A Randomized Controlled Trial of Psilocybin for the Treatment of Obsessive-Compulsive Disorder
Online Publication Service of Würzburg University (Würzburg University) – January 01, 2026
Source: OpenAlex
Summary
Psilocybin shows promising potential as a treatment for severe, treatment-resistant Obsessive Compulsive Disorder (OCD), with symptom reductions ranging from 23% to complete remission in participants. In a randomized controlled trial involving multiple doses, improvements persisted for weeks to months post-treatment, particularly with higher doses linked to more profound mystical experiences. Notably, no severe side effects were reported. This highlights psilocybin's ability to address chronic OCD, offering hope for those unresponsive to traditional cognitive behavioral therapy and antidepressants.
Abstract
Obsessive Compulsive Disorder (OCD) is a prevalent mental disorder, with a lifetime prevalence of 2-3%, characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions). These thoughts and behaviors take up a significant amount of time, cause immense distress, and compromise the quality of life of those who suffer from OCD. In addition to psychological factors such as maladaptive thought patterns and cognitive biases, the underlying mechanisms include biological factors, such as an impaired function of the Cortico-Striato-Thalamo-Cortical (CSTC) circuit, a hyperfunctioning Default Mode Network (DMN), and genetic predispositions. Furthermore, OCD patients show increased Error-related Negativity (ERN) and Correct-Response Negativity (CRN) amplitudes, indicating an overactive error-monitoring system. Currently OCD is most effectively treated with cognitive behavioral therapy (CBT), specifically exposure response prevention therapy (ERP), as well as pharmacologic agents, such as selective serotonin response inhibitors (SSRIs). Unfortunately, a large number of patients do not respond or only partially respond to these available treatments, making OCD a chronic condition for many and underscoring the urgent need for novel therapeutic approaches. Psilocybin is a psychedelic substance with a long history of ritualistic and therapeutic use. It primarily acts on serotonin receptors (5HT2a), with the potential to break rigid neuronal patterns, enhance neural plasticity, and reset hyperactive brain networks like the DMN. Earlier anecdotal reports and one groundbreaking research study from 2006 point to psilocybin as a safe and promising treatment alternative for treatment-resistant OCD. In this randomized placebo-controlled trial, we investigated psilocybin as a treatment for severe, treatment-resistant OCD. Participants received up to 8 doses of psilocybin at weekly intervals in a safe clinical setting with constant monitoring and support. We administered, in a randomized double-blind fashion, either a low (non-hallucinogenic), a high dose (clearly hallucinogenic), or a placebo during the first 4 sessions, followed by 4 high doses for every participant in a single-blind fashion during the last 4 sessions. Symptom severity was assessed with the Yale-Brown Obsessive-Compulsive Scale (YBOCS), along with other instruments to evaluate suicidality, side effects, psychotic symptoms, psychological well-being, and the quality of the psychedelic experience. Additionally, we investigated changes in brain activity by recording ERN and CRN with electroencephalography (EEG) at baseline, after session 4, and after session 8. Psilocybin led to a significant reduction in OCD symptoms, ranging from moderate improvement (23%) to complete remission (100%). These improvements outlived the acute effects of the drug and lasted for weeks to months after the last dose, with higher doses being associated with more pronounced psychedelic (mystical) experiences, and stronger mystical experiences being associated with greater symptom reduction. We did not observe any severe side effects. Interestingly, despite clinical improvements, no reduction in ERN or CRN as immediate indicators of the response to the treatment was found, and potential explanations for this discrepancy are discussed. The results of this work point to psilocybin as a promising treatment alternative for severe, treatment-resistant OCD when administered in a supportive clinical context. Future research is required to address questions regarding dosing optimization, the role of mystical experiences in therapeutic outcomes, and the underlying mechanisms of psilocybin’s effects on OCD.