Mebufotenin nasal spray shows rapid antidepressant effects in treatment-resistant depression trial

Phase 2b trial finds single-dose synthetic 5-MeO-DMT provides benefits lasting at least eight weeks, but experts urge caution

By LineZotpaper AI staff

Published26 October 2026

Updated26 October 2026

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Illustration: Mebufotenin nasal spray shows rapid antidepressant effects in treatment-resistant depression trial

A new phase 2b clinical trial published in JAMA reports that a single-dose nasal spray of mebufotenin (5-MeO-DMT), a synthetic version of a compound found in Sonoran Desert toad venom, produced rapid and sustained antidepressant effects in patients with difficult-to-treat depression. However, independent experts caution that the benefits were incomplete and the study excluded patients with suicidality, leaving questions about safety and long-term maintenance.

The trial, funded by biotech company AtaiBeckley (a subsidiary of Eli Lilly and Company), enrolled 193 participants with moderate to severe major depression who had not responded to two to five standard antidepressants. Each participant received a single dose of mebufotenin benzoate nasal spray containing either 0.3 mg, 8 mg, or 12 mg of the active ingredient, without knowing which dose they received. All participants received psychological support before, during, and after the session.

Most patients were ready for discharge within about two hours after dosing, once acute psychedelic effects subsided. Benefits typically began around two days after treatment and continued for at least eight weeks. The 8 mg and 12 mg doses improved depression scores by 6.2 and 5.3 points more than the lowest dose, respectively. The 8 mg dose was selected for phase 3 trials as it offered the best balance of safety and efficacy.

Adverse side effects were mostly mild or moderate, including headache, nausea, and nasal pain that resolved on the day of dosing. One participant experienced two severe panic attacks during treatment.

Independent psychopharmacology researcher Chittaranjan Andrade, of India's National Institute of Mental Health and Neurosciences, said the results were not as strong as they appear. "The antidepressant effect was incomplete," he wrote in an accompanying opinion piece in JAMA. "The average patient became only about 30 percent better, and the response and remission rates were below those typically seen, for example, with ketamine and electroconvulsive therapy."

Andrade also noted that the trial used a fairly lenient definition of treatment-resistant depression: no participants had previously tried ketamine or electroconvulsive therapy, and patients reporting suicidality were excluded. He described the condition in these patients as "difficult-to-treat" rather than truly treatment-resistant. He also raised concerns about long-term maintenance, as the trial tested mebufotenin as monotherapy and offered no guidance on transitioning to conventional antidepressants.

The researchers, led by neuropsychiatry researcher David Feifel, argued that mebufotenin's rapid clearance and sustained effect could offer practical advantages over existing treatments. "Esketamine and transcranial magnetic stimulation require frequent retreatment, and psilocybin and LSD require four to twelve hours of monitoring due to longer acute subjective effects," they reported.

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Analysis

Why This Matters

Over 30 percent of depression patients do not respond to standard treatments, creating urgent need for new options.
Mebufotenin's rapid onset (about two hours) and single-dose durability could offer practical advantages over longer-duration psychedelics.
The drug is still a Schedule 1/Class A substance; phase 3 trials are needed before any potential approval.

Background

Psychedelic compounds like psilocybin and ketamine have gained traction as treatments for depression. Mebufotenin, a short-acting psychedelic structurally related to DMT but with less intense visual effects, is being developed by AtaiBeckley (an Eli Lilly subsidiary). The compound originates from the Sonoran Desert toad, but the trial used a synthesized form.

Key Perspectives

David Feifel and team (researchers): The rapid return to baseline after dosing and long antidepressant durability give mebufotenin "important potential advantages" over esketamine, psilocybin, and LSD, which require longer monitoring or frequent retreatment. Chittaranjan Andrade (independent psychopharmacology researcher): The antidepressant effect was incomplete (only about 30 percent improvement) and the trial's definition of treatment-resistant depression was too lenient. He also questioned the lack of guidance on maintenance therapy and the exclusion of patients with suicidality.

