Editing Ketamine (section)

== Pharmacology ==
=== Pharmacodynamics ===
==== Mechanism of action ====
Ketamine is a mixture of equal amounts of two [[enantiomer]]s: [[esketamine]] and [[arketamine]]. Esketamine is a far more [[potency (pharmacology)|potent]] NMDA receptor pore blocker than arketamine.<ref name="Hashimoto2019" /> Pore blocking of the [[NMDA receptor]] is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine.<ref name="pmid29945898">{{cite journal |vauthors=Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EF, Albuquerque EX, Thomas CJ, Zarate CA, Gould TD |title=Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms |journal=Pharmacol Rev |volume=70 |issue=3 |pages=621–660 |date=July 2018 |pmid=29945898 |pmc=6020109 |doi=10.1124/pr.117.015198 }}</ref><ref name="pmid27028535">{{cite journal |vauthors=Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI |title=Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy |journal=Clin Pharmacokinet |volume=55 |issue=9 |pages=1059–77 |date=September 2016 |pmid=27028535 |doi=10.1007/s40262-016-0383-6 |s2cid=5078489 }}</ref> Blocking of the NMDA receptor results in analgesia by preventing [[central sensitization]] in [[posterior horn of spinal cord|dorsal horn]] neurons; in other words, ketamine's actions interfere with pain transmission in the [[spinal cord]].<ref name="Quibell2011">{{cite journal | vauthors = Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A | title = Ketamine* | journal = Journal of Pain and Symptom Management | volume = 41 | issue = 3 | pages = 640–9 | date = March 2011 | pmid = 21419322 | doi = 10.1016/j.jpainsymman.2011.01.001 | url = http://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext | type = Therapeutic Review | doi-access = free | title-link = doi | access-date = 28 July 2014 | archive-date = 16 September 2018 | archive-url = https://web.archive.org/web/20180916035324/https://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext | url-status = live }}</ref>

The mechanism of action of ketamine in alleviating depression is not well understood, but it is an area of active investigation. Due to the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant.<ref name="Hashimoto2019" /> However, multiple other [[NMDA receptor antagonist]]s, including [[memantine]], [[lanicemine]], [[rislenemdaz]], [[rapastinel]], and [[4-chlorokynurenine]], have thus far failed to demonstrate significant effectiveness for depression.<ref name="Hashimoto2019" /><ref name="GarayZarate2018">{{cite journal | vauthors = Garay R, Zarate CA, Cavero I, Kim YK, Charpeaud T, Skolnick P | title = The development of glutamate-based antidepressants is taking longer than expected | journal = Drug Discovery Today | volume = 23 | issue = 10 | pages = 1689–1692 | date = October 2018 | pmid = 29501913 | pmc = 6211562 | doi = 10.1016/j.drudis.2018.02.006 }}</ref> Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as [[(2R,6R)-hydroxynorketamine|(2''R'',6''R'')-hydroxynorketamine]], the [[metabolite]] with negligible affinity for the NMDA receptor but potent [[alpha-7 nicotinic receptor]] antagonist activity, may have antidepressant action.<ref name="Hashimoto2019" /><ref name="pmid23183107"/> This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine.<ref name="Hashimoto2019" /><ref name="AdisInsight-HR-071603">{{cite web | url=https://adisinsight.springer.com/drugs/800056158 | title=Arketamine – Jiangsu Hengrui Medicine – AdisInsight | access-date=13 November 2019 | archive-date=13 April 2021 | archive-url=https://web.archive.org/web/20210413141717/https://adisinsight.springer.com/drugs/800056158 | url-status=live }}</ref><ref name="GarayZarate2018" /> Acute inhibition of the [[lateral habenula]], a part of the brain responsible for inhibiting the [[mesolimbic reward pathway]] and referred to as the "anti-reward center", is another possible mechanism for ketamine's antidepressant effects.<ref name="pmid29532791" /><ref name="pmid29879390">{{cite journal | vauthors = Kim D, Cheong E, Shin HS | title = Overcoming Depression by Inhibition of Neural Burst Firing | journal = Neuron | volume = 98 | issue = 5 | pages = 878–879 | date = June 2018 | pmid = 29879390 | doi = 10.1016/j.neuron.2018.05.032 | doi-access = free | title-link = doi }}</ref><ref name="pmid29446381">{{cite journal | vauthors = Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H | title = Ketamine blocks bursting in the lateral habenula to rapidly relieve depression | journal = Nature | volume = 554 | issue = 7692 | pages = 317–322 | date = February 2018 | pmid = 29446381 | doi = 10.1038/nature25509 | s2cid = 3334820 | bibcode = 2018Natur.554..317Y }}</ref>

