Dr. Axe Wire · Study decoded · health

Single Nasal Dose of Psychedelic Drug Eases Resistant Depression in 193 Adults

A single nasal dose of an investigational psychedelic drug lowered depression scores more than a low dose, in a trial of hard-to-treat adults.

By Dr. Josh Axe · October 30, 2026 · 1 source · Understand

At a glance

What they found: Both higher doses stayed significantly ahead of the low dose at every checkpoint from day 2 through day 57.
Who was studied: 193 adults, ages 18 to 75, with moderate to severe depression that had not responded to 2 to 5 antidepressant trials.
What it doesn't show: Whether the change lasts beyond 8 weeks.

A single nasal dose of the investigational psychedelic drug mebufotenin benzoate reduced depression scores significantly more than a low-dose comparator, according to a randomized trial published October 26, 2026 in JAMA.

193adults studied

11.1pt drop, 12 mg

78-85%ready in 2 hrs

99.7%mild/moderate AEs

In a phase 2b randomized, double-blind trial, 193 adults ages 18 to 75 with moderate to severe treatment-resistant depression received a single nasal dose of mebufotenin benzoate at 8 milligrams, 12 milligrams, or a low 0.3-milligram comparator dose, alongside psychological support, at 38 sites in Australia, Europe and the US between September 2023 and April 2025.

Average age was 41, and 59.1% of participants were female. By day 29, the 12-milligram dose lowered depression scores on a standard 0-to-60 rating scale by an average of 11.1 points, compared with 5.5 points in the low-dose group, a difference of 5.3 points. The 8-milligram dose lowered scores by 12.5 points over the same period, a difference of 6.2 points versus the low dose. Both higher doses stayed significantly ahead of the low dose at every checkpoint from day 2 through day 57. By day 29, 35% of the 8-milligram group and 34% of the 12-milligram group had responded to treatment, compared with 12% on the low dose; full remission was reached by 26%, 18% and 8%, respectively.

Mebufotenin acts on two serotonin receptors in the brain, the same signaling system targeted by other fast-acting psychedelic depression treatments, and produces a short-lived altered state of consciousness rather than the many-hour experience tied to psilocybin. Most participants, 85% on the 8-milligram dose and 78% on the 12-milligram dose, were judged ready for discharge within two hours of dosing.

Depression Score Drop by Day 29: 12 mg vs Low Dose

JAMA, 2026, Feifel et al.

Side effects were common on every dose: 76% of the 8-milligram group and 85% of the 12-milligram group reported one, against 73% on the low dose, and 99.7% of all events were mild or moderate. Follow-up ran eight weeks, so durability beyond that window is not established, and the comparator was a very low dose of the same drug rather than placebo or an existing antidepressant.

Dr. Axe’s Take

A two-hour clinic visit and an 11- to 12.5-point drop on a 60-point scale in people who'd failed multiple antidepressants is meaningful. But this drug doesn't address why someone became treatment-resistant in the first place — chronic stress, poor sleep, blood sugar swings and nutrient gaps all shape mood and deserve attention regardless of what medication is used. The cost here is side effects in 76% to 85% of people on the active doses, mostly mild or moderate. Keep taking any prescribed medication, and make changes only with your prescriber, based on your numbers. I'd want six-to-twelve-month data before calling this settled.

— Dr. Axe

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Study summary

Who: 193 adults, ages 18-75, average age 41, 59.1% female, with moderate to severe depression unresponsive to 2-5 antidepressant trials.
Design: Phase 2b randomized, double-blind trial, 38 sites in Australia, Europe and the US, September 2023 to April 2025, 8-week follow-up.
Dose: Single intranasal dose: 8 mg (n=46), 12 mg (n=73), or 0.3 mg low-dose comparator (n=74), with psychological support.
Primary result: Depression score fell 11.1 points (12 mg) and 12.5 points (8 mg) vs 5.5 points (0.3 mg) by day 29; difference of 5.3 and 6.2 points, respectively.
Secondary: Day 29 response rates: 35% (8 mg), 34% (12 mg), 12% (0.3 mg); remission: 26%, 18%, 8%. Side effects in 76% (8 mg), 85% (12 mg) and 73% (0.3 mg); 99.7% mild/moderate.
Funding / conflicts: Competing interests: Authors own shares; authors are employed; authors consult. Funding not reported in the abstract.
Date: Oct 26, 2026