Toad Venom Psychedemic Nasal Spray Eases Depression for Eight Weeks

"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," Feifel and team report.

What were the results?

The 8 mg and 12 mg doses beat the 0.3 mg dose. Depression scores improved by 6.2 and 5.3 more points respectively than the lowest dose. Benefits typically began two days after the session and lasted at least eight weeks.

Most patients had side effects, but nearly all were mild or moderate: headaches, nausea and nasal pain that passed quickly on dosing day. One participant experienced two severe panic attacks during treatment.

The 8 mg dose moves to phase 3, where it will be tested in a much larger group and compared against existing treatments. The team believes the short session time gives mebufotenin an edge over alternatives like esketamine and psilocybin, though the research isn't there yet.

"Esketamine and transcranial magnetic stimulation require frequent retreatment, and psilocybin and LSD require four to twelve hours of monitoring due to longer acute subjective effects," the researchers write.

Why are experts cautious?

Psychopharmacologist Chittaranjan Andrade of India's National Institute of Mental Health and Neurosciences, who was not involved in the trial but wrote an accompanying JAMA opinion piece, sees real promise but clear limits.

"Single-day dosing with mebufotenin appears to be effective for postpartum depression – and now for difficult-to-treat depression – and the benefits are sustained with or without retreatment for eight days to six months," he said.

Still, he's skeptical. "The antidepressant effect was incomplete," he points out. "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 also flags the trial's fairly loose definition of "treatment-resistant" depression — no participant had tried ketamine or electroconvulsive therapy, so "difficult-to-treat" fits better. The study excluded patients reporting suicidality, leaving the drug's safety and effectiveness for them unknown.

Because mebufotenin was tested alone, the trial says nothing about when or how patients should transition to a conventional antidepressant, or whether the drug could serve as long-term maintenance, he writes.

And the drug remains Schedule 1/Class A — legal in medicine nowhere outside research settings. Ketamine, psilocybin, MDMA, LSD and DMT have all traveled this road from party drug to research compound, with a few now prescribed in some countries for depression that standard treatment can't fix. Mebufotenin may join them. Phase 3 will decide.

The bottom line: one nasal spray of synthetic toad-venom psychedelic relieved hard-to-treat depression for at least eight weeks, but modest effect sizes and unanswered safety questions mean it's early days.