Possible biochemical mechanisms of ketamine's antidepressant action include direct action on the [[N-Methyl-D-aspartic acid|NMDA]] receptor and downstream effects on regulators such as [[Brain-derived neurotrophic factor|BDNF]] and [[mTOR]].<ref name="pmid29532791"/> It is not clear whether ketamine alone is sufficient for antidepressant action or its metabolites are also important; the active metabolite of ketamine, [[hydroxynorketamine]], which does not significantly interact with the NMDA receptor but nonetheless indirectly activates AMPA receptors, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.<ref name="pmid29945898" /><ref name="pmid29532791">{{cite journal | vauthors = Zanos P, Gould TD | title = Mechanisms of ketamine action as an antidepressant | journal = Molecular Psychiatry | volume = 23 | issue = 4 | pages = 801–811 | date = April 2018 | pmid = 29532791 | pmc = 5999402 | doi = 10.1038/mp.2017.255 }}</ref><ref name="pmid29516301">{{cite journal | vauthors = Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD | title = Convergent Mechanisms Underlying Rapid Antidepressant Action | journal = CNS Drugs | volume = 32 | issue = 3 | pages = 197–227 | date = March 2018 | pmid = 29516301 | pmc = 6005380 | doi = 10.1007/s40263-018-0492-x }}</ref> In NMDA [[receptor antagonist|receptor antagonism]], acute blockade of NMDA receptors in the brain results in an increase in the release of [[Glutamate (neurotransmitter)|glutamate]], which leads to an activation of [[α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor]]s (AMPA receptors), which in turn modulate a variety of downstream [[signaling pathway]]s to influence [[neurotransmission]] in the [[limbic system]] and mediate antidepressant effects.<ref name="pmid29736744" /><ref name="pmid29532791" /><ref name="pmid29668918">{{cite journal |vauthors=Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA |title=Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling |journal=The International Journal of Neuropsychopharmacology |volume=21 |issue=8 |pages=740–747 |date=August 2018 |pmid=29668918 |pmc=6070027 |doi=10.1093/ijnp/pyy041}}</ref> Such downstream actions of the activation of AMPA receptors include [[upregulation]] of [[brain-derived neurotrophic factor]] (BDNF) and activation of its signaling receptor [[tropomyosin receptor kinase B]] (TrkB), activation of the [[mammalian target of rapamycin]] (mTOR) pathway, deactivation of [[glycogen synthase kinase 3]] (GSK-3), and inhibition of the [[phosphorylation]] of the [[eukaryotic elongation factor 2]] (eEF2) [[kinase]].<ref name="pmid29736744" /><ref name="pmid29532791" /><ref name="pmid26519901">{{cite journal | vauthors = Björkholm C, Monteggia LM | author-link2 = Lisa Monteggia | title = BDNF – a key transducer of antidepressant effects | journal = Neuropharmacology | volume = 102 | pages = 72–79 | date = March 2016 | pmid = 26519901 | pmc = 4763983 | doi = 10.1016/j.neuropharm.2015.10.034 }}</ref><ref name="pmid27425886">{{cite journal | vauthors = Castrén E, Kojima M | title = Brain-derived neurotrophic factor in mood disorders and antidepressant treatments | journal = Neurobiology of Disease | volume = 97 | issue = Pt B | pages = 119–126 | date = January 2017 | pmid = 27425886 | doi = 10.1016/j.nbd.2016.07.010 | hdl-access = free | s2cid = 644350 | hdl = 10138/311483 }}</ref>

