Ketamine: More than Just NMDA Blocker

Ketamine has been used in medicine for over 50 years, yet its precise mechanism remains unclear. It induces dissociative anesthesia—a state of profound analgesia, amnesia, light sleep, immobility, and dissociation—and has been studied as a model for psychosis and as a rapidly acting antidepressant. The drug inhibits NMDARs, particularly in interneurons, and its hypnotic effects involve blocking NMDA and HCN1 receptors, while also modulating choline, amine, and opioid systems. Its lasting effects on chronic pain and depression may stem from a hyperglutamatergic state that increases structural synaptic connectivity. This review highlights ketamine's actions on multiple biochemical processes beyond NMDA receptors, explaining its diverse roles.

Study at a glance

Abstract

Ketamine has been extensively used in the medical field for more than 50 years, but its exact mechanism of action remains unknown. It’s used to induce dissociative anesthesia (a state of profound analgesia, amnesia with light sleep, immobility, and a sense of disassociation from one’s own body and surroundings). Clinical studies on ketamine as a dissociative anesthetic, a model for psychosis, and as a rapidly acting antidepressant have sparked great interest in understanding its effects at the molecular and cellular level. It exerts uncompetitive inhibitory effects on NMDARs (N-Methyl-D-asperate) and may preferentially affect the function of NMDARs in interneurons. The hypnotic effects of this drug are attributed to its blocking action on NMDA and HCN1 receptors; however, both positive and negative modulation of choline, amine, and opioid systems appears to occur. It is likely that ketamine\'s effect on chronic pain and depression far outlasts its actual levels. This could be due to the hyperglutamatergic state induced by ketamine causing a secondary increase in structural synaptic connectivity. The authors of this review have attempted to highlight the action of ketamine not only on NMDA receptors but also on a variety of biochemical processes and functions found in intercellular environments, which may explain its diverse role in many diseases.