Beyond the Hallucination

The focus of a new study led by Daniel Wacker, PhD, is 5-MeO-DMT, a powerful psychedelic naturally found in the venom of the Colorado River toad.

Unlike other psychedelics, which interact with a receptor known as 5-HT2A, 5-MeO-DMT also interacts heavily with a different sensor called the 5-HT1A receptor. While 5-HT1A is a known target for treating anxiety and depression, scientists have not fully understood how psychedelic molecules "plug into" it or which of their effects— the healing or the hallucinogenic—come from this specific connection.

Mapping the Molecular "Lock and Key"

To overcome this challenge, Dr. Wacker and his collaborators used cryo-electron microscopy (a high-tech imaging tool) to take atomic-level snapshots of 5-MeO-DMT as it binds to the 5-HT1A receptor. By comparing these images with the way LSD and existing anti-anxiety medications interact with the brain, the team was able to deconstruct the molecule and identify exactly which parts of the chemical structure trigger a response and which parts determine how selective the drug is. They also developed a new version of 5-MeO-DMT designed to target only the 5-HT1A receptor, while ignoring the 5-HT2A receptor, the one responsible for psychedelic hallucinations.