A Modified Psychedelic Toad Toxin Reduces Signs of Depression and Anxiety in Mice, Study Suggests

Colorado River toads produce a psychoactive toxin that some have claimed has medical benefits. The new research suggests these benefits could be achieved without hallucinations

A medium close-up of a Colorado River Toad, with green skin and yellow eyes, sitting on a rock.
Toxins from the Colorado River toad have been ingested by some for their psychedelic and medicinal effects. kuhnmi via Flickr under CC BY 2.0 DEED

The Colorado River toad, a species native to Arizona’s Sonoran Desert and parts of northwest Mexico, has gained fame for its production of a toxin with psychoactive properties—and, some say, medicinal benefits.

Now, new research from Mount Sinai Hospital and Columbia University has put that toxin to the test. In a study published Wednesday in the journal Nature, scientists found that a modified analog of the toad’s secretion reduces symptoms of depression and anxiety in mice.

“We became intrigued by numerous reports of powerful, unique and life-changing experiences associated with its ritualistic or experimental clinical use, which made us wonder about its therapeutic potential and the underlying mechanisms,” David Lankri, a neuropharmacologist at Columbia University and a co-author of the study, tells Gizmodo’s Ed Cara.

Two Colorado River toads sit side by side, facing the camera face-on.
Scientists modified the toads' secreted toxin in an attempt to reduce its hallucinogenic effects while retaining its potential antidepressant and anti-anxiety offerings. kuhnmi via Flickr under CC BY 2.0 DEED

When threatened or startled, the Colorado River toad (also called the Sonoran desert toad) exudes 5-MeO-DMT, a hallucinogenic compound that discourages predators, from glands in its skin. Similar in structure to psilocybin, the psychedelic component of “magic mushrooms,” the toxin—which people ingest either by licking toads directly or extracting and smoking it—has been said to have dissociative effects and benefits as an antidepressant and anti-anxiety agent.

Most well-known psychedelic molecules (such as LSD) bind to serotonin receptors in the brain called 5-HT2A, which leads to the hallucinations typical of psychedelic experiences.

But by slightly modifying the 5-MeO-DMT toad toxin compound, the researchers created another compound, called 4-F,5-MeO-PyrT. This new molecule interacts primarily with similar yet lesser-studied serotonin receptors called 5-HT1A, a pathway that appears to offer the same antidepressant and anti-anxiety effects without inducing hallucinogenic trips.

Testing this new compound in mice, the team observed how their modified toxin did not produce the head-twitching effects attributed to the hallucinogenic properties of the toad toxin. They gave the newly created molecule to stressed mice—and the animals subsequently spent more time with peers and drank more sugary water, evidence of lowered anxiety and depression levels.

“It’s our hope that down the line, someone could use the findings of our study to help design novel antidepressants for humans, but that’s certainly a long way out,” Audrey Warren, a biochemist at Mount Sinai Hospital and a co-author of the study, says to New Scientist’s Corryn Wetzel.

An extreme close-up of a Colorado River Toad.
When trialed in mice, the chemically altered toad toxin showed signs of reducing the rodents' stress and anxiety. kuhnmi via Flickr under CC BY 2.0 DEED

But Warren adds that the research is still in its infancy, and ingesting the toads’ toxin comes with significant risks—including side effects of vomiting, seizures, anxiety and death. And experts have cautioned that the toxin’s popularity is threatening the health of the toad in the wild. In California, the species is believed to be locally extinct, while in New Mexico, the toad is listed as threatened.

“There’s a perception of abundance, but when you begin to remove large numbers of a species, their numbers are going to collapse like a house of cards at some point,” Robert Villa, the president of the Tucson Herpetological Society, told the New York Times Simon Romero in 2022.

Psychedelics are gaining popularity for potential medical uses. Researchers and legislators alike have recently looked at MDMA, psilocybin and the lesser-known ibogaine for their potential to treat conditions such as PTSD, anxiety and depression. As this intersection continues to be explored, the new paper raises the possibility that such medical benefits could be achieved without the hallucinations.

The research is “a really nice example of how structural biology can shed light on medicinal chemistry results,” David E. Olson, the director of the University of California Davis Institute for Psychedelics and Neurotherapeutics who was not involved in the study, tells Chemical and Engineering News’ Bethany Halford.

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