In brief
- A double-blind phase 2b trial in 193 adults with treatment-resistant depression compared a single nasal dose of mebufotenin (5-MeO-DMT), 8 or 12 mg, with a low 0.3 mg dose.
- At day 29, MADRS depression scores fell 5.3 points more with 12 mg than with 0.3 mg; with 8 mg, 6.2 points more.
- Blinded follow-up lasted eight weeks and the compound is still investigational: it is not approved as a medicine.
On October 26, 2026, JAMA published online a randomized clinical trial of mebufotenin benzoate, an intranasal formulation of 5-MeO-DMT, the short-acting tryptamine also found in the secretion of the Sonoran Desert toad. The first author is David Feifel of the Kadima Neuropsychiatry Institute (La Jolla); the last author is affiliated with AtaiBeckley, the company developing the compound, and the sponsor listed in the registry is Beckley Psytech. The question is a practical one: whether a short-acting psychedelic can ease treatment-resistant depression with less in-clinic monitoring time.
How it was done
The trial ran from September 2023 to April 2025 at 38 sites in Australia, Europe and the United States. Participants were adults aged 18 to 75 with moderate to severe major depression that had not responded to two to five antidepressants in the current episode; mean age was 41 and 59.1% were women. After antidepressant washout where needed, each person received a single nasal dose with psychological support: 8 mg (46 people), 12 mg (73) or 0.3 mg (74). The registry describes that minimal dose as sub-therapeutic and uses it as an active comparator to maintain blinding: it is not an inert placebo.
The primary endpoint was the change in the MADRS, which ranges from 0 to 60 points, from baseline to day 29, comparing 12 mg with 0.3 mg. There were also 18 secondary endpoints, and readiness for discharge was assessed from 90 minutes after dosing.
What it found
With 12 mg, MADRS scores fell by a mean of 11.1 points, versus 5.5 with 0.3 mg: a difference of 5.3 points (95% confidence interval, −8.9 to −1.8; P = .003). In the secondary comparison, the 8 mg dose lowered scores by 12.5 points, 6.2 more than the comparator (95% CI, −10.2 to −2.1). According to the abstract, the active doses also stayed ahead at other assessments between days 2 and 57; without the full text we could not review each time point.
At day 29, 35% of the 8 mg group, 34% of the 12 mg group and 12% of the 0.3 mg group had responded, and 26%, 18% and 8% reached remission, using definitions the abstract does not detail. Within the first two hours, 85% of the 8 mg group and 78% of the 12 mg group were ready for discharge.
Safety
Treatment-emergent adverse events occurred in 76% of the 8 mg group, 85% of the 12 mg group and 73% of the 0.3 mg group; 99.7% were mild or moderate. The results posted in the registry (NCT05870540) list, for the core period, one serious adverse event in the 0.3 mg group (depression), one in the 8 mg group (agitation) and none in the 12 mg group, with no deaths. In the subsequent open-label extension, the registry records three participants with serious events, including cases of suicidal ideation, and notes that of the study’s five serious adverse events only one, suicidal ideation, was considered related to the drug.
What we still don’t know
This is a single phase 2b trial, with one dose and eight weeks of blinded follow-up: it does not show how long the improvement lasts or whether repeat dosing would be needed. The 0.3 mg group also improved by 5.5 points, a reminder that expectations, support and natural course also matter. According to the registry, 64 of 74 people on 0.3 mg, 41 of 46 on 8 mg and 69 of 73 on 12 mg completed the core period. We could only read the article’s key points and abstract, so we do not know how those dropouts were handled, whether blinding was assessed or what the funding statement says.
What it means
The result supports further study of mebufotenin in larger and longer trials, not its use outside them. The study conditions, with screening, supervised antidepressant washout, a known pharmaceutical dose and trained staff, bear no resemblance to a ceremony using toad secretion or a product of uncertain origin, where dose and purity are unknown. A few days ago we covered a review of DMT and 5-MeO-DMT in depression; for broader context, see our ayahuasca and DMT guide.
Sources
- Feifel D, Seynaeve M, Cubała WJ, et al. Single Intranasal Administration of the Psychedelic Mebufotenin for Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA, published online October 26, 2026. Key points and abstract consulted; full text not consulted.
- Europe PMC bibliographic record (PMID 42931733), with abstract and author affiliations.
- Trial registration NCT05870540 on ClinicalTrials.gov, with results posted by the sponsor on September 10, 2026.
Illustrative image: “Nasal Spray“, NIAID, via Wikimedia Commons, licensed under CC BY 2.0. It does not show the trial drug or its participants.
Educational content produced from a harm-reduction perspective and with respect for individual freedom. It does not replace advice from a healthcare professional and is not intended to encourage or condemn any drug use.
