Inhaled Psychedelic Therapy Shows Rapid TRD Relief in Phase 2b Trial
Key Clinical Summary
- In a randomized, double-blind phase 2b trial at 16 European sites, single-day inhaled mebufotenin (GH001) significantly improved depressive symptoms in adults with treatment-resistant depression (TRD) compared with placebo by day 8 posttreatment.
- Remission occurred in 57.5% of patients receiving GH001 versus 0% with placebo, and response rates were 60.0% versus 0%, respectively.
- GH001 was associated with frequent but mostly mild to moderate adverse events, with no severe or serious adverse events, no discontinuations due to adverse events, and no suicidal behaviors reported during the placebo-controlled period.
A phase 2b randomized clinical trial published in JAMA Psychiatry found that inhaled GH001, a synthetic formulation of mebufotenin, produced rapid antidepressant effects in adults with treatment-resistant depression (TRD).
The trial was conducted at 16 sites in Europe and compared a single-day individualized dosing regimen of GH001 with placebo over a 7-day double-blind period, followed by a 6-month open-label extension.
Study Findings
The study enrolled adults aged 18 to 64 years with treatment-resistant depression, defined as nonresponse to 2 to 5 oral antidepressant treatments and a current depressive episode lasting up to 2 years. Of 128 patients assessed, 81 were randomized, with 40 assigned to GH001 and 41 assigned to placebo. All participants completed the placebo-controlled portion of the trial.
Patients received an individualized dosing regimen of up to 3 escalating inhaled doses on day 1 (6, 12, and 18 mg) spaced 1 hour apart. In the GH001 group, 22.5% received 1 dose, 52.5% received 2 doses, and 25.0% received all 3 doses; median psychoactive effects ranged from 9.0 to 14.0 minutes across doses.
The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 8. Least squares mean MADRS change was −15.2 with GH001 versus 0.3 with placebo, for a least squares mean difference of −15.5 (1.7; P < .001; Cohen d, -2.0). Day 8 remission rates were 57.5% with GH001 and 0% with placebo, while response rates were 60.0% and 0%, respectively; the number needed to treat was 2 for both remission and response.
Secondary endpoints also favored GH001. The least squares mean differences versus placebo were −10.0 for Hamilton Rating Scale for Anxiety, −2.5 for Clinical Global Impression-Severity, and 21.4 for Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form scores.
Clinical Implications
For clinicians managing treatment-resistant depression, the findings suggest that GH001 may offer a rapid-acting intervention after inadequate response to multiple antidepressant trials. The study’s placebo-controlled data showed clinically meaningful symptom improvement within 8 days after a single-day dosing regimen, which is notable in a population with substantial unmet treatment needs.
Safety will remain central to interpretation. Treatment-emergent adverse events occurred in 72.5% of GH001-treated patients versus 7.3% of placebo-treated patients, but all adverse events in the GH001 group were mild or moderate. The most common events were nausea, salivary hypersecretion, paresthesia, dysgeusia, and headache. No patients discontinued treatment because of adverse events.
The trial also reported no suicidal behaviors during scheduled assessments and no evidence of treatment-emergent positive psychotic symptoms or clinically significant dissociation after psychoactive effects had subsided. Most patients were discharge-ready 1 hour after dosing.
Expert Commentary
Wiesław J. Cubałam MD, PhD, Department of Psychiatry, Medical University of Gdańsk, Poland, and co-authors concluded that “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.”
