Single Intranasal Mebufotenin Dose Reduces Symptoms in Treatment-Resistant Depression

A single dose of intranasal mebufotenin benzoate reduced depressive symptoms at day 29 vs a low-dose comparator in adults with treatment-resistant depression, according to a phase 2b randomized clinical trial published online in JAMA.

Mebufotenin (5-methoxy-N,N-dimethyltryptamine) is a 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A agonist associated with brief psychedelic experiences. The investigators noted that the long in-clinic monitoring needed with psilocybin and lysergic acid diethylamide is a logistical barrier to wider use.

The double-blind trial (NCT05870540), with 8 weeks of blinded follow-up, included 193 adults aged 18 to 75 years at 38 sites in Australia, Europe, and the US whose moderate to severe major depressive disorder had not responded to 2 to 5 antidepressant trials in the current episode. After antidepressant washout as needed, participants were randomly assigned to a single dose of 8mg (n=46), 12mg (n=73), or a subperceptual 0.3mg comparator (n=74), alongside psychological support. On the primary end point, change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 29, scores fell by 11.1 points with 12mg vs 5.5 points with the comparator (mean difference, −5.3; 95% CI, −8.9 to −1.8).

In a secondary comparison, scores fell by 12.5 points with 8mg. Reductions with both doses were similar and significantly greater than with the comparator at all other time points from day 2 to day 57. At day 29, response rates were 35%, 34%, and 12% and remission rates were 26%, 18%, and 8% with 8mg, 12mg, and 0.3mg, respectively. Treatment-emergent adverse events occurred in 76%, 85%, and 73% of participants, and 99.7% of events were mild or moderate. Most participants were deemed ready for discharge within 2 hours of dosing (85% with 8mg and 78% with 12mg).

The investigators concluded that single doses "were well tolerated and produced rapid, robust, and durable reductions in depressive symptoms." They said the treatment could improve access because it needs a shorter monitoring period than psilocybin and fewer clinic visits than esketamine. 

Source: Feifel D, Seynaeve M, Cubała WJ, et al. Single intranasal administration of the psychedelic mebufotenin for treatment-resistant depression: a randomized clinical trial. JAMA. Published online October 26, 2026. doi:10.1001/jama.2026.18380