====Molecular targets====
{| class="wikitable floatright" style="font-size:small;"
|+ Ketamine and biological targets (with K<sub>i</sub> below 100 μM)

|-
! Site !! Value ([[Micromolar|μM]]) !! Type !! Action !! Species !! Ref
|-
| {{abbrlink|NMDA|N-Methyl-D-aspartate receptor}} || 0.25–0.66 || K<sub>i</sub> || Antagonist || Human || <ref name="pmid28829612">{{cite journal | vauthors = Morris PJ, Moaddel R, Zanos P, Moore CE, Gould TD, Zarate CA, Thomas CJ | title = Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites | journal = Organic Letters | volume = 19 | issue = 17 | pages = 4572–4575 | date = September 2017 | pmid = 28829612 | pmc = 5641405 | doi = 10.1021/acs.orglett.7b02177 }}</ref><ref name="pmid23527166">{{cite journal |author1-link= Bryan Roth | vauthors = Roth BL, Gibbons S, Arunotayanun W, Huang XP, Setola V, Treble R, Iversen L | title = The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e59334 | year = 2013 | pmid = 23527166 | pmc = 3602154 | doi = 10.1371/journal.pone.0059334 | bibcode = 2013PLoSO...859334R | doi-access = free | title-link = doi }}</ref>
|-
| {{abbrlink|MOR|μ-Opioid receptor}} || 42 || K<sub>i</sub> || Antagonist || Human || <ref name="pmid9915326">{{cite journal | vauthors = Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG | title = Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells | journal = Anesthesiology | volume = 90 | issue = 1 | pages = 174–82 | date = January 1999 | pmid = 9915326 | doi = 10.1097/00000542-199901000-00023 | doi-access = free | title-link = doi }}</ref>
|-
| {{abbrlink|MOR<sub>2</sub>|μ-Opioid receptor}} || 12.1
| K<sub>i</sub>
| Antagonist || Human || <ref name="pmid14530949">{{cite journal | vauthors = Hirota K, Sikand KS, Lambert DG | title = Interaction of ketamine with mu2 opioid receptors in SH-SY5Y human neuroblastoma cells | journal = Journal of Anesthesia | volume = 13 | issue = 2 | pages = 107–9 | year = 1999 | pmid = 14530949 | doi = 10.1007/s005400050035 | s2cid = 9322174 }}</ref>
|-
| {{abbrlink|KOR|κ-Opioid receptor}} || 28<br />25
| K<sub>i</sub><br />K<sub>i</sub>
| Antagonist<br />Agonist || Human ||<ref name="pmid9915326"/><br /><ref name="pmid20358363">{{cite journal |vauthors=Nemeth CL, Paine TA, Rittiner JE, Béguin C, Carroll FI, Roth BL, Cohen BM, Carlezon WA |title=Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats |journal=Psychopharmacology (Berl) |volume=210 |issue=2 |pages=263–74 |date=June 2010 |pmid=20358363 |pmc=2869248 |doi=10.1007/s00213-010-1834-7 }}</ref>
|-

| [[Sigma-2 receptor|σ<sub>2</sub>]] || 26 || K<sub>i</sub> || {{abbr|ND|No data}} || Rat || <ref name="pmid21911285">{{cite journal |vauthors=Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR |title=Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo |journal=Eur Neuropsychopharmacol |volume=22 |issue=4 |pages=308–17 |date=April 2012 |pmid=21911285 |doi=10.1016/j.euroneuro.2011.08.002 |s2cid=24494428 }}</ref>
|-
| [[D2 receptor|D<sub>2</sub>]] || 0.5<br/>&gt;10 || K<sub>i</sub><br />K<sub>i</sub> || Agonist<br />{{abbr|ND|No data}} || Human || <ref name="pmid12232776">{{cite journal | vauthors = Kapur S, Seeman P | title = NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia | journal = Molecular Psychiatry | volume = 7 | issue = 8 | pages = 837–44 | year = 2002 | pmid = 12232776 | doi = 10.1038/sj.mp.4001093 | doi-access = free | title-link = doi }}</ref><br /><ref name="pmid23527166" /><ref name="pmid27469513">{{cite journal | vauthors = Can A, Zanos P, Moaddel R, Kang HJ, Dossou KS, Wainer IW, Cheer JF, Frost DO, Huang XP, Gould TD | title = Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 359 | issue = 1 | pages = 159–70 | date = October 2016 | pmid = 27469513 | pmc = 5034706 | doi = 10.1124/jpet.116.235838 }}</ref><ref name="pmid16730695" />
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 45 || K<sub>i</sub> || {{abbr|ND|No data}} || Human || <ref name="pmid12456425">{{cite journal |vauthors=Hirota K, Hashimoto Y, Lambert DG |title=Interaction of intravenous anesthetics with recombinant human M1-M3 muscarinic receptors expressed in chinese hamster ovary cells |journal=Anesth Analg |volume=95 |issue=6 |pages=1607–10, table of contents |date=December 2002 |pmid=12456425 |doi=10.1097/00000539-200212000-00025 |s2cid=25643394 | doi-access = free | title-link = doi }}</ref>

