysis showed divergent effects between the different psychedelic compounds. Specifically, people who had used LSD or psilocybin in their lifetimes had slightly greater odds of substance dependence or abuse in the past year, while individuals who had used peyote or mescaline in their lifetimes had a significantly lower likelihood of substance dependence or abuse in the past year (aOR = 0.68, p < 0.001). This suggests that even naturalistic use of peyote/mescaline could bear a protective effect against illicit drug or alcohol dependence or abuse and may even serve as a protective factor against nicotine dependence. Controlling for the confounding effects of age, sex, education level, race, past year mental illness severity, marital status, family income level, how often the respondent likes to test self with risky behavior, and having ever used any of the aforementioned drugs resulted in considerably adjusted odds ratios. Interestingly, the older an individual was at the time of interview seems to have resulted in lower odds of having an SUD. While this effect was not significant across the board, this does follow a trend which shows that age likely served as a confounding variable. Similarly, sex seemed like an obvious confounder as females have significantly lower odds of SUD and are similarly a smaller percentage of psychedelic users as shown in Table. Controlling for race revealed that some races seemed to have a significantly greater aOR for SUD compared to the non-Hispanic white population, which justifies including it as a control variable. However, future research should be done on these differences because, for example, while the Native American population had greater odds of having SUD, there are also traditions like the Native American Church which use psychedelics in a ceremonial context for healing. Past year mental illness and how often one likes to test oneself with risky behavior both showed clear, significant trends which also make it likely that these variables were confounders. In addition, marital status was a significant control variable, suggesting that it too was a confounding variable. As is expected, people who had used almost all other drugs which were included as a control variable had significantly greater odds of SUD, excluding users of PCP, inhaled anesthetics and amyl nitrite. People who had used inhaled anesthetics indeed had significantly lower odds of SUD which is a phenomenon worth investigating in future research as well. Lastly, the two socioeconomic status control variables, income and education level, did not seem to show any clear, significant trend. This perhaps suggests that the effect of psychedelic use on SUD is independent of socioeconomic status. This was a cross-sectional study and so the effect of time was necessarily taken out of the equation. Nonetheless, by differentiating LSD users by how long ago they had last used LSD, we were able to see if there were immediate and/or longterm effects. Interestingly, there was a significant downward trend in unadjusted odds for SUD as time since last use of LSD passed, although no such trend was found for nicotine dependence or when adjusting for control variables.
The difference between the various classic psychedelics studied are most obviously explained by two possibilities which should be investigated in further research: chemical/pharmacological differences between the different compounds and differences in the set and setting in which different psychedelics are used. One notable chemical difference is that mescaline is a phenylalkylamine whereas LSD and psilocybin are indoleamines. While it is well established that classic psychedelics share a common attribute of agonist activity at the serotonin 5HT 2A receptor, there is also evidence that other receptor sites are involved in bringing about the psychopharmacological effects of classic psychedelics. One difference between phenylalkylamines and indoleamines that may be consequential in explaining the differences seen between the compounds studied in this work is that phenylalkylamines, like mescaline, are selective 5-HT 2 receptor agonists, whereas indoleamines are non-selective for 5-HT receptors. While the research on this is still in its early stages, it seems that the non-addictive nature of classic psychedelics is at least partially associated with serotonin 5-HT 2C receptor agonism. Another possible explanation for why mescaline use in our study was associated with decreased SUD while LSD and psilocybin use were not, could be that mescaline is typically used in a more supportive context than LSD or psilocybin. While the influence of set and setting was not accounted for in this study due to survey limitations, set and setting could have contributed to the different SUD outcomes seen in the LSD or psilocybin users vs. mescaline users in this study. The use of peyote/mescaline has a long history of being used in religious and therapeutic contexts and its illicit use is less common than illicit use of cocaine or cannabis. Furthermore, LSD and psilocybin use is associated with use of other illicit substances. While this is hardly evidence for different set and setting, the possibility that mescaline users are more likely to enjoy a therapeutic context for their mescaline use than most LSD and psilocybin users is worth investigating in future research, given the extensive evidence on contextual factors (set and setting) mediating the kinds of benefits realized by psychedelic users. It is important to note that these two possible explanations for why decreased substance dependence or abuse was observed for mescaline only and not LSD or psilocybin are not mutually exclusive. Nonetheless, future research could compare the effects of LSD, psilocybin, and mescaline use for treating SUD, using a unified set and setting protocol. This could provide greater evidence for or against the hypothesis that pharmacological differences between classic psychedelics mediate therapeutic effects for treating SUD. Furthermore, the outcome measure for this cross-sectional study was the (adjusted) odds ratio. This measure is based on the prevalence of SUD among people who had used psychedelics and not the incidence of SUD among psychedelic users. However, a cohort study of people who have used other substances and which measures the relative risk of developing SUD among psychedelic users compared to the psychedelically naïve would show greater evidence for the idea that naturalistic use of classic psychedelics can be a protective factor against substance use disorders.
There were several limitations in this study. Firstly, there was incomplete information on the outcome of substance use disorder and we therefore used two response variables-illicit drug or alcohol dependence or abuse and nicotine dependence. While illicit drug or alcohol dependence or abuse was a good variable for capturing dependence or abuse of a large variety of substances that people abuse or are dependent on, this variable did not include information on substance cravings which is a criterion that is included in the DSM-5 diagnosis of substance use disorder. While there was not a singular SUD outcome variable, significant and meaningful associations were found for both outcome variables. Another limitation was that we were not able to include several control variables, such as set and setting, frequency, dose of psychedelics used and, unlike in Krebs and Johansen study, "lifetime exposure to an extremely stressful event." These would have been helpful to control for, given that recent research has highlighted the importance of consuming a greater dose for eliciting the peak experience which enable greater therapeutic effect, how common exposure to adverse childhood events and other lifetime stressful events are among people who are substance dependent and how much harder it is for these people to decrease their consumption. This study was a cross-sectional study and therefore, limited in that it was unable to show temporality or causality. Nonetheless, by using lifetime use of psychedelics as the primary exposure variable and past year drug or alcohol dependence or abuse and past year nicotine dependence as the outcome variables, much of the exposure likely preceded the outcomes. Furthermore, by using the recency of LSD use variable, a better picture emerged of how the outcome variables changed as time passed since last LSD use. Though no strong conclusions could be drawn from the inclusion of this variable, it does appear that there was a downward trend of SUD among people the more time had passed since their last LSD use which should be investigated further in future research.
The main hypothesis of this study was that naturalistic use of each of the classic psychedelics LSD, psilocybin, and peyote/mescaline would be associated with a lower likelihood of substance use disorder when controlling for demographic and mental health related variables. While this was not found for LSD or psilocybin users, it was confirmed for people who had used peyote/mescaline. This study suggests that naturalistic use of different psychedelics may have different effects and should thus be investigated and compared in future research, while taking into account other possible mediating factors.
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