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Revision as of 11:46, 16 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 477128398 of page Ketamine for the Chem/Drugbox validation project (updated: '').  Latest revision as of 09:14, 23 December 2024 edit 2402:a00:408:29d0:cc43:9354:e042:5819 (talk)No edit summaryTag: Visual edit 
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{{Short description|Dissociative anesthetic and anti-depressant}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{For|the functional group referred to as ketimine|Imine}}
{{drugbox
{{Use dmy dates|date=March 2023}}
| verifiedrevid = 464370142
{{cs1 config|name-list-style=vanc|display-authors=6}}
| IUPAC_name = (''RS'')-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
{{Infobox drug
| image = Ketamine.svg
| Watchedfields = changed
| verifiedrevid = 477168837
| image = Ketamine2DCSD.svg
| width = 150 | width = 150
| alt =
| image2 = Ketamine.pdb.gif
| image2 = S-ketamine-from-HCl-xtal-3D-balls.png
| width2 = 200
| width2 = 175
| imagename = 1 : 1 mixture (racemate)
| drug_name = Ketamine | alt2 = (''S'')-Ketamine ball-and-stick model


<!--Clinical data--> <!--Clinical data-->
| tradename = Ketalar, others
| Drugs.com = {{drugs.com|CDI|ketamine}}
| Drugs.com = {{drugs.com|monograph|ketamine-hydrochloride}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| DailyMedID = Ketamine
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_AU = B3
| pregnancy_category = B
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Ketamine (Ketalar) Use During Pregnancy | website=Drugs.com | date=22 November 2019 | url=https://www.drugs.com/pregnancy/ketamine.html | access-date=18 May 2020 | archive-date=26 June 2020 | archive-url=https://web.archive.org/web/20200626125239/https://www.drugs.com/pregnancy/ketamine.html | url-status=live }}</ref>
| addiction_liability = Moderate–high<ref>{{cite web |title=Drug Scheduling |url=https://www.dea.gov/drug-information/drug-scheduling |publisher=U.S. ] |access-date=29 December 2023 |archive-date=8 April 2024 |archive-url=https://web.archive.org/web/20240408102758/https://www.dea.gov/drug-information/drug-scheduling |url-status=live }} Ketamine is listed in Schedule III.</ref><ref>Huang, MC., Lin, SK. (2020). "Ketamine Abuse: Past and Present". In: Hashimoto, K., Ide, S., Ikeda, K. (eds.) ''Ketamine''. Springer, Singapore. {{doi|10.1007/978-981-15-2902-3_1}}.</ref>
| routes_of_administration = Any<ref>{{cite journal | vauthors = Bell RF, Eccleston C, Kalso EA | title = Ketamine as an adjuvant to opioids for cancer pain | journal = The Cochrane Database of Systematic Reviews | volume = 6 | pages = CD003351 | date = June 2017 | issue = 9 | pmid = 28657160 | pmc = 6481583 | doi = 10.1002/14651858.CD003351.pub3 | url = http://opus.bath.ac.uk/57535/1/Published_Version.pdf | access-date = 10 September 2018 | archive-date = 12 January 2024 | archive-url = https://web.archive.org/web/20240112122726/http://opus.bath.ac.uk/57535/1/Published_Version.pdf | url-status = live }}</ref><ref>{{cite journal | vauthors = Moyse DW, Kaye AD, Diaz JH, Qadri MY, Lindsay D, Pyati S | title = Perioperative Ketamine Administration for Thoracotomy Pain | journal = Pain Physician | volume = 20 | issue = 3 | pages = 173–184 | date = March 2017 | pmid = 28339431 }}</ref><ref name="MathewZarate2016">{{cite book | vauthors = Mathew SJ, Zarate Jr CA |title=Ketamine for Treatment-Resistant Depression: The First Decade of Progress |url=https://books.google.com/books?id=QDOgDQAAQBAJ&pg=PA22|date=25 November 2016 |publisher=Springer |isbn=978-3-319-42925-0 |pages=8–10, 14–22 |url-status=live |archive-url=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=QDOgDQAAQBAJ&pg=PA22 |archive-date=8 September 2017 }}</ref><ref name="MD">{{cite web|title=Ketamine Hydrochloride: Martindale: The Complete Drug Reference|date=9 January 2017|access-date=24 August 2017|veditors=Brayfield A|publisher=Pharmaceutical Press|website=MedicinesComplete|url=https://www.medicinescomplete.com/mc/martindale/current/ms-3114-h.htm|location=London, UK|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828134205/https://about.medicinescomplete.com/wp-content/themes/mc-marketing/assets/images/favicons-tiles/favicon.ico|url-status=live}}</ref>
| class = ]; ]; ]; ]; ]
| ATC_prefix = N01
| ATC_suffix = AX03

| legal_AU = S8 | legal_AU = S8
| legal_BR = C1
| legal_CA = Schedule I | legal_CA = Schedule I
| legal_UK = CD | legal_DE = Anlage III
| legal_UK = Class B
| legal_US = Schedule III | legal_US = Schedule III
| legal_UN = Unscheduled
| routes_of_administration = ], ], ]d, oral, ]
| legal_status = In general Rx-only
| dependency_liability= Medium


