Plant hallucinogens: springboards for psychotherapeutic drug discovery

Medicinal chemists have traditionally looked to the biosynthetic diversity found in nature to provide structural templates for the development of novel therapeutic agents, and the field of hallucinogen chemistry is similar to other fields in this respect. Even LSD, for many psychopharmacologists the prototype hallucinogen, is not itself a natural compound but rather is a semisynthetic analogue of alkaloids found in plants and fungi. A similar statement could be made about the other major structural classes of hallucinogenic agents: the phenylethylamine derivatives, the tryptamine derivatives, and the beta-carboline derivatives. In each case, compounds occurring naturally in some plant, usually associated with a long tradition of ethnomedical or ceremonial use, have been the starting point for the synthesis of numerous analogues. Some of these, such as the methoxylated amphetamine derivatives, display a pharmacological profile that differs in important respects from their natural product templates. In some instances the analogues have proven to be useful tools in the hands of neurobiologists characterizing the structure and function of brain neurotransmitter systems; in other cases, they have led to the development of new psychopharmacological agents with realized or potential clinical utility. This paper gives a brief historical overview of the role of natural products in the history and development of medicinal chemistry and experimental pharmacology, particularly with respect to the development of psychopharmacology and the discovery of CNS-active agents. It discusses the potential for the discovery of new medications with psychotherapeutic and/or research applications though the investigation of plants and natural compounds with serotonergic activities. Finally, consideration is given to some lesser known plant hallucinogens which may provide further useful leads for psychotherapeutic drug discovery.