Ketamine and the glutamatergic system: A systematic review of NMDA receptor modulation

Abstract

Background: Ketamine was first synthesized in 1962 by Calvin Stevens as an alternative to phencyclidine. Its effects stem primarily from glutamatergic modulation, particularly from the antagonism of N-methyl-D-aspartate receptors (NMDAR) [1]. Objective: This study aims to systematically review the pharmacodynamics of ketamine, with particular attention to its effects on the glutamatergic system. Methods: The bibliographic search was conducted using books and scientific databases (PubMed and ScienceDirect), using the following terms: “ketamine”, “NMDA receptors”, “ketamine pharmacology”. Only articles published in English from 2000 to 2025 were considered. A total of 7 articles were included. Results: Both enantiomers of ketamine, (S)-ketamine and (R)-ketamine, are noncompetitive antagonists of NMDARs; however, (S)-ketamine has an affinity/potency for NMDARs that is approximately four times greater [2]. In Xenopus oocytes expressing recombinant NMDAR GluN2A–D subunits, in the absence of Mg²⁺, ketamine shows a higher affinity for NMDARs-GluN2B subtype [3]. However, the affinity depends not only on the subunits that constitute the receptor but also on Mg²⁺ levels and affinity for the receptor [4]. D-serine acts as a coagonist of ketamine by binding to the glycine_B site of NMDARs. In PC-12 cells, ketamine influences intra- and extraneuronal levels of D-serine: (S)-ketamine increases intraneuronal levels and reduces extraneuronal levels, while (R)-ketamine decreases both. Furthermore, studies in rats have demonstrated that ketamine modulates the transcription of the gene encoding for serine racemase (Srr), increasing Srr mRNA levels in the striatum, hippocampus and cortex, but decreasing them in the forebrain [5]. Conclusions: The glutamatergic system plays a major role in short-term memory retention and consolidation, as well as in cognition [6]. Interference with this system leads to decreased memory retention, cognitive impairment, and dissociation [1]. Ketamine exerts both direct and indirect effects on the glutamatergic system, which explains the characteristic effects of its use. These effects underlie its use in recreational contexts [1] and as a facilitator drug in sexual assaults [7].