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Initial evidence suggests that longitudinal functional and structural brain changes implicate fronto\u2010striatal\u2010thalamic (FST) circuitry, a broad system involved in goal\u2010directed behavior and motivational states. Here, we performed secondary analyses and applied computational modeling to resting\u2010state fMRI data from a within\u2010subject longitudinal psilocybin trial in psychedelic\u2010na\u00efve healthy volunteers. We first showed that dynamic FST activity increased 4\u2009weeks after a full dose of psilocybin. We then proceeded to mechanistically account for these changes by providing tentative model\u2010based support that reductions in the structure\u2013function coupling contribute to increased dynamic FST activity postpsilocybin. Finally, we used computational approaches to show that psilocybin induces longitudinal increases in bottom\u2010up and reduced top\u2010down modulation of FST circuits. We then used publicly available receptor maps to show that cortical reductions in top\u2010down modulation are linked to regional 5\u2010HT2A receptor availability, while increased information outflow via subcortical and limbic regions relates to local D2 receptor availability. Together, these findings suggest that increased FST flexibility weeks after a high dose of psilocybin is linked to serotonergic\u2010mediated decreases in top\u2010down information flow and dopaminergic\u2010mediated increases in bottom\u2010up information flow. This long\u2010term functional re\u2010organization of FST circuits may represent a common mechanism contributing to the potential clinical efficacy of psilocybin across various neuropsychiatric disorders including substance abuse, major depression, and anorexia nervosa.<\/jats:p>","DOI":"10.1002\/hbm.70596","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:10:13Z","timestamp":1782886213000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeled Long\u2010Term Effects of Psilocybin on Dynamic Activity and Effective Connectivity of Fronto\u2010Striatal\u2010Thalamic Circuits"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7899-7061","authenticated-orcid":false,"given":"Lorenzo","family":"Pasquini","sequence":"first","affiliation":[{"name":"Department of Neurology University of California, San Francisco  California San Francisco USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0994-5054","authenticated-orcid":false,"given":"Jakub","family":"Vohryzek","sequence":"additional","affiliation":[{"name":"Computational Neuroscience Group Universitat Pompeu Fabra  Barcelona Spain"},{"name":"Centre for Eudaimonia and Human Flourishing, Linacre College University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anira","family":"Escrichs","sequence":"additional","affiliation":[{"name":"Computational Neuroscience Group Universitat Pompeu Fabra  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonatan Sanz","family":"Perl","sequence":"additional","affiliation":[{"name":"Computational Neuroscience Group Universitat Pompeu Fabra  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Ponce\u2010Alvarez","sequence":"additional","affiliation":[{"name":"Department of Mathematics Polytechnic University of Catalonia  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Idesis","sequence":"additional","affiliation":[{"name":"Computational Neuroscience Group Universitat Pompeu Fabra  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manesh","family":"Girn","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California, San Francisco  California San Francisco USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leor","family":"Roseman","sequence":"additional","affiliation":[{"name":"Centre for Psychedelic Research Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California, San Francisco  California San Francisco USA"},{"name":"Department of Psychiatry and Behavioral Sciences University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Gazzaley","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California, San Francisco  California San Francisco USA"},{"name":"Department of Psychiatry and Behavioral Sciences University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Kringelbach","sequence":"additional","affiliation":[{"name":"Centre for Eudaimonia and Human Flourishing, Linacre College University of Oxford  Oxford UK"},{"name":"Department of Psychiatry University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1286-1401","authenticated-orcid":false,"given":"David J.","family":"Nutt","sequence":"additional","affiliation":[{"name":"Centre for Psychedelic Research Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Lyons","sequence":"additional","affiliation":[{"name":"Centre for Psychedelic Research Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin L.","family":"Carhart\u2010Harris","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California, San Francisco  California San Francisco USA"},{"name":"Centre for Psychedelic Research Imperial College London  London UK"},{"name":"Department of Psychiatry and Behavioral Sciences University of California, San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8995-7583","authenticated-orcid":false,"given":"Gustavo","family":"Deco","sequence":"additional","affiliation":[{"name":"Computational Neuroscience Group Universitat Pompeu Fabra  Barcelona Spain"},{"name":"Instituci\u00f3 Catalana de la Recerca i Estudis Avan\u00e7ats (ICREA)  Barcelona 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