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = * ]: 100%<ref name="MathewZarate2016" />
| metabolism = Hepatic, primarily by CYP3A4<ref>{{Cite journal|author=Hijazi Y, Boulieu R|title=Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes|journal=Drug Metabolism and Disposition|volume=30|issue=7|pages=853–8|year=2002|month=July|pmid=12065445|doi=10.1124/dmd.30.7.853}}</ref>
* ]: 93%<ref name="MathewZarate2016" />
| elimination_half-life = 2.5–3 hours.
* ]: 77%<ref name="Kintz2014">{{cite book | vauthors = Kintz P |title=Toxicological Aspects of Drug-Facilitated Crimes |url=https://books.google.com/books?id=YgnUAgAAQBAJ&pg=PA87|date=22 March 2014 |publisher=Elsevier Science |isbn=978-0-12-416969-2 |pages=87– |url-status=live |archive-url=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=YgnUAgAAQBAJ&pg=PA87 |archive-date=8 September 2017 }}</ref>
| excretion = renal (>90%)
* ]: 45–50%<ref name="MathewZarate2016" /><ref name="pmid23521979">{{cite journal |vauthors=Marland S, Ellerton J, Andolfatto G, Strapazzon G, Thomassen O, Brandner B, Weatherall A, Paal P |title=Ketamine: use in anesthesia |journal=CNS Neurosci Ther |volume=19 |issue=6 |pages=381–9 |date=June 2013 |pmid=23521979 |pmc=6493613 |doi=10.1111/cns.12072 }}</ref>
* ]: 24–30%<ref name="MathewZarate2016" /><ref name="Hashimoto2019">{{cite journal | vauthors = Hashimoto K | title = Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | journal = Psychiatry and Clinical Neurosciences | volume = 73 | issue = 10 | pages = 613–627 | date = October 2019 | pmid = 31215725 | pmc = 6851782 | doi = 10.1111/pcn.12902 }}</ref>
* ]: 25–30%<ref name="pmid23521979"/>
* ]: 16–20%<ref name="MathewZarate2016" /><ref name="pmid23521979"/>
| protein_bound = 23–47%<ref name="pmid6884418">{{cite journal |vauthors=Dayton PG, Stiller RL, Cook DR, Perel JM |title=The binding of ketamine to plasma proteins: emphasis on human plasma |journal=Eur J Clin Pharmacol |volume=24 |issue=6 |pages=825–31 |date=1983 |pmid=6884418 |doi=10.1007/BF00607095 |s2cid=807011 }}</ref>
| metabolism = ], ] (oral):
* Major: ], ]<ref name="MathewZarate2016" /><ref>{{cite journal | vauthors = Hijazi Y, Boulieu R | title = Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes | journal = Drug Metabolism and Disposition | volume = 30 | issue = 7 | pages = 853–8 | date = July 2002 | pmid = 12065445 | doi = 10.1124/dmd.30.7.853 | s2cid = 15787750 }}</ref><ref name="pmid27763887"/>
| metabolites = * ]
* ]
* ]
| onset = * Intravenous: seconds<ref name=sinner>{{cite book | vauthors = Sinner B, Graf BM |chapter= Ketamine |title= Modern Anesthetics | veditors = Schüttler J, Schwilden H |series= Handbook of Experimental Pharmacology |year= 2008 |volume= 182 |issue= 182 |pages= 313–33 |isbn= 978-3-540-72813-9 |doi=10.1007/978-3-540-74806-9_15 |pmid=18175098}}</ref>
* Intramuscular: 1–5 min<ref name="sinner" /><ref name="Quibell2011" />
* Subcutaneous: 15–30 min<ref name="Quibell2011" />
* Insufflation: 5–10 min<ref name="sinner" />
* By mouth: 15–30 min<ref name="sinner" /><ref name="Quibell2011" />
| elimination_half-life = * Ketamine: 2.5–3 hours<ref name="sinner" /><ref name="MathewZarate2016" />
* Norketamine: 12 hours<ref name="Quibell2011" />
| duration_of_action = * Intramuscular: 0.5–2 hours<ref name="Quibell2011" />
* Insufflation: 45–60 min<ref name="sinner" />
* By mouth: 1–6+ hours<ref name="sinner" /><ref name="Quibell2011" />
| excretion = * ]: 91%<ref name="pmid4603048"/>
* ]: 3%<ref name="pmid4603048"/>


<!--Identifiers--> <!--Identifiers-->
| index2_label = HCl
| CASNo_Ref = {{cascite|correct|CAS}}
| IUPHAR_ligand = 4233
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 6740-88-1 | CAS_number = 6740-88-1
| CAS_number2_Ref = {{cascite|correct|??}}
| ATC_prefix = N01
| CAS_number2 = 1867-66-9
| ATC_suffix = AX03
| CAS_supplemental = {{plainlist|
| ATC_supplemental = {{ATC|N01|AX14}}
* 33643-46-8 (])
* 33643-49-1 (])
}}
| ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 6121 | ChEBI = 6121
Line 45: Line 83:
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08098 | KEGG = D08098
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D00711
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 742 | ChEMBL = 742
| synonyms = CI-581; CL-369; CM-52372-2<ref name="MortonHall2012">{{cite book | vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms |url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA159|date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-94-011-4439-1 |pages=159– |url-status=live |archive-url=https://web.archive.org/web/20170411144623/https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA159 |archive-date=11 April 2017 }}</ref>


<!--Chemical data--> <!-- Chemical and physical data -->
| IUPAC_name = (''RS'')-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
| C=13 | H=16 | Cl=1 | N=1 | O=1
| C = 13
| molecular_weight = 237.725 g/mol
| H = 16
| smiles = CNC1(CCCCC1=O)c2ccccc2Cl
| Cl = 1
| InChI = 1/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3
| N = 1
| O = 1
| chirality = ]:<ref name="sinner" />
* ] (''S''(+)-isomer)
* ] (''R''(−)-isomer)
| SMILES = Clc1ccccc1C2(NC)CCCCC2=O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3 | StdInChI = 1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YQEZLKZALYSWHR-UHFFFAOYSA-N | StdInChIKey = YQEZLKZALYSWHR-UHFFFAOYSA-N
| melting_point = 262 | density =
| density_notes =
| melting_point = 92 <ref>{{cite book |vauthors=Sass W, Fusari S |date=1977 |chapter=Ketamine |title=Analytical Profiles of Drug Substances |volume=6 |publisher=Academic Press |pages=297–322 |doi=10.1016/S0099-5428(08)60347-0 |isbn=9780122608063 }}</ref>
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}

<!-- Definition and medical uses -->
'''Ketamine''' is a ] used medically for induction and maintenance of ]. It is also used as a treatment for ] and in ].<ref name="Sachdeva_2023">{{Cite journal | vauthors = Sachdeva B, Sachdeva P, Ghosh S, Ahmad F, Sinha JK |date=March 2023 |title=Ketamine as a therapeutic agent in major depressive disorder and posttraumatic stress disorder: Potential medicinal and deleterious effects |journal=Ibrain |language=en |volume=9 |issue=1 |pages=90–101 |doi=10.1002/ibra.12094 |pmid=37786516 |pmc=10528797 |s2cid=257117630 |issn=2769-2795| doi-access = free | title-link = doi }}</ref> Ketamine is an ] which accounts for most of its psychoactive effects.<ref name="pmid29945898" />

At anesthetic doses, ketamine induces a state of dissociative anesthesia, a ]-like state providing pain relief, ], and ].<ref name="GreenRoback2011" /> Its distinguishing features as an anesthestic are preserved breathing and airway reflexes, stimulated heart function with increased ], and moderate ].<ref name="GreenRoback2011">{{cite journal | vauthors = Green SM, Roback MG, Kennedy RM, Krauss B | title = Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update | journal = Annals of Emergency Medicine | volume = 57 | issue = 5 | pages = 449–461 | date = May 2011 | pmid = 21256625 | doi = 10.1016/j.annemergmed.2010.11.030 | doi-access = free | title-link = doi }}</ref> At lower, sub-anesthetic doses, it is a promising agent for treatment of ] and ].<ref name=Zhang2018>{{cite journal | vauthors = Zhang K, Hashimoto K | title = An update on ketamine and its two enantiomers as rapid-acting antidepressants | journal = Expert Review of Neurotherapeutics | volume = 19 | issue = 1 | pages = 83–92 | date = January 2019 | pmid = 30513009 | doi = 10.1080/14737175.2019.1554434 | s2cid = 54628949 }}</ref> As with many antidepressants, the results of a single administration wane with time.<ref name="acschemneuro.9b00493">{{cite journal | vauthors = Hibicke M, Landry AN, Kramer HM, Talman ZK, Nichols CD | title = Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression | journal = ACS Chemical Neuroscience | volume = 11 | issue = 6 | pages = 864–871 | date = March 2020 | pmid = 32133835 | doi = 10.1021/acschemneuro.9b00493 | s2cid = 212418003 | doi-access = free | title-link = doi }}</ref> <!-- Recreational use and Adverse effects -->

