Roughly one in six American adults has depression, and 30% of them have tried multiple medications without finding relief. Now, a phase 2b randomized clinical trial published in the Journal of the American Medical Association indicates that a single-dose nasal spray derived from a psychedelic compound found in toad venom could offer rapid relief for treatment-resistant depression, researchers report.
The active ingredient in the treatment is mebufotenin, also known as 5-MeO-DMT, a psychedelic compound naturally found in the skin, venom, and eggs of the Sonoran Desert toad, also called the Colorado River toad or Incilius alvarius. Biotech firm AtaiBeckley, a subsidiary of pharmaceutical giant Eli Lilly and Company, developed the synthetic nasal spray formula tested in the study, according to NewsNation. Toads are not harmed in the process, as the compound is synthesized directly in a laboratory.
Evaluating Doses and Patient Outcomes
The clinical trial enrolled 193 adults aged 18 to 75 across the United States, Australia, and Europe who suffered from treatment-resistant depression, NewsNation reported. Participants were randomly assigned to receive a single dose of mebufotenin benzoate nasal spray containing 0.3 mg (used as a control), 8 mg, or 12 mg, accompanied by psychological support before, during, and after administration.
Researchers evaluated symptom changes using the Montgomery-Åsberg Depression Rating Scale, where higher scores reflect more severe depression. Patients who received the 8 mg and 12 mg doses showed significant score reductions persisting for weeks after a single treatment. The 8 mg group experienced an average drop of 12 points on a 60-point scale, with a quarter of those participants achieving remission, meaning their symptoms fell below the clinical threshold for qualifying depression.
Comparing Duration and Side Effects
Unlike longer-acting psychedelics such as psilocybin, which can last over six hours, mebufotenin acts rapidly and subsides quickly, ScienceAlert reported. Between 78% and 85% of patients treated with the nasal spray were able to leave the clinic within two hours, a discharge timeline comparable to the FDA-approved nasal spray esketamine.
Adverse events were common during the trial. ScienceAlert reported that 76% of patients in the 8 mg group and 85% in the 12 mg group experienced side effects, though 99.7% of those events were classified as mild or moderate. The most frequently reported side effects included nasal discomfort, nausea, vomiting, headaches, tingling sensations, and excessive saliva. One participant experienced two severe panic attacks during treatment, according to ScienceAlert.
Future Regulatory Steps and Unanswered Questions
Despite the promising phase 2b results, the experimental treatment must successfully complete large-scale phase 3 clinical trials before receiving regulatory approval from the FDA. Independent psychopharmacology researcher Chittaranjan Andrade of India’s National Institute of Mental Health and Neurosciences pointed out limitations in the current trial design, noting that because mebufotenin was tested as a monotherapy, the study leaves open questions regarding how and when patients should transition to maintenance therapy or if mebufotenin itself can be used long-term, ScienceAlert reported.
Frequently Asked Questions About Toad-Derived Depression Treatment
Are real toads used to manufacture the mebufotenin nasal spray?
No, the pharmaceutical company AtaiBeckley synthesizes the active ingredient, mebufotenin (5-MeO-DMT), in a laboratory setting, meaning no animals are harmed or overharvested.
How long do patients need to stay in the clinic after receiving the dose?
Between 78% and 85% of participants were able to leave the clinical facility within two hours of administration, a recovery window similar to existing non-psychedelic clinical nasal sprays like esketamine.
What were the specific symptom reductions observed in the trial?
Participants receiving the 8 mg dose saw an average 12-point reduction on a 60-point depression scale, and a quarter of patients on that dose achieved symptom remission after a single treatment.
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