Word is out.
Ketamine can treat both physical and psychological pain. That’s why this once anesthetic-only drug has gained new applications outside the operating rooms and procedural suites. But we would not have known about its other uses until science broke the mystery wide open.
We used to think that ketamine was merely a noncompetitive NMDA receptor antagonist. But this does not completely explain its effects or why it has such a potent antidepressant action.
This article rounds up the most recent findings on ketamine’s mechanisms of action. The information here will help you understand how the drug works for various conditions and why its two most popular commercial forms perform differently.
How Does Ketamine Work?
Ketamine acts on various signaling systems in the body. We describe here the most important ones that researchers have found so far.
Ketamine’s chief pharmacological target is the glutamatergic system. As the name suggests, the amino acid glutamate is its primary agonist. Of the receptors belonging to this pathway, ketamine works on the NMDA receptor (NMDAR) directly and the AMPA receptor (AMPAR) indirectly (Zanos & Gould, 2018).
NMDARs are ion channel receptors that trigger metabolic processes when activated. They are present throughout the CNS, and their location determines their function (Mion & Villevieille, 2013).
In the nociceptive tracts, NMDAR stimulation relays pain signals to the brain (Mion & Villevieille, 2013).
Thalamocortical NMDARs are vital to sensorimotor functions (Arakawa et al., 2014).
NMDARs in the hippocampus and prefrontal cortex regulate memory, learning, and other parts of cognition (Luscher & Malenka, 2012).
The lateral habenula is a crucial reward-processing and aversive behavior center. NMDAR activation in this region is key to survival (Browne et al., 2018).
However, pathological conditions can stem from NMDAR hyperstimulation.
Increased calcium influx in the nociceptive neurons stimulates prostaglandin and nitric oxide synthesis. This mechanism is thought to be responsible for the central sensitization and hyperalgesia associated with some chronic pain syndromes (Mion & Villevieille, 2013).
NMDARs found in GABAergic interneurons and extrasynaptic sites inhibit BDNF secretion. BDNF is the most important neurotrophic factor promoting synaptic plasticity in the brain. Excessive NMDAR activity leads to excitotoxicity and cell death, causing mental health problems and neurodegenerative disorders (Zanos et al., 2018; Abdallah et al., 2016).
NMDAR hyperstimulation in the lateral habenula correlates with depressive symptoms (Browne et al., 2018).
In the resting state, the NMDAR channel is blocked by a magnesium ion. Activation requires membrane depolarization dislodging this ion, as well as the simultaneous binding of glutamate and glycine or D-serine (Zanos et al., 2018).
Ketamine binds to the receptor, not on glutamate’s binding site but that of phencyclidine. That makes it a noncompetitive inhibitor, stabilizing the NMDAR’s inactive state (Abdallah et al., 2016).
A Schematic Model of the NMDA Receptor
(Lisek et al., 2020)
Ketamine’s NMDAR blockade disrupts the neural pathways mentioned above. High doses bring about dissociative anesthesia and amnesia. But subanesthetic levels produce analgesia, psychotomimetic effects and mood elevation (Zanos et al., 2018).
Of its two enantiomers, esketamine is the more potent NMDA receptor suppressor than arketamine. The same goes for the enantiomers of norketamine, the main ketamine metabolite in humans (Yang et al., 2018).
Meanwhile, AMPARs are normally fewer than NMDARs. But NMDAR inhibition upregulates synaptic AMPARs by producing a transient glutamate surge and stimulating BDNF secretion (Luscher & Malenka, 2012; Abdallah et al., 2016; Akinfiresoye & Tizabi, 2013).
AMPAR activation promotes neuroplasticity, enhancing cognition, sensorimotor function and psychological resiliency. Neuroplasticity is the impetus behind ketamine’s sustained antidepressant effects (Aleksandrova et al., 2017).
The opioid system is the main target of opiate drugs like morphine. Opioid receptors are mainly involved in pain control. They are found in the CNS and peripheral tissues (Zanos et al., 2018). Mu subtypes produce physical dependence (Wang, 2019). NMDAR and opioid receptor crosstalk contributes to the opioid tolerance and hyperalgesia associated with neuropathic pain (Mion & Villevieille, 2013).