Ketamine is used as a recreational drug for its ] and ] effects.<ref name="morgan11">{{cite journal |vauthors=Morgan CJ, Curran HV |date=January 2012 |title=Ketamine use: a review |journal=Addiction |volume=107 |issue=1 |pages=27–38 |doi=10.1111/j.1360-0443.2011.03576.x |pmid=21777321 |s2cid=11064759}}</ref> When used recreationally, it is found both in crystalline powder and liquid form, and is often referred to by users as "Special K" or simply "K". The long-term effects of repeated use are largely unknown and are an area of active investigation.<ref name="pmid33065824" /><ref name="pmid33174760" /><ref name="pmid33162856" /> Liver and urinary toxicity have been reported among regular users of high doses of ketamine for recreational purposes.<ref name="Or">{{cite book |title=StatPearls |vauthors=Orhurhu VJ, Vashisht R, Claus LE, Cohen SP |date=April 2022 |publisher=StatPearls Publishing |location=Treasure Island (FL) |chapter=Ketamine toxicity |pmid=31082131 |access-date=18 August 2022 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK541087/ |archive-url=https://web.archive.org/web/20220516231947/https://www.ncbi.nlm.nih.gov/books/NBK541087/ |archive-date=16 May 2022 |url-status=live}}</ref>

<!-- Discovery and Legal status -->
Ketamine was first synthesized in 1962, derived from ] in pursuit of a safer anesthetic with fewer hallucinogenic effects.<ref>{{cite journal |vauthors=Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI |date=September 2016 |title=Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy |journal=Clinical Pharmacokinetics |volume=55 |issue=9 |pages=1059–77 |doi=10.1007/s40262-016-0383-6 |pmid=27028535 |s2cid=5078489}}</ref><ref name="pmid29870458" /> It was approved for use in the United States in 1970.<ref name="Sachdeva_2023" /> It has been regularly used in ] and was extensively used for ] in the ].<ref name="pmid20693870" /> It is on the ].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available as a ].<ref name="KetPres2013">{{cite web |title=Ketamine Injection |url=https://www.drugs.com/pro/ketamine-injection.html |website=] |access-date=1 December 2014 |url-status=live |archive-url=https://web.archive.org/web/20141210181630/http://www.drugs.com/pro/ketamine-injection.html |archive-date=10 December 2014 }}</ref>

{{TOC limit}}

== Medical uses ==

=== Anesthesia ===
The use of ketamine in anesthesia reflects its characteristics. It is a drug of choice for short-term procedures when ] is not required.<ref name="Ketamine">{{cite book|vauthors=Rosenbaum SB, Gupta V, Palacios JL|chapter=Ketamine|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK470357/|title=StatPearls|publisher=StatPearls Publishing|pmid=29262083|access-date=5 March 2020|archive-date=12 November 2020|archive-url=https://web.archive.org/web/20201112215028/https://www.ncbi.nlm.nih.gov/books/NBK470357/|url-status=live}}</ref> The effect of ketamine on the ] and ]s is different from that of other anesthetics. It suppresses breathing much less than most other available anesthetics.<ref name="heshmati">{{cite journal | vauthors = Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A | title = Use of ketamine in severe status asthmaticus in intensive care unit | journal = Iranian Journal of Allergy, Asthma, and Immunology | volume = 2 | issue = 4 | pages = 175–80 | date = December 2003 | pmid = 17301376 | url = http://ijaai.tums.ac.ir/index.php/ijaai/article/view/52/52 | url-status = live | archive-url = https://web.archive.org/web/20141006100116/http://ijaai.tums.ac.ir/index.php/ijaai/article/view/52/52 | archive-date = 6 October 2014 }}</ref> When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system.<ref>{{cite journal | vauthors = Adams HA | title = | language = DE | journal = Der Anaesthesist | volume = 46 | issue = 12 | pages = 1081–7 | date = December 1997 | pmid = 9451493 | doi = 10.1007/s001010050510 | s2cid = 36323023 | trans-title = S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation }}</ref> Protective airway reflexes are preserved,<ref name="WongLee2014">{{cite journal | vauthors = Wong JJ, Lee JH, Turner DA, Rehder KJ | title = A review of the use of adjunctive therapies in severe acute asthma exacerbation in critically ill children | journal = Expert Review of Respiratory Medicine | volume = 8 | issue = 4 | pages = 423–41 | date = August 2014 | pmid = 24993063 | doi = 10.1586/17476348.2014.915752 | s2cid = 31435021 }}</ref> and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways.<ref name="Ketamine"/> ] effects limit the acceptance of ketamine; however, ]<ref name="pmid10711913" /> and ]<ref name="pmid11750186" /> decrease psychotomimetic effects and can also be counteracted by ]s or ] administration.<ref name="pmid32826629" /> ] is a combination of ketamine and ].

Ketamine is frequently used in severely injured people and appears to be safe in this group.<ref name="The effect of ketamine on intracran">{{cite journal | vauthors = Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM | title = The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review | journal = Annals of Emergency Medicine | volume = 65 | issue = 1 | pages = 43–51.e2 | date = January 2015 | pmid = 25064742 | doi = 10.1016/j.annemergmed.2014.06.018 }}</ref> It has been widely used for emergency surgery in field conditions in war zones,<ref name="pmid25886322"/> for example, during the ].<ref name="pmid28731926">{{cite journal |vauthors=Mion G |title=History of anaesthesia: The ketamine story – past, present and future |journal=Eur J Anaesthesiol |volume=34 |issue=9 |pages=571–575 |date=September 2017 |pmid=28731926 |doi=10.1097/EJA.0000000000000638 |s2cid=27536846 }}</ref> A 2011 ] supports the use of ketamine as a ] in ], including during physically painful procedures.<ref name="GreenRoback2011" /> <!-- Ketamine was called a "dissociative" anesthetic because of its effect on electroencephalography (EEG): it caused EEG dissociation between limbic and thalamoneocortical areas.
-->It is the drug of choice for people in ] who are at risk of ].<ref>{{cite web | vauthors = Nickson C |url=http://lifeinthefastlane.com/education/ccc/rapid-sequence-induction-of-the-shock-patient/ |title=Intubation, Hypotension and Shock |publisher=Critical Care Compendium |website=Life in the Fastlane |date=7 August 2013 |access-date=10 April 2014 |type=blog |url-status=dead |archive-url=https://web.archive.org/web/20140209161412/http://lifeinthefastlane.com/education/ccc/rapid-sequence-induction-of-the-shock-patient/ |archive-date=9 February 2014 }}{{unreliable medical source|date=July 2014}}</ref> Ketamine is unlikely to lower blood pressure, which is dangerous for people with severe head injury;<ref>{{cite journal | vauthors = Manley G, Knudson MM, Morabito D, Damron S, Erickson V, Pitts L | title = Hypotension, hypoxia, and head injury: frequency, duration, and consequences | journal = Archives of Surgery | volume = 136 | issue = 10 | pages = 1118–23 | date = October 2001 | pmid = 11585502 | doi = 10.1001/archsurg.136.10.1118 | doi-access = free | title-link = doi }}</ref> in fact, it can raise blood pressure, often making it useful in treating such injuries.<ref>{{cite journal | vauthors = Hemmingsen C, Nielsen JE | title = Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia | journal = Acta Anaesthesiologica Scandinavica | volume = 35 | issue = 8 | pages = 755–7 | date = November 1991 | pmid = 1763596 | doi = 10.1111/j.1399-6576.1991.tb03385.x | s2cid = 1324453 }}</ref><ref>{{cite journal | vauthors = Wong DH, Jenkins LC | title = The cardiovascular effects of ketamine in hypotensive states | journal = Canadian Anaesthetists' Society Journal | volume = 22 | issue = 3 | pages = 339–48 | date = May 1975 | pmid = 1139377 | doi = 10.1007/BF03004843 | doi-access = free | title-link = doi }}</ref>

