A single intranasal dose of the short-acting psychedelic mebufotenin significantly reduced symptoms in adults with treatment-resistant depression during a 193-person clinical trial published in JAMA on October 26, 2026, offering patients a rapid mental health intervention that requires less clinic monitoring than older options like psilocybin.
Patients struggling with difficult-to-treat depression saw their symptom scores drop by an average of 11.1 points on a 12-milligram dose and 12.5 points on an 8-milligram dose, according to trial results published in the journal JAMA. By comparison, a control group receiving a tiny 0.3-milligram dose saw an average drop of 5.5 points on the 60-point depression scale.
The study, which tracked 193 participants across 38 sites in Australia, Europe, and the United States between September 2023 and April 2025, tested a synthetic formulation of 5-MeO-DMT known as mebufotenin benzoate or BPL-003. This condition affects roughly 30 percent of all individuals diagnosed with major depression, trapping patients in a cycle of high health care utilization and persistent emotional distress.
Clinical Trial Design and Dosing at 38 Sites Across Three Continents
The randomized clinical trial evaluated adults aged 18 to 75 suffering from moderate to severe depression that had failed to improve on two to five standard antidepressants. Participants stopped their previous medications under medical supervision prior to receiving a single spray administered by a trained clinician in a private room. Every patient received psychological support before, during, and after the dosing session.
Participants were divided into three groups: 73 individuals received a 12-milligram dose, 46 received an 8-milligram dose, and 74 received the 0.3-milligram control dose. Independent raters who scored depression severity over video calls, along with patients and attending physicians, remained unaware of who received which dosage.
Shorter Clinic Stays Compared to Psilocybin Sessions
Unlike longer-acting psychedelics such as psilocybin—which can require medical monitoring for four to twelve hours—mebufotenin produces an unusually brief psychedelic experience. Its psychoactive effects typically peak within 8 to 15 minutes and subside completely within 45 to 60 minutes. Most patients who received active doses were medically ready to leave the clinic within two hours.
Many people living with treatment-resistant depression have tried multiple treatments without lasting relief. These Phase 2b results for investigational BPL-003 showed that a single dose significantly reduced depressive symptoms, with benefit seen through the end of the eight-week study. We’re encouraged by these results and look forward to further evaluating BPL-003 in the Phase 3 program.
Eli Lilly Spokesperson, via Newsweek
The biotech firm AtaiBeckley—recently acquired by Eli Lilly—funded the trial and assisted with study design, data analysis, and manuscript preparation. Eli Lilly is betting heavily on the compound, having backed the acquisition with a $2.8 million upfront payment alongside up to $1 billion in potential additional milestone payments.
Remission Rates and Adverse Side Effects Tracked Through Eight Weeks
By day 29 of the study, between 18 and 26 percent of patients taking the active doses achieved full remission, compared to just 8 percent of those in the low-dose control group. Roughly one-third of active-dose participants experienced at least a 50 percent reduction in their overall symptom scores, with therapeutic benefits appearing as early as the day after dosing and persisting through the eight-week follow-up period.
Side effects were common on the day of administration but categorized by researchers as mostly mild or moderate
. Headaches affected nearly 30 percent of participants, around 24 percent reported nausea, and approximately 16 percent experienced administration site pain. No participants dropped out due to side effects, although 19 individuals withdrew for other reasons, and one patient experienced two severe panic attacks during treatment.
Expert Perspectives and Limitations Identified in the JAMA Study
Independent experts note that while the data points toward a promising new psychiatric tool, significant questions remain. Albert Garcia-Romeu, a professor of psychedelics and consciousness at Johns Hopkins University who was not involved in the research, highlighted the drug’s logistical advantages over other compounds.
compelling because the shorter-acting effects of 5-MeO-DMT (lasting less than 2 hours) could help increase scalability and access to these treatments relative to other longer-acting psychedelics like psilocybin, which can take about six hours to administer.
Albert Garcia-Romeu, Professor of Psychedelics and Consciousness at Johns Hopkins University
Writing an independent commentary published alongside the study in JAMA, psychopharmacologist Chittaranjan Andrade of India’s National Institute of Mental Health and Neurosciences observed that the average patient improved by about 30 percent, noting that response and remission rates were lower than those typically seen with ketamine or electroconvulsive therapy. Andrade also pointed out that patients with suicidal tendencies were excluded from the trial, leaving the safety and efficacy of mebufotenin for that vulnerable population unverified.
Study authors acknowledged additional limitations, including the challenge of maintaining proper blinding when psychedelic effects are difficult to conceal, and an altered randomization ratio partway through recruitment that left the 8-milligram arm smaller than initially planned. Researchers concluded that the 8-milligram dose achieved the optimal balance of safety and efficacy to advance into Phase 3 clinical trials.
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