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Obsessive-Compulsive Disorder (OCD)Set & Setting

Improvement in OCD symptoms associated with serotoninergic psychedelics: a retrospective online survey

In a retrospective online survey of 174 participants, classic serotoninergic psychedelics were the only substances reported to reduce OCD symptoms. Reduction correlated with the intensity of acute effects (itself linked to dose), persisted variably from weeks to months with no clear predictors, and larger/more persistent improvements predicted subsequent intake frequency.

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Authors

Valerie Bonnelle

Published

August 17, 2023

Scientific Reports

individual Study

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Abstract

A renewed interest in the use of psychedelics for treating obsessive compulsive disorder (OCD) has emerged in the last 20 years. But pre-clinical and clinical evidence remain scarce, and little is known about the factor determining the magnitude and persistence of the therapeutic effect. We therefore designed a retrospective online survey to explore, in the general population using psychoactive drugs, their impact on OCD symptoms. We also assessed the attitude of the participants towards the substance in term of frequency of intakes. In a sample of 174 participants, classic psychedelics were reported as the only substances effective at reducing OCD symptoms. In classic psychedelics users, symptoms reduction was associated with the intensity of acute effects, itself correlated to the dose. Reports on the persistence of the therapeutic effect varied from weeks to months, but we could not find any predicting factor. Finally, the occurrence and frequency of subsequent intakes, which seemed to be limited in our sample, were predicted by the magnitude and persistence of the therapeutic effect, respectively. Our observations support the hypothesis of classic psychedelics efficacy in reducing OCD symptoms but a careful evaluation of the persistence of this effect is still needed.

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Research Summary of 'Improvement in OCD symptoms associated with serotoninergic psychedelics: a retrospective online survey'

Introduction

OCD is a chronic, often disabling psychiatric disorder featuring intrusive obsessions and repetitive compulsions. Standard treatments combine cognitive and behavioural therapy with high-dose selective serotonin reuptake inhibitors (SSRIs), but many patients have incomplete response, long delays to benefit and 30–40% non-response. This gap has renewed interest in alternative approaches, including classic serotoninergic psychedelics such as LSD and psilocybin, but clinical and preclinical evidence for their efficacy in OCD is limited, long-term outcomes are poorly characterised, and placebo/expectation effects are difficult to rule out in open or uncontrolled work. Buot and colleagues therefore conducted a retrospective, anonymous online survey in people with OCD symptoms to identify which psychoactive substances users perceived as changing their OCD, to examine whether any improvement related to features of the acute subjective experience (intensity, pleasantness), mindset and setting, and to document the occurrence and frequency of subsequent intakes. The survey targeted a broad set of substances and sought to explore determinants of both the magnitude and persistence of any self-reported therapeutic effects in a real-world sample.

References (23)

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Long-term Amelioration of OCD Symptoms in a Patient with Chronic Consumption of Psilocybin-containing Mushrooms

Lugo-Radillo, A., Cortes-Lopez, J. L. · Journal of Psychoactive Drugs (2020)

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Reduced death anxiety and obsessive beliefs as mediators of the therapeutic effects of psychedelics on obsessive compulsive disorder symptomology

Moreton, S. G., Burden-Hill, A., Menzies, R. E. · Clinical Psychologist (2022)

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King, C., Nichols, D. E. · Nature Reviews Neuroscience (2013)

Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes

Agin-Liebes, G. I., Lancelotta, R., Uthaug, M. V. et al. · ACS Pharmacology and Translational Science (2021)

