Comparison of the Effects of Dextromethorphan, Dextrorphan, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis

Abstract

Dextromethorphan is a weak noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It is metabolized in vivo to dextrorphan, a more potent noncompetitive NMDA antagonist that is the dextrorotatory enantiomer of the opioid agonist levorphanol. The present study characterized the effects of the acute administration of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal (HPA) axis in the rat and tested the involvement of opioid receptors in the responses produced by dextrorphan and levorphanol. Although both dextromethorphan and dextrorphan increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone, the dextromethorphan-induced responses occurred more rapidly than the dextrorphan-induced responses. The analysis of plasma levels of dextrorphan produced after the administration of dextromethorphan indicates that the concentration of dextrorphan formed was too low to be pharmacologically relevant, suggesting that at least some of the effects on the HPA axis are due to the parent compound, and not the metabolite. Naloxone (2 mg/kg) had no effect on the dextrorphan-induced increases in plasma levels of ACTH and corticosterone, but it blocked the levorphanol-induced increases. These results support the hypothesis that dextromethorphan has pharmacological activity aside from its biotransformation to dextrorphan and demonstrate that the effects of dextrorphan are not mediated by opioid receptors.

NMDA receptor modulators: an updated patent review (2013 – 2014)

“…Dextromethorphan ( 6 ), the active ingredient in common over-the-counter (OTC) antitussives, and its primary metabolite, dextrorphan ( 7 ), are also noncompetitive NMDA receptor antagonists that act at a binding site within the pore [44–46]. While the demethylated metabolite 7 is more potent than dextromethorphan 6 at NMDA receptors [45,47], both compounds are also active at sigma 1 and sigma 2 receptors [48,49]. In 2010, the FDA approved a combination of dextromethorphan hydrobromide and quinidine sulfate, referred to as Nuedexta, for the treatment of pseudobulbar affect (PBA) [50].…”

Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment

“…For example, dextromethorphan (DXM), an NMDAR antagonist, is used as a suppressant for coughs, diabetic neuropathic pain, and pseudobulbar affect as well as a treatment for nonketotic hyperglycinemia [23][24][25] . DXM is a widely used non-competitive NMDAR antagonist with little cross-reactivity to opioid receptors unless overdosed 26 . It has few adverse effects, even upon long-term use, and is sold as an over-the-counter medication 23 .…”

Syntheses and Pharmacological Evaluations of Novel N‐Substituted Bicyclo‐Heptane‐2‐amines at N‐Methyl‐d‐Aspartate Receptors

“…A slightly similar case is known with the antitussive agent dextromethorphan (DXM) which itself has low activity at NMDA, whereas one of its metabolites, dextrophan (DX), has μ m affinity (38,39). It has been speculated that some of the therapeutic effects of DXM are mediated by DX (40). DXM has been found to have neuroprotective activity in the MES test.…”