Psychedelic nasal spray eases treatment-resistant depression for eight weeks

Clinical takeaway: A single dose of investigational mebufotenin nasal spray significantly reduced depressive symptoms in adults with treatment-resistant depression, with benefits emerging within days and persisting for 8 weeks. The treatment's short psychedelic duration and limited monitoring requirements may help address practical barriers associated with psychedelic therapies.

Interest in psychedelic-based treatments for depression continues to grow, but many investigational approaches require prolonged supervision and clinic visits. Mebufotenin (5-MeO-DMT) is a short-acting psychedelic and potent 5-HT1A and 5-HT2A receptor agonist designed to pair rapid administration with durable antidepressant effects. Investigators hypothesize that its strong 5-HT1A activity may contribute to sustained clinical benefit despite psychedelic effects that typically resolve within about an hour.

In a phase 2b randomized trial, 193 adults with moderate-to-severe treatment-resistant depression received a single intranasal dose of mebufotenin 8 mg (n=46), 12 mg (n=73), or a low-dose comparator (n=74), alongside psychological support.

Improvement was evident by day 2, increased through week 4, and remained through the 8-week follow-up. The study's primary endpoint, mean MADRS scores at day 29, had fallen by 12.5 points with the 8 mg dose and 11.1 points with the 12 mg dose, compared with 5.5 points in the comparator group. Approximately one-third of patients receiving mebufotenin achieved a clinical response at day 29 (35% with 8 mg and 34% with 12 mg), compared with 12% of patients receiving the low-dose comparator. Remission rates reached 26%, 18%, and 8% in the 8 mg, 12 mg, and comparator groups, respectively.

Notably, the lower and higher doses produced similar antidepressant benefits, suggesting that greater psychedelic intensity may not be necessary to achieve clinical effect. Improvements were also observed across measures of illness severity, depressive symptoms, and quality of life.

Treatment was generally well tolerated. Most adverse events were mild or moderate and occurred on the day of dosing, with headache, nausea, and nasal administration-site discomfort among the most commonly reported events. No participants discontinued treatment because of adverse events. No suicidal behavior occurred during the trial, and investigators reported no suicide-related safety signals. Additionally, 85% of patients receiving 8 mg and 78% receiving 12 mg were considered ready for discharge within 2 hours of administration.

The results suggest that durable antidepressant benefits may be achievable without the prolonged psychedelic experiences and extended monitoring requirements associated with some other investigational psychedelic therapies.

Source: Feifel D, et al. (2026 Oct 26) JAMA.Single Intranasal Administration of the Psychedelic Mebufotenin for Treatment-Resistant Depression: A Randomized Clinical Trial