The largest study of mebufotenin in adults with treatment-resistant depression to date has shown promising results, but one expert explains why there’s still a long way to go.
Major depressive disorder affects nearly 300 million people across the world, with roughly a third of these individuals having treatment-resistant depression – meaning they have had an inadequate response to two or more different antidepressants.
In recent years there has been a shift towards trying psychedelic treatments for people with treatment-resistant depression, primarily driven by the possibility (or hope) of obtaining sustained benefits after a single dose. However, psychedelics like psylocibin or LSD often come with practical concerns, such as the extensive in-clinic observation time, which reduces the appeal of single session administration.
Enter mebufotenin benzoate nasal spray, a synthetic version of the fast-acting psychedelic mebufotenin (5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) found in certain plant species and at least one kind of toad venom.
Mebufotenin is a potent agonist of both 5-HT1A and 5-HT2A receptors, which have been associated with relatively brief psychedelic experiences. Pharmacodynamic studies suggest the acute psychedelic effects peak eight to 15 minutes after intranasal administration of the synthetic version and return to baseline after 45 to 60 minutes.
“The current phase 2b trial evaluated the efficacy, safety, and tolerability of single 8mg and 12mg doses of intranasal mebufotenin benzoate compared with a low-dose comparator [0.3mg] in adults with treatment-resistant depression,” the researchers behind the recent study wrote in JAMA.
Researchers recruited 193 adults with treatment-resistant depression from 38 sites across Australia, Germany, Poland, Spain, the UK, and the US as part of the low-dose comparator-controlled phase 2b trial. Participants were between 18 and 75 years of age, had been diagnosed with single-episode or recurrent major depressive disorder, had at least moderately severe depression (defined as a Hamilton Depression Rating Scale Score ≥19 and a Clinical Global Impression-Severity Score ≥4 at screening and baseline), and were non-responsive to between two and five antidepressants after eight weeks.
Participants who were taking antidepressants at the time of screening underwent a supervised washout period (completed at least two weeks before mebufotenin dosing) to ensure the treatment was administered as a monotherapy. All participants received manualised psychological support from qualified facilitators before, during, and after the mebufotenin was administered.
Unspecified operational reasons saw a change in the randomisation process during the study, resulting in 74 participants in the 0.3mg group, 46 in the 8mg group, and 73 in the 12mg group. These participants had a mean Montgomery-Åsberg Depression Rating Scale (MARDS) score of 31.8 (MARDS scores range from 0-60, with higher scores indicating more severe depression), had been living with major depressive disorder for an average of 13.4 years, and had “failed” an average of 2.3 antidepressant treatments.
The trial’s primary outcome – the difference in the mean change in MARDS score between baseline and day 29 between the 0.3mg and 12mg groups – was met.
Participants in the 0.3mg group displayed a mean MARDS score change from 31.7 at baseline to 26.1 and day 29, while participants in the 12mg group changed from 32.5 to 21.2. This translates to a least-squares mean difference of -5.3 (95% confidence interval -8.9 to -1.8) in favour of the 12mg group.
Improvements in secondary outcomes were also observed. The least-squares mean difference in MADRS score change from baseline to day 29 between the 8mg and 0.3mg doses was -6.2 (-10.2 to -2.1).
The proportion of participants who responded to treatment (i.e., experienced a ≥50% reduction in MADRS score) by day 57 increased with dose (10.8% in the 0.3mg group, 28.3% in the 8mg group, and 31.5% in the 12mg group). The proportion of patients who were deemed to be remitters at the same time point (i.e., a MADRS score ≤10) was higher in the 8mg and 12mg groups compared to the 0.3mg group: 26.1% and 19.3% versus 8.1%.
Self-reported improvements in depressive symptom severity (as measured by the 16-item Quick Inventory of Depressive Symptomatology-Self Report) and the impact of depressive symptoms and treatment effects on quality of life (as measured by the Quality of Life in Depression Scale) were observed for participants in the 8mg and 12mg group compared to the 0.3mg group, although the differences in the former scale were only observed for the first 28 days after mebufotenin was administered.
The average time for participants to be ready for discharge after the administration of mebufotenin was under two hours for each dose: 106.2 minutes for the 0.3mg group, 113.7 minutes for the 8mg group, and 117.3 minutes for the 12mg group.
More than two thirds of participants in each group were ready for discharge at 90 minutes post-administration (90.5% in the 0.3mg group, 67.4% in the 8mg group, and 68.5% in the 12mg group). This figure exceeded three quarters at the two-hour mark (97.3%, 84.8%, and 78.1% for 0.3mg, 8mg, and 12mg, respectively).
