AMSTERDAM — An investigational inhaled psychedelic therapy was associated with significant improvement in treatment-resistant depression (TRD), with benefits reported within 2 hours of treatment and persisting for at least 6 months, a new study showed.

GH001, under development by GH Research PLC, is a vaporized synthetic formulation of the psychedelic mebufotenin, a nonselective serotonin (5-HT) agonist.

Compared with the placebo group, which showed no response or remission by day 8 of the phase 2b double-blind trial, participants who received GH001 demonstrated a 60% response rate, with 57.5% achieving remission. This effect was mostly maintained through the 6-month open-label extension (OLE) phase.

Most adverse events were mild-to-moderate, and there was no evidence of treatment-emergent suicidal ideation or behavior, investigators reported.

“GH001 has demonstrated a rapid onset of action and a favourable safety profile, low incidence adverse events, and rapid resolution of psychoactive effects within minutes. This facilitates prompt discharge readiness, distinguishing it from other psychoactive and dissociative molecules,” senior author Wiesław J. Cubala, MD, PhD, professor of psychiatry at the Medical University of Gdańsk in Gdańsk, Poland, told Medscape Medical News.

The findings were presented on October 13 at the 38th European College of Neuropsychopharmacology Congress (ECNP) 2025.

An Unmet Need

Nearly one third of patients with depression don’t respond to initial antidepressant treatments, creating a need for therapies that target TRD, researchers noted. 

“Despite the availability of multiple antidepressant therapies, their onset of action is often slow, and nearly 30% of patients continue to experience significant depressive symptoms, with only about 15% achieving remission,” Cubala said.

Following completion of a phase 1 and a phase 1/2 trial, researchers launched a double-blind, placebo-controlled, phase 2b study with 81 nonpsychotic patients with TRD  (mean age, 43 years; 57% female) whose current major depressive episode had lasted a mean of 57.1 weeks and whose first depressive episode occurred a mean of 11.7 years earlier.

At baseline, the cohort’s mean Hamilton Depression Rating Scale-17 score was 24.8, and the mean Montgomery−Åsberg Depression Rating Scale (MADRS) score was 28.6. Treatment response was defined as a MADRS score of ≤ 10, and remission was defined as a ≥ 50% reduction in MADRS from baseline.

Participants received an individualized dosing regimen of up to three escalating doses of GH001 (6, 12, and 18 mg) or placebo on a single day.

Compared with the placebo after an 8-day double-blind, placebo-controlled initial phase, patients treated with GH001 had a mean reduction of -15.5 in the MADRS score from baseline to day 8 (P < .0001).

The treatment group also reported significantly better rates of response (60% vs 0%; P < .0001) and remission (57.5% vs 0%; P < .0001), for a number-needed-to-treat of two, “which is not commonly seen in psychiatry,” Cubala noted.

Long-Term Benefits

All participants in the original trial entered the 6-month OLE, with 63 completers. During this phase, patients visited the clinic on day 15 and monthly thereafter for assessments and standard of care psychological support. If needed, they could receive a readministration of GH001, up to a total of five individualized doses during the study period. 

Participants who received a placebo during the initial phase reported the same rapid and significant drop in MADRS score at 2 hours after treatment with GH001 in the OLE phase, said Cubala.

After a mean of four readministrations over the 6-month OLE, the remission rate was 73%.

“It’s really interesting to see that with the concept of individualized dosing regimens and repetitive dosing, you can sustain remission across 6 months and durability of the effect,” said Cubala.

Treatment-emergent adverse effects (TEAEs) were reported in the majority (89%) of participants, but most were mild-to-moderate. One serious adverse event was reported, but researchers said it was most likely unrelated to the treatment.

TEAEs reported in at least 10% of participants included nausea (46%), paresthesia (38%), salivary hypersecretion (30%), headache (14%), muscle tightness (16%), feeling cold (14%), oral paresthesia (12%), and anxiety (10%).

“What was of prime interest was there was no treatment-emergent suicidality, which is always a concern for patients with mood disorders, especially in treatment-resistant depression, and there were no issues regarding the respiratory system, which is very important because this is an inhaled formulation of the compound,” said Cubala.

He said the median duration of the psychoactive effect, “which is a high-intensity psychedelic experience,” was 11 minutes, with patients being ready for discharge within an hour of dosing.

Promising Findings

Asked to comment, session co-chair Mark Weiser, MD, chairman of the Division of Psychiatry, Sheba Medical Center, and professor of psychiatry at Tel Aviv University School of Medicine, Tel Aviv, Israel, said the findings are promising.

“The results are amazing. We never see results this great. This is not the first study on psychedelics, and not all psychedelics show you such a robust improvement. It’s a huge effect,” he said.

But Weiser, who was not involved in the research, pointed out that blinding is almost impossible in psychedelic studies, including this one.

“Because, almost by definition, you get to get a buzz, and you can’t really hide that. Probably it’s best not to use a placebo and maybe give something that gives some sort of a psychological effect, even just like a benzodiazepine so that it’s not so obvious,” he said.

Weiser also suggested an improvement to the research would be to include an active control group, rather than a placebo.

The study was funded by GH Research PLC. Cubala reported receiving grants from Acadia, Angelini, Beckley Psytech, GH Research PLC, HMNC Brain Health, Intra-Cellular Therapies, Janssen Pharmaceuticals, Merck Sharp & Dohme (MSD), Neumora, Novartis, Otsuka, and Recognify Life Sciences and reported receiving honoraria from Angelini, GH Research PLC, Janssen, and Novartis. He also reported sitting on advisory boards for Douglas Pharmaceuticals, GH Research PLC, Janssen, MSD, and Novartis. Weiser reported having no conflict.