Psilocybin's effects on obsessive-compulsive behaviors: A systematic review of preclinical and clinical evidence

Psilocybin, a serotonergic psychedelic, shows growing evidence for reducing obsessive-compulsive symptoms. A systematic review of 13 studies (4 clinical trials, 9 preclinical) found that single doses rapidly reduced symptoms in patients with OCD and body dysmorphic disorder. In wild-type mice, psilocybin briefly decreased marble-burying behavior only on the first day. In SAPAP3 knockout mice, a genetic model of compulsive behavior, a single dose produced robust, lasting reductions in excessive grooming, replicated across labs and doses. Chronic hallucinogenic doses did not improve anxiety or compulsive behavior in these mice, but chronic sub-hallucinogenic doses in rats reduced self-grooming and increased synaptic markers in the paraventricular thalamus. The evidence suggests transient clinical effects and lasting anti-compulsive effects in animal models, warranting larger placebo-controlled trials with neuroimaging.

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Abstract

Psilocybin is a serotonergic psychedelic with growing evidence for efficacy in mood disorders, and its therapeutic potential in obsessive—compulsive disorder (OCD) and related conditions is increasingly recognised but remains understudied. We systematically evaluated clinical and preclinical evidence on psilocybin's effects on obsessive and compulsive behaviours with attention to translational relevance. A systematic search identified 13 eligible studies (4 clinical trials and 9 preclinical investigations examining psilocybin or psilocin on obsessive—compulsive symptoms or behaviours), and reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In clinical studies, single doses of psilocybin led to rapid reductions in obsessive-compulsive symptoms, including in patients with OCD and body dysmorphic disorder. In wild-type mice, psilocybin acutely decreased marble-burying behaviour, although this effect was transient and not observed beyond the first day after administration. In contrast, in SAPAP3 knockout mice—a validated genetic model of compulsive behaviour—a single administration of psilocybin produced robust, enduring reductions in excessive grooming, and these lasting anti-compulsive effects were replicated across independent laboratories and doses. Additionally, chronic hallucinogenic doses of psilocybin did not improve anxiety-like or compulsive-like behaviour in SAPAP3 knockout mice; however, a separate study in Long—Evans rats found that chronic sub-hallucinogenic psilocybin reduced self-grooming and enhanced expression of synaptic markers in the paraventricular thalamus. Together, the evidence suggests that psilocybin transiently reduces obsessive—compulsive symptoms in clinical populations and produces lasting anti-compulsive effects in validated animal models. Future clinical studies should include larger placebo-controlled trials and incorporate neuroimaging to assess psilocybin's impact on fronto-striatal circuitry implicated in OCD pathophysiology.