Single-Dose Psychedelic Nasal Spray Shows Rapid Relief in Hard-to-Treat Depression, Trial Finds

A single dose of an experimental nasal spray made from a psychedelic compound found in toad venom eased symptoms of depression within days in people who had failed multiple standard antidepressants, according to a mid-stage clinical trial published Monday in JAMA.

The trial tested intranasal mebufotenin benzoate, known by the developmental name BPL-003, in 193 adults with treatment-resistant depression at 38 sites in Australia, Europe and the United States. Patients given either of two active doses showed significantly larger improvements on a standard depression scale than those given a very low comparator dose, with benefits apparent within days that persisted through eight weeks of follow-up.

The drug is a synthetic version of mebufotenin, also called 5-MeO-DMT, a compound first identified in the venom of the Sonoran Desert toad and in several plants. It acts on some of the same serotonin receptors as other psychedelics, such as psilocybin, but its acute effects wear off within roughly 90 minutes, far faster than the four to six hours typical of psilocybin or the many hours associated with LSD. Researchers have pursued that shorter duration specifically because it could make psychedelic-based treatment more practical to deliver outside specialized clinics.

The study, led by David Feifel of the Kadima Neuropsychiatry Institute in La Jolla, California, Mathieu Seynaeve of King's College London and Wiesław Jerzy Cubała of the Medical University of Gdańsk in Poland, was funded by Beckley Psytech, part of AtaiBeckley, the company developing the drug. It was registered in advance on ClinicalTrials.gov.

How the Trial Was Run

Researchers enrolled 196 adults aged 18 to 75 with moderate to severe major depressive disorder who had not responded to two to five antidepressant courses in their current episode; 193 were included in the final analysis. Participants had a mean age of 41, and 59.1 percent were women. They were randomly assigned, in a 3:2:3 ratio stratified by region, to a single spray in one nostril of either an 8-milligram dose, a 12-milligram dose, or a 0.3-milligram "subperceptual" comparator dose designed to produce minimal psychoactive effect while preserving the trial's blinding. Existing antidepressants were tapered off beforehand as needed. Dosing was administered by a trained clinician, followed by more than four hours of monitoring and structured psychological support, before patients were assessed for discharge.

The primary measure, detailed in the full trial report, was change in score on the Montgomery-Åsberg Depression Rating Scale, a 60-point clinician-administered scale, from the start of the trial to day 29:

• 8 mg (46 patients): symptoms improved by an average of 12.5 points, a statistically significant 6.2-point advantage over the comparator group.
• 12 mg (73 patients): symptoms improved by an average of 11.1 points, a statistically significant 5.3-point advantage over the comparator group.
• 0.3 mg comparator (74 patients): symptoms improved by an average of 5.5 points.

By day 29, 35 percent of patients on the 8-milligram dose and 34 percent on the 12-milligram dose had responded to treatment, meaning their symptoms had dropped by at least half, compared with 12 percent of the comparator group. Twenty-six percent of patients on 8 milligrams and 18 percent on 12 milligrams met the criteria for full remission, compared with 8 percent of the comparator group. The advantage over the comparator dose held at every assessment point from two days after dosing through day 57, the last day measured.

Side effects were common but mostly mild. Across the three groups, 73 to 85 percent of patients reported at least one treatment-related adverse event, and the study authors said more than 99 percent of those events were mild or moderate, with no reports of serious drug-related harm. Most patients were judged ready to leave the clinic within two hours of dosing: 85 percent in the 8-milligram group and 78 percent in the 12-milligram group.

A Large and Underserved Population

Depression affected an estimated 21 million adults in the United States in the year before they were surveyed, or 8.3 percent of the adult population, according to the National Institute of Mental Health's most recent national data. A substantial share of those patients do not get adequate relief from standard treatment: an analysis published in The Journal of Clinical Psychiatry estimated that close to a third of adults medicated for major depressive disorder meet common definitions of treatment-resistant depression, a group that accounts for a disproportionate share of the condition's overall cost and disability.

Existing options for that group include ketamine-based treatments, such as the already approved nasal spray Spravato, and psilocybin, which is being tested in late-stage trials but typically requires a daylong supervised session because its effects last several hours. The authors of the new trial argued that mebufotenin's short duration could allow a shorter monitoring window and fewer total clinic visits than those alternatives, potentially widening access to psychedelic-based treatment if later trials confirm the results.

Independent Caution

An editorial published alongside the study in JAMA, written by Chittaranjan Andrade and not affiliated with the trial's sponsor, placed the findings in the context of a wave of recent research showing that psilocybin and other psychedelics can have substantial antidepressant effects in hard-to-treat patients.

Existing psychedelic treatments "require careful, time-intensive management by an experienced treatment team," Andrade wrote, framing the central question raised by the new trial as whether a faster-acting formulation can deliver meaningful benefit without that same intensive supervision.

The study's own authors, in their published findings, flagged several limitations. Because psychedelic drugs produce noticeable perceptual effects, many patients and clinicians could likely tell who had received an active dose despite the trial's blinding procedures, a problem known as functional unblinding that can inflate apparent benefits in psychiatric drug trials. The 8-milligram group was smaller than originally planned after a change made partway through enrollment. Participants were required to stop their existing antidepressants before dosing, which may not reflect how the drug would be used in ordinary practice, and the trial population had limited ethnic diversity. The researchers also noted that the trial was not designed to separate the drug's pharmacological effect from that of the structured psychological support given alongside it.

What Comes Next

The Food and Drug Administration granted the drug breakthrough therapy designation in October 2025, a status meant to speed development of treatments that show early promise for serious conditions, based on earlier results from the same research program. The study authors and the JAMA editorial both said the results need to be confirmed in larger, longer and more rigorously blinded trials, including the Phase 3 studies the drug's developers have said they plan to pursue, before mebufotenin could be considered for approval or widespread clinical use. In the meantime, the drug remains investigational and is not available outside clinical trials.