Single-Day GH001 for TRD Shows Rapid Response, With Michael E. Thase, PhD

A single-day dose of inhaled mebufotenin (GH001), a psychedelic-based intervention, demonstrated rapid and clinically meaningful improvements in depressive symptoms among adults with treatment-resistant depression (TRD), a new phase 2b study showed. GH001 improved depression severity within 1 week.

Rapid-acting treatments, including neuromodulation and glutamatergic agents, have expanded the therapeutic landscape of TRD. Yet, these treatments often require repeated visits and prolonged monitoring. The GH001 individualized dosing approach, allowing up to 3 escalating doses administered on a single day, was designed to optimize response while minimizing treatment burden.

“An 8-hour visit really taxes your clinical space,” Thase said. “It is true that you might have a dosing space for the first hour or 2 where it's more medical and then a recovery room area for the subsequent 4 to 6 hours…but you do have to have staff available, even if you're not emphasizing the psychotherapeutic aspects of a psychedelic experience. In the GH study, we had kindly professional people who prepared the patients for the treatment, who were there with the patient when they had the treatment and [the]… debriefing…we did not attempt to involve the patient's recollection of their experience with any kind of growth-oriented psychotherapy.”

Thase said when you add the psychotherapy component, you need more space and need to spend more money on a psychotherapist. Without psychotherapy, it is more scalable for practices to treat patients with GH001.

“The GH001 is taken through a warm, aerosolized inhalation, and so it is not excessively medical,” he continued. “You don’t need a nurse or a physician because you're giving a controlled substance. It’s not the same thing as putting an IV in. It has about the same medical complexity as intranasal esketamine.”

Intranasal esketamine requires a patient to stay in the clinic for 2 hours post-administration. The required observation period for GH001, if any, would be determined after the FDA reviews phase 3 data.

“That's several years from now, at the soonest,” he said.

In the randomized, double-blind phase 2b trial, 81 adults with TRD were assigned to individualized GH001 dosing (6 mg, 12 mg, and 18 mg) or placebo. The primary endpoint—change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 8—favored GH001, with a least squares mean difference of −15.5 points (P <.001) and a large effect size. Remission at day 8 occurred in 57.5% of GH001-treated participants compared with none receiving placebo, corresponding to a number needed to treat of 2. Investigators also observed improvements in anxiety, global illness severity, and quality-of-life measures.

The individualized dosing strategy permitted escalation at 1-hour intervals when tolerated and when peak psychoactive effects were not achieved. Median psychoactive effects lasted approximately 9 to 14 minutes, depending on dose. Most patients were discharge-ready approximately 1 hour after dosing, suggesting compatibility with outpatient care workflows.

The safety profile observed in the trial was consistent with prior psychedelic research. Treatment-emergent adverse events occurred in 72.5% of GH001-treated participants, most commonly nausea, salivary hypersecretion, and paresthesia. All events were mild or moderate, and no serious adverse events, discontinuations, or clinically significant changes in vital signs were reported. No treatment-emergent suicidal behavior occurred.

Durability findings from the 6-month open-label extension suggested that many responders required intermittent retreatment. Median time to first retreatment was approximately 6 weeks, and most patients who achieved remission after initial dosing maintained remission with infrequent additional treatments. These findings indicate potential for periodic maintenance rather than continuous therapy.

Thase highlighted the potential role of GH001 in patients who have not responded to multiple pharmacologic classes. He emphasized that rapid onset may allow clinicians to determine effectiveness within days, which may be particularly valuable in urgent clinical scenarios.

“We did not have anybody who didn't really respond and then slowly got better,” Thase said. “People were either better [or not], and it was clear at the end of a week that they got a good response. Knowing for certain if the treatment is going to be valuable quickly is a real advantage.”

Part 1 of the interview with Thase can be viewed here.

Relevant disclosures for Thase include Otsuka Pharmaceutical, Janssen Scientific Affairs, E.R. Squibb & Sons, Eli Lilly and Company, H. Lundbeck A S, Boehringer Ingelheim International GmbH, and ITI, Inc. (d/b/a Intra-Cellular Therapies, Inc.).

References

Cubala WJ, Bajbouj M, Bauer M, et al. GH001 vs Placebo in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online March 25, 2026. doi:10.1001/jamapsychiatry.2026.0096