Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings)

Abstract

For more than 50 years, ketamine has proven to be a safe anesthetic drug with potent analgesic properties. The active enantiomer is S(+)-ketamine. Ketamine is mostly metabolized in norketamine, an active metabolite. During "dissociative anesthesia", sensory inputs may reach cortical receiving areas, but fail to be perceived in some association areas. Ketamine also enhances the descending inhibiting serotoninergic pathway and exerts antidepressive effects. Analgesic effects persist for plasma concentrations ten times lower than hypnotic concentrations. Activation of the (N-Methyl-D-Aspartate [NMDA]) receptor plays a fundamental role in long-term potentiation but also in hyperalgesia and opioid-induced hyperalgesia. The antagonism of NMDA receptor is responsible for ketamine's more specific properties. Ketamine decreases the "wind up" phenomenon, and the antagonism is more important if the NMDA channel has been previously opened by the glutamate binding ("use dependence"). Experimentally, ketamine may promote neuronal apoptotic lesions but, in usual clinical practice, it does not induce neurotoxicity. The consequences of high doses, repeatedly administered, are not known. Cognitive disturbances are frequent in chronic users of ketamine, as well as frontal white matter abnormalities. Animal studies suggest that neurodegeneration is a potential long-term risk of anesthetics in neonatal and young pediatric patients.

In the evidence

This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.

• State of the evidence: Ketamine ↕Mixed

  Describes ketamine as a safe anesthetic with analgesic and antidepressant effects acting mainly through NMDA antagonism, without neurotoxicity in usual practice, but notes cognitive disturbances and frontal white matter abnormalities in chronic users and unknown consequences of repeated high doses.

  Synthesized October 25, 2026

Comparable studies

Other narrative reviews on ketamine, most cited first.