A single intranasal dose of the psychedelic mebufotenin benzoate helps improve symptoms in adults with treatment-resistant depression (TRD), with the benefit emerging as early as day 1 after dosing and persisting for 8 weeks, according to a phase IIb trial said to be the largest clinical evaluation to date of mebufotenin administered as a nose spray.
From baseline to day 29, the primary endpoint of total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) decreased by 11.1 points with the 8-mg mebufotenin benzoate dose and by 12.5 points with the 12-mg dose vs 5.5 points with the 0.3-mg dose (comparator), for a mean difference of –5.3 points (95 percent confidence interval [CI], −8.9 to −1.8; p=0.003) and −6.2 points, 95 percent CI, −10.2 to −2.1; p=0.003), respectively. [JAMA 2026;doi:10.1001/jama.2026.18380]
“Response (≥50-percent reduction in MADRS total score) and remission (MADRS total score ≤10 points) rates were higher in both active groups vs the low-dose comparator group at all time points (from 2 to 57 days post dose),” noted lead investigator Dr David Feifel from Kadima Neuropsychiatry Institute, La Jolla, California, US, and colleagues.
The proportion of responders was 21.7 percent in the 8-mg group, 23.3 percent in the 12-mg group, and 5.4 percent in the 0.3-mg group at day 2, and 28.3 percent, 31.5 percent, and 10.8 percent, respectively at day 57. Remission was achieved in 15.2 percent, 11 percent, and 4.1 percent at day 2, and 26.1 percent, 19.2 percent, and 8.1 percent at day 57, respectively.
“Additionally, the significant improvements in outcomes assessing global severity (CGI-S) and quality of life (QLDS) across all time points for both active doses indicate benefits beyond symptom reduction, including functional recovery—a treatment goal considered important by patients with TRD,” Feifel and colleagues pointed out.
Treatment-emergent adverse events (TEAEs) occurred in 76.1 percent of participants in the 8-mg, 84.9 percent in the 12-mg, and 73 percent in the 0.3-mg dose groups. Most of these events were mild or moderate in intensity, occurring on the day of dosing and resolving withing 24 h. Headache (29.5 percent), nausea (23.8 percent), and administration site pain (15.5 percent) were the most common TEAEs.
Drug-related TEAEs were more frequents in the 12-mg group than in the than the 8-mg and 0.3-mg groups (82.2 percent, 69.6 percent, and 33.8 percent, respectively). Serious TEAEs occurred in one patient each in the 8-mg and 0.3-mg groups, with the events deemed unrelated to study treatment. No suicidal behaviour was reported during the trial.
No need for prolonged in-clinic monitoring
“A key distinguishing feature of intranasal mebufotenin benzoate is the brief duration of the acute psychedelic experience,” Feifel and colleagues said.
Between 78 percent and 85 percent of patients in the 8-mg and 12-mg groups were deemed ready for discharge within 2 hours after dosing.
According to Feifel and colleagues, the rapid return of dosed participants to baseline, along with the potential for infrequent dosing, sets mebufotenin benzoate apart from other psychedelics or treatment options available or being investigated for TRD. For instance, esketamine and transcranial magnetic stimulation require frequent retreatment, while psilocybin and lysergic acid diethylamide require 4–12 hours of monitoring due to longer acute subjective effects, they added.
Taken together, the findings indicate that “intranasal mebufotenin benzoate may improve treatment access and convenience, requiring a shorter monitoring period and fewer clinic visits compared with psilocybin and esketamine, respectively,” the investigators said.
The trial was conducted at 38 sites across Australia, Europe, and the US. A total of 193 adults (mean age 41 years, 59.1 percent female, 82.6 percent White) with moderate-to-severe major depressive disorder showing no response to 2–5 antidepressant medications during their current episode.
The participants underwent a supervised antidepressant washout before being randomly assigned to receive a single dose of intranasal mebufotenin benzoate at 8 mg (n=46), 12 mg (n=73), or 0.3 mg (n=74), which was administered alongside psychological support.
Mebufotenin promise tempered by modest response
“Research on psychedelic treatment now suggests a possible paradigm shift in the management of depression, and not merely difficult-to-treat depression. Patients with depression are currently treated with medications that take weeks or longer to work, if indeed they do work,” wrote Dr Chittaranjan Andrade from the National Institute of Mental Health and Neurosciences in Bangalore, India, in a linked editorial. [JAMA 2026;doi:10.1001/jama.2026.17333]
“The emerging evidence from trials of psychedelic treatment in depression offers the promise of immediate and usually substantial relief,” Andrade added.
However, despite the “seemingly substantial efficacy” and brief psychedelic effect with mebufotenin, Andrade noted that the drug’s “antidepressant effect was incomplete.”
“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. Clearly, at least in difficult-to-treat depression, either an 8-mg to 12-mg dose of mebufotenin nasal spray is insufficient or a single dose of the drug is insufficient,” he pointed out.
Andrade emphasized the need for additional investigation to examine whether a higher dose or administering escalating doses or a treatment course would yield better results.