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Official websites use. Share sensitive information only on official, secure websites. This article was submitted to Addictive Disorders, a section of the journal Frontiers in Psychiatry. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. 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. 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. A total of 56, 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. Past use of classic psychedelics was not associated with nicotine dependence. Future research should investigate why naturalistic use of different psychedelics is associated with different substance use disorder effects. Keywords: psychedelic agents, mescaline, addiction, substance use disorder, population study. Alcohol and drug addiction pose a major threat to public health 1. In , illicit drug dependence accounted for 20 million disability adjusted life years 2. In , 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 3 , 4. The public health burden of these diseases is likely to grow as the global prevalence of substance use disorders continues to rise 4. Substance use disorders SUD are complex conditions and treatment is not effective for many patients 5. Relapse rates for addictions are similar to those of chronic diseases like diabetes and asthma 6. In recent years there has been renewed interest in the use of classic psychedelics to aid in the treatment of SUD 9 , Classic psychedelics are serotonin 2A 5-HT 2A receptor agonists, such as lysergic acid diethylamide LSD , psilocybin and mescaline that induce hallucinogenic and mystical-type experiences and have anti-depressive, anxiolytic, and antiaddictive effects 10 — 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. 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 12 , 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 9 , 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 7 , 15 — Still, the plasticity-inducing effects of 5-HT 2A receptor agonism make the psychedelic experience especially sensitive to context 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 21 , 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 11 , Examples of such sacramental use include religious consumption of ayahuasca 12 , 23 and 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 15 , 24 — Similarly, ibogaine is often used in ceremonial contexts and in clinical research for addiction treatment 27 , 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 9 , 29 — In addition to the extraordinary effects of psychedelic assisted psychotherapy seen in clinical trials, large population-based studies of naturalistic i. 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 11 , 34 — 37 , including smoking cessation 38 and decreased risk of opioid use disorder 39 , 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. 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. The 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. 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 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 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. 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, 43 , 44 a categorical variable on presence and severity of past year mental illness was included as a control variable. The Krebs and Johansen study 35 also included a control variable on lifetime exposure to an extremely stressful event. The 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. 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. All data analysis was done using SPSS version All tests were two-sided. Lifetime exposure to at least one of the classic psychedelics was reported by 6, individuals Further summary data can be found in Table 1. Summary demographic and mental health data of individuals who have and have not used any of the classic psychedelics included in this study. The unadjusted odds of past year drug or alcohol dependence or abuse among individuals exposed to LSD in their lifetimes was 5. When including control variables, however, we computed an aOR of 1. The results from these logistic regressions, including the attenuating affect of control variables are summarized in Table 2. Results of logistic regression showing adjusted odds ratio for past year substance use disorder among users of any of the classic psychedelics in this study, as a class of substances and individually. When looking at nicotine dependence as the outcome variable, the odds ratio for individuals exposed to any psychedelic was 4. When including control variables, we found no significant association between nicotine dependence and exposure to psychedelics. These results are summarized in Table 3. Odds ratios OR and adjusted odds ratios aOR of past year illicit drug or alcohol dependence or abuse and nicotine dependence among individuals exposed to classic psychedelics in comparison to individuals in the sample who have never used these psychedelics. 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 These same individuals had 4. Similarly, for individuals who had used LSD more than a month prior but in the past year, the odds of past year SUD were This group those who had used LSD within the past year but more than 30 days prior had 3. In the absence of control variables, individuals who had last used LSD more than a year prior had 4. This same group had 5. When including control variables in the analysis, individuals whose last use of LSD was more than a year prior had just 1. The adjusted odds ratio of drug or alcohol dependence for those who last used LSD more than a year prior was 0. No other associations were significant when controlling for other variables. These results are summarized in Table 4. Odds ratios OR and adjusted odds ratios aOR of past year illicit drug or alcohol dependence or abuse and nicotine dependence among individuals based on recency of last LSD use. 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 26 , 46 , 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. 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 1. 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. 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. One notable chemical difference is that mescaline is a phenylalkylamine whereas LSD and psilocybin are indoleamines 48 , While it is well established that classic psychedelics share a common attribute of agonist activity at the serotonin 5HT 2A receptor 49 , 50 , 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 26 , 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. Furthermore, LSD and psilocybin use is associated with use of other illicit substances 52 — 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 18 , 19 , 21 , 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. 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. 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. 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. Publicly available datasets were analyzed in this study. As such, JR performed the research, analysis, and writing of this manuscript under the supervision of her thesis advisors, SL-R and RG. SL-R and RG provided their expertise in psychiatry, reviewed and approved the statistical analysis, proceeding results, and contributed their oversight to the writing of the manuscript. In addition, SL-R advised on all matters related to addiction and substance use disorders. RG advised on all matters related to epidemiology and psychopharmacology, as well as his background in clinical use of psychedelics. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past collaboration with the author, SL-R. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Front Psychiatry. Find articles by Jonina Rabinowitz. Find articles by Shaul Lev-Ran. Find articles by Raz Gross. Edited by: Ben H. Received Oct 10; Accepted Dec 13; Collection date Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Lifetime use of classic psychedelics. Lifetime non-medical use of heroin or opiate pain relievers. Lifetime non-medical use of tranquilizers or sedatives. Lifetime non-medical use of inhaled anesthetics nitrous oxide, ether. Ever used classic psychedelics. Ever used LSD. Ever used psilocybin. Illicit drug or alcohol dependence or abuse. Nicotine dependence. P -value. Last LSD use more than 30 days but within the past 12 months.
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The association between naturalistic use of psychedelics and co-occurring substance use disorders
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The association between naturalistic use of psychedelics and co-occurring substance use disorders
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