Methods

The investigators deployed a bilingual (French and English) anonymous online survey from September 2021 to March 2022, advertised on OCD support organisation websites, psychedelic research and user forums, and related social media pages. Inclusion criteria were age >18 years, presence of OCD symptoms, and at least one lifetime use of listed psychoactive substances (including LSD, MDMA, psilocybin, DMT, ayahuasca, ketamine, 2C-B, Salvia, mescaline, ibogaine). Participants provided informed consent and data were collected in REDCap; IPs and identifying data were not recorded. The questionnaire comprised sections on sociodemographics, health and OCD history, current therapies and medications, lifetime substance use, and detailed questions about the single substance that the participant judged to have produced the strongest change in OCD symptoms. OCD severity was assessed with the short Obsessive Compulsive Inventory (OCI‑r). Change in OCD was measured across six domains (negative emotions, obsessions, compulsions/rituals, anxiety, acceptance, avoidance) on a −100 (worsening) to +100 (improvement) slider. Persistence of change, mindset (expectations), setting (context of intake), reported dose/onset/duration, whether the substance was taken again and frequency were collected. Acute subjective effects were rated on 13 positive/alteration items and 21 unpleasant items on 0–100 scales; a pleasantness score was computed as 100 minus the mean unpleasantness. Data processing included translation alignment, duplicate checks, exclusion of incomplete or incoherent responses, and grouping substances into five categories: classic psychedelics (LSD, psilocybin, DMT, mescaline, ayahuasca), entactogens (MDMA, ecstasy), ketamine, delirogens (Salvia, Datura) and novel psychoactive substances (2C‑B). Persistence and frequency categories were collapsed to ensure cell sizes adequate for regression. Intensity of general acute effects was used as a proxy for dose after showing a positive association with reported dose in a subset. Statistical analyses used chi-squared tests and one-sample t-tests for initial comparisons. Subsequent analyses focused on LSD and psilocybin users (n = 90). Linear regressions tested predictors of magnitude of OCD change and of pleasantness; an ordinal regression model examined predictors of persistence. Occurrence of subsequent intake was modelled with logistic regression and intake frequency with ordinal regression among repeat users. Regressors included substance, mindset, setting, intensity and pleasantness of acute effects, OCI‑r score, magnitude and persistence where appropriate. Multicollinearity was checked using generalized variance inflation factors (GVIF). Multiple testing correction used the Benjamini–Hochberg procedure and standard regression diagnostics and parallel‑slopes checks were applied.

Results

From 227 initial respondents, 33 were excluded (no consent, incoherent or incomplete), leaving 174 participants who met the study criteria (either clinician diagnosis, OCI‑r > 18, or both). The sample was predominantly English respondents (76%), mean age 29 (range 18–65), 54% female, mean OCI‑r 36.37 (SD 12.82). Most reported no therapy (58%) or CBT (20%), and either no medication (52%) or antidepressant use (30%). Lifetime use of substance categories in the sample was high for classic psychedelics (84%), entactogens (72%) and ketamine (49%); smaller proportions reported NPS, delirogens or ibogaine. Within classic psychedelics users, 92% had used psilocybin mushrooms and 77% LSD. When asked whether any substance produced a change in OCD, classic psychedelics were selected as the most impacting by 66% of their users, compared with 15% for entactogens and 7% for ketamine; a chi‑square test showed these proportions differed by substance category (χ2(2) = 113.5, P < 0.001). Mean change scores were significantly positive only for classic psychedelics (mean ± SE = +42.62 ± 3.79, t(95) = 11.24, P < 0.001), while entactogens and ketamine did not produce significant mean changes. Within classic psychedelics, psilocybin (mean +44.22 ± 4.66) and LSD (mean +40.23 ± 5.95) both showed significant mean improvements. Analyses focused on LSD and psilocybin users (n = 90). Thirty‑six per cent had expected OCD improvement before intake and 66% reported taking the substance in no particular context. Reported onset was most commonly 30–60 minutes and duration 5–12 hours. Across participants, acute intensity averaged 67.07 (SE 1.61) and pleasantness 73.91 (SE 1.92). In a subset where dose could be estimated, intensity of acute effects correlated positively with measured dose (β = 0.02, t = 3.48, P = 0.001), supporting intensity as a dose proxy. A linear regression (n = 89) found that greater magnitude of OCD improvement was significantly associated with both higher intensity (β = 0.87, t = 3.86, Padj = 0.003) and greater pleasantness (β = 0.76, t = 3.96, Padj = 0.003) of the acute experience. Substance (psilocybin vs LSD), mindset, setting and baseline OCI‑r did not significantly predict magnitude. A separate model found no significant predictors of pleasantness. Reported persistence of improvement clustered at two modes: less than one week (33%) and more than three months (33%), with 21% reporting 1 week–1 month and 12% reporting 1–3 months. An ordinal regression (n = 90) did not identify any significant predictors of persistence among substance, intensity, pleasantness, magnitude of improvement or OCI‑r. Seventy‑seven per cent of classic psychedelic users reported taking the substance again; 47% of repeat users did so at most three times per year, 14% once a month and 16% at least once a week. Logistic regression showed that occurrence of subsequent intake was predicted only by the magnitude of OCD improvement (β = 0.03, z = 2.92, Padj = 0.03), indicating higher likelihood of re‑use when benefit was larger. Among the 69 repeat users, ordinal regression indicated that longer persistence of improvement (> 3 months) was associated with a greater probability of lower intake frequency (being in the at most three times per year category; β more3months‑less1week = -1.76, z = -2.53, P = 0.01). Other regressors (substance, intensity, pleasantness, magnitude) were not significant for frequency. In the subgroup taking the substance at least weekly, 57% reported microdosing regimens, 21% regular doses and 21% gave no dose information.

