Improvement in OCD symptoms associated with serotoninergic psychedelics: a retrospective online survey — TEI-tagged view

BuotpersName, PallarespersName, OganesyanpersName, DaurépersName, BonnellepersName, BurguièrepersName, Dos SantospersName, N’DiayepersName (2023date). “Improvement in OCD symptoms associated with serotoninergic psychedelics: a retrospective online survey.” Scientific Reportstitle·j.

Object of study — whether people with OCDterm symptoms who have taken psychoactive drugs report symptom change, and which drugs

Research question — which substancesterm·var are reported as improving OCDterm symptoms, and what predicts the size and persistenceterm of the reported effect

Contribution — reports that classic psychedelicsterm alone were associated with improvement in this sample, with the reported gain tracking the intensity of acute effectsterm and the intensity tracking dose

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Abstract. A renewed interest in the use of psychedelics for treating obsessive compulsive disorder (OCDterm) 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 persistenceterm of the therapeutic effect. We therefore designed a retrospective online surveyterm·mth to explore, in the general population using psychoactive drugs, their impact on OCDterm symptoms. We also assessed the attitude of the participants towards the substanceterm·var in term of frequency of intakes. In a sample of 174 participants, classic psychedelicsterm were reported as the only substancesterm·var effective at reducing OCDterm symptoms. In classic psychedelicsterm users, symptoms reduction was associated with the intensity of acute effectsterm, itself correlated to the dose. Reports on the persistenceterm of the therapeutic effect varied from weeks to months, but we could not find any predicting factor. Finally, the occurrence and frequency of subsequent intakesterm·var, which seemed to be limited in our sample, were predicted by the magnitude and persistenceterm of the therapeutic effect, respectively. Our observations support the hypothesis of classic psychedelicsterm efficacy in reducing OCDterm symptoms but a careful evaluation of the persistenceterm of this effect is still needed. Introduction Obsessive–compulsive disorder (OCDterm) is a debilitating psychiatric condition, characterized by intrusive thoughts called obsessions, repetitive behaviors called compulsions, and avoidance behaviors 1 . The main therapeutical approach for OCDterm relies on psychological interventions, mainly cognitive and behavioral therapy (CBT), and pharmacological interventions, with first-line use of selective serotonin reuptake inhibitors (SSRIsterm) given at higher doses than in other indications 2 , 3 . OCDterm tends to be chronic and persistent, and impairment is common even with the best medical therapy 3 . Disadvantages of current medications include difficulty in finding an effective medication and long delays of several weeks or even months before symptoms’ improvement 4 . Finally, 30–40% of patients do not respond at all to SSRIterm treatment and many of the patients who do respond continue to have problematic residual symptoms 3 . OCDterm is therefore one of the few psychiatric disorders for which invasive brain surgery is an accepted treatment option, despite difficulties of access to this treatment as part of research protocols 5 . For these reasons, new treatment strategies that could act both on pharmacological and psychotherapeutic dimensions with a good level of acceptance are of great interest. In this context, it has been suggested that classic psychedelicsterm, such as lysergic acid diethylamide (LSDterm) and psilocybinterm (the main active compound of so-called magic mushrooms), might be used to decrease OCDterm symptoms. Classic psychedelicsterm are also called serotoninergic hallucinogens since these substancesterm·var are thought to exert their effects by a partial agonist action on 5-hydroxytryptamine (5-HTterm) 2A receptors. Some evidence of the therapeutic property of classic psychedelicsterm came from clinical studies from the 70’s 6 – 8 but also from more recent case reports 9 – 11 and an online surveyterm·mth 12 . Evidence remains scarce with the most substantial study being an open-label trial, in which 9 patients with moderate to severe OCDterm were exposed to various doses of psilocybinterm ranging from low sub-hallucinogenic to high hallucinogenic ones 13 . This trial suggested that psilocybinterm might be efficient in decreasing OCDterm symptoms, but the follow-up was limited to 24 h and long-term effects were not assessed. Also placebo or expectation effects, which are important confounding factors in psychedelic assisted psychotherapy 14 , were not assessed. But controlled studies are underway with multiple ongoing clinical trials 15 – 17 . Evidence from preclinical studies is also scarce, with some studies assessing the effect of psychedelics in animal models of compulsive behavior such as the serotonin transporter heterozygous (Sert + / − ) mice 18 or on the marble burying test 19 , 20 . Whereas serotoninergic psychedelics such as DOI (2,5-dimethoxy-4-iodoamphetamine) and psilocybinterm seemed to be efficient in decreasing digging behavior, LSDterm had no effect on grooming behavior in the Sert heterozygous model. Since psychedelics have been classified under Schedule I in the 1971 conventions of the United Nations 21 and remain illegal in many countries, observational studies such as anonymous online surveysterm·mth have been used to assess the use, misuse and potential therapeutic properties of psychedelics 22 – 26 . The present retrospective, online and anonymous surveyterm·mth aimed to evaluate, in the general population with OCDterm symptoms, which substancesterm·var among multiple psychoactive drugs might have a therapeutic effect. The second aim was to explore whether these putative improvements were related to specific characteristics of the acute subjective experience, such as the intensity and pleasantnessterm of acute effectsterm, as well as the mindsetterm (i.e., the expectations or state of mind when taking the substanceterm·var) and settingterm (i.e., the context of the intake). The latter two parameters were explored since it has been considered as important factors in shaping the acute response to psychedelics 27 . The third aim was to evaluate the occurrence and frequency of substanceterm·var