What to Watch

Phase 3 trial outcomes comparing mebufotenin to existing treatments.
Whether the drug can be safely used in patients with suicidality.
Regulatory decisions on transitioning from research to medical use.

Sources

Scientists Tested a Toad Venom Psychedelic on Treatment-Resistant Depression. Here's What Happened. · ScienceAlert

Checked

12 claims in this story checked against 1 source: 9 supported.

Show each claim

Partly supportedThe trial shows rapid antidepressant effects in treatment-resistant depression.ScienceAlert: “The trial, funded by biotech company AtaiBeckley (a subsidiary of pharmaceutical giant Eli Lilly and Company), suggests a single-dose nasal spray formula of the substance could be a safe and speedy option for patients with difficult-to-treat depression.”
SupportedA single dose of synthetic 5-MeO-DMT provided benefits lasting at least eight weeks.ScienceAlert: “Typically, patients started experiencing benefits about two days after the session, and these benefits continued for at least eight weeks.”
Partly supportedIndependent experts urge caution about the trial’s results.ScienceAlert: “Andrade was not involved in the new clinical trial, but has written an opinion piece on the research, also published in JAMA.”
SupportedThe trial enrolled 193 people with moderate to severe major depression who had not responded to two to five antidepressants.ScienceAlert: “The trial included 193 participants undergoing treatment for moderate to severe major depression at institutions across Australia, Europe, and the US. They had tried two to five different antidepressant drugs during their current depressive episode, to no effect.”
SupportedThe study excluded patients reporting suicidality, and no patients had undergone ketamine or electroconvulsive therapy.ScienceAlert: “He also notes the study had a fairly lenient definition of 'treatment-resistant' depression: no patients had undergone ketamine or electroconvulsive therapy, for instance. The study also excluded any patients who reported suicidality”
SupportedAndrade wrote, “The antidepressant effect was incomplete,” and said the average patient became only about 30 percent better, with response and remission rates below those typically seen with ketamine and electroconvulsive therapy.ScienceAlert: ““The antidepressant effect was incomplete,” he points out. “The average patient became only about 30 percent better, and the response and remission rates were below those typically seen, for example, with ketamine and electroconvulsive therapy.””
SupportedAndrade described the patients’ condition as “difficult-to-treat” rather than truly treatment-resistant.ScienceAlert: “'Difficult-to-treat' depression is, in his eyes, a more accurate description of these patients.”
SupportedAndrade raised concerns about long-term maintenance because the trial tested mebufotenin as monotherapy and offered no guidance on transitioning to conventional antidepressants.ScienceAlert: “because mebufotenin was examined as monotherapy, the trial offers no insight on when and how the transition to a conventional antidepressant should be made or whether mebufotenin itself might be used for maintenance”
SupportedThe 8 mg and 12 mg doses improved depression scores by 6.2 and 5.3 points more than the lowest dose, respectively.ScienceAlert: “The 12 mg and 8 mg doses both performed better than the 0.3 mg dose, improving depression scores by 5.3 and 6.2 more points than the lowest dose, respectively.”
SupportedThe 8 mg dose was selected for phase 3 trials as the best balance of safety and efficacy.ScienceAlert: “The 8 mg dose will proceed to phase 3 since it seemed to produce the best balance of safety and efficacy.”
SupportedSide effects were mostly mild or moderate, and one participant experienced two severe panic attacks during treatment.ScienceAlert: “The majority of patients experienced adverse side effects, but almost all of these were mild or moderate: things like headaches, nausea, and nasal pain, which quickly passed and occurred only on the day of dosing. However, one person experienced two severe panic attacks during their treatment.”
Partly supportedThe researchers argued that mebufotenin’s rapid clearance and sustained effect could offer practical advantages over existing treatments.ScienceAlert: “This rapid return of dosed participants to baseline, together with infrequent dosing indicated by the long antidepressant durability after a single dose, can offer important potential advantages for patients and clinicians compared with treatment options currently available or in advanced stages of development”

Correction

26 October 2026An earlier version of this story reversed the improvements in depression scores for the two higher doses. The 8 mg dose improved scores by 6.2 points more than the lowest dose, and the 12 mg dose by 5.3 points.