Ketamine is an option in children as the sole anesthetic for minor procedures or as an induction agent followed by ] and ].<ref name="pmid25886322">{{cite journal | vauthors = Kurdi MS, Theerth KA, Deva RS | title = Ketamine: Current applications in anesthesia, pain, and critical care | journal = Anesthesia: Essays and Researches | volume = 8 | issue = 3 | pages = 283–90 | date = September 2014 | pmid = 25886322 | pmc = 4258981 | doi = 10.4103/0259-1162.143110 | doi-access = free | title-link = doi }}</ref> In particular, children with ] and ] are good candidates for ketamine anesthesia.<ref name="pmid32826629">{{cite journal |vauthors=Barrett W, Buxhoeveden M, Dhillon S |title=Ketamine: a versatile tool for anesthesia and analgesia |journal=Current Opinion in Anesthesiology |volume=33 |issue=5 |pages=633–638 |date=October 2020 |pmid=32826629 |doi=10.1097/ACO.0000000000000916 |s2cid=221236545 }}</ref><ref>{{Cite journal |date=2024-04-24 |title=Clinical Uses of Ketamine in Children: A Narrative Review - PMC |pmc=9389002 |journal=Cureus |volume=14 |issue=7 |pages=e27065 |doi=10.7759/cureus.27065 | doi-access = free | title-link = doi |pmid=35989801 | vauthors = Bali A, Dang AK, Gonzalez DA, Kumar R, Asif S }}</ref>

Due to the bronchodilating properties of ketamine, it can be used for anesthesia in people with ], ], and with severe reactive airway disease including active ].<ref name="pmid25886322"/><ref name="pmid32826629"/><ref name="Goyal">{{cite journal | vauthors = Goyal S, Agrawal A | title = Ketamine in status asthmaticus: A review | journal = Indian Journal of Critical Care Medicine | volume = 17 | issue = 3 | pages = 154–61 | date = May 2013 | pmid = 24082612 | pmc = 3777369 | doi = 10.4103/0972-5229.117048 | doi-access = free | title-link = doi }}</ref>

=== Pain ===
Ketamine infusions are used for acute pain treatment in emergency departments and in the perioperative period for individuals with refractory pain. The doses are lower than those used for anesthesia, usually referred to as sub-anesthetic doses. Adjunctive to ] or on its own, ketamine reduces morphine use, pain level, nausea, and vomiting after surgery. Ketamine is likely to be most beneficial for surgical patients when severe post-operative pain is expected, and for opioid-tolerant patients.<ref name="pmid29870457">{{cite journal |vauthors=Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP |title=Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists |journal=Reg Anesth Pain Med |volume=43 |issue=5 |pages=456–466 |date=July 2018 |pmid=29870457 |pmc=6023582 |doi=10.1097/AAP.0000000000000806 }}</ref><ref>{{cite journal | vauthors = Sin B, Ternas T, Motov SM | title = The use of subdissociative-dose ketamine for acute pain in the emergency department | journal = Academic Emergency Medicine | volume = 22 | issue = 3 | pages = 251–7 | date = March 2015 | pmid = 25716117 | doi = 10.1111/acem.12604 | s2cid = 24658476 | doi-access = free | title-link = doi }}</ref>

Ketamine is especially useful in the pre-hospital setting due to its effectiveness and low risk of respiratory depression.<ref name="SvensonBiedermann2011">{{cite journal| vauthors = Svenson J, Biedermann M |title=Ketamine: a unique drug with several potential uses in the prehospital setting|journal=Journal of Paramedic Practice|volume=3|issue=10|year=2011|pages=552–556|doi=10.12968/jpar.2011.3.10.552}}</ref>
Ketamine has similar efficacy to opioids in a hospital emergency department setting for the management of acute pain and the control of procedural pain.<ref name="pmid30019434">{{cite journal | vauthors = Karlow N, Schlaepfer CH, Stoll CR, Doering M, Carpenter CR, Colditz GA, Motov S, Miller J, Schwarz ES | title = A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department | journal = Academic Emergency Medicine | volume = 25 | issue = 10 | pages = 1086–1097 | date = October 2018 | pmid = 30019434 | doi = 10.1111/acem.13502 | doi-access = free | title-link = doi }}</ref> It may also prevent ]<ref name="pmid26495312">{{cite journal | vauthors = Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD | title = Role of ketamine in acute postoperative pain management: a narrative review | journal = BioMed Research International | volume = 2015 | page = 749837 | year = 2015 | pmid = 26495312 | pmc = 4606413 | doi = 10.1155/2015/749837 | doi-access = free | title-link = doi }}</ref><ref name="pmid21412369">{{cite journal | vauthors = Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L | title = A comprehensive review of opioid-induced hyperalgesia | journal = Pain Physician | volume = 14 | issue = 2 | pages = 145–61 | year = 2011 | doi = 10.36076/ppj.2011/14/145 | pmid = 21412369 | doi-access = free | title-link = doi }}</ref> and ].<ref>{{cite journal | vauthors = Zhou Y, Mannan A, Han Y, Liu H, Guan HL, Gao X, Dai MS, Cao JL | title = Efficacy and safety of prophylactic use of ketamine for prevention of postanesthetic shivering: a systematic review and meta analysis | journal = BMC Anesthesiology | volume = 19 | issue = 1 | page = 245 | date = December 2019 | pmid = 31888509 | pmc = 6937868 | doi = 10.1186/s12871-019-0910-8 | doi-access = free | title-link = doi }}</ref>

For chronic pain, ketamine is used as an intravenous analgesic, mainly if the pain is ].<ref name="pmid29870458">{{cite journal |vauthors=Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM |title=Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists |journal=Reg Anesth Pain Med |volume=43 |issue=5 |pages=521–546 |date=July 2018 |pmid=29870458 |pmc=6023575 |doi=10.1097/AAP.0000000000000808 }}</ref> It has the added benefit of counteracting ] or ] experienced with ].<ref name="elia">{{cite journal | vauthors = Elia N, Tramèr MR | title = Ketamine and postoperative pain—a quantitative systematic review of randomised trials | journal = Pain | volume = 113 | issue = 1–2 | pages = 61–70 | date = January 2005 | pmid = 15621365 | doi = 10.1016/j.pain.2004.09.036 | s2cid = 25925720 }}</ref> In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after a traumatic spine injury, ], and ] (CRPS).<ref name="pmid29870458"/> However, the 2018 consensus guidelines on chronic pain concluded that, overall, there is only weak evidence in favor of ketamine use in spinal injury pain, moderate evidence in favor of ketamine for CRPS, and weak or no evidence for ketamine in mixed neuropathic pain, fibromyalgia, and ]. In particular, only for CRPS, there is evidence of medium to longer-term pain relief.<ref name="pmid29870458"/>