|-
| {{abbrlink|α<sub>2</sub>β<sub>2</sub>|Nicotinic acetylcholine receptor}}|| 92 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635">{{cite journal |vauthors=Yamakura T, Chavez-Noriega LE, Harris RA |title=Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine |journal=Anesthesiology |volume=92 |issue=4 |pages=1144–53 |date=April 2000 |pmid=10754635 |doi=10.1097/00000542-200004000-00033 |s2cid=23651917 | doi-access = free | title-link = doi }}</ref>
|-
| {{abbrlink|α<sub>2</sub>β<sub>4</sub>|Nicotinic acetylcholine receptor}} || 29 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-

| [[alpha-3 beta-2 nicotinic receptor|α<sub>3</sub>β<sub>2</sub>]] || 50 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-

| [[alpha-3 beta-4 nicotinic receptor|α<sub>3</sub>β<sub>4</sub>]] || 9.5 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />

|-
| [[alpha-4 beta-2 nicotinic receptor|α<sub>4</sub>β<sub>2</sub>]] || 72 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />

|-
| [[alpha-4 beta-4 nicotinic receptor|α<sub>4</sub>β<sub>4</sub>]] || 18 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-
| [[Alpha-7 nicotinic receptor|α<sub>7</sub>]] || 3.1 ([[Hydroxynorketamine|HNK]]) || IC<sub>50</sub> || [[Negative allosteric modulation|NAM]]|| Rat || <ref name="pmid23183107">{{cite journal |vauthors=Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, Rosenberg A, Tran T, Xiao Y, Zarate CA, Wainer IW |title=Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors |journal=Eur J Pharmacol |volume=698 |issue=1–3 |pages=228–34 |date=January 2013 |pmid=23183107 |pmc=3534778 |doi=10.1016/j.ejphar.2012.11.023 }}</ref>

|-
| {{abbrlink|ERα|Estrogen receptor alpha}} || 0.34 || K<sub>i</sub>|| {{abbr|ND|No data}} || Human || <ref name="pmid29621538">{{cite journal | vauthors = Ho MF, Correia C, Ingle JN, Kaddurah-Daouk R, Wang L, Kaufmann SH, Weinshilboum RM | title = Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression | journal = Biochemical Pharmacology | volume = 152 | pages = 279–292 | date = June 2018 | pmid = 29621538 | pmc = 5960634 | doi = 10.1016/j.bcp.2018.03.032 }}</ref>

|-
| {{abbrlink|NET|Norepinephrine transporter}} || 82–291 || IC<sub>50</sub> || Inhibitor || Human ||<ref name="pmid9523822">{{cite journal |vauthors=Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, Tohyama M |title=Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells |journal=Anesthesiology |volume=88 |issue=3 |pages=768–74 |date=March 1998 |pmid=9523822 |doi=10.1097/00000542-199803000-00029 |s2cid=30159489 | doi-access = free | title-link = doi }}</ref><ref name="pmid18815045">{{cite journal |vauthors=Zhao Y, Sun L |title=Antidepressants modulate the in vitro inhibitory effects of propofol and ketamine on norepinephrine and serotonin transporter function |journal=J Clin Neurosci |volume=15 |issue=11 |pages=1264–9 |date=November 2008 |pmid=18815045 |pmc=2605271 |doi=10.1016/j.jocn.2007.11.007 }}</ref>
|-
| {{abbrlink|DAT|Dopamine transporter}} || 63 || K<sub>i</sub> || Inhibitor || Rat || <ref name="pmid9523822" />

