One Intranasal Dose of Mebufotenin Eased Treatment-Resistant Depression for Eight Weeks in a Phase 2b Trial
In a 193-patient JAMA trial, one 12 mg dose beat a 0.3 mg comparator by 5.3 MADRS points at day 29. Most patients were ready to leave within two hours.
A single intranasal dose of mebufotenin, the psychedelic also known as 5-MeO-DMT, reduced depression scores more than a near-inactive dose in adults with treatment-resistant depression, in a 193-patient phase 2b trial published in JAMA on Oct. 26.
The drug, a mebufotenin benzoate nasal spray developed as BPL-003 by AtaiBeckley, is not approved. Its pitch is logistics as much as efficacy: the authors argue that a short monitoring period and fewer clinic visits could make it easier to deliver than psilocybin or esketamine.
What did the trial show?
A moderate, sustained separation from a low-dose comparator. The double-blind trial (NCT05870540) enrolled adults 18 to 75 with moderate to severe major depressive disorder that had not responded to two to five antidepressant trials in the current episode, at 38 sites in Australia, Europe and the United States from September 2023 to April 2025. Patients received one dose of 8 mg (n = 46), 12 mg (n = 73) or a subperceptual 0.3 mg (n = 74), with psychological support.
On the primary endpoint, change in Montgomery-Asberg Depression Rating Scale score at day 29, the 12 mg group fell 11.1 points and the 0.3 mg group 5.5, a difference of -5.3 (95% CI, -8.9 to -1.8; P = .003). The 8 mg group fell 12.5 points, a difference of -6.2 (95% CI, -10.2 to -2.1; P = .003). Both doses stayed ahead of the comparator at every time point from day 2 to day 57.
Response at day 29 was 35 percent with 8 mg, 34 percent with 12 mg and 12 percent with 0.3 mg. Remission was 26 percent, 18 percent and 8 percent. By The Script Pad's arithmetic from those rounded rates, about 4 to 5 patients would need treatment for one additional response at either active dose, and about 6 would need the 8 mg dose for one additional remission, against about 10 with 12 mg.
The lower dose did at least as well as the higher one, and the comparator was a sub-psychedelic dose of the same drug. That is a reasonable phase 2 design, but it leaves blinding and dose selection as open questions for phase 3.
Safety and the clinic day
Treatment-emergent adverse events occurred in 76 percent of the 8 mg group, 85 percent of the 12 mg group and 73 percent of the comparator group, and 99.7 percent of events were mild or moderate. Discharge readiness was assessed from 90 minutes after dosing, and 85 percent of the 8 mg group and 78 percent of the 12 mg group were judged ready within two hours.
What are the caveats?
This is a phase 2b trial with eight weeks of blinded follow-up and unequal arms. The comparator was the same drug at 0.3 mg rather than placebo or an active antidepressant, and patients who feel a psychedelic effect may guess their assignment. Author affiliations include AtaiBeckley and Beckley Psytech. The company has said the U.S. Food and Drug Administration granted Breakthrough Therapy designation in October 2025, and that two placebo-controlled phase 3 trials, ReConnection 1 with about 350 patients and ReConnection 2 with about 300, will run 12 weeks each with 52-week open-label extensions, OINDPnews reported in March.
What it means in clinic
Nothing changes in prescribing today, and mebufotenin is not available outside trials. Patients with treatment-resistant depression may ask about it, and the accurate answer is that one dose produced a durable signal in a mid-stage trial, with phase 3 still to come. For context on how the FDA is approaching psychedelic trial design, see our report on its request for input on ibogaine studies, and on depression subtypes, our piece on a proposed circadian subtype.
Reported, fact-checked and edited by The Script Pad's editorial staff. See How we use AI.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
