Phenylpropanolamine (PPA) is the primary ingredient in over 139 prescription and non-prescription cold remedy and weight control products as well as over 80 percent of the pills and capsules sold """"""""on the street"""""""" (OTS) as """"""""speed"""""""". The use and abuse of PPA-containing products increased dramatically when amphetamine was restricted by the Controlled Substances Act of 1970. Reports of adverse affects resulting from use of these products appear to be increasing. The primary health related goal of this study is to determine the safety of PPA alone and in combination with caffeine by examing acute (mins to hrs) and chronic (days to wks) effects on: l) the cardiovascular system, 2) mood and behavior, and 3) catecholamine (CA) neurotransmission. This proposal will also explore the hypothesis that PPA like amphetamine causes its cardiovascular and behavioral effects by increasing CA neurotransmission. PPA's similarities to amphetamine are more than superficial. In fact, their chemical structures differ only by a beta OH-group, both have simultaneous use as an appetite suppressant and an OTS stimulant, both had initial reputations for safety and the adverse side effects of both include gypertension, intracerebral hemorrhage, arrhythmias and acute psychotic episodes. Further, in lever testing, rats responded identically to amphetamine versus a combination of PPA and caffeine. Increased understanding of the mechanisms of the action of PPA will enhance our ability to treat pharmacologically disorders caused by PPA ingestion. If PPA elevates plasms CA levels, its combination with caffeine which also increases CA neurotransmission may cause supra-additive effects, especially in individuals who are sensitive to caffeine. To test this hypothesis, 2 groups of healthy subjects (18 habitual caffeine users and 18 sensitive non-users) will take PPA alone, caffeine alone and the combination of PPA and caffeine in a double-blind, placebo controlled Latin Square design. The pharmacokinetic and pharmacodynamic properties of PPA will be defined by determining the relationships between plasma PPA levels and changes in blood pressure, heart rate, mood, and CA levels. Caffeine's effects on these parameters will be studied. These data will enable us to identify certain individuals or characteristics associated with specific side effects. In summary, this prospective investigation of PPA's adverse effects and mechanisms of action is designed to facilitate an informed assessment of FDA policy on PPA.
