Frontiers in Psilocybin Research for OCD: Neural Mechanisms, Treatment Response, and Clinical Implications

Obsessive-Compulsive Disorder (OCD) is a profoundly disabling psychiatric condition, with severity that can warrant consideration of invasive brain surgery in refractory cases. While existing pharmacological treatments can provide benefit, they are characterized by significant limitations: a therapeutic lag time of 2-6 weeks, persistent residual symptoms even among treatment responders, and adverse effects that often compromise treatment adherence. Recent research suggests psilocybin may offer a promising therapeutic approach, with studies demonstrating acute and sometimes enduring clinical benefits following single-dose administration. Here, we present results from clinical studies investigating psilocybin as a treatment for OCD and mechanisms underlying therapeutic effects in three parts. In part 1, we present neuroimaging changes in default mode network connectivity and their relationship to symptom improvement, in a double-blind, placebo-controlled design with single weight-based psilocybin dosing. In part 2, we will present preliminary safety, feasibility/tolerability, and efficacy data from our ongoing clinical trial of repeated, fixed-dose psilocybin administrations combined with non-directive support for OCD with a waitlist-controlled design. In part 3, we will present a mixed-methods case series comparing non-responders vs. responders from our aforementioned psilocybin-OCD trials in an effort to identify plausible predictors of treatment response.