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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 Psychedelics Medical study Hallucinogen therapy Research trial Mood disorder LSD Lysergic Aci |
| Citations | 21 |
| Registration | NCT03866252 |
| Key findings | 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.