Toad-Venom Compound Nasal Spray Eased Depression in Phase 2b Trial

A single nasal dose of mebufotenin, a psychedelic compound that originates in the venom of the Sonoran Desert toad, eased symptoms of difficult-to-treat depression for at least eight weeks in a phase 2b randomised clinical trial. The results, from a team led by neuropsychiatry researcher David Feifel, were published on October 26 in JAMA. The trial was funded by the biotech company AtaiBeckley.

What was tested

The active ingredient, also known as 5-MeO-DMT, is one component of the street drug "bufo", which is usually sold as dried toad venom. The researchers used a synthesised, pure form, mebufotenin benzoate, as a nasal spray. It is not the first trial of the drug, but ScienceAlert describes it as the largest and most rigorous yet to test it as a nasal spray. Its psychedelic effects begin rapidly and fade within about an hour.

The trial included 193 people with moderate to severe major depression, treated at sites in Australia, Europe and the United States, who had already tried two to five antidepressants during the current episode without effect. Each person received one dose, without knowing which: 0.3 milligrams, 8 milligrams or 12 milligrams. All received psychological support before, during and after the session.

What it found

• Most participants were ready to leave the treatment session within about two hours, after confirming that the acute psychedelic effects had ended.
• Benefits typically began about two days after the session and lasted at least eight weeks.
• The 12 milligram and 8 milligram doses improved depression scores by 5.3 and 6.2 more points than the 0.3 milligram dose.
• Most participants had side effects, but almost all were mild or moderate: headache, nausea and nasal pain that passed on the day of dosing. One person had two severe panic attacks.

The 8 milligram dose, which gave the best balance of safety and effect, will go on to phase 3, where it will be tested in a much larger group and compared with existing treatments. "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," Feifel and colleagues write, contrasting it with esketamine and transcranial magnetic stimulation, which need frequent retreatment, and with psilocybin and LSD, which need four to twelve hours of monitoring.

A sceptical reading

Psychopharmacology researcher Chittaranjan Andrade of India's National Institute of Mental Health and Neurosciences, who was not involved, wrote an opinion piece on the study in JAMA and is not convinced. "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," he writes. He notes that the definition of "treatment-resistant" was lenient, since no participant had tried ketamine or electroconvulsive therapy, and that people reporting suicidality were excluded, so safety and effect in them are unclear. Because mebufotenin was tested alone, he adds, the trial says nothing about when to move patients to a conventional antidepressant or whether the drug could serve for maintenance.

The drug is still a long way from medical use outside research. More in our Health section.