intakes. Methods Surveyterm·mth administration The surveyterm·mth 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 ( https://www.sorbonne-universite.fr/en/universite/our-commitments/research-ethics-committee , 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 OCDterm symptoms and at least one experience with one of the following psychoactive drugs: LSDterm, ecstasy, MDMA, psilocybinterm, DMTterm, ayahuasca, ketamineterm, 2C-B, Salvia divinorum, mescalineterm, ibogaine. From September 2021 to March 2022, the surveyterm·mth was advertised online on several platforms including webpages dedicated to OCDterm such as the AFTOC ( www.aftoc.org ), AETOC ( www.aetoc.ch ), FQTOC ( www.fqtoc.com ), LIGUETOC ( www.liguetoc.wordpress.com ) which are the French, Swiss, Canadian and Belgian association for people with OCDterm, respectively; webpages dedicated to usage and research on psychoactive drugs such as of the Beckley Foundation ( www.beckleyfoundation.org ), the French psychedelic society ( www.societepsychedelique.fr ), the Swiss psychedelic society ( www.eleusis-society.ch ), the French forum for psychoactive drugs users ( www.psychonaut.fr ). The surveyterm·mth was also posted on Facebook pages dedicated to OCDterm (French pages: Lutter contre le TOC , Troubles anxieux , AFTOC ; English pages: Obsessive Compulsive Disorder sufferers friendship and support group , OCDterm Only support group , Intrusive Thoughts and Pure OCDterm , OCDterm Recovery Group , OCDterm support group ) . At the beginning of the surveyterm·mth, a short introduction presented the aim of the study ( To characterize the use of psychedelic substancesterm·var in people with OCDterm and their possible effects on the disorder ), the inclusion criteria and the general structure of the surveyterm·mth. Links to psychological support websites and phone lines were also provided for participants in need of help regarding OCDterm or drugs use. To start the surveyterm·mth, participants had to explicitly give their informed consent. The completion of the surveyterm·mth took 15 to 20 min. At any time, participants could interrupt the surveyterm·mth 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 28 . Measurements Sociodemographic information In part I, sociodemographic information (i.e., age, gender, height, weight, social status and environment of living) was collected. Health information In part II, health information was collected. Concerning OCDterm symptoms, participants were asked if they had been diagnosed, who made the diagnosis (possible choices: a health professional, yourself, other ) and when. Participants then had to fill in the short version of the Obsessive Compulsive Inventory (OCI-rterm) 29 to get a severity scoreterm·var. Participants were also asked whether they were currently in therapy and if yes which type of therapy (possible choices: cognitive-behavioral therapy (CBT), psychoanalytic-psychodynamic therapy, eye movement desensitization and reprocessing (EMDR), mindfulness (MBCT), systemic or family therapy, relaxation, art therapy, hypnosis, alternative therapies, other ); whether they took medications and if yes which type of medications (possible choices: antidepressants, neuroleptics, anxiolytics, alternative/complementary medications, other ) and at which frequency (possible choices: every day, several times a week, more than once a month, once a month, other ). Usage of psychedelics In part III, the usage of psychoactive drugs was assessed. Participants add to select which substancesterm·var they had used (multiple answers possible) within the following list: LSDterm, ecstasy, 3,4-methylenedioxymethamphetamin (MDMA), psilocybinterm mushrooms, dimethyltryptamine (DMTterm), ayahuasca, ketamineterm, 2CB (4-bromo-2,5-dimethoxyphenetylamine), Salvia divinorum, mescalineterm, ibogaine, other . Link between the intake of psychoactive drugs and changes in OCD symptomsterm·var In part IV, the impact of psychoactive drugs on OCDterm symptoms was assessed. The first question was “ Have you experienced a change in your OCDterm as a result of taking a psychedelic? ” Participants answering No were redirected toward the end of the surveyterm·mth, whereas participants answering Yes had to select the substanceterm·var that induced the strongest changes in OCD symptomsterm·var, among the list presented in part III. From there, all subsequent questions/answers were relative to this given substanceterm·var. Participants who selected a given substanceterm·var as the most impacting but did not previously select it as a used one were discarded from the analysis for uncoherent responses (n = 4). Changes in OCD symptomsterm·var triggered by the intake of the given substanceterm·var were assessed using 6 items: negative emotions, obsessions, compulsions/rituals, anxiety, acceptance of condition, and avoidance of possible anxiogenic situations. Each item was scored by moving a cursor on a 100-point scale (2-point step) starting at midpoint (0: no change ) and ranging from -100 ( Worsening ) to + 100 ( Improvement ). Participants who did not score any of the items were discarded due to missing responses (n = 6). The persistenceterm of these changes was also examined with participants choosing between a few hours, less than a day, one to three days, three days to a week, between a week and a month, one to three months, more than three months, permanently . Mindsetterm, settingterm and dose The mindsetterm was investigated by asking participants about their expectations before the drug intake (possible choices: recreational experience, personal development, spiritual or religious purpose, OCDterm improvement, other therapeutic purpose, curiosity/discovery, none, other ); and the settingterm by asking participants in which context they had taken the substanceterm·var (possible choices: no particular event, at a party or concert, shamanic type ceremony, with therapeutic support, clinical research, retreat, other ). Participants were also asked about the substanceterm·var dose, the delay between the intake and the appearance of the subjective effects (possible choices: 0–15 min, 15–30 min, 30–60 min, 60–90 min, > 90 min ), and the duration of the effects (possible choices: 30–60 min, 1–3 h, 3–5 h, 5–12 h, > 12 h, I don’t know ). Finally, participants were asked if they had taken the substanceterm·var again and how often by choosing between no, less than once a year, one to three times a