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Hard-to-Treat Depression Eased by Psychedelic Nasal Spray With Brief Effects
In A Nutshell
- In a 193-person trial of treatment-resistant depression, a psychedelic nasal spray cut depression scores about twice as much as a near-zero dose.
- Most patients on active doses were medically ready to leave within two hours, though the study required a four-hour stay.
- Side effects were mostly mild or moderate, and improvements largely held through week eight.
- Larger trials must confirm the results, and the study was funded by Beckley Psytech.
A single spray of a psychedelic drug into one nostril eased depression that had resisted standard medications, and most patients on active doses were medically ready to leave the clinic within two hours. Psilocybin and LSD sessions, by comparison, can eat up 4 to 12 hours of monitoring, up to a full day off work for someone already struggling to get through one.
A clinical trial published in JAMA tested a drug called mebufotenin, also known as 5-MeO-DMT, whose psychedelic experience is unusually short. Earlier research cited in the paper found its effects peak 8 to 15 minutes after dosing and fade within 45 to 60 minutes.
A shorter treatment day could matter to a lot of people. Treatment-resistant depression, meaning depression that fails to improve after two or more antidepressants, affects about one-third of people with major depression, according to the paper. These patients tend to report lower quality of life, more emotional distress, and a higher suicide risk than people whose depression responds to treatment. Ketamine-based treatments and magnetic brain stimulation exist, but both demand frequent clinic visits.
193 Adults With Treatment-Resistant Depression Tested the Psychedelic Nasal Spray
Between September 2023 and April 2025, 193 adults ages 18 to 75 took part at 38 sites across Australia, Europe, and the United States. All had moderate to severe depression that had not improved on two to five antidepressants. Their average age was 41, 59% were female, and 89% were white.
Participants were randomly assigned to 12 milligrams of the spray (73 people), 8 milligrams (46), or a 0.3-milligram comparison dose (74) too small to cause a noticeable psychedelic effect. Participants, doctors, and the independent raters who scored depression over video calls were all kept unaware of who received which dose. Each person got one spray from a trained clinician in a private room with a doctor nearby, plus psychological support before, during, and after. Those taking antidepressants first stopped them under supervision.
Depression was scored on a 60-point scale, with higher numbers meaning worse symptoms. Scores were compared at day 29, and participants were tracked through day 57. Beckley Psytech funded the study, and its employees helped design the trial, analyze the data, and prepare the manuscript.
Psychedelic Nasal Spray Doses Cut Depression Scores About Twice as Much as a Tiny Dose
By day 29, scores had dropped an average of 11.1 points on the 12-milligram dose and 12.5 points on the 8-milligram dose. Participants on the near-zero dose improved too, by 5.5 points, so the real gap was about 5 to 6 points, large enough that chance is an unlikely explanation. Both active doses performed similarly and stayed ahead of the comparison dose at every check-in through day 57. Improvements showed up the day after treatment and largely held through week eight, so the benefit may last longer than the trial measured.
Also at day 29, about a third of people on active doses had seen their symptoms drop by at least half, versus 12% on the comparison dose. Symptoms fell to very low levels for 18% to 26% of the active groups, versus 8%.
Side effects were common in every group, including the comparison group, but nearly all (99.7%) were mild or moderate. Headache, nausea, and pain at the spray site topped the list. One person on 12 milligrams had two severe panic attacks judged treatment-related, and nobody left the trial because of side effects. Heart rate and blood pressure rose briefly after dosing but returned to normal within an hour. Six participants on active doses reported thoughts of suicide without intent, all with a history of such thoughts. Seven did on the comparison dose, and no suicidal behavior occurred in the trial. Researchers chose the 8-milligram dose for the next phase of testing because it offered the best balance of benefit and side effects.
Most Patients on Active Doses Met Discharge Criteria Within Two Hours
Starting 90 minutes after dosing, staff checked every 30 minutes whether patients met preset criteria for leaving, including signs that the drug’s effects had worn off. By the two-hour mark, 85% of the 8-milligram group and 78% of the 12-milligram group qualified. Study rules still required everyone to stay at least four hours.
How participants rated their psychedelic experience did not predict how much their depression improved, and the authors say a prolonged psychedelic trip does not appear necessary for lasting relief. A trial this size cannot rule out that trip length matters for some patients.
Caveats apply. Participants and doctors could often guess who received the real drug, and eight weeks is a short window for judging lasting relief.
Larger trials with longer follow-up must confirm that the benefits last. If they do, a treatment that wears off in hours could spare patients the all-day clinic stays that psilocybin and LSD can require, and the next question is whether the health care system can make it accessible enough to fit into their lives.
Disclaimer: This article summarizes one clinical trial for general information only. It is not medical advice and does not recommend any treatment. The nasal spray described is still being tested and is not an approved treatment. Anyone dealing with depression should talk with a qualified health care professional.
Paper Notes
Limitations
Study authors identified several limitations. Keeping participants and clinicians unaware of treatment group (blinding) was difficult because psychedelic effects are noticeable, even with a low-dose comparison group, though blinding held better for the independent raters scoring symptoms. The 8-milligram group was smaller than planned because the randomization ratio was changed partway through recruitment, which may have limited the ability to detect differences on some secondary measures. Because the drug was tested as a standalone treatment, participants on antidepressants had to stop them beforehand, which may not reflect future clinical practice, although an additional analysis found treatment effects were consistent regardless of whether participants had stopped antidepressants. The study lacked diverse ethnic representation and may underrepresent the most severe cases of treatment-resistant depression. Prior psychedelic use, drawn from medical history, may have been underreported. The effect of the psychological support offered around dosing was not evaluated. The follow-up lasted eight weeks, and the authors note that longer-term durability will be tested in phase 3 studies.
Funding and Disclosures
Beckley Psytech Ltd, an AtaiBeckley company, funded the study. Employees of the sponsor were involved in the study’s design and conduct, data collection, management, analysis, and interpretation, manuscript preparation, review and approval, and the decision to submit for publication. Two authors reported being employees of AtaiBeckley and two reported being employees of Beckley Psytech. One author reported holding stock or stock options in AtaiBeckley, and four authors reported a pending patent for uses of particular doses of 5-MeO-DMT to treat depression, with ownership and commercial rights waived. Several other authors reported grants, consulting fees, clinical trial contracts, or stock holdings tied to other psychedelic and pharmaceutical companies. Medical writing support was funded by AtaiBeckley. Full individual disclosures appear in the original publication.
Publication Details
Title: Single Intranasal Administration of the Psychedelic Mebufotenin for Treatment-Resistant Depression: A Randomized Clinical Trial | Authors: David Feifel, MD, PhD; Mathieu Seynaeve, MD; Wiesław Jerzy Cubała, MD, PhD; Fiona Dunbar, MB, BCh; Gerhard Gründer, MD; Rosa María Dueñas Herrero, MD; Chandni Hindocha, PhD; Paul Liknaitzky, PhD; Sean M. McGuigan, BSc; Sejal Mehta, MD; Mimi Pierce, MD; Dimitris Repantis, MD; Claire Roberts, PhD; Frank Wiegand, MD, PhD; Robert Conley, MD | Corresponding Author: Mathieu Seynaeve, MD, King’s College London and AtaiBeckley, United Kingdom | Journal: JAMA, published online October 26, 2026 (accepted August 17, 2026) | DOI: 10.1001/jama.2026.18380 | Trial Registration: ClinicalTrials.gov Identifier NCT05870540
