551. PSYCHEDELICS AND OCD: TRANSLATIONAL APPROACHES

Abstract Background Obsessive-compulsive disorder (OCD) is associated with significant personal suffering and functional impairment. At least a third of OCD patients do not respond to conventional treatments. There is a substantial anecdotal literature suggesting that psychedelic agents, specifically psilocybin and psilocybin-containing psychedelic mushroom extract (PME), may be therapeutic in patients with OCD. Several preclinical studies in mice employing the marble burying test (MBT) support this possibility as does an open label trial of several doses of psilocybin in 9 patients with OCD (Moreno et al J Clin Psychiatry. 2006 Nov;67(11):1735-40). Aims & Objectives To evaluate the potential therapeutic efficacy of psilocybin, PME and psychedelic-derived new chemical entities (PD-NCEs) in OCD, using preclinical models. Method Psilocybin was obtained from USONA and PME from Parow Entheobiosciences (PEB). The PD-NCEs HBL20016 and HBL20017, were designed in our laboratory and synthesized by Pharmaron Inc. under contract. Potential efficacy in OCD was assessed in our laboratory using the MBT and the SAPAP3-knockout (SAPAP2-KO) mouse model of OCD. Results Psilocybin was effective in the MBT and the effect was demonstrable even when the head twitch response (HTR), a mouse correlate of the psychedelic trip in humans, was prevented by prior treatment with the 5-HT1A agonist, buspirone (Singh et al, Transl Psychiatry. 2023; 13(1):164.). Psilocybin was also effective in reducing excessive self-grooming, Tourette’s Syndrome-like tics and anxiety-like features in SAPAP3-KO mice, the efficacy of a single dose extending beyond 21 days. PME at the same psilocybin dose showed slightly greater efficacy (Brownstien et al, Mol Psychiatry. 2024 Oct 11.). Both the hallucinogenic PD-NCE, HBL20016 and the non-hallucinogenic HBL20017, were effective in the MBT and the SAPAP3 model, with extended efficacy of a single dose. Discussion & Conclusions Anecdotal reports and an open clinical study support the therapeutic potential of psilocybin in OCD. Our findings in mouse models provide substantial preclinical support with possibly superior therapeutic effects of mushroom extract, indicate long-term efficacy and suggest efficacy in Tourette’s Syndrome. A novel psychedelic-derived therapeutic agent (HBL20017) may have efficacy in OCD without inducing psychedelic effects.