Phenethylaminylation: Preliminary In Vitro Evidence for the Covalent Transamidation of Psychedelic Phenethylamines to Glial Proteins using 3,5-Dimethoxy-4-(2-Propynyloxy)-Phenethylamine as a Model Compound.
bioRxiv : the preprint server for biology February 17, 2025 Rajiv S Rangan, R Max Petty, Suchismita Acharya et al. preprint
Psychedelics can produce lasting changes in brain function beyond their immediate mind-altering effects, which is being explored for treating mental health disorders. The authors propose that psychedelics may modify proteins by covalently attaching to them through a process called transamidation, mediated by transglutaminase enzymes. They synthesized a modified version of mescaline, a psychedelic phenethylamine from cacti, and used click-chemistry in human astrocyte cell cultures to identify potential protein targets. Preliminary results suggest many glial proteins could be substrates for this modification, which they term phenethylaminylation. This speculative mechanism may help explain long-term cognitive changes from single psychedelic doses.