Pharmacological effects of phenylalanine on seizure susceptibility: an overview

The effects of excessive doses of phenylalanine on seizure susceptibility were examined in animal models in the past, primarily because of their relevance to phenylketonuria. It was thought that such effects might involve brain monoaminergic mechanisms. Recently, this issue has been pursued with a renewed interest but for a different reason. The dipeptide sweetener, aspartame, contains a phenylalanine residue. In the last three years, a number of studies involving as many as nine animal models of seizures have reexamined the effects of phenylalanine (and aspartame) on seizure thresholds. Data from these studies are in general agreement that aspartame at dosage levels below 1,000 mg/kg, or phenylalanine at equimolar doses, is without an effect on seizure susceptibility in animals. When the dosage level of aspartame reaches 1,000 mg/kg, the findings between various laboratories and from different animal models of seizures are inconsistent, showing either no effect or a proconvulsant effect. The Acceptable Daily Intake of aspartame in humans set by the Food and Drug Administration is 50 mg/kg/day. Thus, the data from the excessive bolus doses in rodents do not appear to be relevant to human use. This article provides a detailed review of the data from both early and recent studies and points out the methodological problems apparent at such high doses.