Ketamine infusion can alleviate chronic and acute pain (Balzer et al., 2020; Morrison et al., 2017; Rigo et al., 2017). Experts attribute some of its analgesic properties to its weak opioid agonist action, though the exact mechanisms are unclear. Naloxone has no effect on ketamine analgesia (Zanos et al., 2018; Kraus et al., 2019). Ketamine disrupts NMDAR and opioid receptor crosstalk (Mion & Villevieille, 2013).
Esketamine is more potent than arketamine on opioid receptors (Mion & Villevieille, 2013; Zanos et al., 2018). Ketamine poses less respiratory depression risk than opioids (Balzer et al., 2020).
How Agonists Affect the Different Opioid Receptor Subtypes
GABAergic interneurons are mainly inhibitory neurons. They synthesize the neurotransmitter GABA, which reduces the presynaptic nerve cell’s firing by increasing its chloride conductance (Mion & Villevieille, 2013).
GABA can produce analgesia and anesthesia. But the ketamine levels required to elicit these effects from GABA receptors are much higher than the usual clinical doses (Mion & Villevieille, 2013; Zanos et al., 2018).
However, GABA receptor potentiation is useful in the treatment of refractory status epilepticus and major depressive disorder. These conditions are associated with excitotoxicity and best alleviated by subanesthetic ketamine’s immediate neuroplastic effects (Borris et al., 2000; Abdallah et al., 2016; Gaspard et al., 2013).
How Ketamine-Induced Synaptic Changes Boost Neuroplasticity. NMDAR inhibition on two sites is thought to account for ketamine’s rapid antidepressant effect. The “go pathway” involves the GABAergic interneuron, which prevents excitotoxicity by modulating presynaptic firing. On the other hand, the “stop pathway” has the extrasynaptic NMDAR causing excitotoxicity and BDNF suppression when hyperstimulated (Abdallah et al., 2016).
The monoamines norepinephrine, dopamine and serotonin are neurotransmitters implicated in the development of depression. Ketamine not only acts as an agonist on their receptors but also blocks their reuptake. These mechanisms contribute to the drug’s antidepressant efficacy (Mion & Villevieille, 2013; Zanos et al., 2018).
Norepinephrine regulates wakefulness, attention and mental focus. Noradrenergic stimulation is thought to cause some of ketamine’s psychotomimetic side effects (Mion & Villevieille, 2013).
Dopamine is essential to movement control, motivation, attention and other higher-order functions. Ketamine’s great affinity for D2 receptors may also explain its psychotomimetic effects (Mion & Villevieille, 2013; Zanos et al., 2018).
Norepinephrine and dopamine are catecholamines that can increase the heart rate and blood pressure. They can likewise dilate the bronchioles. These actions make IV ketamine a suitable anesthetic agent for critical patients (Jabre et al., 2009; Tran et al., 2014; Esmailian et al., 2018; Tiwari et al., 2016).
Serotonin–a “happy hormone''–elevates mood, improves sleep and relieves physical pain. Stimulation of the serotonin 1b receptor contributes to ketamine’s antidepressant effect. Ketamine induces nausea and vomiting which can be easily relieved with ondansetron, a 5-HT3 serotonin receptor antagonist (Mion & Villevieille, 2013; Zanos et al., 2018). Esketamine exhibits greater sympathomimetic and serotonergic activity than arketamine (Mion & Villevieille, 2013; Yang et al., 2018).
The neurotrophic hypothesis of depression attributes depressive symptoms to deficient or dysfunctional nerve growth factors, mainly BDNF. This molecule stimulates neuroplasticity, triggering neurogenesis and synaptic reorganization. The theory explains why depressed patients have atrophied limbic brain regions on imaging studies and low hippocampal BDNF postmortem (Duman & Li, 2012).
The neurotrophic hypothesis also supports why ketamine eliminates suicidality and depression much faster than conventional antidepressants. BDNF serum levels rise within a few hours of intravenous ketamine treatment, but it takes weeks to increase using other modalities. It also explains why the antidepressant response after a single IV infusion can last up to 7 days (Duman & Li, 2012; Abdallah et al., 2016).
The drug acts on various parts of the BDNF signaling system. Incidentally, its enantiomers use different BDNF pathway molecules to elicit neuroplasticity.
For example, esketamine and its metabolites interact with mTORC1, whereas their mirror images use ERK upstream and the 4E-BPs downstream of mTORC1. Both enantiomers influence gene expression and protein synthesis by inactivating the ribosomal regulatory kinase eEF2K (Wei et al., 2021; Zanos & Gould, 2018).