=== Depression ===
{{See also|Esketamine#Depression}}

Ketamine is a rapid-acting ],<ref name="Sachdeva_2023" /> but its effect is transient.<ref name="pmid28249076">{{cite journal | vauthors = Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB | title = A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | journal = JAMA Psychiatry | volume = 74 | issue = 4 | pages = 399–405 | date = April 2017 | pmid = 28249076 | doi = 10.1001/jamapsychiatry.2017.0080 | s2cid = 28320520 }}</ref> Intravenous ketamine infusion in ] may result in improved mood within 4 hours reaching the peak at 24 hours.<ref name=Zhang2018 /><ref name="pmid33065824">{{cite journal |vauthors=Marcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H, Richard-Devantoy S, Beauchamp S |title=A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 – January 2019 |journal=J Affect Disord |volume=277 |pages=831–841 |date=December 2020 |pmid=33065824 |doi=10.1016/j.jad.2020.09.007 |s2cid=223557698 }}</ref> A single dose of intravenous ketamine has been shown to result in a response rate greater than 60% as early as 4.5 hours after the dose (with a sustained effect after 24 hours) and greater than 40% after 7 days.<ref name="pmid29736744"/> Although only a few pilot studies have sought to determine the optimal dose, increasing evidence suggests that 0.5&nbsp;mg/kg dose injected over 40 minutes gives an optimal outcome.<ref name="Sanacora Katz 2018 pp. 243–250">{{cite journal | vauthors = Sanacora G, Katz R | title = Ketamine: A Review for Clinicians | journal = Focus | volume = 16 | issue = 3 | pages = 243–250 | date = July 2018 | pmid = 31975918 | pmc = 6493090 | doi = 10.1176/appi.focus.20180012 | publisher = American Psychiatric Association Publishing }}</ref> The antidepressant effect of ketamine is diminished at 7 days, and most people relapse within 10 days. However, for a significant minority, the improvement may last 30 days or more.<ref name="pmid33065824" /><ref name="pmid33174760">{{cite journal |vauthors=Swainson J, McGirr A, Blier P, Brietzke E, Richard-Devantoy S, Ravindran N, Blier J, Beaulieu S, Frey BN, Kennedy SH, McIntyre RS, Milev RV, Parikh SV, Schaffer A, Taylor VH, Tourjman V, van Ameringen M, Yatham LN, Ravindran AV, Lam RW |title=The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur |journal=Can J Psychiatry |pages=113–125 |date=November 2020 |volume=66 |issue=2 |pmid=33174760 |doi=10.1177/0706743720970860 |pmc=7918868 }}</ref><ref name="pmid29736744">{{cite journal | vauthors = Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sánchez E, Gutiérrez-Rojas L, Meana JJ | title = Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review | journal = CNS Drugs | volume = 32 | issue = 5 | pages = 411–420 | date = May 2018 | pmid = 29736744 | doi = 10.1007/s40263-018-0519-3 | s2cid = 13679905 }}</ref><ref name="pmid28395988">{{cite journal | vauthors = Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane R | title = Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight | journal = The Lancet. Psychiatry | volume = 4 | issue = 5 | pages = 419–426 | date = May 2017 | pmid = 28395988 | doi = 10.1016/S2215-0366(17)30102-5 | url = http://discovery.ucl.ac.uk/1552865/ | hdl-access = free | hdl = 10871/30208 | s2cid = 28186580 | access-date = 10 September 2018 | archive-date = 9 March 2019 | archive-url = https://web.archive.org/web/20190309081101/http://discovery.ucl.ac.uk/1552865/ | url-status = live }}</ref>

One of the main challenges with ketamine treatment can be the length of time that the antidepressant effects last after finishing a course of treatment. A possible option may be maintenance therapy with ketamine, which usually runs twice a week to once in two weeks.<ref name="pmid33065824"/><ref name="pmid33174760"/><ref name="pmid33162856">{{cite journal |vauthors=Bobo WV, Riva-Posse P, Goes FS, Parikh SV |title=Next-Step Treatment Considerations for Patients With Treatment-Resistant Depression That Responds to Low-Dose Intravenous Ketamine |journal=Focus (Am Psychiatr Publ) |volume=18 |issue=2 |pages=181–192 |date=April 2020 |pmid=33162856 |doi=10.1176/appi.focus.20190048 |pmc=7587874 }}</ref> Ketamine may decrease ]s for up to three days after the injection.<ref name="pmid31729893">{{cite journal |vauthors=Witt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, Cipriani A, Hawton K |title=Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials |journal=Aust N Z J Psychiatry |volume=54 |issue=1 |pages=29–45 |date=January 2020 |pmid=31729893 |doi=10.1177/0004867419883341 |s2cid=208035394 |url=https://ora.ox.ac.uk/objects/uuid:25219d6c-5c8f-4842-91d9-41a9fd7fb1bd |access-date=18 January 2021 |archive-date=2 July 2022 |archive-url=https://web.archive.org/web/20220702024708/https://ora.ox.ac.uk/objects/uuid:25219d6c-5c8f-4842-91d9-41a9fd7fb1bd |url-status=live |hdl=1959.4/unsworks_76229 |hdl-access=free }}</ref>

An ] of ketamine {{ndash}} '']'' commercially sold as ''Spravato'' {{ndash}} was approved as an antidepressant by the ] in 2019.<ref>{{cite web|title=Spravato (esketamine)|publisher=European Medicines Agency|date=8 July 2022|accessdate=20 July 2022|url=https://www.ema.europa.eu/en/medicines/human/EPAR/spravato|archive-date=23 November 2020|archive-url=https://web.archive.org/web/20201123231245/https://www.ema.europa.eu/en/medicines/human/EPAR/spravato|url-status=live}}</ref> Esketamine was approved as a nasal spray for ] in the United States<ref name="fda-spravato">{{cite web |title=FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic |url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified |publisher=US Food and Drug Administration |access-date=29 July 2022 |date=5 March 2019 |archive-date=23 July 2021 |archive-url=https://web.archive.org/web/20210723022112/https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified |url-status=live }}</ref> and elsewhere in 2019 (see ]). The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends esketamine as a third-line treatment for depression.<ref name="pmid33174760"/>