year, once a month, once a week, two to six times a week, daily, other . Subjective experience In part V, participants had to rate acute general effects by scoring the 13 following items: emotional arousal, euphoria/ecstasy/bliss, altered body sensations, changes in vision and/or hearing, musical ecstasy, knowledge/insights on existential subjects (death, love, divine, man's place in the universe), space–time distortion effect, mystical/transcendent/spiritual experience (feeling of unity), trauma resolution, hallucination(s), delirium/confusion, ego dissolution (complete loss of subjective self-identity), bodily boundaries dissolution . Each item was scored by moving a cursor on a 100-points scale (1-point step) starting from 0 ( Not at all ) to 100 ( Significantly ). Using the same scale, participants also had to rate the acute unpleasant effects on the 21 following items: Diarrhea, Constipation, Nausea, Vomiting, Headache, Sedation/Drowsiness, Tachycardia, Shaking, Feeling of heat, Feeling of coldness, Difficulty concentrating, Memory impairment, Indigestion/Stomach troubles, Discomfort, Anxiety, Sadness/Melancholy, Revival of traumatic memories, Terror/Paranoia/Panic, Depersonalization, Aggressive behavior towards yourself, Aggressive behavior towards others . Additional questions were asked that are not reported here. The full surveyterm·mth is available at the following link: https://osf.io/x2sk7/?view_only=5ef581a60b7a4d5685a2c233a0435a15 . Data transformation Data were exported from RedCap and imported in R 3.5.1 (R Core Team 2018). All answers from the French version were translated to match the English one and the two datasets were merged. We checked for duplicates by comparing the combination of age, gender, height and weight across participants. We then screened participants who did not meet the inclusion criteria, did not give their consent, or did not reach the end of the surveyterm·mth (n = 33, Fig. 1 ). Participants who did not provide answers on some questions but completed the surveyterm·mth until the end were kept for analysis. Figure 1 Flow chart showing steps in participants selection. When needed, new variables were created to reclassify answers. First, substancesterm·var were grouped into 5 substance categoriesterm·def based on their chemical properties and subjective effects as follows: classic psychedelicsterm including LSDterm, psilocybinterm mushrooms, DMTterm, mescalineterm and ayahuasca ; entactogensterm including ecstasy and MDMA ; ketamineterm ; delirogens including Salvia divinorum and Datura ; and novel psychoactive substancesterm·var (NPS ) including 2CB. Participants selecting ibogaine as the most impacting substanceterm·var were discarded due to the small sample size (n = 2) not being appropriate for regressionterm·stat analyses. Second, to get enough answers per category, persistenceterm data were reclassified into the 4 categories less than a week, between 1 week and 1 month, between one and three months, and more than three months; and frequency of subsequent intake data were reclassified into the 3 categories maximum 3 times a year , once a month and at least once a week. Third, to get enough answers per category, settingterm data were reclassified into 3 categories as follow: No particular event stayed n o particular event , at a party or concert became recreational settingterm , and shamanic type ceremony, with therapeutic support, clinical research and retreat were grouped in the ceremonial group settingterm category. Sixteen answers from participants who selected other and provided details could be reclassified in the abovementioned categories based on explanation. Finally, since participants could provide multiple answers when asked about their mindsetterm, we selected the item which was the most relevant for our study: OCDterm improvement and transformed it into a Yes/No binary variable. For the magnitude of changes in OCD symptomsterm·var, intensity and pleasantnessterm of acute effectsterm, we used the within-participant mean of the ratingsterm·stat on the different subscales: mean of the OCDterm dimensions’ ratings for the magnitude of changes in OCDterm, mean of general effects’ ratings for intensity, mean of unpleasant effects’ ratings subtracted from 100 for pleasantnessterm (to get scores that increased with pleasantnessterm). Statistical analyses We then proceeded to statistical analyses. A chi-squaredterm·stat (χ 2 ) test was used to test if the proportion of users declaring a given substanceterm·var as the most impacting one varied according to the substanceterm·var, and one-sample Student’s t-teststerm·stat were used to evaluate if the magnitudes of the changes induced by the different substancesterm·var were significantly different from 0. In subsequent analyses, we focused on LSDterm and psilocybinterm mushrooms users (n = 90, Fig. 1 ). To evaluate which factor might predict the magnitude of the changes in OCD symptomsterm·var, a linear regressionterm·stat was used that included 6 independent variables: the substanceterm·var ( LSDterm vs Psilocybinterm mushrooms ), the mindsetterm (binary yes/no variable indicating whether subjects expected OCDterm improvement), the settingterm ( no particular event, recreational settingterm, ceremonial group settingterm ), the intensity and pleasantness of the acute effectsterm·var and the OCI-rterm score (all three are continuous variables). A linear regressionterm·stat was also used to evaluate which factor might predict the pleasantnessterm of acute effectsterm, which included 5 independent variables: the substancesterm·var, the mindsetterm, the settingterm, the intensity of the acute effectsterm·var and the OCI-rterm score. To evaluate which variables might predict the persistenceterm of the changes in OCD symptomsterm·var, an ordinal regressionterm·stat was used with 5 regressors: the substancesterm·var, the intensity and pleasantnessterm of acute effectsterm, the magnitude of changes in OCD symptomsterm·var and the OCI-rterm 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 regressionterm·stat with 6 regressors: the substancesterm·var, the intensity and pleasantness of the acute effectsterm·var, the OCI-rterm score, the magnitude and the persistenceterm of the changes in OCD symptomsterm·var. Subsequent intake frequency was then analyzed in the subset of participants with subsequent intakes, using an ordinal regressionterm·stat with the 5 following regressors: the substanceterm·var, the intensity and pleasantnessterm of acute effectsterm, the magnitude and persistenceterm of the changes in OCD symptomsterm·var. Since multiple regressionsterm·stat were performed on the same sample of participants (magnitude of the changes in OCD symptomsterm·var, pleasantnessterm of acute effectsterm, persistenceterm of the changes in OCD symptomsterm·var, occurrence of subsequent intakes), the associated p-values were corrected for multiple comparison using the Benjamini–Hochberg procedureterm·stat. For these analyses, adjusted p-values are reported. Additionally, multicollinearity between independent variables has been assessed for all regressionsterm·stat using the generalized variance inflation factor (GVIF)term·stat. 