An Open-Label Multidose Psilocybin Intervention for Obsessive-Compulsive Disorder

Repeated psilocybin administration was generally well tolerated and showed preliminary evidence of efficacy in reducing OCD symptoms

In this study the authors found that two supervised doses of psilocybin, given two weeks apart (20 mg followed by 30 mg if tolerated), were associated with significant reductions in obsessive-compulsive disorder (OCD) symptoms among adults who had previously tried medication or evidence-based psychotherapy.

Among the 37 participants enrolled, 30 completed the one-month follow-up, and the group receiving psilocybin immediately showed significantly greater improvement on the Yale–Brown Obsessive Compulsive Scale than the waitlist control group. Improvements persisted one month after the second dose, and greater symptom reductions were associated with aspects of participants’ acute psychedelic experiences. Treatment was generally well tolerated in this small sample. However, the findings are preliminary because the study is a non-peer-reviewed preprint, was open-label, involved a small number of participants and had only short-term follow-up; larger, controlled trials are needed to establish efficacy and safety

Abstract

Importance Obsessive-Compulsive Disorder (OCD) has a 2% global prevalence, but only about 50% of patients respond to conventional treatment, underscoring the need for additional effective interventions.

Objective To assess the feasibility, safety, and preliminary evidence for efficacy of repeated psilocybin administration in OCD patients who had previously attempted psychotherapy or pharmacotherapy.

Design Waitlist-controlled open label randomized clinical trial.

Setting Data were collected at the Johns Hopkins University School of Medicine.

Participants Data were analyzed from 30 participants (total randomized N=37, by age, sex and OCD severity) with a failed previous attempt at either pharmacotherapy or evidence-based psychotherapies such as exposure response prevention (ERP).

Intervention Participants received two psilocybin doses over two weeks (20 mg followed by 30 mg, if well-tolerated) under supportive conditions. The immediate-treatment arm received the drug within a month following enrollment, and the waitlist-control arm received identical support and dosing after an 8-week waiting period.

Main Outcome Clinician-administered Y-BOCS scores was collected one week post each drug administration and one month post session 2. Self-assessed reports were collected for acute subjective effects (Mystical Experience Questionnaire (MEQ), Challenging Experience Questionnaire (CEQ), and 11-Dimensional Altered States of Consciousness (11D-ASC)), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory-II (BDI-II), and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q).

Results A total of 37 participants were enrolled in the study (age: 38.4±11.6 years; 21 [56.75%] female), with 30 [81.08%] completing the 1-month follow-up. We show that two successive doses of psilocybin over two weeks were well-tolerated, leading to reduction in OCD symptoms. Compared with the waitlist group (N=14), the immediate-treatment group (N=16) showed a reduction in the Y-BOCS scores (F(2,56)=16.17, p<0.001, η2□=0.37) post session. This improvement persisted one month after the second psilocybin dose for both groups post treatment crossover for waitlisted group (F(3,84)=29.91, p<0.001, η2□=0.52). Y-BOCS scores were correlated with several acute subjective effects measures, including total scores on MEQ, and individual factors on CEQ and 11D-ASC. Conclusions and Relevance: Repeated psilocybin administration is tolerable and potentially efficacious in reducing OCD symptoms. These results support further investigation of multi dose psilocybin protocols as a viable therapeutic approach.

Tiwari, P., Nayak, S.M., Sepeda, N.D., Ehrenkranz, R., Levine, M.A., Rohde, J.S., Miller, E., Beritela, C.M., Scott, J.V., Nestadt, G., Barrett, F.S. and Yaden, D.B. (2026) ‘An open-label multidose psilocybin intervention for obsessive-compulsive disorder’. medRxiv [Preprint] Read Paper

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