Inhaled mebufotenine improves symptoms of depression in a phase 2 trial

This is a study that evaluates the effect of mebufotenin (5-MeO-DMT), a fast-acting psychoactive molecule (peak effect within minutes and duration <1 hour), as a treatment for treatment-resistant depression (non-response to more than two antidepressants).

The study is a randomized clinical trial with 40 patients who received mebufotenin and 41 who received placebo.

The results show a high efficacy of the treatment (more than a 15-point reduction on a 60-point scale compared to placebo) as early as two hours after administration. The effect was maintained one week later.

In addition, nearly 60% of patients achieved remission of depression (minimal symptoms) in the treatment group, compared to 0% in the placebo group.

No serious adverse effects were observed; those reported were mild to moderate and transient.

Limitations

Mebufotenin is administered by inhalation, requires supervision, and produces a psychedelic effect that may be distressing for many people, making prior preparation and professional supervision necessary.

Participation in the study requires discontinuation of antidepressant treatment for at least two weeks, which may lead to clinical worsening and potentially amplify the observed treatment effect.

The response lasts for one week after a single administration (it is not a daily treatment). However, in medium- to long-term follow-up (six months), patients experience depressive relapses, most of which are resolved with re-administration (87% remain in remission after additional doses; these results will be published in another article).

Blinding effect: although the study is randomized, the psychedelic effect is difficult to conceal. The placebo does not produce perceptual changes (sensory alterations, ego changes, or mystical experiences), so blinding is limited.

Selection bias: participants know they may receive a psychedelic, which may introduce expectation bias (greater placebo effect).

Conclusions

This is an effective, rapid treatment without serious adverse effects.

It has a clearly different profile compared to classical antidepressants: rapid effect, no need for daily administration, and efficacy within hours rather than weeks.

The main limitation is the induction of transient psychedelic effects, which requires supervised administration by trained professionals, making at-home use unfeasible.

In this study, psychotherapy was not administered, which could potentially increase the treatment’s effectiveness.

The use of psychedelics opens a very promising therapeutic avenue for treatment-resistant depression.