High‐dose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies

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Abstract
Much interest has focused on the role of glutamate‐mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high‐dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N‐methyl‐D‐aspartate subtype of the glutamate receptor. Thirteen patients were given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most common side effects were light‐headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long‐term administration of high‐dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.