A ] of ]s in adults with unipolar ],<ref name="Sachdeva_2023" /> found that when compared with placebo, people treated with either ketamine or esketamine experienced reduction or remission of symptoms lasting 1 to 7 days.<ref name="dean2">{{cite journal | vauthors = Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A| title = Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder | journal = The Cochrane Database of Systematic Reviews | volume = 9 | pages = CD011612 | date = September 2021 | issue = 11 | pmid = 34510411 | pmc = 8434915 | doi = 10.1002/14651858.CD011612.pub3 }}</ref> There were 18.7% (4.1 to 40.4%) more people reporting some benefit and 9.6% (0.2 to 39.4%) more who achieved remission within 24 hours of ketamine treatment. Among people receiving esketamine, 2.1% (2.5 to 24.4%) encountered some relief at 24 hours, and 10.3% (4.5 to 18.2%) had few or no symptoms. These effects did not persist beyond one week, although a higher dropout rate in some studies means that the benefit duration remains unclear.<ref name=dean2/>

Ketamine may partially improve depressive symptoms<ref name="Sachdeva_2023" /> among people with ] at 24 hours after treatment, but not three or more days.<ref name="dean">{{cite journal | vauthors = Dean RL, Marquardt T, Hurducas C, Spyridi S, Barnes A, Smith R, Cowen PJ, McShane R, Hawton K, Malhi GS, Geddes J, Cipriani A | title = Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | pages = CD011611 | date = October 2021 | issue = 10 | pmid = 34623633 | pmc = 8499740 | doi = 10.1002/14651858.CD011611.pub3 }}</ref> Potentially, ten more people with bipolar depression per 1000 may experience brief improvement, but not the cessation of symptoms, one day following treatment. These estimates are based on limited available research.<ref name=dean/>

In February 2022, the US ] issued an alert to healthcare professionals concerning ] nasal spray products containing ketamine intended to treat depression.<ref name="fda-2/22">{{cite web |title=FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray |url=https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-professionals-potential-risks-associated-compounded-ketamine-nasal-spray |publisher=US Food and Drug Administration |access-date=29 July 2022 |date=16 February 2022 |archive-date=31 August 2022 |archive-url=https://web.archive.org/web/20220831210903/https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-professionals-potential-risks-associated-compounded-ketamine-nasal-spray |url-status=live }}</ref>

===Seizures===
Ketamine is used to treat ]<ref name="pmid33923061">{{cite journal | vauthors = Ghosh S, Sinha JK, Khan T, Devaraju KS, Singh P, Vaibhav K, Gaur P | title = Pharmacological and Therapeutic Approaches in the Treatment of Epilepsy | journal = Biomedicines | volume = 9 | issue = 5 | date = April 2021 | page = 470 | pmid = 33923061 | pmc = 8146518 | doi = 10.3390/biomedicines9050470 | doi-access = free | title-link = doi }}</ref> that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use.<ref>{{cite journal | vauthors = Gomes D, Pimentel J, Bentes C, Aguiar de Sousa D, Antunes AP, Alvarez A, Silva ZC | title = Consensus Protocol for the Treatment of Super-Refractory Status Epilepticus | journal = Acta Médica Portuguesa | volume = 31 | issue = 10 | pages = 598–605 | date = October 2018 | pmid = 30387431 | doi = 10.20344/amp.9679 | url = https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/9679 | doi-access = free | title-link = doi | access-date = 11 February 2020 | archive-date = 29 August 2020 | archive-url = https://web.archive.org/web/20200829074412/https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/9679 | url-status = live }}</ref><ref name="pmid30232735">{{cite journal |vauthors=Rosati A, De Masi S, Guerrini R |title=Ketamine for Refractory Status Epilepticus: A Systematic Review |journal=CNS Drugs |volume=32 |issue=11 |pages=997–1009 |date=November 2018 |pmid=30232735 |doi=10.1007/s40263-018-0569-6 |s2cid=52302073 }}</ref>

===Asthma===
Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment.<ref name="Jat_2012">{{cite journal | vauthors = Jat KR, Chawla D | title = Ketamine for management of acute exacerbations of asthma in children | journal = The Cochrane Database of Systematic Reviews | volume = 11 | issue = 11 | pages = CD009293 | date = November 2012 | pmid = 23152273 | pmc = 6483733 | doi = 10.1002/14651858.CD009293.pub2 | collaboration = Cochrane Airways Group }}</ref> This is due to its ] effects.<ref name="Jat_2012" /> A 2012 Cochrane review found there were minimal adverse effects reported, but the limited studies showed no significant benefit.<ref name="Jat_2012" />

== Contraindications ==
Some major ]s for ketamine are:<ref name="pmid29870458" /><ref name="pmid29870457" />
* Severe ] such as ] or poorly controlled ]
* Increased ] or ] pressure (however these remain controversial, with recent studies suggesting otherwise)<ref name="pmid29870457" />
* Poorly controlled ]
* Severe liver disease such as ]
* ]
* Active ] (for serial ketamine injections)
* Age less than 3 months<ref name="pmid23521979" />

== Adverse effects ==
]

At anesthetic doses, 10–20% of adults and 1–2% of children<ref name="pmid23521979" /> experience adverse psychiatric reactions that occur during emergence from anesthesia, ranging from dreams and ] to hallucinations and ].<ref name="StrayerNelson2008">{{cite journal |vauthors=Strayer RJ, Nelson LS |title=Adverse events associated with ketamine for procedural sedation in adults |journal=The American Journal of Emergency Medicine |volume=26 |issue=9 |pages=985–1028 |date=November 2008 |pmid=19091264 |doi=10.1016/j.ajem.2007.12.005 |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0026626/ |url-status=live |archive-url=https://web.archive.org/web/20170908185727/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0026626/ |archive-date=8 September 2017}}</ref> Psychotomimetic effects decrease adding ]<ref name="pmid10711913" /> and ]<ref name="pmid11750186" /> and can be counteracted by pretreatment with a ] or ].<ref name="StrayerNelson2008" /><ref name="pmid32826629" /> Ketamine anesthesia commonly causes ]-] movements (greater than 10% of people) and rarely ].<ref name="Quibell2011" /><ref name="StrayerNelson2008" /> Vomiting can be expected in 5–15% of the patients; pretreatment with propofol mitigates it as well.<ref name="pmid23521979" /><ref name="StrayerNelson2008" /> ] occurs only rarely with ketamine. Ketamine, generally, stimulates breathing; however, in the first 2–3 minutes of a high-dose rapid intravenous injection, it may cause a transient respiratory depression.<ref name="StrayerNelson2008" />

At lower sub-anesthetic doses, psychiatric side effects are prominent. Most people feel strange, spacey, woozy, or a sense of floating, or have visual distortions or numbness. Also very frequent (20–50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating.{{Citation needed|date=April 2024}} The symptoms of psychosis such as going into a hole, disappearing, feeling as if melting, experiencing colors, and hallucinations are described by 6–10% of people. Dizziness, blurred vision, dry mouth, hypertension, nausea, increased or decreased body temperature, or feeling flushed are the common (>10%) non-psychiatric side effects. All these adverse effects are most pronounced by the end of the injection, dramatically reduced 40 minutes afterward, and completely disappear within 4 hours after the injection.<ref name="pmid31791675">{{cite journal |vauthors=Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA, Park LT |title=Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression |journal=J Affect Disord |volume=263 |pages=568–575 |date=February 2020 |pmid=31791675 |doi=10.1016/j.jad.2019.11.028|pmc=8457026 }}</ref>

