Over the past decade, recreational drugs have shifted from natural materials like marijuana and opium, and natural products like morphine and cocaine, toward synthetic agents that are often more potent, sometimes less harmful in the short term, or combine properties from different drug classes. These agents, called smart drugs, have become popular for personal use and at rave parties. The transition is driven by regulatory and commercial factors: new analogues evade forensic detection, and their perceived natural status and low acute toxicity appeal to users. The internet has enabled rapid information sharing and online purchase of these agents or their precursors. Most new drugs are unfamiliar to organic chemists and healthcare providers.
Much of neuroscience knowledge has come from studying mind-altering natural products, yet the underlying causes of CNS disorders remain elusive. Past successes suggest that continued investigation of these compounds can yield novel medications and identify new therapeutic targets. This Highlight reviews the history of research into several classes of mind-altering natural products and discusses their recent and potential therapeutic applications.
Iboga alkaloids, a family of natural products including the anti-addictive compound ibogaine and the chemotherapeutic precursor catharanthine, have inspired chemists and biologists for over 120 years. This review covers advances from 2000 to 2020 in their biosynthesis and chemical synthesis, as well as their development as next-generation neurotherapeutics for mental illness. The authors provide historical context for recent discoveries and highlight unresolved questions. Although significant progress in chemistry and pharmacology has occurred since the 1960s, the iboga alkaloids continue to drive scientific innovation.
Salvinorin A, a hallucinogenic compound from the plant Salvia divinorum, is a potent and selective activator of the kappa-opioid receptor (KOR), a promising target for new painkillers. Unlike typical opioids, it lacks a basic nitrogen, enters the brain rapidly, and has a short duration of action. Since 2000, extensive medicinal chemistry using semi-synthesis from plant extracts has explored its properties. Total synthesis efforts have produced multiple routes to create salvinorin A and related analogs, aiming to improve its activity for various therapeutic effects. This review covers those total syntheses and identifies remaining challenges for future synthetic chemistry to address.