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 regressionsterm·stat were performed using the lm and glm functions of the stats package, respectively, and ordered regressionsterm·stat 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 regressionsterm·stat 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 regressionsterm·stat, we checked the assumption of parallel slopes using the brant package. Results Participants selection A flow chart representing the selection procedure is shown in Fig. 1 . During recruitment, 227 participants entered the surveyterm·mth. Thirty-three participants were discarded because of no consent, incoherent or missing responses, or incomplete questionnaire (see Methods for details). We then selected our population of interest based on OCDterm symptoms and kept for analyses the data from participants who had either a diagnosis of OCDterm performed by a health professional (n = 9), or an OCI-rterm score superior to 18 (n = 62) 29 or both (n = 103). The rationale was to include participants who had not been screened by a psychiatrist or a psychologist (participants without diagnosis but OCI-rterm > 18), and participants in remission when filling out the surveyterm·mth (participants with a diagnosis but OCI-rterm < 18). Using these criteria, we identified 174 participants (76% from the English surveyterm·mth). Participants socio-demographic and health characteristics Participants’ socio-demographic and health information are described in Tables 1 and 2 , for each subgroup of participants used for analyses. As shown, participants were aged on average 29 years old (range: 18–65), with 54% of female. They were mainly employees or students and lived in cities or suburbs. Regarding their OCDterm symptomatology, the mean(SD) OCI-rterm score was 36.37 (12.82), ranging from 6 to 62. Most of the participants declared undergoing either no therapy (58%) or cognitive-behavioral therapy (CBT, 20%); and used either no treatment (52%) or antidepressant medication (30%). The intake frequency of treatments is shown in Table 2 . Table 1 Demographic information. OCDterm participants (n = 174) OCDterm participants declaring a change (n = 129) LSDterm and Psilocybinterm users (n = 90) Mean (SD) or % Age in years 29.49 (8.58) 29.40 (8.65) 29.31 (8.66) Gender Female 54 50 44 Male 46 50 56 Height in cm 170.51 (10.74) 170.83 (11.32) 172.09 (11.37) Weight in kg 69.98 (17.15) 70.85 (18.11) 73.95 (19.26) Surveyterm·mth language English 76 85 84 French 24 15 16 Social status Employee 45 44 48 Student 23 24 25 Self-employed 16 15 13 Unemployed 10 12 10 Other 5 4 3 Retired < 1 < 1 1 Residence City 61 61 59 Suburb 25 28 30 Country 14 11 11 Table 2 Health information. OCDterm participants (n = 174) OCDterm participants declaring a change (n = 129) LSDterm and Psilocybinterm users (n = 90) Mean (SD) or % OCI-rterm 36.37 (12.82) 36.94 (12.69) 36.30 (13.31) OCDterm diagnosed by a health professional 62 67 70 Therapy * No 58 55 60 CBT 20 21 20 Other / No answer 10 12 11 Psychoanalytic therapy 5 5 3 Alternative therapies 3 4 3 Relaxation 1 0 0 Systemic therapy 1 2 1 EMDR < 1 < 1 1 MBCT < 1 < 1 1 Medications * and intake frequency No medication 52 52 53 Antidepressant 30 27 27 Every day 98 97 100 Several times a week 2 3 0 Anxiolytic 12 13 11 Every day 53 54 100 Several times a week 20 23 0 > once a month 27 23 0 Neuroleptic 3 < 1 0 Every day 100 100 0 Alternative medicines 8 9 10 Comorbidities Psychological troubles* 59 60 62 Anxiety disorders 48 48 54 Depressive disorders 36 36 42 Others 53 55 53 Neurological troubles 7 5 5 Physical troubles 29 29 31 Inflammatory diseases 10 12 13 * Multiple possible answers. OCI-rterm = Obsessive compulsive inventory-revised version, CBT = cognitive behavioral therapy, EMDR: eye movement desensitization and reprocessing, MBCT: mindfulness-based cognitive therapy. Use of psychoactive substancesterm·var in our population To evaluate the use of psychoactive drugs in our population, a list was presented among which participants had to select the ones they had already used. As shown in Table 3 , the most used substance categoriesterm·def among our OCDterm population were classic psychedelicsterm (84%), entactogensterm (72%) and ketamineterm (49%); whereas NPS, delirogens and ibogaine were used by 22%, 16% and 2% of the participants, respectively. When looking at combinations of substancesterm·var, we observed that 82% of classic psychedelicsterm users had also used at least one other substanceterm·var category. This proportion was 92% for entactogensterm users, 95% for ketamineterm users, 97% for NPS users and 100% for delirogens and ibogaine users. Among classic psychedelicsterm users, 92% of participants used psilocybinterm mushrooms, 77% used LSDterm, 29% used DMTterm, 11% used mescalineterm and 9% used ayahuasca. Looking at combinations, we observed that 79% of psilocybinterm users had also used at least one other substanceterm·var and this proportion was 94% for LSDterm users and 100% for DMTterm, mescalineterm or ayahuasca users. Table 3 Use of psychoactive drugs in our OCDterm population. Substancesterm·var* % (n) Classic psychedelicsterm 84** (146) Psilocybinterm mushrooms 92 + (135) LSDterm 77 + (113) DMTterm 29 + (42) Mescalineterm 11 + (16) Ayahuasca 9 + (13) Entactogensterm 72** (126) MDMA 93 + + (117) Ecstasy 75 + + (94) Ketamineterm 49** (86) NPS 22** (39) Delirogens 16** (28) Salvia divinorum 100 O (30) Ibogaine 2** (4) *Multiple answers possible. **Percentage of participants with OCDterm (n = 174). + Percentage of classic psychedelicsterm users. + + Percentage of entactogensterm users. o Percentage of delirogens users. LSDterm = Lysergic Acid