Dextromethorphan as a potential rapid-acting antidepressant

Med Hypotheses. 2011 May;76(5):717-9. doi: 10.1016/j.mehy.2011.02.003. Epub 2011 Mar 1.


Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin 1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA-to-NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Calcium Channel Blockers / pharmacology
  • Chemistry, Pharmaceutical / methods
  • Depressive Disorder, Major / drug therapy*
  • Dextromethorphan / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Humans
  • Models, Biological
  • Receptors, Cholinergic / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, Opioid, mu / agonists
  • Receptors, Serotonin / metabolism
  • Receptors, sigma / agonists


  • Antidepressive Agents
  • Calcium Channel Blockers
  • Excitatory Amino Acid Antagonists
  • Receptors, Cholinergic
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid, mu
  • Receptors, Serotonin
  • Receptors, sigma
  • sigma-1 receptor
  • Dextromethorphan