New frontiers in the biosynthesis of psychoactive specialized metabolites

The relaxation of psychedelic drug regulations has spurred clinical research into treating mental health conditions with natural compounds like psilocybin and synthetic analogs like LSD. Understanding the biosynthetic pathways of hallucinogenic metabolites—ibogaine, mescaline, psilocybin, lysergic acid, and DMT—from plants, fungi, and animals offers opportunities for synthetic biology to create novel derivatives with improved pharmacological properties. This review covers these metabolic pathways and their reconstitution in microorganisms, highlighting the integration of native and non-native enzymes to produce new compounds.

Study at a glance

Abstract

The recent relaxation of psychedelic drug regulations has prompted extensive clinical investigation into their potential use to treat diverse mental health conditions including anxiety, depression, post-traumatic stress, and substance-abuse disorders. Most clinical trials have relied on a small number of known molecules found in nature, such as psilocybin, or long-known synthetic analogs of natural metabolites, including lysergic acid diethylamide (LSD). Elucidation of biosynthetic pathways leading to several psychedelic compounds has established an opportunity to use synthetic biology as a complement to synthetic chemistry for the preparation of novel derivatives with potentially superior pharmacological properties compared with known drugs. Herein we review the metabolic biochemistry of pathways from plants, fungi and animals that yield the medicinally important hallucinogenic specialized metabolites ibogaine, mescaline, psilocybin, lysergic acid, and N,N-dimethyltryptamine (DMT). We also summarize the reconstitution of these pathways in microorganisms and comment on the integration of native and non-native enzymes to prepare novel derivatives.