Diethylamide, DMTterm = N,N-Dimethyltryptamine, MDMA = 3,4-Methylenedioxymethamphetamine. Changes in OCD symptomsterm·var induced by psychoactive drugs To evaluate the impact of psychoactive drugs on OCDterm, participants were first asked whether they had experienced a change (irrespective of the valence of the change) in their OCDterm symptoms after taking one of the above-mentioned substancesterm·var. Participants answering Yes had to select the substanceterm·var which induced the strongest change in OCDterm symptoms (only one possible answer) and characterize the changes. Among the participants who had used a given substanceterm·var category, we calculated the proportion of participants declaring: the strongest change with this substanceterm·var category, the strongest change with another substanceterm·var category or no change with any type of substanceterm·var. Results are reported in Fig. 2 . Classic psychedelicsterm were selected as the most impacting substancesterm·var by 66% of the participants who declared using them. This proportion was 15% for entactogensterm, 7% for ketamineterm, 7% for delirogens and 0% for NPS. A χ 2 test applied to categories with sufficient number of observations (n > 5) revealed that the proportion of participants declaring a substanceterm·var category as the most impacting one varied according to the substanceterm·var category (χ 2 (2) = 113.5, P < 0.001; Fig. 2 A), with a significant difference in proportion between classic psychedelicsterm and entactogensterm (P < 0.001) and between classic psychedelicsterm and ketamineterm (P < 0.001) but no difference between entactogensterm and ketamineterm (P = 0.11). The same analysis was performed among classic psychedelicsterm (Fig. 2 B). Within this category, the proportion of users declaring the substanceterm·var as the most impacting was 42% for psilocybinterm mushrooms, 30% for LSDterm, 31% for ayahuasca, 5% for DMTterm and 0% for mescalineterm. These proportions did not differ between psilocybinterm mushrooms and LSDterm (χ 2 (1) = 2.96, P = 0.08; other categories not tested due to insufficient number of observations). Figure 2 Changes in OCD symptomsterm·var induced by psychoactive drugs. ( A ) Proportion of users declaring the given substanceterm·var (dark green), another substanceterm·var (light green) or no substanceterm·var (light blue) as the most impacting on OCDterm symptoms (irrespective of the valence of the changes). Proportions were compared using a χ 2 test ( B ). Same representation for substancesterm·var belonging to the classic psychedelicsterm category. ( C ) Magnitude of changes in OCD symptomsterm·var for each substanceterm·var category, expressed in arbitrary unit. Responses were provided on a scale ranging from -100 (= worsening ) to + 100 (= improvement ). Green dots represent the magnitude of the change per participant, black dots and bars represent the means and standard errors across participantterm·stat, respectively. Significance was assessed using one-sample t-teststerm·stat. ( D ) Same representation for psilocybinterm mushrooms and LSDterm users. The magnitude of the changes for NPS, delirogens, ayahuasca, DMTterm and mescalineterm were not computed due to small sample size (n < 5). *** P < .001, ** P < .01, * P < .05, ns non-significant. When looking at the changes in OCD symptomsterm·var induced by the intake of each substanceterm·var, we observed that mean changes were positive and significant for classic psychedelicsterm (mean(SE) = + 42.62 (3.79), t(95) = 11.24, P < 0.001) but not for entactogensterm (mean(SE) = + 4.73 (10.69), t(18) = 0.44, P = 0.66) or ketamineterm (mean(SE) = + 8.00 (13.65), t(5) = 0.59, P = 0.58; Fig. 1 C). Within the classic psychedelicsterm category, mean changes were positive and significant for both psilocybinterm mushrooms (mean(SE) = + 44.22 (4.66), t(55) = 9.49, P < 0.001) and LSDterm (mean(SE) = + 40.23 (5.95), t(33) = 6.76, P < 0.001; Fig. 1 D). Classic psychedelicsterm appeared as the only substanceterm·var category inducing a significant improvement in OCDterm symptoms, both in terms of the proportion of users declaring a change and the direction of the change. Therefore, we selected psilocybinterm mushrooms and LSDterm users (i.e., classic psychedelicsterm users with a sufficient number of users) as our population of interest for the rest of the analysis (n = 90, characteristics in Table 1 ). Characteristics of the psychedelic experience Data are shown in Table 4 . For the mindsetterm, 36% of the participants expected an improvement in their OCDterm symptoms. On the settingterm, a majority of participants declared that the intake occurred in no particular context (66%) . For the delay of onset and duration of the psychedelic experience, most of the participants reported a delay of onset between 30 to 60 min (62%) and a duration of 5–12 h (48%). Table 4 Characteristics of the psychedelic experience. % Mean (SD) Expectations * Acute general effects Spiritual or religious purpose 73 Altered body sensations 80.61(16.38) Personal development 69 Changes in vision or hearing 79.98(18.21) Curiosity/Discovery 58 Euphoria 79.05(18.94) Recreational experience 56 Emotional arousal 77.87(22.00) OCDterm improvement 36 Insights 77.45(26.13) None 1 Musical ecstasy 74.32(24.30) Other expectations 1 Spiritual experience 74.30(29.89) Space time distortion 71.65(25.81) Trauma resolution 62.67(30.53) Context of the dosing Hallucination 58.11(31.76) No particular event 66 Bodily boundaries dissolution 50.97(30.01) Recreational settingterm 16 Ego dissolution 47.95(32.68) Ceremonial settingterm 18 Confusion 35.39(30.40) With therapeutic support 50 Acute unpleasant effects Retreat 29 Difficulty concentrating 44.85(30.12) Shamanic type ceremony 21 Nausea 38.00(31.29) Clinical research 0 Feeling of heat 35.99(31.76) Anxiety 34.14(30.38) Discomfort 34.09(29.75) Delay of onset of acute effectsterm Feeling of coldness 33.54(33.55) Less than 30 min 17 Depersonalization 31.64(31.98) 0 to 15 min 7 Memory impairment 31.39(30.04) 15 to 30 min 93 Revival of traumatic memories 31.16(32.94) 30 to 60 min 62 Sadness 28.14(30.93) More than 60 min 17 Indigestion 26.02(29.39) No answer 4 Sedation 23.71(27.16) Shaking 22.33(26.65) Panic 21.19(30.74) Duration of acute effectsterm Tachycardia 17.41(23.34) Less than 5 h 28 Headache 15.25(23.20) 1–3 h 20 Diarrhea 14.98(23.24) 3–5 h 80 Vomiting 12.13(21.51) 5–12 h 48 Constipation 9.79(18.47) > 12h 