=== Urinary and liver toxicity ===
Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20–30% of frequent users having bladder complaints.<ref name="pmid29870458" /><ref name="pmid21102971">{{cite journal |vauthors=Smith HS |title=Ketamine-induced urologic insult (KIUI) |journal=Pain Physician |volume=13 |issue=6 |pages=E343–6 |date=2010 |doi=10.36076/ppj.2010/13/E343 |pmid=21102971| doi-access = free | title-link = doi }}</ref> It includes a range of disorders from ] to ] to ].<ref name="pmid32212278">{{cite journal |vauthors=Castellani D, Pirola GM, Gubbiotti M, Rubilotta E, Gudaru K, Gregori A, Dellabella M |title=What urologists need to know about ketamine-induced uropathy: A systematic review |journal=Neurourol Urodyn |volume=39 |issue=4 |pages=1049–1062 |date=April 2020 |pmid=32212278 |doi=10.1002/nau.24341|s2cid=214643776 }}</ref> The typical symptoms of ketamine-induced cystitis are ], ], and ] sometimes accompanied by pain during urination and ].<ref name="Middela2011">{{cite journal |vauthors=Middela S, Pearce I |title=Ketamine-induced vesicopathy: a literature review |journal=International Journal of Clinical Practice |volume=65 |issue=1 |pages=27–30 |date=January 2011 |pmid=21155941 |doi=10.1111/j.1742-1241.2010.02502.x |s2cid=25034266 |url=https://hal.archives-ouvertes.fr/hal-00600043 | doi-access = free | title-link = doi |access-date=10 September 2018 |archive-date=19 September 2018 |archive-url=https://web.archive.org/web/20180919123758/https://hal.archives-ouvertes.fr/hal-00600043 |url-status=live }}</ref> The damage to the bladder wall has similarities to both ] and ]. The wall is thickened and the functional bladder capacity is as low as 10–150 mL.<ref name="pmid32212278" /> Studies indicate that ketamine-induced cystitis is caused by ketamine and its metabolites directly interacting with ], resulting in damage of the ] of the bladder lining and increased permeability of the urothelial barrier which results in clinical symptoms.<ref>{{cite journal | title = Changes to the bladder epithelial barrier are associated with ketamine-induced cystitis | pmid = 28966667 | pmc = 5615221 | doi = 10.3892/etm.2017.4913 | vauthors = Qixin D, Tianpeng W, Xiaochun Y, Lingqi L, Jiantao Y, Zhongjie L | journal = Experimental and Therapeutic Medicine | date = 20 January 2017 | volume = 14 | issue = 4 | pages = 2757–2762}}</ref>

Management of ketamine-induced cystitis involves ketamine cessation as the first step. This is followed by ]s and ]s and, if the response is insufficient, by ]. The second line treatments are epithelium-protective agents such as oral ] or ] of ]. Intravesical ] is also useful.<ref name="pmid32212278" />

Liver toxicity of ketamine involves higher doses and repeated administration. In a group of chronic high-dose ketamine users, the frequency of liver injury was reported to be about 10%.{{Citation needed|date=April 2024}} There are case reports of increased liver enzymes involving ketamine treatment of chronic pain.<ref name="pmid32212278" /> Chronic ketamine abuse has also been associated with ],<ref>{{cite journal | pmid = 27330331 | pmc = 4898409 | title = Chronic biliary colic associated with ketamine abuse | vauthors = Ahamed AN, Yahya AA | date = 2 June 2016 | pages = 135–137 | journal = International Medical Case Reports Journal | volume = 9 | doi = 10.2147/IMCRJ.S100648 | doi-access = free | title-link = doi }}</ref> ], ], ], and ].<ref>{{cite journal | doi = 10.1080/08998280.2014.11929117 | vauthors = Joseph P, Binu R, Sebastian T, Fahmy H | journal = Baylor University Medical Center Proceedings | volume = 27 | issue = 3 | date = 11 December 2017 | pages = 223–225 | title = Multiorgan Dysfunction Related to Chronic Ketamine Abuse| pmid = 24982568 | pmc = 4059572 }}</ref>

=== Near-death experience ===
Most people who were able to remember their dreams during ketamine anesthesia report ]s (NDEs) when the broadest possible definition of an NDE is used.<ref name="Jansen2001b">{{Cite book |title=Ketamine: Dreams and Realities |vauthors=Jansen K |publisher=Multidisciplinary Association for Psychedelic Studies |year=2001 |isbn=978-0-9660019-3-8 |page=122}}</ref> Ketamine can reproduce features that commonly have been associated with NDEs.<ref name="Peinkhofer">{{cite journal |vauthors=Peinkhofer C, Dreier JP, Kondziella D |date=July 2019 |title=Semiology and Mechanisms of Near-Death Experiences |journal=Current Neurology and Neuroscience Reports |volume=19 |issue=9 |page=62 |doi=10.1007/s11910-019-0983-2 |pmid=31352520 |s2cid=198965307}}</ref> A 2019 large-scale study found that written reports of ketamine experiences had a high degree of similarity to written reports of NDEs in comparison to other written reports of drug experiences.<ref>{{cite journal |vauthors=Martial C, Cassol H, Charland-Verville V, Pallavicini C, Sanz C, Zamberlan F, Vivot RM, Erowid F, Erowid E, Laureys S, Greyson B, Tagliazucchi E |date=March 2019 |title=Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports |journal=Consciousness and Cognition |volume=69 |pages=52–69 |doi=10.1016/j.concog.2019.01.011 |pmid=30711788 |s2cid=73432875 |hdl-access=free |hdl=2268/231971}}</ref>

=== Dependence and tolerance ===
Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketamine dependence. Animal experiments also confirm the risk of misuse.<ref name=morgan11 /> Additionally, the rapid onset of effects following ] may increase potential use as a recreational drug. The short duration of effects promotes ]. Ketamine ] rapidly develops, even with repeated medical use, prompting the use of higher doses. Some daily users reported ] symptoms, primarily anxiety, shaking, sweating, and palpitations, following the attempts to stop.<ref name=morgan11 /> Cognitive deficits as well as increased dissociation and delusion symptoms were observed in frequent recreational users of ketamine.<ref name="Morgan2009">{{cite journal |vauthors=Morgan CJ, Muetzelfeldt L, Curran HV |title=Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study |journal=Addiction |volume=105 |issue=1 |pages=121–33 |date=January 2010 |pmid=19919593 |doi=10.1111/j.1360-0443.2009.02761.x}}</ref>