|-
| {{abbrlink|HCN1|Hyperpolarization-activated cyclic nucleotide-gated channel 1}} || 8–16 || EC<sub>50</sub> || Inhibitor || Mouse || <ref name="pmid19158287">{{cite journal | vauthors = Chen X, Shu S, Bayliss DA | title = HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine | journal = The Journal of Neuroscience | volume = 29 | issue = 3 | pages = 600–9 | date = January 2009 | pmid = 19158287 | pmc = 2744993 | doi = 10.1523/JNEUROSCI.3481-08.2009 }}</ref>
|-
|[[TRPV1]]
|1-100
|K<sub>i</sub>
|Agonist
|Rat
|<ref>{{cite journal | vauthors = da Costa FL, Pinto MC, Santos DC, Carobin NV, de Jesus IC, Ferreira LA, Guatimosim S, Silva JF, Castro Junior CJ | title = Ketamine potentiates TRPV1 receptor signaling in the peripheral nociceptive pathways | journal = Biochemical Pharmacology | volume = 182 | pages = 114210 | date = December 2020 | pmid = 32882205 | doi = 10.1016/j.bcp.2020.114210 | s2cid = 221497233 }}</ref>
|- class="sortbottom"
| colspan="6" style="width: 1px;" | The smaller the value, the stronger the interaction with the site.
|}

Ketamine principally acts as a pore blocker of the [[NMDA receptor]], an [[ionotropic glutamate receptor]].<ref name="pmid28418641">{{cite journal | vauthors = Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ | title = Classics in Chemical Neuroscience: Ketamine | journal = ACS Chemical Neuroscience | volume = 8 | issue = 6 | pages = 1122–1134 | date = June 2017 | pmid = 28418641 | doi = 10.1021/acschemneuro.7b00074 }}</ref> The ''S''-(+) and ''R''-(–) [[stereoisomer]]s of ketamine bind to the dizocilpine site of the NMDA receptor with different [[Binding affinity|affinities]], the former showing approximately 3- to 4-fold greater affinity for the receptor than the latter. As a result, the ''S'' isomer is a more potent anesthetic and analgesic than its ''R'' counterpart.<ref name="pmid8942324">{{cite journal | vauthors = Hirota K, Lambert DG | title = Ketamine: its mechanism(s) of action and unusual clinical uses | journal = British Journal of Anaesthesia | volume = 77 | issue = 4 | pages = 441–4 | date = October 1996 | pmid = 8942324 | doi = 10.1093/bja/77.4.441 | df = dmy-all | doi-access = free | title-link = doi }}</ref>

Ketamine may interact with and inhibit the NMDAR via another [[allosteric site]] on the receptor.<ref name="Orser">{{cite journal | vauthors = Orser BA, Pennefather PS, MacDonald JF | title = Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors | journal = Anesthesiology | volume = 86 | issue = 4 | pages = 903–17 | date = April 1997 | pmid = 9105235 | doi = 10.1097/00000542-199704000-00021 | s2cid = 2164198 | doi-access = free | title-link = doi }}</ref>

With a couple of exceptions, ketamine actions at other receptors are far weaker than ketamine's antagonism of the NMDA receptor (see the activity table to the right).<ref name="MathewZarate2016" /><ref name="pmid26075331">{{cite journal | vauthors = Lodge D, Mercier MS | title = Ketamine and phencyclidine: the good, the bad, and the unexpected | journal = British Journal of Pharmacology | volume = 172 | issue = 17 | pages = 4254–76 | date = September 2015 | pmid = 26075331 | pmc = 4556466 | doi = 10.1111/bph.13222 }}</ref>