20 Self-aggressive behavior 8.11(19.50) I don't know 4 Aggressive behavior 4.41(13.68) *Multiple possible answers. **Pleasantnessterm score = 100 – mean(Acute unpleasant effects). For general effects, mean ratings across-participants were all above 50 (except for confusion and ego dissolution ) whereas for unpleasant effects, mean ratings across-participants were all below 50. The resulting intensity scores reached a mean(SE) of 67.07 (1.61) across participants, ranging from 20.77 to 100; and the pleasantnessterm scores reached a mean(SE) of 73.91 (1.92), ranging from 21.1 to 100. Proxy for the dose When asked if they knew the substanceterm·var dose they had taken, 67% of the participants answered positively (Fig. 3 A). Based on the provided dosage and associated unit, 8% of them were discarded due to missing or absurd information (e.g., participants declaring the intake of 4g of LSDterm). For psilocybinterm mushrooms, most of the doses were expressed as grams of dried mushrooms, which we converted into milligrams of psilocybinterm by multiplying by a 0.0063 factor (appropriate for Psilocybe cubensis type of mushrooms according to 30 ). Following this transformation, the mean(SD) dose of psilocybinterm was 20.30 (16.74)mg, ranging from 1 to 88 and the mean(SD) dose of LSDterm was 131.56 (69.85)μg, ranging from 10 to 250 (Fig. 3 B). Figure 3 Relating self-reported dose to intensity of acute effectsterm. ( A ). Percentage of participants who declared knowing the substanceterm·var dose (n = 60) or not (n = 30). Light purple data represent participants discarded because of uninterpretable dose (n = 7). ( B ). Distribution of doses for psilocybinterm (left panel) and LSDterm (right panel). Black bars represent means. ( C ). Dose of substanceterm·var as a function of the intensity of the acute effectsterm·var. Doses are expressed as z-scores to include both psilocybinterm mushrooms and LSDterm in the same analysis. One dot is one participant, the line and ribbon represent the estimated regressionterm·stat line and its 95% confidence intervalterm·stat. Note that β represents the regressor for intensity in the statistical model used to predict the dose. Since doses were exploitable in a subset of participants only, we looked for a variable available in all participants that could constitute a proxy for the dose, by running a linear regressionterm·stat with 3 factors (delay of onset, duration, intensity of acute effectsterm; all GVIF < 2). We did not include the pleasantnessterm of acute effectsterm as a regressor since previous study did not observe its association with the dose 31 . Five participants were removed from the analysis because of missing data (n = 4 for the delay of onset and n = 1 for the duration), leading to 48 participants included in the analysis. Results showed that the intensity of acute effectsterm was positively associated with the dose (β = 0.02, t = 3.48, P = 0.001; Fig. 3 C). None of the other regressors significantly predicted the dose (Delay of onset: β less30-30to60 = 0.09, t = 0.34, P = 0.73, β more60-30to60 = 0.06, t = 0.22, P = 0.82; Duration: β 5to12h-more12h = 0.37, t = 1.28, P = 0.21, β less5h-more12h = 0.26, t = 0.82, P = 0.41). This analysis shows that in our dataset, the intensity of acute effectsterm can be used as a proxy for the dose, with increasing doses leading to more intense experiences. Predicting the magnitude of OCDterm improvement To study which factors predicted the magnitude of OCDterm improvement, a linear regressionterm·stat including 6 independent variables (substanceterm·var, mindsetterm, context, intensity and pleasantnessterm of acute effectsterm, OCI-rterm score; all GVIF < 2) was used. One participant was removed from the analysis because of missing data, ending in 89 observations included. In our dataset, the magnitude of OCDterm improvement was positively associated with both the intensity (β = 0.87, t = 3.86, P adj = 0.003; Fig. 4 A) and pleasantnessterm (β = 0.76, t = 3.96, P adj = 0.003; Fig. 4 B) of acute effectsterm. None of the other factors was significant (substanceterm·var: β Psilo-LSD = 5.67, t = 0.77, P adj = 0.67; mindsetterm: β Expectation-NoExpectation = 2.80, t = 0.36, P adj = 0.81; settingterm: β Recreational-Noparticular = -9.09, t = -0.9, P adj = 0.61; β Ceremonial-NoParticular = 6.27, t = 0.69, P adj = 0.70; OCI-rterm score: β = 0.03, t = 0.1, P adj = 0.92). This analysis shows that the improvement in OCDterm symptoms was not associated with the mindsetterm or context of intake but was larger for more intense and more pleasant acute effectsterm. Figure 4 Modeling the magnitude of OCDterm improvement. OCDterm improvement as a function of intensity (A) and pleasantnessterm (B) of acute effectsterm of psychedelics, assessed in 90 participants. One dot is one participant, the line and ribbon represent the estimated regressionterm·stat line and 95% confidence intervalsterm·stat. Note that β represents the regressor for intensity (respectively pleasantnessterm) in the linear regressionterm·stat used to predict the magnitude of OCDterm improvement. Pleasantnessterm of acute effectsterm Since the pleasantnessterm of acute effectsterm appeared as a predictive factor of OCDterm improvement magnitude, a linear regressionterm·stat with 5 regressors (substanceterm·var, mindsetterm, context, intensity of acute effectsterm, OCI-rterm score; all VIF values < 2) was used to study which factors were predictive of pleasantnessterm. One participant was discarded from the analysis because of missing data, ending in 89 observations included in the analysis. None of the factors included in the analysis significantly predicted the pleasantnessterm of acute effectsterm (substanceterm·var: β Psilo-LSD = -3.75, t = -0.89, P adj = 0.61; mindsetterm: β Expectation-NoExpectation = 5.76, t = 1.30, P adj = 0.54; settingterm: β Recreational-NoParticular = -3.82, t = -0.66, P adj = 0.70; β Ceremonial-NoParticular = 1.27, t = 0.24, P adj = 0.84; intensity: β = -0.18, t = -1.37, P adj = 0.54; OCI-rterm score: β = -0.29, t = -1.91, P adj = 0.39). Persistenceterm of the improvement in OCDterm symptoms Improvement in OCDterm symptoms was mostly reported to persist for less than a week and more than 3 months , with 33% (n = 30) in each. An additional 21% of participants (n = 19) selected between 1 week and 1 month and the remaining 12% (n = 11) selected between 1 and 3 months (Fig. 5 B). We acknowledge that reports