Discussion

Buot and colleagues interpret their findings as supporting a perceived therapeutic association between classic serotoninergic psychedelics (principally psilocybin and LSD) and reductions in self‑reported OCD symptoms in a community sample. Classic psychedelics were the only substance category to show a significant mean improvement in the survey, and within that class psilocybin and LSD did not differ significantly in their reported effects. The authors emphasise that in their sample the magnitude of reported symptom improvement correlated with the intensity of the acute psychedelic experience, and that intensity itself was associated with higher reported doses, suggesting that moderate to high doses may be required to obtain measurable benefit. The authors note that pleasantness of the acute experience also correlated with improvement, but they caution this may reflect a carry‑over or global‑impression bias in retrospective self‑ratings rather than a causal mechanism. Mindset and setting did not emerge as predictors in their models, but the investigators acknowledge that their measurement of these factors was coarse and may have lacked sensitivity. Persistence of benefit varied widely; approximately 30% of respondents reported effects lasting beyond three months, but no baseline or acute‑experience variables predicted persistence in their analyses. The authors stress the imprecision of persistence estimates because the survey did not capture the time elapsed between intake and survey completion, limiting interpretation. Limitations the authors acknowledge include reliance on retrospective, self‑selected online reporting subject to recall and selection bias, lack of temporal anchoring for persistence estimates, possible carry‑over effects in subjective ratings, and inability to infer causality from observational data. They also note that approximately 10% of participants reported worsening of OCD after use and that risk factors for adverse outcomes require assessment in controlled settings. Regarding safety and misuse, the sample did not show evidence of high‑frequency problematic use; repeated use appeared linked to experienced benefit rather than to hedonic effects. For future research, the authors recommend well‑controlled clinical trials to determine efficacy and durability of effect, more fine‑grained study of the phenomenology of acute experiences and their therapeutic relevance, and specific evaluation of different symptom dimensions (obsessions, compulsions, depressive comorbidity). They also highlight neurobiological hypotheses such as drug‑induced neuroplasticity as one potential mechanism worth investigating in relation to sustained clinical effects.

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METHODS

Survey administration. The survey was designed by the authors with a French and an English version. Our research procedure was in accordance with the relevant guidelines and regulations (1964 Declaration of Helsinki and its later amendments, methodological reference of CNIL for data management), and was approved by the Research Ethics Committee of Sorbonne University (. sorbo nne-unive rsite. fr/ en/ unive rsite/ our-commi tments/ resea rch-ethics-commi ttee, CER n°2021-067). Specifically, all data was confidential-no IP address or other identifying data was acquired. Eligible participants had to be more than 18 years old, have OCD symptoms and at least one experience with one of the following psychoactive drugs: LSD, ecstasy, MDMA, psilocybin, DMT, ayahuasca, ketamine, 2C-B, Salvia divinorum, mescaline, ibogaine. From September 2021 to March 2022, the survey was advertised online on several platforms including webpages dedicated to OCD such as the AFTOC (www. aftoc. org), AETOC (www. aetoc. ch), FQTOC (www. fqtoc. com), LIGUETOC (www. ligue toc. wordp ress. com) which are the French, Swiss, Canadian and Belgian association for people with OCD, respectively; webpages dedicated to usage and research on psychoactive drugs such as of the Beckley Foundation (www. beckl eyfou ndati on. org), the French psychedelic society (www. socie tepsy chede lique. fr), the Swiss psychedelic society (www. eleus is-socie ty. ch), the French forum for psychoactive drugs users (www. psych onaut. fr). The survey was also posted on Facebook pages dedicated to OCD (French pages: Lutter contre le TOC, Troubles anxieux, AFTOC; English pages: Obsessive Compulsive Disorder sufferers friendship and support group, OCD Only support group, Intrusive Thoughts and Pure OCD, OCD Recovery Group, OCD support group). At the beginning of the survey, a short introduction presented the aim of the study (To characterize the use of psychedelic substances in people with OCD and their possible effects on the disorder), the inclusion criteria and the general structure of the survey. Links to psychological support websites and phone lines were also provided for participants in need of help regarding OCD or drugs use. To start the survey, participants had to explicitly give their informed consent. The completion of the survey took 15 to 20 min. At any time, participants could interrupt the survey by simply closing their browsers. In this case, data was tagged as incomplete allowing us to detect and discard the participant. Study data were collected and managed using REDCap electronic data capture web application hosted at Paris Brain Institute.

