Single-Day GH001 Produces Rapid Remission in TRD, With Michael E. Thase, MD

A single-day, individualized dosing regimen of inhaled mebufotenin (GH001) was associated with rapid and substantial reductions in depressive symptoms among adults with treatment-resistant depression (TRD), with more than half of treated patients achieving remission by day 8.1 In an interview with HCPLive, Michael E. Thase, MD, from the Perelman School of Medicine at the University of Pennsylvania, provided a clinical perspective on the magnitude of effect and considerations for interpreting the findings.

In the randomized, double-blind phase 2b trial of 81 patients, participants were assigned 1:1 to GH001 (n = 40) or placebo (n = 41) and received up to 3 escalating inhaled doses (6 mg, 12 mg, and 18 mg) within a single day. The primary endpoint, which was the 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 compared with placebo (P < .001; effect size, −2.0). Remission (MADRS ≤10) occurred in 57.5% of patients in the GH001 group versus 0% in the placebo group, corresponding to a number needed to treat of 2. Response rates were 60.0% and 0%, respectively.

“The effect size is the effect of the active treatment divided by the effect of the inactive treatment,” Thase explained. “When the placebo has little effect, you can have a very large effect size. A little more than half of the patients who received…GH001 got substantially better quickly, and no one in the placebo group [did]. The fact that it's about [a] 55% rapid remission is a wonderful thing.”

He added that while the observed remission rate is clinically meaningful, placebo response rates are likely to increase in larger phase 3 trials.

The study’s design may have contributed to the lack of placebo response. GH001 produces a short-duration psychoactive experience, with a median duration of approximately 9 to 14 minutes across doses, allowing for repeated dosing within a single treatment session. Patients who did not achieve a sufficient psychoactive effect were eligible for up to 2 additional doses at 1-hour intervals. All placebo-treated participants received 3 administrations without meaningful psychoactive effects.

“If you got randomized to placebo…you got 3 duds,” Thase said. “You had 3 times the chance to say, ‘hey, this isn't the real thing.’ I don’t think that 50 plus percent remission rate is just a glorified placebo response, but I do think that the 0% absence of real benefit in the placebo arm reflects the fact that folks were expecting a psychedelic experience. By the end of that long morning, they deduce that they lost the coin flip in this study.”

He described this as functional unblinding, a recognized challenge in psychedelic trials, particularly when subjective effects are closely linked to therapeutic outcomes. The US Food & Drug Administration (FDA) brought up this concern with psychedelics during the advisory committee meeting for MDMA-assisted therapy to treat PTSD.2

To reduce bias, efficacy assessments were conducted by independent raters who were not involved in treatment administration and were unaware of patients’ subjective experiences.1 Patients were instructed not to disclose details of their psychoactive response. Despite these measures, Thase acknowledged the limitations of maintaining blinding in this context and noted that regulators have raised similar concerns in prior evaluations of psychedelic therapies.

Beyond the double-blind phase, all 41 placebo non-responders received GH001 in the open-label extension and demonstrated response rates comparable to those initially assigned to active treatment, according to Thase.

“That kind of internal replication within a study is really reassuring that there’s something substantial here,” he said.

Secondary endpoints also favored GH001, with improvements observed in anxiety symptoms, global illness severity, and quality of life measures by day 8. The treatment was generally well tolerated. Treatment-emergent adverse events occurred in 72.5% of patients receiving GH001 and 7.3% receiving placebo, with nausea, salivary hypersecretion, and paresthesia among the most frequently reported events. All adverse events were mild or moderate, and no serious adverse events, discontinuations, or deaths were reported.

Follow-up data from the 6-month extension phase suggest that remission can be maintained with intermittent retreatment. Among patients who achieved remission at day 8, 87% remained in remission at 6 months, typically with limited additional dosing.

For clinicians, Thase emphasized focusing on the observed remission rate rather than the magnitude of the effect size alone.

“A rapid 50-plus percent remission rate is a really good thing,” he said. “Let's hope that…[a] positive result is confirmed in phase 3.”

References

1. 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

2. Kunzmann K. FDA Psychopharmacologic Advisory Committee Votes Against Supporting Effectiveness of MDMA for PTSD. HCPLive. Published on June 4, 2024. Accessed on March 31, 2026. https://www.hcplive.com/view/live-updates-fda-psychopharmacologic-advisory-committee-meeting-mdma-ptsd