{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T18:27:01Z","timestamp":1793125621439,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Due to their potential impact on mood and wellbeing there has been increasing interest in the potential of serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) in the treatment of major depressive disorder (MDD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>The aim of Part A of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) profile of escalating doses of SPL026 (DMT fumarate) in psychedelic-na\u00efve healthy participants to determine a dose for administration to patients with MDD in the subsequent Phase 2a part of the trial (Part B: not presented in this manuscript).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the Phase 1, randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial, psychedelic-na\u00efve participants were randomized to placebo (<jats:italic>n<\/jats:italic>\u2009=\u20098) or four different escalating doses [9, 12, 17 and 21.5\u2009mg intravenously (IV)] of SPL026 (<jats:italic>n<\/jats:italic>\u2009=\u20096 for each dose) together with psychological support from 2 therapy team members. PK and acute (immediately following dosing experience) psychometric measures [including mystical experience questionnaire (MEQ), ego dissolution inventory (EDI), and intensity rating visual analogue scale (IRVAS)] were determined. Additional endpoints were measured as longer-term change from baseline to days 8, 15, 30 and 90. These measures included the Warwick and Edinburgh mental wellbeing scale and Spielberger\u2019s state-trait anxiety inventory.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SPL026 was well tolerated, with an acceptable safety profile, with no serious adverse events. There was some evidence of a correlation between maximum plasma concentration and increased IRVAS, MEQ, and EDI scores. These trends are likely to require confirmation in a larger sample size. Using the analysis of the safety, tolerability, PD, PK results, doses of 21.5\u2009mg SPL026 were the most likely to provide an intense, tolerated experience.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Based on the data obtained from this part of the trial, a dose of 21.5\u2009mg SPL026 given as a 2-phase IV infusion over 10\u2009min (6\u2009mg\/5\u2009min and 15.5\u2009mg\/5\u2009min) was selected as the dose to be taken into patients in Part B (to be presented in a future manuscript).<\/jats:p><jats:p><jats:bold>Clinical trial registration:<\/jats:bold><jats:ext-link>www.clinicaltrials.gov<\/jats:ext-link>, identifier NCT04673383; <jats:ext-link>https:\/\/www.clinicaltrialsregister.eu<\/jats:ext-link>, identifier 2020-000251-13; <jats:ext-link>https:\/\/www.isrctn.com\/<\/jats:ext-link>, identifier ISRCTN63465876.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2023.1305796","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T17:04:55Z","timestamp":1704992695000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial"],"prefix":"10.3389","volume":"14","author":[{"given":"Ellen","family":"James","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Erritzoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffanie","family":"Benway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelah","family":"Joel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Timmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Good","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Agnorelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Barba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Baker Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Topping","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm","family":"Boyce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Routledge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2520","DOI":"10.3390\/molecules27082520","article-title":"Psychedelics: alternative and potential therapeutic options for treating mood and anxiety disorders","volume":"27","author":"Lowe","year":"2022","journal-title":"Molecules"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/bf02157378","article-title":"Dimethyltryptamine: its metabolism in man; 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