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Available treatments leave 40% or more of people with OCD significantly symptomatic. There is an urgent need for novel therapeutic approaches. Mice that carry a homozygous deletion of the SAPAP3 gene (SAPAP3 KO) manifest a phenotype of excessive self-grooming, tic-like head-body twitches and anxiety. These behaviors closely resemble pathological self-grooming behaviors observed in humans in conditions that overlap with OCD. Following a preliminary report that the tryptaminergic psychedelic, psilocybin, may reduce symptoms in patients with OCD, we undertook a randomized controlled trial of psilocybin in 50 SAPAP3 KO mice (28 male, 22 female). Mice that fulfilled inclusion criteria were randomly assigned to a single intraperitoneal injection of psilocybin (4.4\u2009mg\/kg), psychedelic mushroom extract (encompassing the same psilocybin dose) or vehicle control and were evaluated after 2, 12, and 21 days by a rater blind to treatment allocation for grooming characteristics, head-body twitches, anxiety, and other behavioral features. Mice treated with vehicle (n\u2009=\u200918) manifested a 118.71\u2009\u00b1\u200995.96% increase in total self-grooming (the primary outcome measure) over the 21-day observation period. In contrast, total self-grooming decreased by 14.60\u2009\u00b1\u200917.90% in mice treated with psilocybin (n\u2009=\u200916) and by 19.20\u2009\u00b1\u200920.05% in mice treated with psychedelic mushroom extract (n\u2009=\u200916) (p\u2009=\u20090.001 for effect of time; p\u2009=\u20090.0001 for time \u00d7 treatment interaction). Five mice were dropped from the vehicle group because they developed skin lesions; 4 from the psilocybin group and none from the psychedelic mushroom extract group. Secondary outcome measures such as head-body twitches and anxiety all showed a significant improvement over 21 days. Notably, in mice that responded to psilocybin (n\u2009=\u200912) and psychedelic mushroom extract (n\u2009=\u200913), the beneficial effect of a single treatment persisted up to 7 weeks. Mice initially treated with vehicle and non-responsive, showed a clear and lasting therapeutic response when treated with a single dose of psilocybin or psychedelic mushroom extract and followed for a further 3 weeks. While equivalent to psilocybin in overall effect on self-grooming, psychedelic mushroom extract showed superior effects in alleviating head-body twitches and anxiety. These findings strongly justify clinical trials of psilocybin in the treatment of OCD and further studies aimed at elucidating mechanisms that underlie the long-term effects to alleviate excessive self-grooming observed in this study.<\/jats:p>","DOI":"10.1038\/s41380-024-02786-0","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T15:02:07Z","timestamp":1728658927000},"page":"1172-1183","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Striking long-term beneficial effects of single dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming"],"prefix":"10.1038","volume":"30","author":[{"given":"Michal","family":"Brownstien","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Lazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Botvinnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Shevakh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Blakolmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9189-4991","authenticated-orcid":false,"given":"Leonard","family":"Lerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzuri","family":"Lifschytz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9914-632X","authenticated-orcid":false,"given":"Bernard","family":"Lerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"2786_CR1","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/mp.2008.94","volume":"15","author":"AM Ruscio","year":"2010","unstructured":"Ruscio AM, Stein DJ, Chiu WT, Kessler RC. 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KB is a Founder and CEO of Parow Entheobiosciences (ParowBio). BL is a consultant to Back of the Yards Algae Sciences (BYAS) and Parow Entheobiosciences (ParowBio). LL, BL, and KB submitted an international patent application (No. WO 2023\/164092 A1 \u201cTreatment of Psychiatric Disorders, Brain Injuries, and Autism Spectrum Disorder\u201d) which was published on 31 August 2023 that includes the possibility of treating OCD with psychedelic mushroom extract. Patent assigned to Parow Entheobiosciences.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}