Hallucinogen from the Venom of the Bufo Toad Shows Potential for Treating Mental Disorders

    Mouse research delves into the molecular basis of 5-MeO-DMT and how this compound impacts the brain

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    The Sonoran desert toad (Inciliusalvarius, also known as the Colorado River toad or bufo toad) releases a venom through its skin that contains a psychedelic compound with therapeutic potential. The molecule 5-MeO-DMT, which is naturally secreted by the parotid glands of this amphibian, has hallucinogenic properties, causing temporary distortions of visual, auditory and time perception in those who consume it. But the trips generated by this compound can also have an impact on health and the scientific community is already investigating its properties to treat depression and other mental disorders.

    A study published Wednesday in the journal Nature deepens the knowledge of this type of psychedelic and its medicinal possibilities: researchers at the Icahn School of Medicine at Mount Sinai in New York have mapped the molecular basis of 5-MeO-DMT in the brain and have analyzed how it interacts with the same serotonin receptor used in other antidepressants. The research adds “crucial information,” say the authors, to facilitate the development of new neuropsychiatric therapies.

    In the midst of the renaissance of psychedelic medicine, there are many eyes on the therapeutic potential of 5-MeO-DMT. And it is already being tested in humans with a handful of trials for resistant depression. But the mechanism of action, how this compound impacts the brain, remains unclear. Scientists are looking particularly closely at the interaction of this and other psychedelics with brain receptors that activate a key neurotransmitter for regulating mood: serotonin. This chemical serves as a communication pathway for neurons to send messages to each other and helps regulate a variety of functions, from mood to digestion, temperature, sleep and sexual function. Low serotonin concentration is associated with the development of depression and other mental disorders. Some conventional antidepressants, such as prozac, precisely try to raise serotonin levels.

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    The ‘psychedelic renaissance’: science revives therapeutic potential of psychoactive drugsDaniel 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.

    The trips involve temporal distortions of visual, auditory and time perception, often described as hallucinations, but also so-called subjective effects that can range from pleasant mystical experiences and feelings of oneness to negative experiences including fear, paranoia and vomiting. 5-MeO-DMT in particular has been associated with ego dissolution, i.e., feelings of oneness with the universe, which could substantially contribute 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 may 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 attributed primarily 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 may play a key role,” Wacker advances in an e-mail response.

    Behind that alphanumeric moniker (5-HT1A) lies one of 13 groups of serotonin-activated receptors that “regulate numerous physiological processes, including many brain functions, intestinal motility and even the reproductive system,” the scientist explains. “5-HT1A is the most highly 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 main 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 atomic-level structures in our work,” he adds.

    The researchers analyzed the compound’s interactions with these receptors and modified specific sites on the hallucinogen to evaluate, in mouse models of depression, its potential as a therapeutic agent. “Our studies provide crucial information on an understudied class of psychedelics and related compounds that may facilitate the development of novel neuropsychiatric therapies targeting 5-HT1A,” the research concludes.

    Clinical trials

    Víctor Pérez, who is head of Psychiatry at the Hospital del Mar in Barcelona and has a clinical trial (phase II) underway with 5-MeO-DMT for resistant depression, explains that Wacker and his team “propose part of the mechanisms of action”, but do not resolve all the questions that remain unanswered: “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, there is a qualitative change [remits the depressive symptomatology]. They are substances with tremendous potency and, if you do it 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 trying to map, as in a movie, what happens in the brain when this psychedelic originating from the venom of the buffalo toad is used. But they also reveal 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 efficacy potentially depends on the 5-HT1A and 5-HT2A receptors. This finding could have clinical implications, as the drug could have known 5-HT1A-related side effects, as observed with other 5-HT1A drugs (sleep disorders, headaches, etc.).”

    Apropos of this study, Óscar Soto, president of the Spanish Society of Psychedelic Medicine, stresses that findings such as these will allow “to better identify how [this compound] impacts one receptor or another.” “It opens the door to develop new specific molecules to bind in a specific way to a specific receptor,” assures the physician, who was not involved in the research.

    Soto is a psychiatrist at ParcSanitariSant Joan de Déu, where three clinical trials have just opened to test 5-MeO-DMT and another psychedelic compound, psilocybin, in patients with resistant depression. About the hallucinogen that was traditionally extracted from the venom of the bufo toad, Soto points out that it induces a process of brain plasticity and an altered state of consciousness that is “complex and different from other psychedelics,” but leads to “an acute improvement in symptoms.” “A characteristic of altered states of consciousness is the ineffability, the difficulty of describing that state: many people talk about feeling that they disappear, there are not so many visual alterations, but sometimes they lose track of time. Sometimes they don’t even remember the experience itself,” he says. The trip is short, between 10 minutes and half an hour, but he warns that “these are complex experiences and it is important for the patient to feel safe and accompanied because it can be a difficult process to go through.

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