RESULTS

We then proceeded to statistical analyses. A chi-squared (χ 2 ) test was used to test if the proportion of users declaring a given substance as the most impacting one varied according to the substance, and one-sample Student's t-tests were used to evaluate if the magnitudes of the changes induced by the different substances were significantly different from 0. In subsequent analyses, we focused on LSD and psilocybin mushrooms users (n = 90, Fig.). To evaluate which factor might predict the magnitude of the changes in OCD symptoms, a linear regression was used that included 6 independent variables: the substance (LSD vs Psilocybin mushrooms), the mindset (binary yes/no variable indicating whether subjects expected OCD improvement), the setting (no particular event, recreational setting, ceremonial group setting), the intensity and pleasantness of the acute effects and the OCI-r score (all three are continuous variables). A linear regression was also used to evaluate which factor might predict the pleasantness of acute effects, which included 5 independent variables: the substances, the mindset, the setting, the intensity of the acute effects and the OCI-r score. To evaluate which variables might predict the persistence of the changes in OCD symptoms, an ordinal regression was used with 5 regressors: the substances, the intensity and pleasantness of acute effects, the magnitude of changes in OCD symptoms and the OCI-r score. Finally, the occurrence of subsequent intakes and their frequency were also analyzed. The occurrence of subsequent intake was encoded as a binary variable (1 or 0 corresponding to Yes or No) and was regressed out using a logistic regression with 6 regressors: the substances, the intensity and pleasantness of the acute effects, the OCI-r score, the magnitude and the persistence of the changes in OCD symptoms. Subsequent intake frequency was then analyzed in the subset of participants with subsequent intakes, using an ordinal regression with the 5 following regressors: the substance, the intensity and pleasantness of acute effects, the magnitude and persistence of the changes in OCD symptoms. Since multiple regressions were performed on the same sample of participants (magnitude of the changes in OCD symptoms, pleasantness of acute effects, persistence of the changes in OCD symptoms, occurrence of subsequent intakes), the associated p-values were corrected for multiple comparison using the Benjamini-Hochberg procedure. For these analyses, adjusted p-values are reported. Additionally, multicollinearity between independent variables has been assessed for all regressions using the generalized variance inflation factor (GVIF). All analyses were performed using R and the following packages: dplyr for data frame manipulations (v1.0.10), forcats for handling categorical variables (v0.5.0) and ggplot2 for plotting. Basic statistical analyses were performed using the rstatix package. Linear and logistic regressions were performed using the lm and glm functions of the stats package, respectively, and ordered regressions were performed using the clm function of the ordinal package. GVIF values were computed using the car package. To diagnose if all assumptions of linear regressions were met, we inspected the plots representing the relationship between fitted values and residuals, the distribution of the residuals, the homoscedasticity of the residuals and the presence of influential outlying data. For ordinal regressions, we checked the assumption of parallel slopes using the brant package.

