Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?
Marjorie R. Levinstein, Reece C Budinich, Jordi Bonaventura, Alan F. Schatzberg, Carlos A. Zarate, Michael Michaelides
The American journal of psychiatry March 1, 2025 DOI: 10.1176/appi.ajp.20240378 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Keywords | Ketamine/esketamine #ketamine esketamine Ketalar Special k #antidepressants antidepressant medications Mood elevators #psychopharmacology neuropharmacology Psychotrop |
| Citations | 49 |
| Key findings | Ketamine's pharmacology should be redefined to include opioid receptors, and its antidepressant mechanism may involve synergistic interactions between NMDA and opioid receptors. |
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.