Hallucinogen from Sonoran Desert toad venom shows potential to treat mental disorders

The Sonoran Desert toad (Incilius alvarius, also known as the Colorado River toad or bufo toad) releases a poison through its skin that contains a psychedelic compound with therapeutic potential. The 5-MeO-DMT molecule, which is secreted naturally by the parotid glands of this amphibian, has hallucinogenic properties: when consumed, it causes temporary distortions of vision, sound and time perception. But the trips triggered by this compound may also impact mental health, and the scientific community is investigating its properties to treat depression and other mental disorders. A study published on Wednesday in the journal Nature provides further insight into this type of psychedelic and its medicinal possibilities. Researchers from the Icahn Faculty at Mount Sinai in New York mapped the molecular bases of 5-MeO-DMT in the brain and analyzed how it interacts with the same serotonin receptor that is used in other antidepressants. The researchers believe the study provides “crucial information” to facilitate the development of new neuropsychiatric therapies.

Amid the growing interest in psychedelic medicine, many scientists are looking at the therapeutic potential of 5-MeO-DMT. It is already being tested in humans, in a handful of trials for treatment-resistant depression. But the mechanism of action — i.e. how the compound impacts the brain — remains unclear. Scientists are paying special attention to how it and other psychedelics interact with brain receptors that activate a key neurotransmitter for regulating mood: serotonin. This chemical substance serves as a communication route for neurons, allowing them to send messages to each other. It also helps regulate various functions, such as mood, digestion, temperature, sleep and sexual function. Low concentration of serotonin is associated with the development of depression and other mental disorders. Some conventional antidepressants, such as Prozac, try to raise serotonin levels.

Daniel Wacker, author of the study published in Nature, admits that what they know about the effects of 5-MeO-DMT, “comes from anecdotal reports”: “The psychedelic induces altered states of consciousness, which are often described as trips and cannot be equated to a high like that produced by cannabis. Trips involve [...] hallucinations, but also so-called subjective effects that can range from pleasant mystical experiences and feelings of unity to negative experiences including fear, paranoia and vomiting. 5-MeO-DMT in particular has been associated with ego dissolution, that is, feelings of oneness with the universe, which could contribute substantially to the sustained antidepressant effects of psychedelics. However, this has not yet been demonstrated so far, and other studies, including ours, suggest that other mechanisms could also contribute to the antidepressant effects of 5-MeO-DMT2.”

His research focused on analyzing, in animal models, how this compound interacts with a group of serotonin receptors closely related to anxiety circuits in the brain. “While there have been some studies indicating that other receptors may play a role in the actions of 5-MeO-DMT, the psychoactive effects of psychedelics in general have been primarily attributed to actions at the serotonin 5-HT2A receptor. 5-MeO-DMT has already demonstrated considerable therapeutic effects in humans, although these reports are anecdotal and cannot be equated with controlled clinical trials. Furthermore, the mechanisms by which 5-MeO-DMT and other psychedelics might treat psychiatric disorders are currently unknown. Our studies suggest that for 5-MeO-DMT, binding and activation of the serotonin 5-HT1A receptor could play a critical role,” says Wacker by email.

Behind that alphanumeric nickname (5-HT1A), hides one of the 13 groups of receptors activated by serotonin that “regulate numerous physiological processes, including many brain functions, intestinal motility and even the reproductive system,” explains the scientist. “5-HT1A is the most expressed serotonin receptor in the brain, where it regulates body temperature, memory and learning, mood, and other aspects of human physiology. Interestingly, 5-HT1A is the primary molecular target of several prescription antidepressants, such as vilazodone, buspirone, and gepirone. 5-MeO-DMT binds to the same 5-HT1A pocket that serotonin normally binds to, but interacts with the receptor differently compared to serotonin, as we demonstrate through structures at the atomic level in our work,” he adds.

The researchers analyzed how the compound interacted with these receptors, and modified specific sites of the hallucinogen to evaluate, in mouse models of depression, its potential as a therapeutic agent. “Our studies provide crucial insights into an understudied class of psychedelics and related compounds that may facilitate the development of new neuropsychiatric therapeutics that target 5-HT,” the study concludes.

Víctor Pérez, who is head of Psychiatry at the Hospital del Mar in Barcelona and has a clinical trial underway (Phase II) with 5-MeO-DMT for treatment-resistant depression, explains that Wacker and his team “propose what are part of the mechanisms of action,” but do not resolve all the unsolved questions. “We do not know how the patient’s improvement occurs. A lot remains to be done and I don’t know if we will know what the final mechanism of action is. But it is striking that patients with depression that does not remit to individual treatments and is tremendously desperate, after this therapy, within a few hours, experience a qualitative change [remits the depressive symptomatology]. They are substances with tremendous potency and, if done in the right places [under health control], they are quite safe drugs,” Pérez explains.

Clinical implications

Wacker’s findings shed a little more light on what happens in the brain when this psychedelic from the venom of the Sonoran Desert toad is taken. But the research also reveals the complexity of these mechanisms of action, admits the scientist: “Our research shows that the mechanism by which 5-MeO-DMT acts in the brain is probably more complex than previously assumed, since its clinical effectiveness potentially depends on 5-HT1A and 5-HT2A receptors. This finding could have clinical implications, as the drug could have known 5-HT1A-related side effects, as seen with other 5-HT1A drugs (sleep disorders, headaches, etc.).”

Regarding this study, Óscar Soto, president of the Spanish Society of Psychedelic Medicine, points out that this field of research will allow scientists to “better identify how [this compound] affects one receptor or another.” “It opens the door to developing new specific molecules to specifically bind to a specific receptor,” says Soto, did not take part in the research.

Soto is a psychiatrist at the Parc Sanitari Sant Joan de Déu in Spain, where three clinical trials are testing 5-MeO-DMT and another psychedelic compound, psilocybin, in patients with treatment-resistant depression. Regarding the hallucinogen extracted from the venom of the Sonoran Desert toad, Soto says that it induces a process of brain plasticity and an altered state of consciousness that is “complex and different from other psychedelics.” According to the doctor, this leads to “an acute improvement in symptoms.”

“A characteristic of altered states of consciousness is ineffability, the difficulty of describing that state: many people talk about feeling like they are disappearing, there are not so many visual alterations, but sometimes, they lose track of time. Sometimes you don’t even remember your own experience,” he says. The trip is short, between 10 minutes and half an hour, but he warns that “they are complex experiences, and it is important that the patient feels safe and not alone because it can be a difficult process to navigate.”

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