Single Intranasal Administration of the Psychedelic Mebufotenin for Treatment-Resistant Depression

Importance: Psychedelics represent a potential breakthrough for treatment-resistant depression; however, the prolonged in-clinic monitoring required for compounds such as psilocybin and lysergic acid diethylamide is a logistical hurdle to widespread use. Intranasal mebufotenin (5-methoxy-N,N-dimethyltryptamine), a 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A agonist associated with brief psychedelic experiences, may address this limitation. Objective: To evaluate the safety, efficacy, and time to discharge readiness following a single dose of intranasal mebufotenin benzoate in adults with treatment-resistant depression. Design, Setting, and Participants: Phase 2b, randomized, double-blind trial with an 8-week blinded follow-up conducted between September 2023 and April 2025 at 38 sites in Australia, Europe, and the US. Participants were aged 18 to 75 years with moderate to severe major depressive disorder nonresponsive to 2 to 5 antidepressant trials in the current episode. The last date of follow-up was April 28, 2025. Interventions: After antidepressant washout as needed, participants were randomly assigned to receive a single dose of intranasal mebufotenin benzoate, 8 mg (n = 46), 12 mg (n = 73), or 0.3 mg (a low-dose comparator; n = 74), alongside psychological support. Main Outcomes and Measures: The primary end point was total score change on the Montgomery-Åsberg Depression Rating Scale (MADRS; score range, 0-60; higher scores indicate more severe depression) from baseline to day 29 in the 12-mg vs 0.3-mg dose groups. Eighteen secondary end points were assessed for the 12-mg and 8-mg vs 0.3-mg doses. Discharge readiness was assessed starting 90 minutes after dosing. Results: Among the 193 included participants, the mean age was 41 (SD, 11.1) years and 59.1% were female. From baseline to day 29, treatment with 12-mg intranasal mebufotenin benzoate vs the 0.3-mg dose (the primary end point) was associated with significantly reduced MADRS scores (mean score change, -11.1 [SD, 11.6] vs -5.5 [SD, 9.9], respectively; mean difference, -5.3 [95% CI, -8.9 to -1.8]; P = .003). The 8-mg dose also led to reduced scores from baseline to day 29 (mean score change, -12.5 [SD, 12.7]) vs the 0.3-mg dose (mean difference, -6.2 [95% CI, -10.2 to -2.1]; P = .003). MADRS reductions with the 8-mg and 12-mg doses were similar and significantly greater at all other time points from 2 to 57 days post dose vs the 0.3-mg dose. Day 29 response rates were 35%, 34%, and 12% and remission rates were 26%, 18%, and 8% in the 8-mg, 12-mg, and 0.3-mg dose groups, respectively. Treatment-emergent adverse events were reported in 76%, 85%, and 73% of participants in the 8-mg, 12-mg, and 0.3-mg dose groups, respectively; most events (99.7%) were mild or moderate. Overall, most participants were deemed ready for discharge within 2 hours post dose (85% for 8 mg and 78% for 12 mg). Conclusions and Relevance: In adults with treatment-resistant depression, single doses of intranasal mebufotenin benzoate were well tolerated and produced rapid, robust, and durable reductions in depressive symptoms. Intranasal mebufotenin benzoate may improve treatment access and convenience, requiring a shorter monitoring period and fewer clinic visits compared with psilocybin and esketamine, respectively. Trial Registration: ClinicalTrials.gov Identifier: NCT05870540.