Background: To date, no study has presented data of non-responders to psilocybin for OCD.  We will present our case series analysis of non-responders from a single-site study investigating the safety and clinical effects of psilocybin on OCD with a randomized (1:1), double-blind, placebo-controlled design. 

 Methods: We compared single-dose psilocybin (0.25 mg/kg) vs. active placebo (250 mg niacin) in this trial. Non-directive psychological support was provided by facilitator pairs during preparatory, dosing, and integration visits. We recruited 26 adult participants with a primary diagnosis of OCD, a Y-BOCS score of at least 19, and failure of at least one trial of standard-of-care treatment for OCD. Efficacy was evaluated on the AY-BOCS and self-reported VAS at the primary endpoint of 48 hours post-dosing, and other measures up to 12-week follow-up. Safety was assessed by monitoring AEs, C-SSRS, vitals, SUDs, and medication changes.  

Results: To date, four of our participants who received psilocybin did not experience a clinically significant change in their OCD symptoms as measured on the YBOCS at primary endpoint. An analysis of subjective report during preparatory, dosing, and integration sessions by these non-responders yielded themes including an enmeshed identity with OCD, OCD offering safety, security, and stability in perceiving others and the world, and OCD serving as a “protector” in the aftermath of trauma. 

Conclusion: Continued investigation of the mechanisms underlying treatment non-response is crucial for refining therapeutic approaches and optimizing outcomes in challenging cases.