A single-day dosing of a synthetic formulation of the psychedelic mebufotenin was associated with rapid and significant reductions in depressive symptoms compared to placebo in patients with treatment-resistant depression (TRD), results of a phase 2b study suggested.

Patients reported clinically meaningful improvements in anxiety and quality of life and only mild or moderate treatment-emergent adverse events (TEAEs) after treatment with the drug, GH001, administered in an individualized dosing regimen by inhalation.

“Significant improvements in depression symptoms observed after GH001 vs placebo treatment support its potential as a novel, rapid-acting treatment for treatment-resistant depression,” lead investigator Wiesław J. Cubała, MD, PhD, Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland, and colleagues wrote.

The findings were published online on March 25, 2026, in JAMA Psychiatry.

Unmet Need for TRD Treatments

Few treatments are approved in the US for TRD — defined as failure of at least two trials of antidepressants — which experts say demonstrates a great unmet need for safe, effective pharmacotherapies for the condition.

A growing body of evidence indicates that psychedelics such as psilocybin and N,N-dimethyltryptamine (DMT) may provide rapid symptom reduction in patients with TRD.

Mebufotenin (5-MeO-DMT) is a rapid-acting psychoactive molecule that acts as a nonselective serotonin (5-HT) agonist with high affinity for the 5-HT1A receptor subtype. It is found in nature in seeds, bark, and leaves of a number of plants in the Amazonian rainforest and in the venom of some toad species.

GH001 is a synthetic inhaled formulation of mebufotenin under development by GH Research. Results from a small 2023 phase 1/2 trial showed safety and efficacy in 16 patients with TRD.

The new phase 2b 7-day, double-blind, randomized controlled trial included 81 White adults with TRD at 16 European sites. Participants received either GH001 (mean age, 41.6 years; 60% female) or placebo (mean age, 43.9 years; 53.7% female). Baseline demographic and clinical characteristics were comparable across groups and participants were required to discontinue antidepressant treatment for at least 2 weeks prior to the study.

GH001 was administered via inhalation. Patients received up to three escalating doses of the drug (6, 12, and 18 mg) or a placebo on a single day with a 1-hour interval between doses.

At day 8, the GH001 group reported statistically significant and clinically meaningful improvements in Montgomery-Åsberg Depression Rating Scale score with GH001 (P < .001; effect size, -2.0) and 57.5% were in remission compared to none in the placebo group. Response rate was 60% in the treatment group compared to none in the placebo group.

At day 8, GH001 treatment was also associated with significant improvements in symptoms of anxiety, global illness severity, and patient-reported quality of life compared to placebo.

Favorable Safety Profile

All TEAEs were mild or moderate and did not lead to treatment discontinuation in either group. TEAEs occurred in 72.5% of GH001-treated patients and 7.3% of placebo-treated patients. The most common TEAEs in treated patients were nausea, salivary hypersecretion, paraesthesia, dysgeusia, and headache. In the placebo group, headache was the only reported TEAE.

There was no evidence of treatment-emergent worsening of suicidal ideation or intent, psychotic symptoms, or dissociation at discharge. And results of the Challenging Experience Questionnaire suggested that the psychoactive experience was well tolerated in most patients.

“The favorable safety and tolerability profile, including short duration of psychoactive effects and rapid discharge readiness, further supports its [GH001’s] suitability for clinical use,” the authors wrote.

Following completion of part 1 of the study, all patients were automatically enrolled in a 6-month open-label extension (OLE), during which they were eligible for up to five GH001 treatments.

Time to first retreatment among eligible OLE participants was 6 weeks. Among those who were in remission at the conclusion of part 1, 13% remained in remission during the 6-month OLE and received no additional treatment.

Initial OLE findings indicate that most patients achieved sustained remission with relatively infrequent GH001 treatments. Investigators said that full results from the OLE will be presented in a subsequent report.

GH001’s psychoactive effects are difficult to conceal, which may have limited blinding, investigators noted. Other study limitations included that relatively few patients with an extensive history of treatment resistance or prolonged chronic illness and the short duration of the double-blind part of the trial.

In 2023, the FDA issued a clinical hold on an investigational new drug application and called for the manufacturer, GH Research, to conduct additional safety testing. The agency lifted that hold in January of this year, clearing the way for the company to enroll US participants in clinical studies of the drug, the company reported.

The study received funding from GH Research. Cubała reported receiving grants from GH Research during the conduct of the study; grants from GH Research, Beckley Psytech, Compass Pathways, HMNC Brain Health, Janssen, MindMed, Novartis, and Otsuka; and personal fees from Angelini, Douglas Pharmaceuticals, Polpharma, and Tasman Therapeutics, outside the submitted work. See paper for conflicts of interest of other study authors.