Serotonin and serotonin receptors in hallucinogen action

Hallucinogens are a class of substances that induce profound changes in perception and cognition. A closely related drug, 3,4-methylenedioxymethamphetamine (MDMA), produces euphoria and a feeling of empathy, with minimal sensory distortion. Both of these classes of substances produce their effects by interacting with the serotonergic system. This chapter will review the receptor interactions that contribute to the behavioral effects of serotonergic hallucinogens and MDMA. In rodents, the behavioral effects of hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and mescaline are primarily mediated by activation of 5-HT2A receptors. There is evidence, however, that 5-HT1A receptors, 5-HT2C receptors and dopamine receptors may play a secondary role. The molecular requirements for interaction of hallucinogens with the 5-HT2A receptor are well-defined on the basis of structure-activity relationships. By contrast with the hallucinogens, MDMA is a potent releaser of monoamines that has complex effects on serotonergic, dopaminergic and noradrenergic systems. In recent years, psilocybin and MDMA have been administered to human volunteers in controlled clinical trials. Human studies confirm that the 5-HT2A receptor plays a primary role in mediating the subjective effects of psilocybin, whereas the effects of MDMA are largely attributable to carrier-mediated release of serotonin. These findings emphasize the importance of clinical investigation of hallucinogenic drugs. Additionally, there is a growing consensus that these drugs are likely to show therapeutic efficacy in the treatment of certain psychiatric disorders.