Arketamine also acts on the TGF-β1 and neuregulin-1 signaling systems. This is thought to account for its longer-lasting antidepressant effects despite esketamine’s greater NMDAR potency (Wei et al., 2021).
The Role of AMPARs in Neuroplasticity. NMDAR blockade transiently raises synaptic glutamate levels, stimulating AMPARs. AMPAR activation triggers a signaling cascade leading to the synthesis and release of BDNF, more AMPARs and other synaptic proteins. BDNF perpetuates the cycle by stimulating the TrkB receptor. GSK-3, a lithium pharmacological target, inhibits the pathway (Cui et al., 2018).
Voltage-gated channels have many roles in the body. Ketamine acts on three important types: the sodium channel, the L-type calcium channel and the potassium channel.
Sensory nerve sodium channels are local anesthetic targets. Ketamine administration deactivates these structures, improving the quality of pain control (Mion & Villevieille, 2013; Zanos et al., 2018).
L-type calcium channels are present in smooth and skeletal muscles, myocytes and neurons. Peripheral inhibition relaxes muscle tissues and normalizes tachyarrhythmias. In neurons, their blockade enhances synaptic plasticity, adding to ketamine’s antidepressant action. But it is also partly responsible for the drug’s psychoactive side effects (Zanos et al., 2018).
Suppression of potassium channels explains esketamine’s neuroprotective ability under hypoxic conditions (Proescholdt et al., 2001).
Sigma receptors were originally classed under opioid receptors. Now they are known to be of a different type but able to bind various psychotropic agents. They are found in many parts of the CNS and are involved in higher brain functions, such as memory and drug dependence (Hayashi & Su, 2005).
Sigma receptor activation stimulates neuroplasticity. Arketamine binds more strongly to sigma receptors than esketamine (Zanos et al., 2018).
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
HCNs are ion channels that permit sodium and potassium currents on hyperpolarization, modulated by binding with a cyclic nucleotide like cAMP. They help regulate neuronal excitability, synaptic function and pacemaker currents.
HCN inhibition potentiates ketamine’s anesthetic property. Inactivation in the hippocampus elicits antidepressant effects. The S-enantiomer displays greater activity on these channels than the racemate (Zanos et al., 2018).
Cystitis is a condition associated with long-term heavy ketamine consumption. It involves ATP but uses the purinergic receptor and the endoplasmic reticulum’s stress pathways, not HCNs (Xie et al., 2021).
In the central nervous system, acetylcholine is involved in wakefulness, attention, memory and movement control. Ketamine suppresses both nicotinic and muscarinic receptors, enhancing its hypnotic, analgesic, antidepressant and psychological effects (Mion & Villevieille, 2013; Zanos et al., 2018; Kraus et al., 2019).
Glycogen Synthase Kinase-3
The protein GSK-3 suppresses BDNF synthesis and is a pharmacological target for lithium. Ketamine inhibits GSK-3, stimulating BDNF formation and synaptogenesis and warding off depressive symptoms (Abdallah et al., 2016).
Believe it or not, there’s evidence suggesting that the bacteria in your tummy can also make you moody.
The vagus nerve connects the brain to the visceral organs. Its exposure to some of the short-chain fatty acids made by the gut microbiome is thought to contribute to the development of depression. Splenectomy can aggravate depressive symptoms by disturbing this brain-gut microbiota axis. Preclinical studies show that arketamine, racemic ketamine and vagotomy help improve mood levels (Wei et al., 2021).
And the list goes on. The hunt for a more potent but risk-free ketamine version fuels further research into its action mechanisms.
Why Ketamine Is Not Just a Dissociative Anesthetic
Ketamine’s action mechanisms, especially those enhancing synaptic plasticity, have made it one of the biggest success stories in drug repurposing. Careful dose adjustment can alleviate symptoms of a number of physical and psychological conditions. Knowledge of its mechanisms of action and reliability in diverse clinical settings should boost the clinician’s confidence in choosing this drug to better help their patients.