on persistenceterm are not precise enough since we do not know when the intake occurred relative to the filling of the surveyterm·mth. Notably, participants who filled the surveyterm·mth one week after the intake were not able to evaluate the persistenceterm at three months. But given the importance of this parameter, we still searched for determinants. An ordinal regressionterm·stat with 5 independent variables (substanceterm·var, intensity and pleasantnessterm of acute effectsterm, magnitude of OCDterm improvement, OCI-rterm score; all GVIF < 1.5) was used, including 90 observations. Results showed that none of the regressors significantly predicted the persistenceterm of the improvement (substanceterm·var: β Psilo-LSD = -0.44, z = -1.06, P adj = 0.54; intensity: β = 0.02, z = 1.20, P adj = 0.54; pleasantnessterm: β = -0.02, z = -1.52, P adj = 0.54; magnitude of OCDterm improvement: β = 0.003, z = 0.43, P adj = 0.78; OCI-rterm score: β = -0.02, z = -1.19, P adj = 0.54). Figure 5 Modeling subsequent intake probability and frequency . ( A ) Repeated use of the substanceterm·var. ( B ) Persistenceterm of substance-induced OCDterm improvement. ( C ) Estimated probability of subsequent intake as a function of OCDterm improvement magnitude, as modeled using a logistic regressionterm·stat (n = 90). One dot is one participant; the line and ribbon represent the regressionterm·stat curve and associated standard errorterm·stat. D . Estimated distribution of subsequent intake frequency according to the persistenceterm of OCDterm improvement, as modeled using an ordinal regressionterm·stat (n = 69). Subsequent intakes and their frequency When participants were asked whether they had taken the substanceterm·var again, 23% (n = 21) answered negatively. Among the 77% who took it again, 47% (n = 42) reported an intake frequency of at most 3 times a year , 14% (n = 13) reported once a month and 16% (n = 14) at least once a week (Fig. 5 A). We first searched for factors predicting the occurrence of subsequent intakes (irrespective of the frequency), using logistic regressionterm·stat with 6 independent variables (substanceterm·var, intensity and pleasantnessterm of acute effectsterm, magnitude and persistenceterm of OCDterm improvement, OCI-rterm score; all GVIF < 2) on 90 observations. The only significant factor associated with the occurrence of subsequent intake was the magnitude of OCDterm improvement (β = 0.03, z = 2.92, P adj = 0.03; Fig. 5 C) whereas none of the other factors was significant (substanceterm·var: β Psilo-LSD = -0.30, t = -0.49, P adj = 0.77; intensity: β = -0.02, z = -1.08, P adj = 0.54; pleasantnessterm: β = -0.02, z = -1.09, P adj = 0.54; persistenceterm: β 1weekto1month-less1week = -0.46, z = -0.59, P adj = 0.72; β 1to3months-less1week- = -1.45, z = -1.43, P adj = 0.54; β more3months-less1week = -0.23, z = -0.32, P adj = 0.81; OCI-rterm score: β = 0.03, z = 1.30, P adj = 0.54). This result shows that the probability of subsequent intake increases with stronger improvement in OCDterm symptoms. In the participants who took the substanceterm·var again (n = 69), we then modeled the frequency of intake using an ordinal regressionterm·stat including 5 regressors (substanceterm·var, intensity and pleasantnessterm of acute effectsterm, magnitude and persistenceterm of OCDterm improvement; all GVIF < 2). We observed that subsequent intake frequency was significantly associated with the persistenceterm of OCDterm improvement, with improvements persisting more than 3 month s increasing the probability of being in the category at most 3 times a year (β more3months-less1week = -1.76, z = -2.53, P = 0.01; Fig. 5 D). None of the other factors was significant (substanceterm·var: β Psilo-LSD = 0.30, z = 0.55, P = 0.58; intensity: β = -0.001, z = -0.08, P = 0.94; pleasantnessterm: β = 0.02, z = 1.39, P = 0.17; magnitude of OCDterm improvement: β = -0.007, z = -0.65, P = 0.51). Finally, we explored the substanceterm·var dose used by participants who declared taking the substanceterm·var at least once a week . Among them, 57% (n = 8) used microdosing with doses lower than 10 µg for LSDterm and 4 mg for psilocybinterm, 21% (n = 3) did not provide any information and the remaining 21% (n = 3) reported using regular doses (250 µg for LSDterm and above 35 mg for psilocybinterm). This last analysis shows that in our dataset, the occurrence and frequency of subsequent intakesterm·var were not related to the intensity or pleasantnessterm of acute effectsterm but to the improvement in OCDterm symptoms and its persistenceterm. Discussion In this surveyterm·mth, we assessed, in a sample of participants suffering from OCDterm symptoms, the subjective efficiency of different psychoactive drugs in reducing symptoms. When considering the different substance categoriesterm·def, we observed that the proportion of users reporting a change in OCDterm symptoms (irrespective of its valence) was higher with classic psychedelicsterm than with any other substanceterm·var category. And when characterizing these changes, we observed that only classic psychedelicsterm were associated with significant improvements in OCDterm symptoms. Consequently, we focused on classic psychedelicsterm users for which we had enough participants, meaning psilocybinterm mushrooms and LSDterm users, to study the determinants of the therapeutic effect. We observed that its magnitude was associated with the intensity and pleasantnessterm of acute effectsterm, with the intensity being correlated with the substanceterm·var dose. Regarding the persistenceterm 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, substanceterm·var usage appeared to be tuned to the therapeutic effect. Indeed, the occurrence of subsequent intakes was predicted by the magnitude of OCDterm symptoms improvement, with participants with stronger therapeutic effect being more likely to take the substanceterm·var again. And among the participants who used the substanceterm·var again, the frequency of subsequent intakes was related to the persistenceterm 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 psychedelicsterm as the most efficient for OCDterm symptoms when compared to other substancesterm·var. The self-assessment of the therapeutic effect makes it prone to subjectivity bias, but a vast majority of classic psychedelicsterm users, in our sample, perceived an improvement in their medical conditions following the intake of