Z theor. Biol. (1976) 59, 167-177 Structural Correlation between Apomorphine and LSD: Involvement of Dopamine as Well as Serotonin in the Actions of Hallucinogens DAVID E. NICHOLS Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, U.S.A. (Received 2 June 1975, and in revisedform 1 October 1975) It is suggested that the action of LSD and other hallucinogens depends, not only on stimulation of serotonin receptors, but also on stimulation of central dopamine receptors. Both pharmacological and structural- chemical evidence is presented to support the latter hypothesis. A structural correlation is also demonstrated between LSD and apomorphine, and the probable dopaminergic element in LSD is discussed. 1. Introduction Despite over 20 years of research into the action of LSD, the hallucinogenic tryptamines, mescaline and the phenylisopropylamines (amphetamines), the exact mechanism still remains obscure. Numerous in vioo and in vitro pharmacology studies have failed to bring into focus a definite pattern of events which might result in the unique action observed for hallucinogenic agents. In the discussion that follows evidence will be presented which supports the following hypothesis; that hallucinogens (LSD, mescaline, methoxylated amphetamines) in addition to their ability to stimulate central serotonin (5-HT) receptors, also stimulate dopamine receptors and that this dopamine receptor stimulation is an essential feature of their action. Their ability to exert powerful effects in two different monoamine systems and the resulting changes can explain the diversity of action which is observed for the various agents. Demonstration of cross tolerance between LSD and other psychoto- mimetics and the similar subjective effects reported for the various hallucino- gens have prompted attempts to develop correlations which interrelate the 167