Inhaled 5-MeO-DMT (GH001) vs placebo for treatment-resistant depression: phase 2b trial

The question

Can a single day of treatment with inhaled mebufotenin (GH001), a synthetic form of the psychedelic 5-MeO-DMT, reduce depression symptoms in people whose depression has not responded to several antidepressants?

What they did

This was a phase 2b trial at 16 sites in Europe, running from May 2023 to March 2025. Adults aged 18 to 64 with treatment-resistant depression (no response to 2 to 5 oral antidepressants, current episode up to 2 years) were included; 128 were assessed and 81 were randomized. Participants received either an individualized regimen of up to three escalating doses of GH001 (6, 12 and 18 mg) or a matching placebo regimen, all on a single day. Neither participants nor researchers knew who got what. The main measure was the change in the Montgomery-Åsberg Depression Rating Scale (MADRS, a 0-60 clinician-rated depression score) from the start to day 8.

What they found

Of the 81 people randomized, 40 received GH001 and 41 received placebo. Depression scores fell significantly more with GH001 than with placebo at day 8 (least squares mean difference -15.5, standard error 1.7; P < .001; effect size -2.0). Remission (a MADRS score of 10 or less) at day 8 was reached by 23 of 40 people (57.5%) on GH001 and 0 of 41 (0%) on placebo. No severe or serious adverse events were reported during the placebo-controlled period.

The fine print

The placebo-controlled part of the trial lasted only 7 days, so nothing here shows how long the benefit lasts; a 6-month open-label extension was planned but its results are not in this abstract. With 81 participants this is a mid-sized trial, and the noticeable effects of an inhaled psychedelic make it hard for participants to stay truly blinded, which can inflate apparent benefit. Participants were adults under 65 with episodes lasting up to two years, so the findings may not apply to everyone with treatment-resistant depression. This summary is based on the abstract alone.

What it means

In this randomized trial, a single day of inhaled GH001 produced a large short-term drop in depression scores compared with placebo, with no serious adverse events reported in the first week. Longer and larger studies are needed to show whether the benefit holds up over time.

Evidence grade: Moderate. A randomized, double-blind, placebo-controlled trial, but with a modest sample, only one week of placebo-controlled follow-up, and a strong drug experience that makes true blinding difficult.

This summary is based on the study’s published abstract.