the substanceterm·var. The fact that many participants used multiple substancesterm·var brings additional credits to their choice, since they were likely able to compare between substancesterm·var. Interestingly, ketamineterm, a dissociative substanceterm·var with anesthetic properties at high doses, did not show up as an effective substanceterm·var in alleviating OCDterm symptoms. Previous results on the use of ketamineterm in OCDterm are mixed 32 , but our results are difficult to compare since recreational use differs from therapeutic guidelines in terms of enantiomer, dose and mode of administration. Similarly, DMTterm and mescalineterm were not selected as effective for OCDterm symptoms. Despite being categorized as serotoninergic hallucinogens, DMTterm and mescalineterm have phenomenological and pharmacological profiles that seem to differ from LSDterm or psilocybinterm 33 . Among other differences, DMTterm has no affinity for the serotoninergic receptor 2C, as well as a lower hallucinogenic potency and duration of action in human 34 . Mescalineterm on the other side, seems to have combined psychedelic and entactogenic properties 35 and does not act on raphe neurons 36 . Finally, within the classic psychedelicsterm category, we did not observe any difference between LSDterm and psilocybinterm, which share multiple chemical properties but also differences such as their affinity for dopaminergic receptors 37 . When modeling the magnitude of the therapeutic effect, we observed that it was predicted by the intensity of acute effectsterm. The evaluation of acute effectsterm is intrinsically subjective, and the retrospective design of the study could have affected the scorings due to recall biasterm. However, the observation of an already described and therefore expected link between the intensity of acute effectsterm and the dose 38 , 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 OCDterm 17 , as well as in other pathologies 39 – 41 . 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 OCDterm 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 surveyterm·mth, the magnitude of the therapeutic effect was also correlated with the pleasantnessterm of acute effectsterm, 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 surveyterm·mth has reported, in healthy subjects, the lack of relationship between the pleasantnessterm of acute effectsterm and the enduring well-being induced by psilocybinterm 23 . However, this association should be investigated further in patients since one of the most prevalent adverse effects reported during the acute experience is anxiety 42 , a symptom for which OCDterm patients might be particularly at risk. Investigating the factors influencing the pleasantnessterm 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 OCDterm patients. We also included as factors in the model the mindsetterm 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 pleasantnessterm of the experience. Finally, since LSDterm and psilocybinterm 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 psychedelicsterm 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 persistenceterm 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 persistenceterm of the psychedelic-induced therapeutic effects in OCDterm apart from case studies 7 , 10 , 11 , 43 , 44 . But this is coherent with studies in other pathologies such as depression showing effects persisting from multiple weeks to several months 41 , 45 , 46 . As mentioned in the results section, the persistenceterm 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 surveyterm·mth. This might have impacted the proportion of participants declaring short-lasting effects, with people filling out the surveyterm·mth shortly after the intake of the substanceterm·var 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 neuroplasticterm property of psychedelics, with increased neuronal growth and synaptogenesis observed both in vivo in rodents and in vitro in different species 47 – 49 . In rodent, these structural modifications lasted up to a month, but were not specific to classic psychedelicsterm since it was observed with multiple components including ketamineterm 47 . The last factor that we examined was the occurrence and frequency of subsequent intakesterm·var. We did not observe any apparent case of substanceterm·var 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 psychedelicsterm, neither in humans nor in animals 37 . Importantly, in our dataset, the occurrence of subsequent intakes and their frequency seemed to be closely related to the magnitude and persistenceterm 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 effectsterm·var and the frequency of subsequent intake. Some methodological limitations must be considered beforehand. In general, web-based surveysterm·mth are subject to bias in participant selection. In the context of our study, participants were likely to be favorable to the use of psychedelic drugs, which might have had an impact on their trustfulness and might have induced proselytism when completing the surveyterm·mth. Participants with a pleasant acute experience and positive outcome (i.e., improvement in OCDterm symptoms) were also more likely to enter the surveyterm·mth, limiting the generalizability of our results. Still, we attempted to objectively evaluate symptom severity using the OCI-rterm. The answers provided by our participants with OCDterm symptoms were also coherent with the literature on OCDterm management, with the most used therapy and medications in our sample being cognitive-behavioral therapy and antidepressant, which are the two recommended first-line therapeutic approaches for OCDterm 3 . Also, the ratio between male and female as well as the rate of comorbidities were very similar in our sample when compared to epidemiological studies on OCDterm 50 , 51 . In conclusion, our dataset suggests that classic psychedelicsterm are potentially efficient in reducing OCDterm symptoms, with an impact of the dose on the magnitude of the therapeutic effect, and little risk of substanceterm·var abuse. Our results also highlight the need to carefully assess the persistenceterm of the therapeutic effect in OCDterm. All limitations related to online surveysterm·mth should be kept in mind, and these results should not be generalized to the entire OCDterm population until the outcome of randomized controlled clinical trials confirms our observations.