Daldegan-Bueno, DimitriDonegan, Carina JoySumner, RachaelForsyth, AnnaJeong, Soo HeeEvans, WilliamAlshakhouri, MalakMurphy, Robin JReynolds, LisaHoeh, NicholasAllen, NathanSundram, FrederickMenkes, DavidMuthukumaraswamy, Suresh2026-02-252026-02-252026-02-17Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 0278-5846 (Print); 1878-4216 (Online), Elsevier, 111645-111645. doi: 10.1016/j.pnpbp.2026.1116450278-58461878-4216http://hdl.handle.net/10292/20676INTRODUCTION: Despite growing interest in microdosed psychedelics, clinical trial evidence remains limited. We present daily mood, subjective perception of effects, and pharmacokinetics from an 8-week regimen of microdosed lysergic acid diethylamide (LSD) as a treatment for major depressive disorder in an open-label trial in which participants reported a mean symptom reduction of 60%. METHODS: Participants took 16 sublingual LSD doses: 8 μg onsite, with bloods collected at eight time-points, then twice weekly at home with titration (6-20 μg). Pharmacokinetic parameters were estimated using non-compartmental and compartmental modelling. Daily questionnaires were used to assess depression severity with the self-reported Hamilton Depression Rating Scale (HAMD6), and mood with visual analogue scales (VAS). Drug effects were recorded with VAS scales on each dosing day. Linear mixed models were used to compare dosing days to one- and two-day post-dosing, and to identify linear trends (tolerance/sensitisation) of drug effects. RESULTS: Nineteen participants (males n = 15, 79%) received the intervention. Daily VAS indicated increased scores of mood-related states (e.g., more creative, happier) on dosing days (p = 0.009 to 0.039), but not in depression (p = 0.291). There was no indication of tolerance or sensitisation (p > 0.081). Non-compartmental AUC0-tlast was 836 ± 319 pg.h/mL, Cmax 212 ± 77.7 pg/mL and Tmax 1.17 ± 0.56 h. DISCUSSION: Results suggest short-term improvements in mood following microdosed LSD in people with depression, warranting confirmation in controlled trials. It provides the pharmacokinetic parameters of 8 μg of LSD in a sample of people with depression and indicates no tolerance or sensitisation to repeated microdoses of LSD, despite incremental dose titration.© 2026 The Authors. Published by Elsevier Inc. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You are not required to obtain permission to reuse this article.LSDMajor depressive disorderMicrodosingPharmacokineticsPsychedelics11 Medical and Health Sciences1103 Clinical Sciences1109 Neurosciences17 Psychology and Cognitive SciencesPsychiatry3101 Biochemistry and cell biology3202 Clinical sciences3209 NeurosciencesJournal ArticleOpenAccess10.1016/j.pnpbp.2026.111645