{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:02:07Z","timestamp":1789988527827,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Diamond Therapeutics, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Psilocybin shows therapeutic promise for several psychiatric disorders, but the acute perceptual and cognitive alterations produced by conventional doses (10\u201325 mg) require in-clinic supervision, which limits scalability. Whether the therapeutically relevant pharmacology of psilocybin can be safely separated from its hallucinogenic activity remains unresolved. To address this gap, we conducted a Phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study to characterize the safety, pharmacokinetics, and pharmacodynamics of low doses of psilocybin. Methods: Fifty-six healthy adults received a single oral dose of psilocybin (0.5, 1.0, 1.5, 2.5, 3.5 or 4.0 mg) or matching placebo across seven sequential cohorts, with each dose escalation reviewed by a Drug Safety Review Committee. All participants completed the study with no serious adverse events or discontinuations. Results: Treatment-emergent adverse events were comparable to placebo and most prominently arose as somnolence. Plasma psilocin appeared rapidly with a median time to maximum concentration &lt;1 h with dose-proportional exposure and a short terminal half-life. Subjective drug effects were dose-related and became distinguishable from placebo at doses \u22652.5 mg. Peak subjective ratings increased with dose, while altered-state scores remained low and cognitive changes did not differ from placebo. Psychophysiological engagement was confirmed by a clear dose-dependent pupillary dilation, while cognitive performance (attention, vigilance, working memory, impulse control) showed no dose-dependent decrement, and state anxiety did not increase at any dose. Conclusions: These findings suggest that low-dose psilocybin may produce perceptible pharmacological effects without significant perceptual alterations or cognitive impairment. The results also offer preliminary support for considering controlled outpatient Phase 2 studies assessing the safety and feasibility of repeated, self-administered low-dose psilocybin. Retrospective ClinicalTrials.gov Registration on 17 July 2026 #NCT07710027.<\/jats:p>","DOI":"10.3390\/ph19091496","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:25:43Z","timestamp":1789986343000},"page":"1496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study to Identify a Subperceptual Dose of Psilocybin in Healthy Adults"],"prefix":"10.3390","volume":"19","author":[{"given":"Naama","family":"Levy-Cooperman","sequence":"first","affiliation":[{"name":"Altreos Research Partners, Inc., Toronto, ON M6P 1C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Sellers","sequence":"additional","affiliation":[{"name":"Diamond Therapeutics, Inc., Toronto, ON M5X 1B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Glue","sequence":"additional","affiliation":[{"name":"Diamond Therapeutics, Inc., Toronto, ON M5X 1B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Szeto","sequence":"additional","affiliation":[{"name":"Biopharma Services, Inc., Toronto, ON M9L 3A2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brown","sequence":"additional","affiliation":[{"name":"Thermo Fisher Scientific, Mississauga, ON L5N 7K9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Jarecki-Smith","sequence":"additional","affiliation":[{"name":"Diamond Therapeutics, Inc., Toronto, ON M5X 1B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7758-5022","authenticated-orcid":false,"given":"William J.","family":"Tyler","sequence":"additional","affiliation":[{"name":"Diamond Therapeutics, Inc., Toronto, ON M5X 1B8, Canada"},{"name":"Diamond Therapeutics USA, Inc., Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7460-3598","authenticated-orcid":false,"given":"Michael B.","family":"McDonnell","sequence":"additional","affiliation":[{"name":"Diamond Therapeutics, Inc., Toronto, ON M5X 1B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Carhart-Harris, R.L., Leech, R., Hellyer, P.J., Shanahan, M., Feilding, A., Tagliazucchi, E., Chialvo, D.R., and Nutt, D. 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