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.
Ibogaine appears to produce its effects through selective interactions with multiple brain receptors, specifically 5-HT2A, 5-HT2C, and sigma 2 receptors, with possible involvement of opiate receptors. Sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not play a major role. The hallucinogenic effects may stem from 5-HT2A and 5-HT2C receptor interactions, while antiaddictive properties may result from sigma 2 and opiate receptor interactions. Alternatively, the hallucinogenic properties themselves could underlie the antiaddictive effects, supporting a role for 5-HT2 receptors in therapeutic actions. Many questions remain, and future research combining drug discrimination with other techniques promises to clarify ibogaine's mechanism of action.