Single Intranasal Administration of the Psychedelic Mebufotenin for Treatment-Resistant Depression: A Randomized Clinical Trial.

Single intranasal mebufotenin benzoate (12 mg) in adults with treatment-resistant major depressive disorder is linked to a significantly greater MADRS reduction by day 29 than 0.3 mg.

• Why it matters: Treatment-resistant depression needs better options, but existing psychedelic therapies require prolonged in-clinic monitoring that limits access and scalability.
• What they did: In a phase 2b randomized double-blind trial (38 sites in Australia, Europe, and the US), adults received one intranasal dose of 8 mg (n=46), 12 mg (n=73), or 0.3 mg (n=74) after washout, with MADRS change measured from baseline to day 29.
• The result: MADRS change was -11.1 (SD 11.6) vs -5.5 (SD 9.9) for 12 mg vs 0.3 mg (mean difference -5.3 [95% CI -8.9 to -1.8]; P=.003), with similar effects for 8 mg and most adverse events mild or moderate; 78% and 85% were ready for discharge within 2 hours for 12 mg and 8 mg, respectively.