{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:17:56Z","timestamp":1774621076048,"version":"3.50.1"},"reference-count":105,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Psilocybin has re-emerged as a promising intervention for neuropsychiatric disorders including major depressive disorder, treatment-resistant depression, anxiety associated with life-threatening illness, obsessive compulsive disorder, and substance use disorders. However, conventional randomized controlled trials (RCTs)\u2014the current gold standard in evidence-based medicine\u2014may not adequately capture the therapeutic complexity of psilocybin, which depends not only on pharmacological action but also on contextual, psychological, and interpersonal factors. This critical narrative review aimed to evaluate the adequacy of existing clinical research frameworks for assessing psilocybin\u2019s therapeutic potential and to explore alternative methodologies that may better reflect real-world clinical conditions. Methods: Using the Web of Science Core Collection database, we identified and analysed the ten most cited clinical studies on psilocybin published between 2015 and 2025 inclusive. Additional literature was included through reference cross-checking, systematic reviews, meta-analyses, and interdisciplinary sources covering neurobiology, history, and real-world evidence (RWE). The review synthesizes clinical outcomes, methodological constraints, and epistemic considerations relevant to psychedelic-assisted therapy. Results: Evidence from highly cited trials demonstrates rapid and sustained antidepressant and anxiolytic effects of psilocybin, with notable benefits also observed in addiction treatment. However, significant methodological limitations were identified, including selection bias, challenges in placebo design and blinding, small sample sizes, and the underrepresentation of diverse populations. Psilocybin outcomes were strongly influenced by subjective experience and contextual factors such as set and setting. Emerging RWE studies revealed heterogeneous patterns of response and provided insights unattainable through RCTs alone. Conclusions: Psilocybin shows considerable therapeutic promise, but current RCT methodologies capture only part of its clinical effects. Comprehensive evaluation will require larger and more diverse clinical trials, long-term follow-up, standardized psychotherapeutic protocols, and the integration of RWE to reflect real-world practice. Psychedelic-assisted therapy should be conceptualized as a complex intervention that combines pharmacological and psychotherapeutic components.<\/jats:p>","DOI":"10.3390\/brainsci16040358","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T15:10:24Z","timestamp":1774537824000},"page":"358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Psilocybin in Neuropsychiatric Disorders: Seeking Valuable Evidence in History, Pure Science, Clinical Trials and Real-World Data (RWD)"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5729-8424","authenticated-orcid":false,"given":"Piotr","family":"Skalski","sequence":"first","affiliation":[{"name":"Department of the History and Philosophy of Medical Sciences, Poznan University of Medical Sciences, 60-356 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2068-7957","authenticated-orcid":false,"given":"Katarzyna","family":"P\u0119kacka-Falkowska","sequence":"additional","affiliation":[{"name":"Department of the History and Philosophy of Medical Sciences, Poznan University of Medical Sciences, 60-356 Poznan, Poland"},{"name":"Tadeusz Manteuffel Institute of History, Polish Academy of Sciences, 00-272 Warszawa, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6402-7857","authenticated-orcid":false,"given":"Agnieszka","family":"Pluto-Pr\u0105dzy\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Immunology, Chair of Pathomorphology and Clinical Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9733-7085","authenticated-orcid":false,"given":"Micha\u0142 K.","family":"Owecki","sequence":"additional","affiliation":[{"name":"Department of the History and Philosophy of Medical Sciences, Poznan University of Medical Sciences, 60-356 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.2147\/DDDT.S443177","article-title":"The promise of therapeutic psilocybin: An evaluation of the 134 clinical trials, 54 potential indications, and 0 marketing approvals on ClinicalTrials.gov","volume":"18","author":"Norring","year":"2024","journal-title":"Drug Des. 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