Pathway engineering for the biosynthesis of psychedelics

Naturally occurring psychoactive compounds have been used for cultural and ethnomedical purposes for centuries. Several more such molecules continue to be chemically synthesized, exhibiting a wide range of potency, therapeutic, and hallucinogenic effects. Promising clinical data and a renewed interest in understanding the cellular mechanisms of action have inspired synthetic biology efforts to develop alternative production routes for psychedelic compounds. Here, we highlight the latest biosynthetic accomplishments for indolamines (psilocybin, N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine), ergolines (lysergic acid), and phenethylamines (mescaline) in both eukaryotic and prokaryotic production hosts. We further curate a list of relevant biosynthetic enzymes that have reports of successful in vivo heterologous activity.