Abdallah, C. G., Adams, T. G., Kelmendi, B., Esterlis, I., Sanacora, G. & Krystal, J. H. (2016). Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depression and Anxiety, 33(8), 689-697. https://dx.doi.org/10.1002%2Fda.22501
Akinfiresoye, L. & Tizabi, Y. (2013). Antidepressant Effects of AMPA and Ketamine Combination: Role of Hippocampal BDNF, Synapsin and mTOR. Psychopharmacology, 230(2), 291-298. https://doi.org/10.1007/s00213-013-3153-2
Aleksandrova, L. R., Phillips, A. G. & Wang, Y. T. (2017). Antidepressant Effects of Ketamine and the Roles of AMPA Glutamate Receptors and Other Mechanisms beyond NMDA Receptor Antagonism. Journal of Psychiatry and Neuroscience, 42(4), 222-229. https://doi.org/10.1503/jpn.160175
Arakawa, H., Suzuki, A., Zhao, S., Tsytsarev, V., Lo, F., Hayashi, Y., Itohara, S., Iwasato, T. & Erzurumlu, R. S. (2014). Thalamic NMDA Receptor Function Is Necessary for Patterning of the Thalamocortical Somatosensory Map and for Sensorimotor Behaviors. The Journal of Neuroscience, 34(36), 12001-12014. https://dx.doi.org/10.1523%2FJNEUROSCI.1663-14.2014
Balzer, N., McLeod, S. L., Walsh, C. & Grewal, K. (2020). Low-Dose Ketamine for Acute Pain Control in the Emergency Department: A Systematic Review and Meta-Analysis. Academic Emergency Medicine, 28(4), 444-454. https://doi.org/10.1111/acem.14159
Borris, D. J., Bertram, E. H. & Kapur, J. (2000). Ketamine Controls Prolonged Status Epilepticus. Epilepsy Research, 42(2-3), 117-122. https://doi.org/10.1016/s0920-1211(00)00175-3
Browne, C. A., Hammack, R. & Lucki, I. (2018). Dysregulation of the Lateral Habenula in Major Depressive Disorder. Frontiers in Synaptic Neuroscience, 10, 1-18. https://dx.doi.org/10.3389%2Ffnsyn.2018.00046
Cui, W., Ning, Y., Hong, W., Wang, J. Liu, Z. & Li, M. D. (2018). Crosstalk between Inflammation and Glutamate System in Depression: Signaling Pathway and Molecular Biomarkers for Ketamine’s Antidepressant Effect. Molecular Neurobiology, 56(5), 3484-3500. https://link.springer.com/article/10.1007/s12035-018-1306-3
Duman, R. S. & Li, N. (2012). A Neurotrophic Hypothesis of Depression: Role of Synaptogenesis in the Actions of NMDA Receptor Antagonists. Philosophical Transactions of the Royal Society B, 367(1601), 2475-2484. https://doi.org/10.1098/rstb.2011.0357
Esmailian, M., Esfahani, M. K. & Heydari, F. (2018). The Effect of Low-Dose Ketamine in Treating Acute Asthma Attack: A Randomized Clinical Trial. Emergency, 6(1), 1-5. http://dx.doi.org/10.22037/aaem.v6i1.64
Gaspard, N., Foreman, B., Judd, L. M., Brenton, J. N., Nathan, B. R., McCoy, B. M., Al-Otaibi, A., Kilbride, R., Fernandez, I. S., Mendoza, L., Samuel, S., Zakaria, A., Kalamangalam, G. P., Legros, B., Szaflarski, J. P., Loddenkemper, T., Hahn, C. D., Goodkin, H. P. Claassen, J… Laroche, S. M. (2013). Intravenous Ketamine for the Treatment of Refractory Status Epilepticus: A Retrospective Multicenter Study. Epilepsia, 54(8), 1498-1503. https://doi.org/10.1111/epi.12247
Hayashi, T. & Su, T. P. (2005). The Sigma Receptor: Evolution of the Concept in Neuropsychopharmacology. Current Neuropharmacology, 3(4), 267-280. https://dx.doi.org/10.2174%2F157015905774322516
Jabre, P., Combes, X., Lapostolle, F., Dhaouadi, M., Ricard-Hibon, A., Vivien, B., Bertrand, L., Beltramini, A., Gamand, P., Albizzati, S., Perdrizet, D., Lebail, G., Chollet-Xemard, C., Maxime, V., Brun-Buisson, C., Lefrant, J., Bollaert, P., Megarbane, B., Ricard, J… KETASED Collaborative Study Group (2009). Etomidate versus Ketamine for Rapid Sequence Intubation in Acutely Ill Patients: A Multicentre Randomised Controlled Trial. The Lancet, 374(9686), 293-300. https://doi.org/10.1016/s0140-6736(09)60949-1
