Psychedelic Eased Symptoms of Treatment-Resistant Depression

An individualized dosing regimen of the inhaled psychedelic mebufotenin (GH001) led to significant improvements in depression symptoms in patients with treatment-resistant depression, a randomized placebo-controlled trial showed.

Among 81 patients, the least squares mean change in Montgomery-Åsberg Depression Rating Scale score from baseline to day 8 was -15.2 with a single day of treatment with GH001 compared with 0.3 with placebo (least squares mean difference -15.5, P<0.001), reported Michael Thase, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and co-authors.

Day 8 remission rates were 57.5% with GH001 versus 0% with placebo, and no severe or serious adverse events were reported in the placebo-controlled period of the study, they wrote in JAMA Psychiatry.

Fewer than half of patients with major depressive disorder achieve remission with standard antidepressants, Thase and team noted. There are few treatments for treatment-resistant depression — defined as non-response to two to five oral antidepressants — currently approved in the U.S.; this includes esketamine (Spravato) nasal spray.

Matthew Johnson, PhD, of Johns Hopkins University School of Medicine in Baltimore who was not involved in the study, told MedPage Today that “the thing that really jumps out to me is … the complete lack of placebo response.”

It’s possible everyone in the placebo group knew they weren’t getting active drug, and thought, “I guess this isn’t going to work,” Johnson said. That lack of placebo response may be “artificially inflating” the difference between the active drug and placebo.

However, he said he sees “promise” in GH001, given his knowledge of the field. “My guess is that this psychedelic treatment is really helping people,” he noted, adding that he’d like to see studies comparing GH001 to selective serotonin reuptake inhibitors, in addition to dose-effect studies.

He pointed to the psilocybin trial that included a 1-mg dose in the control arm. Using such a miniscule dose allows participants to feel something, while being unlikely to substantially affect depression, Johnson explained.

He said he would also like to see the researchers “assess the blinding” in future studies — meaning ask participants whether they think they were in the active drug or control arm.

This 7-day double-blind phase IIb trial with a 6-month open-label extension phase was conducted at 16 sites in Europe from May 2023 to March 2025. Patients ages 18 to 64 were eligible for the study if they had treatment-resistant depression, with current episode duration of up to 2 years.

Altogether, 81 adults were randomized and completed the placebo-controlled portion of the trial. In the GH001 arm, mean age was 41.6, and 60% were women, and in the placebo arm, mean age was 43.9, and 53.7% were women. Baseline demographics and clinical characteristics were similar between groups.

Of the 40 patients randomized to GH001, 22.5% received one 6-mg dose, 52.5% received 6- and 12-mg doses, and 25% received 6-, 12-, and 18-mg doses, with 1-hour intervals between doses. The median length of psychoactive effect ranged from 9 to 14 minutes for 6-, 12-, and 18-mg doses, and every patient in the placebo arm received three placebo doses.

Johnson said that the fact that a “trip” with GH001 lasts roughly 14 minutes at most versus 6 hours with psilocybin makes it an “attractive” and much less expensive option, as clinicians would not have to “stand around all day and monitor it.”

Treatment-emergent adverse events occurred in 72.5% of patients who received GH001 versus 7.3% of those given placebo. The most common events in the active drug arm were nausea (42.5%), salivary hypersecretion (20%), paresthesia (20%), dysgeusia (7.5%), and headache (7.5%). Only headache (2.4%) was documented in the placebo group. Thase and team found “no evidence of treatment-emergent worsening of suicidal ideation, treatment-emergent suicidal intent or behavior, psychotic symptoms, or dissociation at discharge.”

The authors observed significant improvements in anxiety symptoms and patient-reported quality of life.

A limitation of the study was that the psychoactive effects of GH001 were hard to hide, and may have biased patients and staff by “possibly amplifying perceived benefit or suppressing response,” the authors noted. In the future, the team plans to explore the longer-term efficacy and safety of GH001.