Although ketamine is a very weak ligand of the [[monoamine transporter]]s (K<sub>i</sub>&nbsp;> 60&nbsp;μM), it has been suggested that it may interact with [[allosteric site]]s on the monoamine transporters to produce [[monoamine reuptake inhibition]].<ref name="pmid23527166" /> However, no functional inhibition ([[IC50|IC<sub>50</sub>]]) of the human monoamine transporters has been observed with ketamine or its [[metabolite]]s at concentrations of up to 10,000&nbsp;nM.<ref name="pmid27469513" /><ref name="pmid28418641"/> Moreover, [[preclinical research|animal studies]] and at least three human [[case report]]s have found no interaction between ketamine and the [[monoamine oxidase inhibitor]] (MAOI) [[tranylcypromine]], which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as [[serotonin syndrome]] or [[hypertensive crisis]].<ref name="pmid28097909">{{cite journal | vauthors = Kraus C, Rabl U, Vanicek T, Carlberg L, Popovic A, Spies M, Bartova L, Gryglewski G, Papageorgiou K, Lanzenberger R, Willeit M, Winkler D, Rybakowski JK, Kasper S | title = Administration of ketamine for unipolar and bipolar depression | journal = International Journal of Psychiatry in Clinical Practice | volume = 21 | issue = 1 | pages = 2–12 | date = March 2017 | pmid = 28097909 | doi = 10.1080/13651501.2016.1254802 | s2cid = 35626369 }}</ref><ref name="pmid26302763">{{cite journal | vauthors = Bartova L, Vogl SE, Stamenkovic M, Praschak-Rieder N, Naderi-Heiden A, Kasper S, Willeit M | title = Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases | journal = European Neuropsychopharmacology | volume = 25 | issue = 11 | pages = 2183–4 | date = November 2015 | pmid = 26302763 | doi = 10.1016/j.euroneuro.2015.07.021 | s2cid = 39039021 }}</ref> Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans.<ref name="pmid28097909" /><ref name="pmid28418641" /><ref name="pmid27469513" /><ref name="pmid26302763" /> Ketamine has been found to increase [[Dopaminergic pathways|dopaminergic neurotransmission]] in the brain, but instead of being due to dopamine reuptake inhibition, this may be via [[upstream and downstream (transduction)|indirect/downstream]] mechanisms, namely through antagonism of the NMDA receptor.<ref name="pmid28418641" /><ref name="pmid27469513" />

