Hallucinogenic compounds that activate multiple receptors, found in Colorado River toads, show “promising transdiagnostic therapeutic with rapid and lasting effects” for conditions such as depression and anxiety, new findings show, and you don’t necessarily need to hallucinate to therapeutically benefit from the compounds. 

While much is known about the serotonin 5-HT2A receptor, this study explored a serotonin receptor called 5-HT1A, which is activated by an altered compound made from toad secretions that’s believed to alleviate depression and anxiety without inducing hallucinations.

A new study, “Structural pharmacology and therapeutic potential of 5-methoxytryptamines,” was published last month in the journal Nature.

When sensing danger, Colorado River toads, sometimes native to the Sonoran Desert (Incilius alvarius or Bufo alvarius) release a hallucinogenic compound bufotenin that’s structurally similar to DMT from glands in their skin. The compound is also similar in structure and effects to psilocybin as well. The marine toad (Bufo marinus) and European green toad (Bufo viridis) release similar toxins that can sometimes be poisonous to the touch, but only the Colorado River toad releases compounds considered a true hallucinogen.

A team of researchers from Mount Sinai Hospital and Columbia University in New York explored the potential health benefits of psychedelic compounds from toad secretions, and created a new compound that doesn’t trigger hallucinations. 

“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, neuropharmacologist at Columbia University and a co-author of the study, told Gizmodo.

Since it’s structurally similar to psilocybin, and based on evidence showing that psilocybin can treat depression in some people, researchers believe there is therapeutic potential with toad secretions as well. 

Most psychedelics research has explored the drug’s effects on a particular kind of serotonin receptor called 5-HT2A. But the team behind the new study focused on a more obscure serotonin receptor called 5-HT1A, which past studies suggest interacts with the toad toxin.

A New Compound Made from Toads

Smithsonian reports that by slightly modifying the 5-MeO-DMT compound, the researchers created another compound called 4-F,5-MeO-PyrT. This new compound interacts primarily with 5-HT1A, a pathway that appears to offer the same antidepressant and anti-anxiety effects without inducing hallucinogenic trips.

It turns out there are already pharmaceutical drugs that target the same receptor.

“Given that 5-HT is the primary target of approved anxiolytic and antidepressant medications, such as buspirone (BuSpar)  and vilazodone (Viibryd), this receptor may contribute to the reported therapeutic effects of 5-MeO-DMT.”

The effects from psychedelic toad secretion compounds suggest long-term effects in overcoming depression-like states.

“Recent preliminary clinical data suggest that 5-MeO-DMT is a promising transdiagnostic therapeutic with rapid and lasting effects. Our work and previous studies have shown that 5-MeO-DMT has comparable signaling potency and efficacy at 5-HT and 5-HT in vitro, and both receptors contribute to its in vivo pharmacology. In light of previous work showcasing 5-HT-selective agonists that alleviate anxiety-like and depression-like states in preclinical models, we wanted to investigate the role of 5-HT in both psychedelic and therapeutic effects of 5-MeO-tryptamines. Although 5-HT is a validated therapeutic target for several approved medications, including vilazodone and buspirone, the importance of 5-HT agonism to the therapeutic effects of tryptamine psychedelics has not been conclusively addressed.”

High Times reported on the toad using its other name, the Sonoran Desert toad, with glands secreting a venom rich in the hallucinogens 5-MeO-DMT and bufotenin, which invaded Arizona last year when monsoon conditions kicked in for the late summer. They can measure up to 7 inches long and have a low-pitched croak that inevitably serenades the night in multiple states during hot wetter months.

Local news stations in Arizona last year reported a surge in Sonoran Desert toad populations now that the rain has started. 

While some researchers aim to bypass the hallucinogenic effects of the toxin, others are trying to enhance it for recreational use. They are sought after so much, toad secretion harvesting has caused them to be endangered in some areas.

Vice Media’s Hamilton Morris documented the Sonoran Desert toad in detail—calling the toads’ secretion the “most potent psychedelic toad venom on Earth,” which also makes it ideal for medical research. Sonoran Desert toad venom should only be vaped or smoked, InStyle reported. Toad venom is scraped from the glands on the animals and dried into paste, which is later smoked. “The experience is going to start within 10 to 30 seconds and then you’re going to be physically incapacitated for 20 to 30 minutes,” Alan Davis, a Johns Hopkins psychedelics researcher, previously explained in Johns Hopkins Magazine. 

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