The researchers felt that the short amount of time it took for participants to achieve a state where they could safely be discharged from observation (i.e., be fully responsive and oriented, have a stable gait and normal muscle coordination, acute psychedelic effects have subsided, etc.) was a key advantage of mebufotenin compared to other treatment alternatives.
“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,” the researchers concluded, pointing to the fact that approaches involving esketamine and transcranial magnetic stimulation typically require multiple sessions of treatment while psylocibin- and LSD-based therapies require longer periods of monitoring due to ongoing psychedelic effects.
Treatment-emergent adverse events were recorded in 73.0% of participants in the 0.3mg group, 76.1% of participants in the 8mg group, and 84.9% of participants in the 12mg group.
The most common TEAEs were headache (reported by 29.5% of all participants), nausea (23.8%), and administration site pain (15.5%). two severe TEAEs (panic attacks) were reported by one participant in the 12mg group and were deemed to be related to the treatment.
The majority of TEAEs in the 8mg (72%) and 12mg (78%) groups occurred on the day the intranasal mebufotenin was administered. However, these TEAEs tended to resolve quickly, with 74% and 78% resolving within 24 hours.
No suicidal behaviours were documented throughout the trial, and all TEAEs of suicidal ideation in the 8mg and 12mg groups were (a) without intent, and (b) occurred only in participants with a history of suicidal ideation.
Adjunct Professor Chittaranjan Andrade, a psychiatrist from Kasturba Medical College, Manipal Academy of Higher Education, India, described two aspects of the current findings as “striking” in an accompanying editorial.
“First, self- and observer-rated depression scores decreased sharply by day two and remained stably attenuated, by roughly one-third, for eight weeks in the high-dose groups,” he wrote.
“This result was obtained even though additional treatment with conventional antidepressants was not permitted during the trial (but patients did receive extensive manualised psychosocial support). Global ratings of severity of illness and ratings of quality of life showed similar improvements. This prolonged efficacy of a single dose of a drug in monotherapy is noteworthy, more so because it was recorded in patients with difficult-to-treat depression.”
The second key finding, according to Professor Andrade, was the brevity of the psychiatric effects.
“[There were] 78% to 85% of patients in the 8-mg and 12-mg groups [who] were ready for discharge no more than two hours after dosing. Because psychedelic drugs such as psilocybin and LSD require patients to be closely supervised for 4 to 12 hours after dosing, this safety outcome is also noteworthy.”
Despite this positivity, Professor Andrade had concerns about the efficacy of the findings.
“The average patient became only about 30% better, and the response and remission rates were below those typically seen, for example, with ketamine and electroconvulsive therapy,” he wrote.
“Clearly, at least in difficult-to-treat depression, either an 8mg to 12mg dose of mebufotenin nasal spray is insufficient or a single dose of the drug is insufficient.”
“One possibility would be to dose higher or to administer escalating doses. A risk is that higher single or cumulative dosing would be less well tolerated or would be associated with slower recovery times, delaying discharge from the treatment centre.
“A second possibility is that instead of single dosing, a treatment course, as with ketamine and electroconvulsive therapy, would bring better results.”
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Professor Andrade argued that the development of psychedelics for depression served as a potential paradigm shift for the treatment of the condition more broadly, rather than limiting them to difficult-to-treat depression.
“Patients with depression are currently treated with medications that take weeks or longer to work, if indeed they do work. The emerging evidence from trials of psychedelic treatment in depression offers the promise of immediate and usually substantial relief,” he wrote.
“Immediate and substantial benefit is what is now considered to be the standard of care, for example for patients in severe pain.
“When psychedelic treatments that can bring about immediate and substantial relief become available, how ethical would it be to deny immediate relief and, instead, trial conventional antidepressant drugs that take four to eight weeks to produce remission, if in fact they do? Or, if immediately acting interventions become available to treat severe depression, is it justifiable to reserve them only for treatment refractory depression?
“When considerable research supports the immediate benefits with ketamine and esketamine, why are ketamine and esketamine not even listed as third-line treatments for depression, but named as merely second-line adjuvants for difficult-to-treat depression?
“The mindset of clinicians treating depression must adjust to the idea that immediately acting antidepressants, especially ketamine and esketamine, have potential for use as first-line treatments to attenuate suicidality, alleviate suffering, improve quality of life, and return patients early to a functional state. Health care systems should adjust to this idea, as well.”
The researchers explained that participants could enrol in an optional open-label extension study, where certain territories would administer an additional 12mg dose of mebufotenin, after the eight-week blinded component. These results will be reported separately.
The researchers also touched on plans for the next phase of this line of research.
“Although both active doses had comparable efficacy and durability, the 8-mg dose had a more optimal balance of efficacy and safety, supporting its selection for phase 3 evaluation,” they said.
JAMA, 26 October 2026 (research)
JAMA, 26 October 2026 (editorial)
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