Psychedelics’ binding depends on receptor mutations

In clinical trials, some participants with depression and posttraumatic stress disorder report improvements to their mental health after treatment with psychedelic substances, while others report no significant effect. A team at the University of North Carolina at Chapel Hill has now reported that natural variations in a serotonin receptor could affect how some psychedelic compounds interact with cells; such variations could be related to whether patients respond to treatments ( ACS Chem. Neurosci. 2022, DOI: 10.1021/acschemneuro.1c00815 ). The team synthesized seven naturally occurring human variants of the 5-HT2A serotonin receptor, which is a protein made in neurons and binds to a precursor of serotonin called 5-hydroxytryptamine. Upon binding, the receptor becomes activated, causing shifts in emotion and cognition. But other molecules, including psychedelic drugs, can also activate this receptor. The researchers gauged the potency of psychedelic compounds, including psilocin, LSD, mescaline, and 5-methoxy- N, N -dimethyltryptamine, in