Phase 2b Trial Finds Potential Benefit for Mebufotenin Spray in Resistant Depression

A single administration of an experimental, fast-acting psychedelic nasal spray containing synthetic mebufotenin benzoate was associated with improved depression scores over 29 days in a phase 2b trial of adults with treatment-resistant depression, according to randomized clinical trial findings published online in JAMA on October 26, 2026, reported by The Indian Practitioner. The multi-center investigation evaluated whether the short-acting psychedelic compound could deliver meaningful clinical benefits while substantially reducing required in-clinic medical observation times compared to traditional psychedelic therapies like psilocybin or LSD. The compound acts pharmacologically as an agonist on 5-HT1A and 5-HT2A serotonin receptors in the human brain to modulate mood regulation networks.

Fast-Acting Psychedelic Trial and Receptor Mechanics

The double-blind clinical study enrolled 193 adult participants aged 18 to 75 across 38 clinical trial sites located throughout the United States, Australia, and Europe. All participating subjects had previously completed between two and five separate antidepressant courses during their current depressive episodes without achieving adequate clinical symptom remission. Investigators randomized participants to receive a single intranasal dose of synthetic mebufotenin benzoate at 8 mg, 12 mg, or a subtherapeutic 0.3 mg control dose designed to preserve experimental blinding protocols without inducing psychedelic effects.

Investigators concluded that the nasal spray may improve treatment access by requiring a shorter monitoring period and fewer clinic visits.

The Phase 2b clinical trial concluded with follow-up completed on April 28, 2025.

Clinical remission rates reached 26% in the 8-mg group and 18% in the 12-mg cohort at day 29, according to PubMed.

Multi-Center Cohort and Blinded Dosing Structure

A primary objective of the clinical trial centered on assessing patient recovery timelines and post-administration discharge readiness. Clinical personnel initiated formal safety and recovery assessments starting 90 minutes post-dose and continued testing every 30 minutes. In the trial's monitored discharge assessments, 85% of subjects receiving the 8 mg dose and 78% of those in the 12 mg cohort successfully met all standardized medical criteria for clinical discharge within two hours. The brief duration of altered awareness contrasts with conventional psychedelic molecules that mandate extended hours of continuous psychiatric monitoring, addressing a major practical bottleneck in psychedelic mental healthcare delivery.

Two-Hour Clinical Discharge and Recovery Timelines

Beyond immediate post-dose stabilization, the intranasal formulation showed evidence of symptom improvement through the day-29 assessment. When measured at four weeks on the Montgomery-Åsberg Depression Rating Scale, participants receiving the 12 mg strength registered an average five-point improvement over the control cohort across the 60-point assessment. The study's prespecified primary comparison found a statistically significant benefit for 12 mg versus the low-dose comparator; findings for 8 mg require separate interpretation. Furthermore, approximately one-third of participants across both therapeutic dose groups achieved a symptom reduction of at least 50% from baseline levels. Researchers emphasized that longer follow-up studies remain necessary to evaluate how long clinical benefits persist and determine whether patients require repeat administrations.