Behold the Colorado River toad. Also known as the Sonoran Desert toad, these bulbous fellas pack a psychedelic punch just below the surface. Their venom, which they can secrete through glands on their skin, contains a hallucinogenic compound, which the scientists behind a new study say could be a potent antidepressant.

Psychedelics have received a lot of attention in recent years for their potential in treating severe depression. Psilocybin – of magic mushrooms fame – is a big hitter in this arena, with a growing body of research leading scientists to conclude it could be a game changer for some of the hardest-to-treat cases. 

Now, there’s a new psychedelic in town, and it comes all wrapped up in a nice amphibious package. A new study has investigated a modified form of the compound 5-MeO-DMT – a relative of DMT that's extracted from the venom of the Colorado River toad (Incilius alvarius) – and concluded it could be an effective treatment option for depression and anxiety.

It’s long been understood that this toad’s venom can cause intense hallucinations and trippy experiences – that’s why authorities are constantly telling us to stop licking them. But how the toads produce their psychoactive slime remains a bit of a mystery, and there are also questions to be answered about how the compounds act on the human brain.  

Structural pharmacologist Daniel Wacker from the Icahn School of Medicine at Mount Sinai, along with colleagues, set out to investigate how 5-MeO-DMT interacts with a type of serotonin receptor called the 5-HT_1A receptor.

Most research on psychedelics up to now has focused on a similar but different receptor, 5-HT_2A, because it’s key to their ability to produce hallucinations. Previous research had shown that 5-HT_1A was worth a closer look when it comes to developing new and improved antidepressants, but not much was known about how psychedelics interact with the receptor. 

To find out more, Wacker and the team modified the structure of the psychedelic compound at different sites, creating variants that could be tested for their potential efficacy.

As well as examining the variants in vitro, they tested one in a mouse model of depression. They compared it to LSD as well as existing drugs that target 5-HT_1A, and found that the toad venom compound had a similar antidepressant and anti-anxiety effect – without getting the mice high.

“We show that a 5-HT_1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals,” they write in their paper. 

The 5-MeO-DMT compound was massively more selective towards the 5-HT_1A receptor compared to 5-HT_2A – 800-fold, in fact – demonstrating once again that this under-researched receptor deserves a closer look. 

Of course, it’s not yet clear whether this compound that works so well in mice could have similar positive results in humans. However, this is not the first time that Colorado River toad venom has been suggested to have antidepressant properties.

“Our studies uncover molecular aspects of 5-HT_1A-targeted psychedelics and therapeutics,” the authors write, “which may facilitate the future development of new medications for neuropsychiatric disorders.”

But we’re afraid you’re going to have to wait for more research. This is not – repeat, not – an invitation to pop down to the southern US or Mexico and start milking toads. No matter how invitingly mystical they look.

The study is published in Nature.