High-dose Dextromethorphan in Amyotrophic Lateral Sclerosis: Phase I Safety and Pharmacokinetic Studies

Ann Neurol. 1994 Dec;36(6):920-4. doi: 10.1002/ana.410360619.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Analysis of Variance
  • Dextromethorphan / administration & dosage*
  • Dextromethorphan / adverse effects
  • Dextromethorphan / pharmacokinetics*
  • Female
  • Humans
  • Male
  • Middle Aged


  • Dextromethorphan