Mebufotenin Shows Rapid Antidepressant Effects in Phase 2b Trial
Key Clinical Summary
- Intranasal mebufotenin benzoate reduced depressive symptoms through 8 weeks after a single dose in a randomized trial involving 193 adults with treatment-resistant depression (TRD).
- Both active doses outperformed a low-dose comparator, and nearly all adverse events were mild or moderate.
- Most participants receiving active treatment met discharge-readiness criteria within 2 hours, although the protocol required at least 4 hours before discharge.
A single administration of mebufotenin benzoate nasal spray produced rapid, sustained reductions in depressive symptoms among adults with TRD, according to a phase 2b trial published in JAMA.
The randomized, double-blind study, conducted at 38 sites across the United States, Europe, and Australia, evaluated the psychedelic compound’s antidepressant efficacy, safety, and recovery after dosing.
Study Findings
Participants were aged 18 to 75 years and had moderate to severe major depressive disorder that had not responded to 2 to 5 antidepressant trials during the current episode. They received intranasal mebufotenin benzoate at 8 mg (46 participants), 12 mg (73 participants), or a low-dose comparator of 0.3 mg (74 participants), alongside psychological support.
At day 29, the 12-mg group had greater improvement on the Montgomery-Åsberg Depression Rating Scale than the comparator group (least-squares mean difference [LSMD], −5.3 points; 95% confidence interval [CI], −8.9 to −1.8; P = .003). The 8-mg group also improved significantly (LSMD, −6.2 points; 95% confidence interval, −10.2 to −2.1; P = .003).
Both active doses showed significantly greater symptom reductions from day 2 through day 57. Response rates at day 29 were higher with 8 mg and 12 mg than with the comparator (34.8%, 34.2%, and 12.2%, respectively).
Treatment-emergent adverse events occurred across all groups (76.1%, 84.9%, and 73.0%, respectively); nearly all events were mild or moderate (99.7%). One participant receiving 12 mg experienced 2 severe panic attacks considered treatment related.
Clinical Implications
In addition to the antidepressant effects, the findings address the logistical burden of psychedelic treatment. The agents closest to FDA-approval (psilocybin and lysergic acid diethylamide [LSD]) require dedicated, time-intensive management during sessions that may last as long as 12 hours. Ketamine and esketamine also require multiple hours of supervision after dosing.
Since mebufotenin is associated with brief psychedelics experiences, study authors tested treatment efficacy as well as how quickly patients would be ready for discharge following a single dose. Participants receiving 8 mg or 12 mg met discharge-readiness criteria within 2 hours (85% and 78%, respectively), although actual discharge during the study was prohibited before 4 hours.
Expert Commentary
“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,” wrote David Feifel, MD, PhD, Kadima Neuropsychiatry Institute, La Jolla, California, and colleagues. “Intranasal mebufotenin benzoate may improve treatment access and convenience, requiring a shorter monitoring period and fewer clinic visits compared with psilocybin and esketamine, respectively.”
The trial supports further evaluation of intranasal mebufotenin benzoate for TRD. Planned phase 3 studies will assess longer-term durability and include an intermediate dose to help address functional unblinding and clarify dose response.
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