Kraus, C., Wasserman, D., Henter, I. D., Acevedo-Diaz, E., Kadriu, B. & Zarate, C. A. J. (2019). The Influence of Ketamine on Drug Discovery in Depression. Drug Discovery Today, 24(10), 2033-2043. https://doi.org/10.1016/j.drudis.2019.07.007
Lisek, M., Zylinska, L. & Boczek, T. (2020). Ketamine and Calcium Signaling–A Crosstalk for Neuronal Physiology and Pathology. International Journal of Molecular Sciences, 21(21), 1-24. https://doi.org/10.3390/ijms21218410
Luscher, C. & Malenka, R. C. (2012). NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD). Cold Spring Harbor Perspectives in Biology, 4(6), 1-15. https://dx.doi.org/10.1101%2Fcshperspect.a005710
Mion, G. & Villevieille, T. (2013). Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings). CNS Neuroscience and Therapeutics, 19(6), 370-380. https://doi.org/10.1111/cns.12099
Morrison, T., Carender, C., Kilbane, B. & Liu, R. W. (2017). Procedural Sedation with Ketamine versus Propofol for Closed Reduction of Pediatric Both Bone Forearm Fractures. Orthopedics, 40(5), 288-294. https://doi.org/10.3928/01477447-20170824-01
Proescholdt, M., Heimann, A. & Kempsi, O. (2001). Neuroprotection of S(+) Ketamine Isomer in Global Forebrain Ischemia. Brain Research, 904(2), 245-251. https://doi.org/10.1016/s0006-8993(01)02465-9
Rigo, F. K., Trevisan, G., Godoy, M. C., Rossato, M. F., Dalmolin, G. D., Silva, M. A., Menezes, M. S., Caumo, W. & Ferreira, J. (2017). Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. Pain Physician, 20, 207-215.
Tiwari, A., Guglani, V. & Jat, K. R. (2016). Ketamine versus Aminophylline for Acute Asthma in Children: A Randomized, Controlled Trial. Annals of Thoracic Medicine, 11(4), 283-288. https://dx.doi.org/10.4103%2F1817-1737.191874
Tran, K. P., Nguyen, Q., Truong, X. N., Le, V., Le, V. P., Mai, N., Husum, H. & Losvik, O. K. (2014). A Comparison of Ketamine and Morphine Analgesia in Prehospital Trauma Care: A Cluster Randomized Clinical Trial in Rural Quang Tri Province, Vietnam. Prehospital Emergency Care, 18(2), 257-264. https://doi.org/10.3109/10903127.2013.851307
Wang, S. (2019). Historical Review: Opiate Addiction and Opioid Receptors. Cell Transplantation, 28(3), 233-238. https://doi.org/10.1177/0963689718811060
Wei, Y., Chang, L. & Hashimoto, K. (2021). Molecular Mechanisms Underlying the Antidepressant Actions of Arketamine: Beyond the NMDA Receptor. Molecular Psychiatry. Advance online publication. https://doi.org/10.1038/s41380-021-01121-1
Xie, X., Liang, J., Huang, R., Luo, C., Yang, J., Xing, H., Zhou, L., Qiao, H., Ergu, E. & Chen, H. (2021). Molecular Pathways Underlying Tissue Injuries in the Bladder with Ketamine Cystitis. The FASEB Journal, 35(7), 1-21. https://doi.org/10.1096/fj.202100437
Yang, C., Kobayashi, S., Nakao, K., Dong, C., Han, M., Qu, Y., Ren, Q., Zhang, J., Ma, M., Toki, H., Yamaguchi, J., Chaki, S., Shirayama, Y., Nakazawa, K., Manabe, T. & Hashimoto, K. (2018). AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine. Biological Psychiatry, 84(8), 591-600. https://doi.org/10.1016/j.biopsych.2018.05.007
Zanos, P. & Gould, T. D. (2018). Mechanisms of Ketamine Action as an Antidepressant. Molecular Psychiatry, 23(4), 801-811. https://dx.doi.org/10.1038%2Fmp.2017.255
Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., Pereira, E. F. R., Albuquerque, E. X., Thomas, C. J., Zarate, C. A. J. & Gould, T. D. (2018). Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacological Reviews, 70(3), 621-660. https://doi.org/10.1124/pr.117.015198