You've probably heard someone say they're on their third or fourth antidepressant. Many people with depression work through a long list of pills, and still the fog won't lift. For roughly one in three, the standard options simply don't do the job.
That is the group a new trial in JAMA set out to help. A single dose of a fast-acting psychedelic nasal spray cut depression symptoms by at least half in about 35 percent of patients whose prior medications had failed. In a comparator group, only 12 percent saw the same drop.
The relief held for up to eight weeks on one spray, and most people in the study were cleared to go home within two hours.
Published October 26, 2026, the phase 2b trial tested a compound called mebufotenin benzoate. It is a short-acting psychedelic chemically related to 5-MeO-DMT, which is found in the venom of the Colorado River toad.
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What a single nasal dose did at four weeks
Researchers enrolled 193 adults with moderate to severe depression at 38 clinics in the United States, Australia and Europe. All had already tried between two and five antidepressants in their current episode without success.
Each person got one puff of mebufotenin benzoate at 12 milligrams, 8 milligrams, or a very low 0.3 milligram dose designed to keep the trial blind. Nobody in the clinic knew which dose was given.
Four weeks later, 35 percent of patients on the 8 milligram dose had seen their depression scores drop by at least half. The 12 milligram dose produced almost the same response. Only 12 percent of the comparator group did.
The improvement started within a day of the single dose and lasted up to eight weeks. Beckley Psytech, the company developing the compound, funded the trial.
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Shorter clinic time than ketamine or psilocybin
Standard psychedelic treatments like psilocybin can tie a patient to a clinic for four to twelve hours per session, according to Medical Xpress. Mebufotenin's effects come on fast and wear off within about an hour.
In the trial, 85 percent of the 8 milligram group were ready to leave within two hours. The 12 milligram group was close behind at 78 percent. Nearly all side effects were rated mild or moderate.
That shorter clinic time matters for people who need regular treatment but can't block out a full day for every session.
What this does and does not mean
This was a phase 2b trial, not a final approval study. Mebufotenin is not available in pharmacies, and a larger phase 3 trial is still needed before regulators can review it.
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Lead author David Feifel of the Kadima Neuropsychiatry Institute in La Jolla reported that one dose eased depression more than the comparator through day 29, with benefit persisting through day 57. Larger phase 3 studies are needed to confirm the findings.
Anyone struggling with depression that hasn't responded to standard medications should talk with their doctor about current options. Both ketamine-based treatments and transcranial magnetic stimulation are already available in US clinics.
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This article is made and published by Mie Hermansen, who may have used AI in the preparation.