Hallucinogenic drugs such as LSD and psilocybin have long been discussed in science as possible remedies for depression. The focus is on their effect on the serotonin receptor 5-HT2A in the brain. A research team has now modified another hallucinogen – Colorado toad venom – so that it interacts more closely with another, related serotonin receptor called 5-HT1A. Structural studies and experiments on mice suggest that hallucinations can be avoided in this way while maintaining an antidepressant effect.
The Colorado toad (Incilius alvarius), native to the southwest of the USA, produces the poison 5-MeO-DMT to ward off predators, which triggers hallucinations and spiritual experiences in people. The substance has a similar effect on the brain as the synthetic drug LSD and the fungal toxin psilocybin, which is found in “magic mushrooms”. The effect is mediated by serotonin receptors in the brain, so-called 5-HT receptors. Studies suggest that such hallucinogens could possibly help against depression and other mental illnesses. The focus of research so far has been primarily on the receptor 5-HT2A, which is responsible, among other things, for the hallucinogenic effects of LSD and psilocybin.
Structure analyzed and modified
“However, another related receptor also appears to play a role in the effects of hallucinogens, the serotonin receptor 5-HT1A,” explains a research team led by Audrey Warren from the Icahn School of Medicine at Mount Sinai Hospital in New York. The toad venom 5-MeO-DMT in particular binds more strongly to this receptor than to its better-studied relative 5-HT2A. “Although 5-HT1A is a validated therapeutic target and there are already approved antidepressant medications that target it, little is known about how psychedelics affect 5-HT1A and what effects are mediated by this receptor.”
To fill this research gap, Warren and her team took a closer look at the interactions between the hallucinogen from toad venom and the serotonin receptor. Using cryo-electron microscopy, they made visible how the structure of the toxin influences binding to the receptor. Using this knowledge, they modified the substance so that it bound 800 times more strongly to 5-HT1A than to 5-HT2A. Using electron micrographs, the researchers demonstrated that the binding of the modified toad venom to the 5-HT1A receptor is structurally very similar to that of already approved antidressants.
Antidepressant effect on mice
In the next step, the researchers tested the actual effect of the modified 5-MeO-DMT. To do this, they used mice that they exposed to social stress until they showed depression-like symptoms. The “depressed” animals sat more often secluded in a corner, interacted less with other animals and drank less of the tasty sugar solution offered. After treatment with the modified toad venom, however, they again behaved similarly to conspecifics in whom no depressive symptoms had previously been triggered.
The treated animals showed no signs of hallucinations or changes in perception. The antidepressant effect of the modified 5-MeO-DMT in the experiments was still similar to that of LSD and already approved antidepressants. “It was previously assumed that the 5-HT2A receptor, which is responsible for the perceptual changes caused by classic psychedelics, also mediates their therapeutic effect,” explains the team. “However, our results show that substances that selectively bind to 5-HT1A still have therapeutic effects without showing any signs of hallucinogenic effects.”
Further studies must show whether these results can be transferred to humans. The new findings could possibly help develop new medications for mental disorders such as depression.
Source: Audrey Warren (Icahn School of Medicine at Mount Sinai, New York) et al., Nature, doi: 10.1038/s41586-024-07403-2