Multiple doses of the dietary supplement L-ephedrine can cause severe hyperthermia and modest dopamine depletions in the rat brain. Since D-amphetamine treatment can result in neurodegeneration, the potential of L-ephedrine to produce similar types of degeneration was investigated. Adult male rats, some implanted in the caudate/putamen (CPu) for microdialysis, were given four doses of 25 mg/kg L-ephedrine or 5 mg/kg D-amphetamine (2 h between doses) at an ambient temperature of 23 degrees C. L-ephedrine-induced degeneration in the forebrain was dependent on the degree of hyperthermia. Layer IV of the parietal cortex was the most sensitive to L-ephedrine treatment with peak body temperatures of at most 40.0 degrees C necessary to produce degeneration. Extensive neurodegeneration in the parietal cortex after L-ephedrine treatment was as pronounced as that previously described for D-amphetamine treatment and also occurred in the intralaminar, ventromedial and ventrolateral thalamic nuclei in rats with severe hyperthermia (peak body temperatures>41.0 degrees C). The neurodegeneration induced by L-ephedrine may have resulted in part from excitotoxic mechanisms involving the indirect pathways of the basal ganglia and related areas. No differences were observed between microdialysis and non-implanted rats with respect to degree of tyrosine hydroxylase (TH) loss in the CPu after either D-amphetamine or L-ephedrine treatment. However, neurodegeneration resulting from D-amphetamine and L-ephedrine was reduced in the microdialysis animals in the hemisphere ipsilateral to the probe, which raises concerns when using the technique of in vivo microdialysis to evaluate neurodegeneration. The results of this study, in conjunction with human clinical evaluation of ephedrine neurotoxicity, indicate that regionally specific damage may occur in the cortex of some humans exposed to ephedrine in the absence of stroke or hemorrhage.