AtaiBeckley’s investigational mebufotenin, a psychedelic compound also found in Sonoran Desert toad secretions, shows antidepressant effects in a Phase 2b depression trial.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
A single intranasal dose of mebufotenin benzoate significantly reduced depressive symptoms in adults with treatment-resistant depression (TRD) compared with a subperceptual low dose in a Phase 2b randomized clinical trial published in JAMA on October 26, 2026. The study (NCT05870540) also found that most participants were considered ready for discharge within two hours of administration, highlighting a potential operational advantage for psychedelic-based treatment.
Mebufotenin, also known as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), is a naturally occurring serotonergic psychedelic found in the defensive gland secretions of the Sonoran Desert toad (Incilius alvarius) and certain plant species. It can also be chemically synthesized for pharmaceutical research. BPL-003 is an investigational intranasal formulation of mebufotenin benzoate developed for TRD. The compound acts primarily through serotonin 5-HT1A and 5-HT2A receptors.
Trial Design: Three Single-Dose Treatment Groups
The double-blind, randomized Phase 2b trial (NCT05870540) enrolled 193 adults aged 18–75 years with moderate-to-severe major depressive disorder that had not responded to two to five antidepressant treatments during the current episode. Conducted across 38 sites in Australia, Europe and the United States between September 2023 and April 2025, the study compared single intranasal doses of mebufotenin at 8 mg (n=46) and 12 mg (n=73) against a 0.3 mg low-dose comparator (n=74), alongside psychological support. The primary endpoint was the change in MADRS total score from baseline to day 29, comparing 12 mg with 0.3 mg, with an eight-week blinded follow-up.
Key Clinical Results
Primary Endpoint: MADRS Score Reduction at Day 29
The 12 mg dose met the primary endpoint, demonstrating a statistically significant reduction in depressive symptoms compared with the 0.3 mg comparator.
Mean MADRS scores decreased by 11.1 points in the 12 mg group and 5.5 points in the comparator group. The reported between-group mean difference was −5.3 points (95% CI −8.9 to −1.8; P=0.003).
Secondary Endpoints: Response, Remission and Duration of Benefit
The 8 mg dose also demonstrated significant improvement over the comparator at day 29. Mean MADRS scores decreased by 12.5 points, with a between-group mean difference of −6.2 points (95% CI −10.2 to −2.1; P=0.003).
Both active-dose groups showed similar reductions in MADRS scores and significantly greater improvements than the comparator at all other assessed time points from day 2 through day 57.
At day 29, response rates were 35% with 8 mg, 34% with 12 mg and 12% with 0.3 mg. Corresponding remission rates were 26%, 18% and 8%, respectively.
Safety Endpoint: Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) were reported in 76% of participants receiving 8 mg, 85% receiving 12 mg and 73% receiving the comparator. Overall, 99.7% of reported events were classified as mild or moderate.
These findings indicate that adverse events were common across all three groups, although most reported events were not severe. Detailed safety assessment remains important in subsequent clinical development.
Discharge Readiness: Most Participants Ready Within Two Hours
Discharge readiness was assessed beginning 90 minutes after dosing. Within two hours, 85% of participants receiving 8 mg and 78% receiving 12 mg were considered ready for discharge.
This finding addresses a practical challenge in psychedelic-assisted treatment, where prolonged supervised monitoring can limit clinical capacity and treatment accessibility. However, discharge readiness should not be interpreted as evidence of complete recovery or absence of subsequent safety risks.
Lilly Takes Ownership of BPL-003
Eli Lilly completed its acquisition of AtaiBeckley on September 11, 2026. The company identified BPL-003 as AtaiBeckley’s lead investigational programme for TRD.
The JAMA abstract does not specify the next clinical development stage or a Phase 3 timeline.
Clinical Interpretation
The Phase 2b results provide randomized evidence that a single intranasal dose of mebufotenin benzoate can reduce depressive symptoms in adults with TRD compared with a subperceptual low-dose comparator. The statistically significant primary endpoint and improvements reported through day 57 support further clinical investigation.
However, the comparator was not an inactive placebo. Participants receiving 0.3 mg also experienced a 5.5-point mean reduction in MADRS scores. In psychedelic trials, treatment expectancy and potential unblinding can influence reported outcomes; the available abstract does not detail how these factors were assessed.
Although both active doses demonstrated improvements, the study does not establish that 8 mg and 12 mg are equivalent or identify an optimal dose. Furthermore, the eight-week follow-up does not establish long-term durability.
The authors suggest that intranasal administration may require shorter monitoring than psilocybin and fewer clinic visits than esketamine. These potential advantages were not established through direct comparative trials.
Overall, the findings position mebufotenin as a candidate for further investigation in TRD, with its short administration-to-discharge window offering a potentially relevant operational advantage alongside its observed antidepressant effects.
References
Feifel D, et al. Single Intranasal Administration of the Psychedelic Mebufotenin for Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA. October 26, 2026, doi: 10.1001/jama.2026.18380
BPL-003 Efficacy and Safety in Treatment Resistant Depression, ClinicalTrials.gov ID NCT05870540
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.