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Review
. 2025 Mar 1;182(3):247-258.
doi: 10.1176/appi.ajp.20240378. Epub 2025 Jan 15.

Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?

Marjorie R Levinstein  1 , Reece C Budinich  1 , Jordi Bonaventura  1 , Alan F Schatzberg  1 , Carlos A Zarate Jr  1 , Michael Michaelides  1
Affiliations
Review

Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?

Marjorie R Levinstein et al. Am J Psychiatry. .

Abstract

Ketamine is a racemic compound and medication comprised of (S)-ketamine and (R)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders such as anxiety, obsessive-compulsive, and opioid use disorders. Despite its complex pharmacology, ketamine is referred to as an N-methyl-d-aspartate (NMDA) receptor antagonist. In this review, the authors argue that ketamine's pharmacology should be redefined to include opioid receptors and the endogenous opioid system. They also highlight a potential mechanism of action of ketamine for depression that is attributed to bifunctional, synergistic interactions involving NMDA and opioid receptors.

Keywords: Antidepressants; Ketamine/Esketamine; Psychopharmacology.

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Conflict of interest statement

Dr. Schatzberg has served as a consultant for Alto, ANeurotech, Axsome, Compass, Douglas, Johnson & Johnson, Magnus, NeuraWell, Otsuka, Parexel, Sage, Signant, and Skyland Trail; he has equity in Alto, ANeurotech, Corcept, Delport, Insight Analytics, Madrigal, Magnus, NeuraWell, Sage, Seattle Genetics, Soneira, Titan, and Xhale. Dr. Zarate is listed as a co-inventor on patents for the use of ketamine compounds in anxiety, anhedonia, major depression, suicidal ideation, neuropathic pain, posttraumatic stress disorder, and suicidal ideation; he has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Michaelides has received research funding from AstraZeneca, Attune Neurosciences, Dompé Farmaceutici, and Redpin Therapeutics. The other authors report no financial relationships with commercial interests.

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