CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS

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The long-term goals of this work are to classify the actions of phenyalkylamine (PAA) and indolealkylamine (IAA) drugs of abuse, to elucidate their structure-activity relationships, and to identify (where applicable) their mechanisms of action, in as much as such information should contribute to a greater understanding of drug abuse and result in improved treatment modalities. PAAs can produce three distinct stimulus effects that are classified as amphetamine-(AMPH)-like, hallucinogen-(or Dom-) like, and as PMMA-like (PMMA = p-methoxymethamphetamine). Depending upon the presence of various substituent groups in the molecules, PAAs can produce any one or a combination of these effects. A series of studies is described that investigates each of these three types of activities and/or the inter-relationships between the different activities. For example, we propose to develop a radioligand that can be used for SPECT imaging studies involving 5-HT2 serotonin receptors- the currently accepted site of action of hallucinogenic agents. Another study describes investigations with the first example of a PAA 5-HT2 antagonist. The majority of the studies center about investigations of PAA designer drugs, "herbal dietary supplements" (e.g.Herbal Ecstacy) whose major constituents are the phenylpropanolamine ephedrine (i.e., beta-hydroxy-methamphetamine) and caffeine, and their components. Drug discrimination studies are proposed using rats trained to discriminate either the PAA stimulant (plus) AMPH, the PAA hallucinogen DOM, the PAA designer drugs MDMA and PMMA, and the phenylpropanolamine ephedrine. Preliminary findings suggest (a) that the actions of the designer drug MDMA (Ecstasy) involve a 5-HT1A component that might explain its use in "candy flipping", (b) that caffeine enhances the stimulus effects of ephedrine and might have similar effects on other PAAs, (c) that similarities exist between stimulus generalization profiles obtained with AMPH-trained and ephedrine-trained animals, but that the former, not the latter, recognize methamphet-amine, (d) that PMMA may represent the parent member of the MDMA-family of designer drugs, (e) that distinct PMMA-like structure-activity relationships exist, (f) that it might be possible to separate PMMA-like effects from MDMA-like effects, (g) that certain psychoactive agents previously defying classification possess PMMA-like actions, and (h) that the PAA classification scheme should explain the actions of IAAs. It is proposed to further investigate each of these concepts by synthesizing (where necessary) and evaluating the appropriate agents.