There has been a substantial amount of interest in the anticonvulsant and neuroprotective actions of dextromethorphan. Its therapeutic efficacy, however, is limited by its extensive first-pass elimination by way of the cytochrome P4502D6 enzyme in humans. The purpose of this research was to determine whether quinidine (a selective inhibitor of cytochrome P4502D6) could improve dextromethorphan systemic delivery in patients with amyotrophic lateral sclerosis (a neurodegenerative disease). In the absence of quinidine, 60 mg dextromethorphan every 12 hours resulted in plasma concentrations of only 12 +/- 13 ng/ml (range, less than 5 to 40 ng/ml; n = 7). The same dose of dextromethorphan in the presence of 75 mg quinidine every 12 hours resulted in dextromethorphan plasma concentrations of 241 +/- 94 ng/ml (range, 157 to 402 ng/ml; n = 5). The achievement of higher dextromethorphan plasma concentrations was also associated with an increased occurrence of adverse effects in some patients. Based on the brain/plasma ratio for dextromethorphan in rats, it is estimated that brain dextromethorphan concentrations of 1.0 to 10 micrograms/gm may be attainable in humans by inhibition of cytochrome P4502D6 activity with quinidine.