This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as partial agonists at 5-HT 2A and other 5-HT 2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HTThe accidental discovery in 1943 of the hallucinogenic properties of the synthetic ergoline compound LSD (dlysergic acid diethylamide) by the chemist Albert Hoffman is well known. Five years later, in 1948, serotonin (later determined to be 5-hydroxytryptamine or 5-HT) was found in bovine blood serum (Rapport et al. 1948). Then, in 1953, during a routine survey of various tissues, relatively high concentrations of 5-HT were found in brain (Twarog and Page 1953). Shortly thereafter, based on the observation that LSD could antagonize 5-HT in peripheral tissues-plus the structural similarity between these two indole-containing structures (Figure 1)-it was proposed independently by Gaddum and Hammeed (1954) and Woolley and Shaw (1954) that the hallucinogenic effects of LSD might result from an antagonism of 5-HT in the central nervous system. This hypothesis was soon modified to include the possibility that LSD could mimic as well as antagonize the actions of 5-HT (Shaw and Woolley 1956). The 5-HT hypothesis was later extended to include such simple indoleamine hallucinogens as psilocin, which are close structural analogs of 5-HT (Figure 1) and the phenethylamine hallucinogens, such as mescaline. Mescaline, despite differences in chemical structure (Figure 1), displayed similar clinical effects and cross tolerance with LSD in human studies (Balestrieri and Fontanari 1959), suggesting that the indoleamine (including ergoline) and phenethylamine classes of hallucinogens may share a common mechanism of action or final common pathway. By the end of the 1950s, three classical questions about the relationship between 5-HT and the hallucinogens had been set into place. First, do the hallucinogens produce their effects through an action upon the central 5-HT system? Second, are hallucinogens agonists or antagonists at 5-HT receptors? Third, do indoleamine and phenethylamine hallucinogens share a common site of action? Received October 19, 1998; revised November 20, 1998; accepted November 30, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 2S Serotonin and Hallucinogens 17S NEURONAL ACTIONS OF HALLUCINOGENIC DRUGS Effects of Hallucinogens on 5-HT Neurons of the Raphe NucleiThe identification of 5-HT as a neurotransmitter was not achieved until the mid-1960s, when monoaminergic neuronal pathways in the brain were discovered and mapped by histochemical fluorescence methods (Dähl-strom and F...