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

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.