Cornell researchers discover brain mechanisms behind psilocybin's effects

Psilocybin is the active ingredient that gives so-called "magic mushrooms" their hallucinogenic kick. It also has a therapeutic potential for treating depression. Now, Cornell University researchers have identified a pair of key neurological mechanisms in the brain – a cell type and receptor – that enable the psychedelic compound's long-lasting effects.

Targeting the pyramidal tract neurons and their specific serotonin 5-HT2A receptor in the medial frontal cortex could enable pharmaceuticals to deliver psilocybin's mood-altering benefits while suppressing the perceptual hallucinatory trip.

The findings were published in Nature. The lab of senior author Alex Kwan, associate professor of biomedical engineering, led the project.

Building off a previous study, we wanted to see where the neuronal connections are grown in the different cell types in the brain. We started playing around with these cell types, and we asked: Which are important for psilocybin's behavioral effects? If we silence some of these neurons, will psilocybin still be able to do its thing and be therapeutic?"

Alex Kwan, associate professor of biomedical engineering, Cornell University

Essentially, the frontal cortex is important for therapeutic effects, whereas the subjective perceptual effects – i.e., "the trip" – likely rely on another region of the brain, such as visual pathways. This could have important implications for pharmaceutical treatment.

"Right now, a huge focus from the pharmaceutical companies is on developing drugs that may be able to take out the trip but still give you the benefit for treating mental illnesses," Kwan said. "But what this work shows is that that could be difficult, because in the end, they target the same receptor. So one might think about just delivering the drug to some specific brain areas, which can be a better way to do it."

The research was supported by the National Institutes of Health; a One Mind–COMPASS Rising Star Award; Source Research Foundation; and the Connecticut Department of Mental Health and Addiction Services.