Ketamine is a widely used anesthetic drug. Synthesized and introduced in humans in the 1960s, ketamine is known as a “dissociative anesthetic” because of the mental state it induces in patients, one characterized by sedation, analgesia, and amnesia.¹ Derived from PCP, an earlier dissociative anesthetic, ketamine is a popular choice for anesthesia because its suppression of the respiratory system is minimal and it stimulates circulation, while other anesthetics tend to significantly repress breathing and depress the circulatory system.² Ketamine has anti-depressant effects and, at sub-anesthetic doses, can cause hallucinations and a sense of detachment from one’s own body; ketamine is taken recreationally by those seeking these kinds of sensations. The mechanism of action of ketamine in anesthesia centers on blocking neural signals that transmit pain and help form memory. 

Ketamine produces anesthesia via several mechanisms of action, though the main mechanism is acting as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a type of receptor found in neurons of the central nervous system. The neurotransmitters glutamate and glycine – and the eponymous N-methyl D-aspartate – bind to NMDA receptors and enable positively-charged ions to enter the cell, which allows for the transmission of an electrical signal.³ When ketamine binds to NMDA receptors, it does not interfere with the binding of NMDA agonists, the neurotransmitters or substances that initiate the neuronal response, but binds to a site within the ion channel that prevents the influx of ions into the cell, thus blocking the signal the neuron would otherwise transmit.⁴ Because the activation of NMDA receptors is associated with pain and memory development,⁵ ketamine can interfere with these processes to produce anesthesia. 

While the interaction of ketamine with NMDA receptors has been well established, ketamine has other mechanisms of actions when it comes to its anesthetic properties. One such mechanism is ketamine’s interactions with mu-opioid receptors, which typically bind opioids, to induce analgesia,⁶ though some studies have yielded more ambiguous results. For example, in their 2012 study, Hardy et al. found that adding ketamine to opioids did not improve cancer-related pain,⁷ suggesting that ketamine does not enact anesthesia via the same mechanisms used by opioids. The connection between ketamine and opioid mechanisms thus remains unresolved. 

There are several other possible mechanisms of action that may be involved in ketamine’s anesthetic properties. It was once thought that ketamine induces local anesthesia by stabilizing neuron membranes and thereby producing a nerve block, but it now seems more likely that the mechanism behind local anesthesia produced by ketamine is its interference with sodium ion channels.⁸ Similarly, there is some indication that sigma receptors, a neurotransmitter receptor distinct from opioid receptors, mediate some of ketamine’s effects, but the evidence is as of yet inconclusive.⁹ 

Ketamine, as noted previously, has several varied effects on physiology, and it may be the case that certain effects result from specific, different mechanisms of action. Ketamine’s anti-depressant activity, for example, may result from the drug’s ability to boost the reuptake by neurons of serotonin and noradrenaline, the neurotransmitters often deficient in those who suffer from depression.¹⁰ Serotonin uptake, however, may also be involved in ketamine’s anesthetic behavior.⁹ It can be difficult to isolate ketamine’s varied effects from one another and identify unique mechanisms of action. To better understand how ketamine produces anesthesia, it may be fruitful to study all of ketamine’s effects. 

References 

1. Green, S. M., Roback, M. G., Kennedy, R. M. & Krauss, B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann. Emerg. Med. 57, 449–461 (2011), DOI: 10.1016/j.annemergmed.2010.11.030 

2. Eikermann, M. et al. Ketamine Activates Breathing and Abolishes the Coupling between Loss of Consciousness and Upper Airway Dilator Muscle Dysfunction. Anesthesiology 116, 35–46 (2012), DOI: 10.1097/ALN.0b013e31823d010a 

3. Li, L. & Vlisides, P. E. Ketamine: 50 Years of Modulating the Mind. Front. Hum. Neurosci. 10, 612 (2016), DOI: 10.3389/fnhum.2016.00612 

4. Zorumski, C. F., Izumi, Y. & Mennerick, S. Ketamine: NMDA Receptors and Beyond. J. Neurosci. 36, 11158–11164 (2016), DOI: https://doi.org/10.1523/JNEUROSCI.1547-16.2016 

5. Li, F. & Tsien, J. Z. Memory and the NMDA Receptors. N. Engl. J. Med. 361, 302–303 (2009), DOI: 10.1056/NEJMcibr0902052 

6. Sarton, E. et al. The Involvement of the μ-Opioid Receptor in Ketamine-Induced Respiratory Depression and Antinociception. Anesth. Analg. 93, 1495 (2001), DOI: 10.1097/00000539-200112000-00031 

7. Hardy, J. et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 30, 3611–3617 (2012), DOI: 10.1200/JCO.2012.42.1081 

8. Persson, J. Ketamine in pain management. CNS Neurosci. Ther. 19, 396–402 (2013), DOI: 10.1111/cns.12111 

9. Smith, D. J. et al. Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology 26, 1253–1260 (1987), DOI: 10.1016/0028-3908(87)90084-0 

10. López-Gil, X. et al. Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine. ACS Chem. Neurosci. 10, 3318–3326 (2019), https://doi.org/10.1021/acschemneuro.9b00288