New frontiers in the biosynthesis of psychoactive specialized metabolites
Current Opinion in Plant Biology – September 16, 2024
Source: OpenAlex
Summary
The relaxation of psychedelic drug regulations has spurred interest in compounds like Psilocybin and Lysergic acid diethylamide (LSD) for mental health. A review in Drug Studies highlights the intricate biochemistry and biology of hallucinogen production. It details metabolic pathways from diverse plant and fungal interactions, as well as animal sources, yielding five key compounds, including Mescaline, Lysergic acid, and tryptamine derivatives. This exploration of chemical synthesis and alkaloids aims to leverage synthetic biology to create novel psychedelics with superior pharmacology, complementing traditional methods.
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.