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Despite widespread interest in their use for conditions marked by social impairments, including depression, anxiety, and anorexia nervosa, the influence of sex as a biological variable on the prosocial effects of psychedelics remains poorly understood. Indeed, enhanced connectedness, sociability and empathy are common outcomes of psychedelic use and these have shaped human social structures for millennia. Here, we investigated the sex-specific effects of a single dose of psilocybin (1.5\u2009mg\/kg) in C57BL\/6\u2009J mice across multiple aspects of social behaviour. Psilocybin acutely enhanced huddling and induced hypothermia selectively in female mice and post-acutely (4\u2009h) enhanced novelty-seeking and grooming in females, with no comparable effects in males. By 24\u2009h, psilocybin-treated males showed reduced grooming and rearing alongside increased sociability directed toward a cage-mate. This was accompanied by blunted novelty-evoked nucleus accumbens dopamine responses that persisted to 7 days post-administration. At 7 days, psilocybin shifted female social preference toward familiarity over novelty, associated with prolonged nucleus accumbens dopamine release during familiar conspecific interactions, while males exhibited increased grooming, opposing the effect observed at 24\u2009h. Both 5-HT1AR and 5-HT2AR contributed to psilocybin\u2019s behavioural effects in sex-specific ways. These findings reveal temporally dynamic, sex-differentiated patterns of social behaviour and dopaminergic modulation following psilocybin, underscoring the importance of sex-informed approaches in preclinical research and clinical application of psychedelic compounds.<\/jats:p>","DOI":"10.1038\/s41386-026-02450-x","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:56:51Z","timestamp":1779692211000},"page":"1588-1598","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Psilocybin modulates social behaviour in male and female mice in a time-dependent manner"],"prefix":"10.1038","volume":"51","author":[{"given":"Sheida","family":"Shadani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaspar","family":"McCoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Greaves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyna","family":"Conn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9097-7944","authenticated-orcid":false,"given":"Zane B.","family":"Andrews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3293-8242","authenticated-orcid":false,"given":"Claire J.","family":"Foldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"2450_CR1","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.tics.2017.10.004","volume":"22","author":"RIM Dunbar","year":"2018","unstructured":"Dunbar RIM. 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Modulation of social cognition via hallucinogens and entactogens. Front Psychiatry. 2019;10:881.","journal-title":"Front Psychiatry"},{"key":"2450_CR5","doi-asserted-by":"publisher","first-page":"729425","DOI":"10.3389\/fpsyg.2021.729425","volume":"12","author":"JM Rodr\u00edguez Arce","year":"2021","unstructured":"Rodr\u00edguez Arce JM, Winkelman MJ. Psychedelics, sociality, and human evolution. Front Psychol. 2021;12:729425.","journal-title":"Front Psychol"},{"key":"2450_CR6","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1038\/s41591-023-02455-9","volume":"29","author":"SK Peck","year":"2023","unstructured":"Peck SK, et al. Psilocybin therapy for females with anorexia nervosa: a phase 1, open-label feasibility study. Nat Med. 2023;29:1947\u201353.","journal-title":"Nat Med"},{"key":"2450_CR7","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1007\/s11920-022-01363-y","volume":"24","author":"GS Barber","year":"2022","unstructured":"Barber GS, Aaronson ST. 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