Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial.
Felix Müller, Hannes Zaczek, Anna M Becker, Laura Ley, Stefan Borgwardt, Joyce Santos de Jesus, Nico Loh, Jan Kohut, Mathias Auernig, Christopher Boehlke, Matthias E Liechti
Med (New York, N.Y.) June 4, 2025 DOI: 10.1016/j.medj.2025.100725 via PubMed
Summary
AI-generated from the abstractIn a double-blind, low-dose controlled trial, 61 patients with moderate-to-severe major depressive disorder received supportive psychotherapy and either two high doses (100 μg then 200 μg) or two low doses (25 μg each) of LSD. At the primary endpoint two weeks after the second session, the high-dose group showed a greater average reduction in self-rated depression scores (11.8 points) compared to the low-dose group (3.9 points), a difference that approached but did not reach statistical significance. Clinician-rated scores also favored the high dose, but significance was lost after adjusting for baseline depression severity. Improvements were numerically maintained through 12 weeks. Adverse events were similar between groups. The authors suggest these exploratory results warrant a larger phase 3 trial.
Study at a glance
| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 61 |
| Population | Patients with moderate-to-severe major depressive disorder |
| Intervention | LSD-assisted therapy |
| Dose | 100 μg + 200 μg or 25 μg + 25 μg |
| Duration | Two dosing sessions; primary endpoint at 2 weeks after second administration; follow-up at 6 and 12 weeks after second administration |
| Topics | Depression LSD Psychedelic-assisted therapy |
| Keywords | Translation to patients Clinical trial Hallucinogens |
| Citations | 21 |
| Registration | NCT03866252 |
| Key finding | High-dose LSD-assisted therapy produced greater reductions in depression scores than low-dose therapy at two weeks, but the difference was not statistically significant after adjusting for baseline severity. |
Abstract
This trial aimed to assess the efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with moderate-to-severe major depressive disorder. This was a randomized, parallel, double-blind, low-dose controlled trial (Clinicaltrials.gov: NCT03866252). Patients were randomly assigned in a 1:1 ratio to receive supportive psychotherapy and either 100 μg + 200 μg LSD or 25 μg + 25 μg LSD in two dosing sessions. The primary endpoints were the changes in scores on the Inventory of Depressive Symptomatology, in the Clinician-Rated (IDS-C) version (assessed by the treating therapist) and the Self-Rated (IDS-SR) version, from baseline to 2 weeks after the second administration. The IDS scores were also assessed 6 and 12 weeks after the second administration. Thirty-one patients were randomized to the low-dose group, and 30 were randomized to the high-dose group. At the primary endpoint, least-squares mean change (LSM) in IDS-SR scores was -3.9 in the low-dose and -11.8 in the high-dose group (difference: -7.9; 95% CI, -16.0 to 0.3; effect size: -0.5; p = 0.059). LSM in IDS-C scores was -3.6 in the low-dose and -12.9 in the high-dose group (difference: -9.2; CI, -17.1 to -1.3; effect size: -0.6; p = 0.023; corrected <0.05). However, significance was not reached after adjusting for baseline depression scores (p = 0.086). Both outcomes remained numerically consistent up to the final follow-up at 12 weeks. Adverse events were comparable between groups. The findings of this exploratory study support further investigation of LSD-assisted therapy in depression in a larger phase 3 trial. Gertrud Thalmann Fund for depression research.