Ergot alkaloids, used in folk medicine for millennia, have been systematically studied for about 100 years. Albert Hofmann's discovery of LSD's intense psychedelic properties spurred worldwide research, leading to the discovery of natural ergot alkaloids and synthesis of unnatural analogs, some used to treat Alzheimer's and Parkinson's disease. Although LSD was never commercially approved, recent clinical studies suggest it can be an innovative treatment for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand natural origins, develop facile production, and enable continued use as medicinal chemistry leads. This review covers major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies, noting that limited applications have yet to bypass ergotism side effects, indicating further studies are needed.
Clavine alkaloids, a subclass of ergot alkaloids found widely in nature, have potent physiological effects but remain understudied compared to well-known psychedelics like LSD and psilocybin. This review summarizes their biological properties, compares their pharmacology to ergolines and related psychedelics, and highlights opportunities for developing new structure–activity relationship profiles. Such advances could expand the currently limited structural variety of psychedelic therapeutics, opening new avenues for medicinal chemistry.