LSD microdosing for major depressive disorder: Mood and pharmacokinetic outcomes from a Phase 2a trial

Can repeated low (“micro”) doses of LSD could improve symptoms in people with major depressive disorder (MDD)?

This Phase 2a study examined whether repeated low (“micro”) doses of LSD could improve symptoms in people with major depressive disorder (MDD), while also characterizing the drug’s pharmacokinetics and tolerability.

Abstract

Introduction: 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.

This Phase 2a trial found that repeated LSD microdosing in people with major depressive disorder:

• was generally tolerable,

• produced measurable pharmacokinetic exposure,

• and was associated with improvements in depressive symptoms despite minimal psychedelic intoxication.

The study showed that some antidepressant effects of psychedelics may occur at low, minimally perceptual doses, though larger controlled trials are needed to determine how robust and clinically meaningful those effects truly are.

Daldegan-Bueno D, Donegan CJ, Sumner R, Forsyth A, Jeong SH, Evans W, Alshakhouri M, Murphy RJ, Reynolds L, Hoeh N, Allen N, Sundram F, Menkes DB, Muthukumaraswamy S. LSD microdosing for major depressive disorder: Mood and pharmacokinetic outcomes from a Phase 2a trial. Prog Neuropsychopharmacol Biol Psychiatry. 2026 Mar 20;145:111645. doi: 10.1016/j.pnpbp.2026.111645. Epub 2026 Feb 17. PMID: 41713673. Read Paper

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