A short-acting psychedelic nasal spray eased hard-to-treat depression

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A single dose of mebufotenin — a fast-acting psychedelic, chemically 5-methoxy-N,N-dimethyltryptamine — delivered as a nasal spray reduced depression symptoms more than a low-dose comparator in adults whose depression had resisted earlier treatment, according to a phase 2b trial in JAMA [s1]. The result is an early, encouraging signal with a practical twist: most patients were ready to leave the clinic within two hours, far faster than the day-long monitoring that psilocybin requires.

Treatment-resistant depression — major depression that has not responded to multiple antidepressants — is where interest in psychedelics has concentrated, because a rapid, durable response could change how the illness is managed. But the logistics are a barrier: compounds like psilocybin and LSD produce experiences lasting many hours, tying up clinic time and staff. Mebufotenin's appeal is that its psychedelic effects are brief, which is the specific problem this trial set out to test [s1].

What the trial did

This was a phase 2b, randomised, double-blind trial run between September 2023 and April 2025 at 38 sites across Australia, Europe and the US, registered as NCT05870540 [s1][s2]. It enrolled 193 adults aged 18–75 with moderate-to-severe major depression that had not responded to two to five antidepressant trials in the current episode [s1]. After tapering off existing antidepressants where needed, participants were randomly assigned to a single intranasal dose of mebufotenin benzoate at 8 mg (46 people), 12 mg (73) or 0.3 mg (74), the last acting as a low-dose comparator, all alongside psychological support [s1]. The primary endpoint was the change in the Montgomery-Åsberg Depression Rating Scale (MADRS, scored 0–60) from baseline to day 29, comparing the 12 mg and 0.3 mg groups [s1].

Using a very low dose rather than an inert placebo is a common compromise in psychedelic trials, because a true blank is hard to maintain when the drug produces obvious sensations. It is also a limitation, because a comparator that does something of its own narrows the measured gap.

What it found

The trial met its primary endpoint. MADRS scores fell by a mean of 11.1 points on 12 mg versus 5.5 on the 0.3 mg comparator — a difference of 5.3 points (95% CI 1.8–8.9; p=0.003) [s1]. The 8 mg dose did slightly better on this measure, a 12.5-point drop, for a difference of 6.2 points versus the comparator (p=0.003) [s1]. Both active doses separated from the comparator at every assessed timepoint from day 2 through day 57 [s1].

Response rates at day 29 — a meaningful reduction in symptoms — were 35% on 8 mg and 34% on 12 mg, against 12% on the comparator; remission rates were 26%, 18% and 8% respectively [s1]. On tolerability, treatment-emergent adverse events occurred in roughly three-quarters to 85% of participants but were almost entirely mild or moderate, and most people were judged ready for discharge within two hours of dosing [s1]. That discharge window is the trial's practical headline: psilocybin trials typically keep patients monitored for most of a day, and esketamine, the approved intranasal option, requires two hours of observation after each of many repeat sessions. A single dose with a two-hour tail would be a markedly lighter burden on patients and clinics, if the benefit proves durable.

How to read it

Several things keep this a signal rather than a verdict. It is a phase 2b trial of fewer than 200 people, with a single dose and a short 8-week follow-up, so durability beyond that is unknown [s1]. The comparator was an active low dose, not a placebo, which both complicates blinding and makes the true effect size harder to pin down. And the between-group difference, while statistically clear, is in the modest range on an absolute scale — around five to six MADRS points. As with the broader psychedelic field, the psychological support wrapped around dosing is part of the intervention, so the drug's effect cannot be cleanly separated from the therapy.

What it means

Mebufotenin now has a positive phase 2b trial behind it, and its short duration of action is a real practical advantage over the longer psychedelics if the benefit holds up. But a larger, longer, placebo-anchored phase 3 trial is the test that would move it toward approval, and none of the convenience matters if the antidepressant effect proves small or short-lived. The fair summary: a brief-acting nasal psychedelic eased hard-to-treat depression more than a low-dose comparator over four weeks, in a trial built to justify a bigger one — not to end the question.