The psychotomimetic effects of ergoline, simple indoleamine and phenethylamine hallucinogens appears to be associated with activation of 5-HT 2A receptors. While 5-HT 2A receptor activation in multiple areas of the brain is probably involved in explaining these psychotomimetic effects, certainly cortical 5HT 2A receptors are a critical site involved in the wide ranging effects on perception, cognition and mood. However, in order to fully explain the mechanism of action of these hallucinogens, one question remains unanswered. Why does not 5-HT itself induce psychotomimetic effects? In particular, psychotomimetic effects are not observed after administration of selective serotonin reuptake inhibitors Ž SSRIs . or monoamine oxidase inhibitors Ž MAOIs . . Both of these treatments enhance the synaptic availability of 5-HT Ž and increase 5-HT 2A receptor activation along with . activation of non-5-HT 2A receptors . Even more striking, co-administration of these drugs causes a profound elevation of 5-HT throughout the brain resulting in the 5-HT syndrome, yet psychotomimetic effects are not observed. In this context, an anecdotal report that the 5-HT precursor 5-hydroxytryptophan Ž 5-HTP . reversed the LSD-induced psychotic symp- toms is of interest Ž Abraham, 1983b . . These clinical correlations suggest that in order to explain the mechanism of action for the three different classes of LSD-like hallucinogens is really a two-stage process. The first stage requires that a site at which all three classes of drugs share a common action must be elucidated. The 5-HT 2A receptor appears to be the most likely candidate. The second stage requires a site at which all three different classes of hallucinogens are inactive, but which 5-HT is active and is able to suppress the effects of the hallucinogens at the 5-HT 2A receptor. Research directed to this latter goal might result in the discovery of novel classes of antipsychotic drugs, which may of be particular benefit for patients with LSD-induced psychosis which generally tend to be treatment refractory.