Single dose of intranasal mebufotenin cut depression scores in a phase 2b trial of 193 adults

A phase 2b randomized, double-blind trial published in JAMA tested a single intranasal dose of mebufotenin benzoate (5-methoxy-N,N-dimethyltryptamine) in 193 adults with treatment-resistant depression. The study ran from September 2023 to April 2025 at 38 sites in Australia, Europe and the US, with an 8-week blinded follow-up. jamanetwork.comJAMAjamanetwork.comOpen source ↗ Mebufotenin is a 5-HT1A and 5-HT2A agonist associated with brief psychedelic experiences.

Trial design

Participants were aged 18 to 75 years and had moderate to severe major depressive disorder that had not responded to 2 to 5 antidepressants in the current episode. After antidepressant washout as needed, they were randomly assigned to a single dose of 8 mg (n = 46), 12 mg (n = 73) or 0.3 mg (n = 74), the last serving as a low-dose comparator. All received psychological support. The mean age was 41 years (SD, 11.1), and 59.1% of participants were female.

The primary end point was the change in total Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 29, comparing 12 mg with 0.3 mg. The scale runs from 0 to 60, and higher scores mean more severe depression. Eighteen secondary end points were assessed for the 12-mg and 8-mg doses against 0.3 mg. Discharge readiness was assessed starting 90 minutes after dosing.

Results

At day 29, the mean MADRS change was -11.1 (SD, 11.6) with 12 mg and -5.5 (SD, 9.9) with 0.3 mg; the mean difference was -5.3 (95% CI, -8.9 to -1.8; P = .003). With 8 mg the change was -12.5 (SD, 12.7), a difference of -6.2 from the comparator (95% CI, -10.2 to -2.1; P = .003). jamanetwork.comJAMAjamanetwork.comOpen source ↗ The reductions with 8 mg and 12 mg were similar and were significantly greater than with 0.3 mg at all other time points from 2 to 57 days after dosing.

Response rates at day 29 were 35% (8 mg), 34% (12 mg) and 12% (0.3 mg). Remission rates were 26%, 18% and 8%, respectively.

Treatment-emergent adverse events were reported by 76%, 85% and 73% of participants in the 8-mg, 12-mg and 0.3-mg groups, and 99.7% of all events were mild or moderate. Within 2 hours after dosing, 85% of participants in the 8-mg group and 78% in the 12-mg group were deemed ready for discharge.

The authors concluded that single doses were well tolerated and produced rapid and durable reductions in depressive symptoms, and that a shorter monitoring period and fewer clinic visits may ease access compared with psilocybin and esketamine. The results cover one treatment session. The trial is registered at ClinicalTrials.gov, NCT05870540. jamanetwork.comJAMAjamanetwork.comOpen source ↗