CONCLUSION

In this survey, we assessed, in a sample of participants suffering from OCD symptoms, the subjective efficiency of different psychoactive drugs in reducing symptoms. When considering the different substance categories, we observed that the proportion of users reporting a change in OCD symptoms (irrespective of its valence) was higher with classic psychedelics than with any other substance category. And when characterizing these changes, we observed that only classic psychedelics were associated with significant improvements in OCD symptoms. Consequently, we focused on classic psychedelics users for which we had enough participants, meaning psilocybin mushrooms and LSD users, to study the determinants of the therapeutic effect. We observed that its magnitude was associated with the intensity and pleasantness of acute effects, with the intensity being correlated with the substance dose. Regarding the persistence of the therapeutic effect, over 30% of participants reported effects lasting for more than three months. However, no significant predictor was detected that could explain the variability of reports. Finally, substance usage appeared to be tuned to the therapeutic effect. Indeed, the occurrence of subsequent intakes was predicted by the magnitude of OCD symptoms improvement, with participants with stronger therapeutic effect being more likely to take the substance again. And among the participants who used the substance again, the frequency of subsequent intakes was related to the persistence of the therapeutic effect, with long-lasting (> 3 months) improvements predicting a lower frequency of intake. As shown, a higher proportion of participants chose classic psychedelics as the most efficient for OCD symptoms when compared to other substances. The self-assessment of the therapeutic effect makes it prone to subjectivity bias, but a vast majority of classic psychedelics users, in our sample, perceived an improvement in their medical conditions following the intake of the substance. The fact that many participants used multiple substances brings additional credits to their choice, since they were likely able to compare between substances. Interestingly, ketamine, a dissociative substance with anesthetic properties at high doses, did not show up as an effective substance in alleviating OCD symptoms. Previous results on the use of ketamine in OCD are mixed, but our results are difficult to compare since recreational use differs from therapeutic guidelines in terms of enantiomer, dose and mode of administration. Similarly, DMT and mescaline were not selected as effective for OCD symptoms. Despite being categorized as serotoninergic hallucinogens, DMT and mescaline have phenomenological and pharmacological profiles that seem to differ from LSD or psilocybin. Among other differences, DMT has no affinity for the serotoninergic receptor 2C, as well as a lower hallucinogenic potency and duration of action in human. Mescaline on the other side, seems to have combined psychedelic and entactogenic propertiesand does not act on raphe neurons. Finally, within the classic psychedelics category, we did not observe any difference between LSD and psilocybin, which share multiple chemical properties but also differences such as their affinity for dopaminergic receptors. When modeling the magnitude of the therapeutic effect, we observed that it was predicted by the intensity of acute effects. The evaluation of acute effects is intrinsically subjective, and the retrospective design of the study could have affected the scorings due to recall bias. However, the observation of an already described and therefore expected link between the intensity of acute effects and the dose, suggests that their evaluations were somewhat trustful. This observation further suggests that moderate to high doses are necessary to obtain a therapeutic effect, which is coherent with preliminary data in OCD, as well as in other pathologies. The intensity of the subjective experience is not, however, solely determined by the dose, but also by its quality (i.e., content of the subjective experience). And how the content of the subjective experience affects the therapeutic effect remains an open question in the field, which calls for a transdisciplinary approach combining phenomenology and ethnography. We should mention that 10% of participants reported a worsening of OCD symptoms. Whether similar proportion are observed in well-controlled clinical trials is an important matter, which would call for an evaluation of risk factors. In our survey, the magnitude of the therapeutic effect was also correlated with the pleasantness of acute effects, but we suspect a carry-over effect. Indeed, the scoring of the therapeutic effect might have been strongly influenced by the global impression of the participants on the acute subjective experience, regardless of any causal relation. Additionally, previous survey has reported, in healthy subjects, the lack of relationship between the pleasantness of acute effects and the enduring well-being induced by psilocybin. However, this association should be investigated further in patients since one of the most prevalent adverse effects reported during the acute experience is anxiety, a symptom for which OCD patients might be particularly at risk. Investigating the factors influencing the pleasantness of the subjective experience is an important matter, not only because it might affect therapeutic effects, but also because it has repercussions on the feasibility of administrating psychedelics in OCD patients. We also included as factors in the model the mindset and context of the intake and did not observe any impact of it. However, we acknowledge that the assessment of these parameters was rather coarse in our study, and it seems reasonable to think that the context of the intake at least, might impact the pleasantness of the experience. Finally, since LSD and psilocybin have been shown to be efficient in reducing depressive symptoms, which were also reported by 42% of participants in our sample, it would be interesting in future trials to specifically assess the effect of classic psychedelics on different dimensions including obsessions, compulsions and depression. In addition to the magnitude of the therapeutic effect, another major component in assessing the efficacy of a treatment is the persistence of the effect. Strikingly, we had 30% of participants reporting therapeutic effects lasting more than three months. There is, to our knowledge, no reported data on the persistence of the psychedelic-induced therapeutic effects in OCD apart from case studies. But this is coherent with studies in other pathologies such as depression showing effects persisting from multiple weeks to several months. As mentioned in the results section, the persistence data were imprecise since we did not have access to the time delay between the intake of the psychoactive drugs and the filling of the survey. This might have impacted the proportion of participants declaring short-lasting effects, with people filling out the survey shortly after the intake of the substance not being able to assess the maintenance of the therapeutic effect in the long term. The mechanism through which psychedelics may induce long-term therapeutic effects also remains unknown. One candidate is the neuroplastic property of psychedelics, with increased neuronal growth and synaptogenesis observed both in vivo in rodents and in vitro in different species. In rodent, these structural modifications lasted up to a month, but were not specific to classic psychedelics since it was observed with multiple components including ketamine. The last factor that we examined was the occurrence and frequency of subsequent intakes. We did not observe any apparent case of substance abuse from participants' reports, with no or very moderate intake repetition in most of them. This is coherent with the literature reporting no reinforcing properties of classic psychedelics, neither in humans nor in animals. Importantly, in our dataset, the occurrence of subsequent intakes and their frequency seemed to be closely related to the magnitude and persistence of the therapeutic effect. The causal relationship between the occurrence of subsequent intake and the therapeutic effect cannot be inferred, mainly due to the retrospective nature of our study. However, it was striking to see no apparent relationship between the pleasantness of the acute effects and the frequency of subsequent intake.

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