Whether ketamine is an agonist of D<sub>2</sub> receptors is controversial. Early research by the [[Philip Seeman]] group found ketamine to be a D<sub>2</sub> partial agonist with a potency similar to that of its NMDA receptor antagonism.<ref name="pmid12232776" /><ref name="pmid18720422">{{cite journal | vauthors = Seeman P, Guan HC | title = Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia | journal = Synapse | volume = 62 | issue = 11 | pages = 819–28 | date = November 2008 | pmid = 18720422 | doi = 10.1002/syn.20561 | s2cid = 206519749 }}</ref><ref name="pmid19391150">{{cite journal | vauthors = Seeman P, Guan HC, Hirbec H | title = Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil | journal = Synapse | volume = 63 | issue = 8 | pages = 698–704 | date = August 2009 | pmid = 19391150 | doi = 10.1002/syn.20647 | s2cid = 17758902 }}</ref> However, later studies by different researchers found the affinity of ketamine of >10&nbsp;μM for the regular human and rat D<sub>2</sub> receptors,<ref name="pmid23527166" /><ref name="pmid27469513" /><ref name="pmid16730695">{{cite journal | vauthors = Jordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, Tadori Y, Kitagawa H, Kikuchi T | title = In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors | journal = European Journal of Pharmacology | volume = 540 | issue = 1–3 | pages = 53–6 | date = July 2006 | pmid = 16730695 | doi = 10.1016/j.ejphar.2006.04.026 }}</ref> Moreover, whereas D<sub>2</sub> receptor agonists such as [[bromocriptine]] can rapidly and powerfully suppress [[prolactin]] [[secretion]],<ref name="Springer2012">{{cite book|title=The Role of Brain Dopamine|url=https://books.google.com/books?id=yjHwCAAAQBAJ&pg=PA23|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73897-5|pages=23–}}</ref> subanesthetic doses of ketamine have not been found to do this in humans and in fact, have been found to dose-dependently ''increase'' prolactin levels.<ref name="pmid8122957">{{cite journal | vauthors = Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS | title = Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses | journal = Archives of General Psychiatry | volume = 51 | issue = 3 | pages = 199–214 | date = March 1994 | pmid = 8122957 | doi = 10.1001/archpsyc.1994.03950030035004 }}</ref><ref name="pmid11282259">{{cite journal | vauthors = Hergovich N, Singer E, Agneter E, Eichler HG, Graselli U, Simhandl C, Jilma B | title = Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial | journal = Neuropsychopharmacology | volume = 24 | issue = 5 | pages = 590–3 | date = May 2001 | pmid = 11282259 | doi = 10.1016/S0893-133X(00)00194-9 | doi-access = free | title-link = doi }}</ref> [[Medical imaging|Imaging]] studies have shown mixed results on inhibition of [[striatum|striatal]] [<sup>11</sup>C] [[raclopride]] binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect.<ref name="pmid17591653">{{cite journal | vauthors = Rabiner EA | title = Imaging of striatal dopamine release elicited with NMDA antagonists: is there anything there to be seen? | journal = Journal of Psychopharmacology | volume = 21 | issue = 3 | pages = 253–8 | date = May 2007 | pmid = 17591653 | doi = 10.1177/0269881107077767 | s2cid = 23776189 }}</ref> However, changes in [<sup>11</sup>C] raclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D<sub>2</sub> receptor.<ref name="pmid17591653" />

==== Relationships between levels and effects ====
[[Dissociative|Dissociation]] and [[psychotomimetic]] effects are reported in people treated with ketamine at plasma concentrations of approximately 100 to 250&nbsp;ng/mL (0.42–1.1&nbsp;μM).<ref name="pmid29945898" /> The typical intravenous antidepressant dosage of ketamine used to treat depression is low and results in maximal plasma concentrations of 70 to 200&nbsp;ng/mL (0.29–0.84&nbsp;μM).<ref name="pmid28249076" /> At similar plasma concentrations (70 to 160&nbsp;ng/mL; 0.29–0.67&nbsp;μM) it also shows analgesic effects.<ref name="pmid28249076" /> In 1–5 minutes after inducing anesthesia by rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60–110&nbsp;μM.<ref name="pmid526385">{{cite journal |vauthors=Idvall J, Ahlgren I, Aronsen KR, Stenberg P |title=Ketamine infusions: pharmacokinetics and clinical effects |journal=Br J Anaesth |volume=51 |issue=12 |pages=1167–73 |date=December 1979 |pmid=526385 |doi=10.1093/bja/51.12.1167 | doi-access = free | title-link = doi }}</ref><ref name="pmid7198883">{{cite journal |vauthors=Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE |title=Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay |journal=Anesth Analg |volume=61 |issue=2 |pages=87–92 |date=February 1982 |doi=10.1213/00000539-198202000-00004 |pmid=7198883 |s2cid=27596215 | doi-access = free | title-link = doi }}</ref> When the anesthesia was maintained using [[nitrous oxide]] together with continuous injection of ketamine, the ketamine concentration stabilized at approximately 9.3 μM.<ref name="pmid526385" /> In an experiment with purely ketamine anesthesia, people began to awaken once the plasma level of ketamine decreased to about 2,600&nbsp;ng/mL (11&nbsp;μM) and became oriented in place and time when the level was down to 1,000&nbsp;ng/mL (4&nbsp;μM).<ref name="pmid3970799">{{cite journal |vauthors=White PF, Schüttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ |title=Comparative pharmacology of the ketamine isomers. Studies in volunteers |journal=Br J Anaesth |volume=57 |issue=2 |pages=197–203 |date=February 1985 |pmid=3970799 |doi=10.1093/bja/57.2.197 | doi-access = free | title-link = doi }}</ref> In a single-case study, the concentration of ketamine in [[cerebrospinal fluid]], a proxy for the brain concentration, during anesthesia varied between 2.8 and 6.5&nbsp;μM and was approximately 40% lower than in plasma.<ref name="pmid7248132">{{cite journal |vauthors=Stenberg P, Idvall J |title=Does ketamine metabolite II exist in vivo? |journal=Br J Anaesth |volume=53 |issue=7 |page=778 |date=July 1981 |pmid=7248132 |doi=10.1093/bja/53.7.778 | doi-access = free | title-link = doi }}</ref>

