GH001 vs Placebo in Patients With Treatment-Resistant Depression
Wiesław Jerzy Cubała, Malek Bajbouj, Michael Bauer, Bernhard T. Baune, Narcis Cardoner, Fabian Devlin, Kelly Doolin, Rosa María Dueñas Herrero, Matilde Elices, Avril Feeney, M. Gałuszko-węgielnik, Katarzyna Jakuszkowiak-wojten, Luboš Janů, John R. Kelly, Kathryn Ledden, Rachael Maclsaac, Santiago Madero, Shane Mcinerney, Ángel Montejo, Alexander Nawka, Tomáš Páleníček, Víctor Pérez Sola, Johannes G. Ramaekers, Andreas Reif, Philipp Ritter, Fiona Ryan, Claus Bo Svendsen, Claire Sweeney, Theis H. Terwey, Madhukar H. Trivedi, Velichka Valcheva, E. Vieta, Michael E. Thase
JAMA Psychiatry March 25, 2026 Peer reviewed DOI: 10.1001/jamapsychiatry.2026.0096 via OpenAlex
Summary
Inhaled mebufotenin (GH001) significantly improved depression symptoms in patients with treatment-resistant depression compared to placebo. Among the 81 participants, those receiving GH001 had a mean decrease of 15.5 points on the Montgomery-Åsberg Depression Rating Scale by day 8, while none in the placebo group achieved remission. GH001 was well tolerated, with no severe adverse events reported during the trial.
Study at a glance
| Design | randomized controlled trial |
|---|---|
| Sample size | 81 |
| Population | adult patients aged 18 to 64 years with treatment-resistant depression |
| Key finding | GH001 resulted in a significantly greater reduction in depression symptoms compared to placebo. |
Abstract
Importance: Few pharmacotherapies are approved for treatment-resistant depression, and many patients do not achieve remission following treatment with those therapies. Objective: To examine the efficacy and safety of single-day treatment with a synthetic formulation of inhaled mebufotenin (GH001) vs placebo in patients with treatment-resistant depression. Design, Setting, and Participants: This was a 7-day, randomized, double-blind, placebo-controlled phase 2b trial with a 6-month open-label extension phase conducted at 16 sites in Europe from May 2023 to March 2025. Adult patients aged 18 to 64 years with treatment-resistant depression, defined as nonresponse to 2 to 5 oral antidepressant treatments, with current episode duration of up to 2 years were included. Of 128 assessed for eligibility, 81 were randomized and completed the placebo-controlled period of the trial. Interventions: Patients were randomly assigned 1:1 to receive an individualized dosing regimen of up to 3 escalating doses of GH001 (6, 12, and 18 mg) or a placebo individualized dosing regimen on a single day (day 1). Main Outcomes and Measures: The primary efficacy end point was the change from baseline to day 8 in Montgomery-Åsberg Depression Rating Scale total score (range, 0-60; higher scores indicate greater severity of depression), comparing GH001 with placebo. Secondary end points included remission (Montgomery-Åsberg Depression Rating Scale score ≤10) at day 8. Results: Among the 81 patients randomized to GH001 (n = 40) or placebo (n = 41), the mean (SD) age was 41.6 (11.4) years and 43.9 (10.9) years and 24 (60.0%) and 22 (53.7%) were female, respectively. Change in Montgomery-Åsberg Depression Rating Scale score from baseline to day 8 was significantly greater for GH001 vs placebo (least squares mean difference [SE], -15.5 [1.7]; P < .001; effect size, -2.0). Day 8 remission rates were 23/40 (57.5%) with GH001 and 0/41 (0%) with placebo. No severe or serious adverse events were reported in the placebo-controlled period. Conclusions and Relevance: In this study, an individualized dosing regimen of inhaled GH001 resulted in significant improvements in depression symptoms relative to placebo and was well tolerated, supporting its potential as a novel, rapid-acting treatment for treatment-resistant depression. Trial Registration: ClinicalTrials.gov Identifier: NCT05800860.