OBJECTIVE To assess the acute effects of dextromethorphan (DM) on human motor cortical excitability. BACKGROUND DM, a noncompetitive N-methyl-D-aspartate receptor antagonist, has recently attracted clinical interest for its potential as a neuroprotective agent in various models of excitotoxicity. We were interested in learning whether this drug can modulate the excitability of the motor cortex in healthy subjects. METHODS The effects of DM on the excitability of the normal human motor cortex were studied in eight healthy volunteers by means of focal transcranial magnetic stimulation before and 1.5, 4, 6.5, and 24 hours after a single oral dose of 150 mg DM. Motor evoked potentials (MEPs) were recorded from the relaxed abductor digiti minimi muscle. Measures of motor cortical excitability were motor threshold, MEP recruitment, duration of the cortical silent period, and intracortical inhibition and facilitation. In addition, the authors explored spinal and neuromuscular excitability by means of F waves, duration of the peripheral silent period, and maximum M wave. RESULTS Intracortical inhibition increased temporarily, intracortical facilitation decreased, and the cortical silent period lengthened slightly. Motor threshold, MEP recruitment, and spinal and peripheral motor excitability were not affected significantly. CONCLUSIONS Our findings suggest that DM can exert a significant suppression of the excitatory drive in the normal human cortex, which may be relevant for its potential therapeutic use in excitotoxicity-related neurologic disease. Furthermore, the noninvasive technique described may prove useful in preclinical studies to assess the effects on motor cortical excitability induced by new modulators of glutamatergic transmission currently under development.