In an effort to improve patients’ mental health, it appears scientists are compiling a list of every “party” psychedelic drug from the last century.
Ketamine, psilocybin, MDMA, LSD, and DMT have all become legitimate investigational drugs in recent decades, with some now established in some countries as prescribed treatment options for cases of depression and other mental illnesses that do not improve with conventional treatment.
Today, a relatively obscure psychedelic compound based on toad venom is being studied for its antidepressant potential. Results of a phase 2b randomized clinical trial were published today in the Journal of the American Medical Association.
The trial, funded by biotechnology company AtaiBeckley (a subsidiary of pharmaceutical giant Eli Lilly and Company), suggests that a single-dose nasal spray formulation of the substance could be a safe and time-saving option for patients suffering from difficult-to-treat depression.
The active ingredient is known as mebufotenin, or 5-MeO-DMT, and comes from the Sonoran Desert toad (Incilius alvarius).
It is one of the components of the notorious but rare street drug “bufo”. Usually sold in the dried form of the toad’s venom, bufo contains both mebufotenin and bufotenin (5-HO-DMT).
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However, in the new clinical trial, researchers were testing a synthesized form of pure 5-MeO-DMT. This is not the first time the drug has undergone clinical trials, but it is the largest and most rigorous trial ever conducted on its use as a nasal spray.
“Single-day administration of 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,” says psychopharmacology researcher Chittaranjan Andrade of India’s National Institute of Mental Health and Neurosciences.
Andrade was not involved in the new clinical trial, but wrote an opinion piece on the research, also published in JAMA.
The unique mystical psychedelic effects of mebufotenin come on quickly and disappear within about an hour, with some variation depending on how the drug is taken. In this respect, it’s similar to DMT, although the visual effects tend to be much less intense.
Neuropsychiatry researcher David Feifel and his colleagues think this rapid psychedelic experience could give mebufotenin an advantage over options like esketamine and psilocybin, although the research isn’t there yet.
Their Phase 2b clinical trial explores the drug’s “safety, effectiveness, and time to readiness to discharge.” The results are promising, but we are still a long way from seeing this Class 1/Class A drug used for medical purposes outside of research.
The trial included 193 participants undergoing treatment for moderate to severe major depression at settings in Australia, Europe and the United States. They had tried two to five different antidepressants during their current depressive episode, with no effect.
Each participant was randomly assigned a single dose of the mebufotenin benzoate nasal spray, containing either 0.3 mg, 8 mg or 12 mg of active substance, but to avoid bias, they did not know their dose.
They also received psychological support before, during and after the “trip”, and followed protocols around the setting and setting typical of existing psychedelic treatments.
Most patients were ready to leave the treatment session about two hours after taking the medication, having confirmed that they no longer felt any acute psychedelic effects.
“This rapid return of dosed participants to baseline, along with infrequent dosing indicated by the long lifespan of the antidepressant after a single dose, may offer important potential benefits for patients and clinicians compared to treatment options currently available or in late stages of development,” Feifel and his team report.
“Esketamine and transcranial magnetic stimulation require frequent reprocessing, and psilocybin and LSD require four to twelve hours of monitoring due to longer acute subjective effects.”
Typically, patients began experiencing benefits about two days after the session, and these benefits continued for at least eight weeks.
The majority of patients experienced adverse side effects, but almost all were mild or moderate: headache, nausea, and nasal pain, which quickly resolved and did not occur until the day of administration. However, one person suffered two severe panic attacks during treatment.
Both the 12 mg and 8 mg doses performed better than the 0.3 mg dose, improving depression scores 5.3 and 6.2 points more than the lowest dose, respectively.
The 8 mg dose will move to phase 3 as it appears to produce the best balance between safety and effectiveness. In phase 3, the drug will be tested on a much larger group of people and compared to other existing treatments.
Andrade isn’t convinced these results bode well for mebufotenin as the next big breakthrough in treating depression.
“The antidepressant effect was incomplete,” he emphasizes.
“The average patient only improved by about 30 percent, and response and remission rates were lower than those typically seen, for example, with ketamine and electroconvulsive therapy.”
He also notes that the study had a fairly lenient definition of “treatment-resistant” depression: no patients had taken ketamine or electroconvulsive therapy, for example. “Difficult to treat” depression is, in his view, a more accurate description of these patients.
The study also excluded any patients who reported suicidal tendencies, meaning it’s unclear how safe or effective mebufotenin would be for them.
He’s also skeptical about how quickly mebufotenin can actually improve people’s lives.
“Patients with difficult-to-treat depression require long-term maintenance therapy, but because mebufotenin has been examined as a monotherapy, the trial
“provides no insight into when and how the transition to a conventional antidepressant should be made or whether mebufotenin itself could be used for maintenance purposes,” he writes.
The research was published in Journal of the American Medical Association.
This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. Although we are proud of our process, we are only human. If you spot an error, please let us know.
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