- Design
- Phase 2b, randomised, double-blind, low-dose controlled
- Population
- 193 adults with treatment-resistant major depression
- Primary outcome
- MADRS change at day 29, 12 mg vs 0.3 mg
- Effect
- −5.3 points (95% CI −8.9 to −1.8)
This double-blind phase 2b trial at 38 sites randomised 193 adults with moderate to severe depression that had not responded to two to five antidepressants. Each received one intranasal dose of mebufotenin (5-MeO-DMT) at 12 mg, 8 mg or a 0.3 mg comparator, with psychological support.
At day 29, MADRS scores fell 11.1 points with 12 mg against 5.5 with the comparator (difference −5.3, 95% CI −8.9 to −1.8); the 8 mg dose was similar. Response rates were about 35% against 12%. Most adverse events were mild or moderate, and roughly four in five participants were ready for discharge within two hours.
The appeal is logistic: psilocybin needs a full day of monitoring. But this is a phase 2b trial, functional blinding is hard with a psychedelic, and the drug is not approved anywhere. It belongs in the reading pile, not the prescription pad.
- Treat this as phase 2b evidence; mebufotenin is not approved by any regulator.
- Continue to use licensed options for treatment-resistant depression, including augmentation and esketamine where available.
- Expect patients to ask about psychedelics; discuss the evidence and the risks of unsupervised use.
- Note the short monitoring time as the main practical difference from psilocybin.
Why it matters
A two-hour psychedelic session would remove the main barrier to delivering these treatments at scale.
Don't overread it
Phase 2b with a low-dose comparator; blinding is difficult when one arm has a psychedelic experience.
The statistics, in plain English
A 5-point MADRS difference is around the threshold many consider clinically meaningful. The interval runs from about 2 to 9 points, so the true effect could be modest.
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