Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial.

Jun 7, 2025Med (New York, N.Y.)

Effectiveness and safety of low versus high doses of LSD therapy in people with major depression

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Abstract

A change of -11.8 in self-rated depression scores was observed in patients receiving high-dose LSD compared to a change of -3.9 in those receiving low-dose LSD.

Thirty-one patients were in the low-dose group and 30 in the high-dose group.
The high-dose group showed a significant reduction in clinician-rated depression scores, with a least-squares mean change of -12.9.
The difference in clinician-rated scores between the low and high-dose groups was -9.2, indicating greater improvement in the high-dose group.
Both groups experienced comparable adverse events, suggesting similar safety profiles.
Significance for the primary endpoint was not reached after adjusting for baseline depression scores.

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BACKGROUND: This trial aimed to assess the efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with moderate-to-severe major depressive disorder.

METHODS: 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.

FINDINGS: 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.

CONCLUSIONS: The findings of this exploratory study support further investigation of LSD-assisted therapy in depression in a larger phase 3 trial.

FUNDING: Gertrud Thalmann Fund for depression research.

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Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial.

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