For many people with depression, the usual treatments simply do not work. When two or more antidepressants have failed, the condition is described as treatment-resistant depression, and options become limited, slow, and often demanding. A single dose of a psychedelic nasal spray may offer another route, but the evidence is still at an early stage.
What the trial tested
The phase 2b trial, published in the Journal of the American Medical Association (JAMA) on 26 October 2026, tested mebufotenin benzoate, a nasal spray form of the psychedelic compound 5-MeO-DMT. Unlike psilocybin or LSD, its effects last only a short time, which could mean far less time spent in a clinic.
The trial enrolled 193 adults aged 18 to 75 with moderate to severe major depression that had not improved after two to five antidepressants in the current episode. It ran between September 2023 and April 2025 at 38 sites in Australia, Europe, and the US. Participants were randomly given a single dose of 8 mg, 12 mg, or a very low 0.3 mg comparator dose, alongside psychological support, with the intended dose hidden from participants and site staff.
What the trial found
Depression was measured on the Montgomery-Åsberg Depression Rating Scale, which runs from 0 to 60, with higher scores meaning more severe symptoms. After four weeks, scores fell by an average of 11.1 points with the 12 mg dose, compared with 5.5 points with the 0.3 mg dose. The 8 mg dose produced a similar fall of 12.5 points.
Both active doses kept their advantage at every check from day two to day 57, about eight weeks after dosing. At four weeks, 35% of the 8 mg group and 34% of the 12 mg group had responded to treatment, compared with 12% on the lowest dose. Remission rates were 26%, 18%, and 8% respectively.
Side effects were common in every group, reported by 73% to 85% of participants, but almost all were mild or moderate. Most people were judged ready to leave the clinic within two hours of their dose.
Why phase 3 trials still matter
This was a mid-stage trial, so the results are not yet enough to bring the spray into routine care. Larger phase 3 trials will need to show that the benefit holds in more people and over a longer period, and that the treatment is safe.
There are other reasons for caution. The comparison was with a very low dose of the same drug rather than an inactive placebo, and psychedelic effects can make it hard for people to stay unaware of which dose they received. Several authors work for, or have financial links with, the company developing the drug.
What it could mean for patients
The authors suggest that, if confirmed, the spray could need a shorter monitoring period than psilocybin and fewer clinic visits than esketamine, another nasal spray used for hard-to-treat depression. Researchers from institutions including King’s College London and Monash University took part.
Anyone struggling with low mood should speak to their GP. In the UK and Ireland, Samaritans is free on 116 123, day or night.