=== Pharmacokinetics ===
Ketamine can be absorbed by many different routes due to both its water and lipid solubility. [[Intravenous]] ketamine [[bioavailability]] is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%,<ref name="MathewZarate2016" /> and [[epidural]] bioavailability is 77%.<ref name="Kintz2014" /> Subcutaneous bioavailability has never been measured but is presumed to be high.<ref name="Mao2016">{{cite book | vauthors = Mao J |title=Opioid-Induced Hyperalgesia |url=https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127|date=19 April 2016 |publisher=CRC Press |isbn=978-1-4200-8900-4 |pages=127– |url-status=live |archive-url=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127 |archive-date=8 September 2017 }}</ref> Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%)<ref name="MathewZarate2016" /><ref name="pmid23521979" /> and oral&nbsp;– the lowest (16–20%).<ref name="MathewZarate2016" /><ref name="pmid23521979" /> Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%.<ref name="MathewZarate2016" /><ref name="Hashimoto2019" /><ref name="pmid23521979" />

After absorption ketamine is rapidly [[distribution (pharmacology)|distributed]] into the brain and other tissues.<ref name="pmid27028535" /> The [[plasma protein binding]] of ketamine is variable at 23–47%.<ref name="pmid6884418" />

[[File:Ketamine metabolites2.png|class=skin-invert-image|thumb|upright=1.7|Major routes of ketamine metabolism<ref name="pmid29945898" />]]
In the body, ketamine undergoes extensive [[metabolism]]. It is [[biotransformation|biotransformed]] by [[CYP3A4]] and [[CYP2B6]] [[isoenzyme]]s into [[norketamine]], which, in turn, is converted by [[CYP2A6]] and CYP2B6 into [[hydroxynorketamine]] and [[dehydronorketamine]].<ref name="pmid29945898" /> Low oral bioavailability of ketamine is due to the [[first-pass effect]] and, possibly, ketamine intestinal metabolism by CYP3A4.<ref name="pmid27763887" /> As a result, norketamine plasma levels are several-fold higher than ketamine following oral administration, and norketamine may play a role in anesthetic and analgesic action of oral ketamine.<ref name="MathewZarate2016" /><ref name="pmid27763887">{{cite journal |vauthors=Rao LK, Flaker AM, Friedel CC, Kharasch ED |title=Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance |journal=Anesthesiology |volume=125 |issue=6 |pages=1103–1112 |date=December 2016 |pmid=27763887 |doi=10.1097/ALN.0000000000001392 |s2cid=41380105 }}</ref> This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.<ref name="pmid27763887" /><ref name="pmid25702819">{{cite journal |vauthors=Li Y, Jackson KA, Slon B, Hardy JR, Franco M, William L, Poon P, Coller JK, Hutchinson MR, Currow DC, Somogyi AA |title=CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects |journal=Br J Clin Pharmacol |volume=80 |issue=2 |pages=276–84 |date=August 2015 |pmid=25702819 |pmc=4541975 |doi=10.1111/bcp.12614 }}</ref>

After an intravenous injection of [[tritium]]-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces.<ref name="pmid4603048">{{cite journal |vauthors=Chang T, Glazko AJ |title=Biotransformation and disposition of ketamine |journal=Int Anesthesiol Clin |volume=12 |issue=2 |pages=157–77 |date=1974 |pmid=4603048 |doi=10.1097/00004311-197412020-00018 |s2cid=30723730 }}</ref> The medication is excreted mostly in the form of [[metabolite]]s, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.<ref name="pmid20693870" />