== Interactions ==
Ketamine ] the sedative effects of ]<ref name="propofol">{{cite journal | vauthors = Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J | title = Additive interactions between propofol and ketamine when used for anesthesia induction in female patients | journal = Anesthesiology | volume = 82 | issue = 3 | pages = 641–8 | date = March 1995 | pmid = 7879932 | doi = 10.1097/00000542-199503000-00005 | s2cid = 24005549 | doi-access = free | title-link = doi }}</ref> and ].<ref name="midazolam">{{cite journal | vauthors = Hong W, Short TG, Hui TW | title = Hypnotic and anesthetic interactions between ketamine and midazolam in female patients | journal = Anesthesiology | volume = 79 | issue = 6 | pages = 1227–32 | date = December 1993 | pmid = 8267198 | doi = 10.1097/00000542-199312000-00013 | s2cid = 12246068 | doi-access = free | title-link = doi }}</ref> ] potentiates psychotomimetic effects of a low dose of ketamine,<ref name="pmid16395307">{{cite journal |vauthors=Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D'Souza DC |title=Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism |journal=Neuropsychopharmacology |volume=31 |issue=8 |pages=1793–800 |date=August 2006 |pmid=16395307 |doi=10.1038/sj.npp.1300994 | doi-access = free | title-link = doi }}</ref> while ]<ref name="pmid10711913">{{cite journal |vauthors=Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH |title=Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists |journal=Arch Gen Psychiatry |volume=57 |issue=3 |pages=270–6 |date=March 2000 |pmid=10711913 |doi=10.1001/archpsyc.57.3.270 | doi-access = free | title-link = doi }}</ref> and ]<ref name="pmid11750186">{{cite journal |vauthors=Krupitsky EM, Burakov AM, Romanova TN, Grinenko NI, Grinenko AY, Fletcher J, Petrakis IL, Krystal JH |title=Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists |journal=Neuropsychopharmacology |volume=25 |issue=6 |pages=936–47 |date=December 2001 |pmid=11750186 |doi=10.1016/S0893-133X(01)00346-3 | doi-access = free | title-link = doi }}</ref> decrease them. ] reduces the increase of salivation, heart rate, and blood pressure during ketamine anesthesia and decreases the incidence of nightmares.<ref name="pmid10773503">{{cite journal |vauthors=Handa F, Tanaka M, Nishikawa T, Toyooka H |title=Effects of oral clonidine premedication on side effects of intravenous ketamine anesthesia: a randomized, double-blind, placebo-controlled study |journal=J Clin Anesth |volume=12 |issue=1 |pages=19–24 |date=February 2000 |pmid=10773503 |doi=10.1016/s0952-8180(99)00131-2 }}</ref>

Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine.<ref name="pmid28858450">{{cite journal | vauthors = Andrade C | title = Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions | journal = The Journal of Clinical Psychiatry | volume = 78 | issue = 7 | pages = e858–e861 | date = July 2017 | pmid = 28858450 | doi = 10.4088/JCP.17f11802 | doi-access = free | title-link = doi }}</ref> It appears most conventional antidepressants can be safely combined with ketamine.<ref name="pmid28858450" />

== Pharmacology ==
=== Pharmacodynamics ===
==== Mechanism of action ====
Ketamine is a mixture of equal amounts of two ]s: ] and ]. Esketamine is a far more ] NMDA receptor pore blocker than arketamine.<ref name="Hashimoto2019" /> Pure blocking of the ] 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 ] in ] neurons; in other words, ketamine's actions interfere with pain transmission in the ].<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 and 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 ]s, including ], ], ], ], and ], 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 ], the ] with negligible affinity for the NMDA receptor but potent ] 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 ], a part of the brain responsible for inhibiting the ] 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 ] receptor and downstream effects on regulators such as ] and ].<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, ], 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 ], acute blockade of NMDA receptors in the brain results in an increase in the release of ], which leads to an activation of ]s (AMPA receptors), which in turn modulate a variety of downstream ]s to influence ] in the ] 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 ] of ] (BDNF) and activation of its signaling receptor ] (TrkB), activation of the ] (mTOR) pathway, deactivation of ] (GSK-3), and inhibition of the ] of the ] (eEF2) ].<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 (]) !! 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>
|-

| ] || 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>
|-
| ] || 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" />
|-
| ] || 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" />
|-

| ] || 50 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-

| ] || 9.5 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />

|-
| ] || 72 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />

|-
| ] || 18 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-
| ] || 3.1 (]) || IC<sub>50</sub> || ]|| 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>
|-
|]
|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 ], an ].<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''-(–) ]s of ketamine bind to the dizocilpine site of the NMDA receptor with different ], 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 ] 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 ]s (K<sub>i</sub>&nbsp;> 60&nbsp;μM), it has been suggested that it may interact with ]s on the monoamine transporters to produce ].<ref name="pmid23527166" /> However, no functional inhibition (]) of the human monoamine transporters has been observed with ketamine or its ]s at concentrations of up to 10,000&nbsp;nM.<ref name="pmid27469513" /><ref name="pmid28418641"/> Moreover, ] and at least three human ]s have found no interaction between ketamine and the ] (MAOI) ], which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as ] or ].<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 ] in the brain, but instead of being due to dopamine reuptake inhibition, this may be via ] 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 ] 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 ] can rapidly and powerfully suppress ] ],<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> ] studies have shown mixed results on inhibition of ] ] 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 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 ====
] and ] 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 ] 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 ], 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. ] ketamine ] is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%,<ref name="MathewZarate2016" /> and ] 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 ] into the brain and other tissues.<ref name="pmid27028535" /> The ] of ketamine is variable at 23–47%.<ref name="pmid6884418" />

]
In the body, ketamine undergoes extensive ]. It is ] by ] and ] ]s into ], which, in turn, is converted by ] and CYP2B6 into ] and ].<ref name="pmid29945898" /> Low oral bioavailability of ketamine is due to the ] 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 ]-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 ]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" />

== Chemistry ==
=== Structure ===
{{multiple image
|align=right
|width=150
|image1=S-ketamine-2D-skeletal.png
|caption1=''(S)''-ketamine
|image2=R-ketamine-2D-skeletal.png
|caption2=''(R)''-ketamine
}}

In chemical structure, ketamine is an ] derivative. Ketamine is a ] compound. The more active enantiomer, ] (''S''-ketamine), is also available for medical use under the brand name Ketanest S,<ref name="Kruger1998">{{cite journal | vauthors = Krüger AD | title = | language = DE | journal = Anaesthesiologie und Reanimation | volume = 23 | issue = 3 | pages = 64–71 | year = 1998 | pmid = 9707751 }}</ref> while the less active enantiomer, ] (''R''-ketamine), has never been marketed as an ] for clinical use. While S-ketamine is more effective as an analgesic and anesthetic through NMDA receptor antagonism, R-ketamine produces longer-lasting effects as an antidepressant.<ref name="Sachdeva_2023" />

The ] of a given enantiomer of ketamine can vary between its ] and ] form. The free base form of (''S'')‑ketamine exhibits ] and is therefore labelled (''S'')‑(+)‑ketamine. However, its ] salt shows ] and is thus labelled (''S'')‑(−)‑ketamine hydrochloride.<ref>{{cite journal| vauthors = Chankvetadze B, Burjanadze N, Breitkreutz J, Bergander K, Bergenthal D, Kataeva O, Fröhlich R, Luftmann H, Blaschke G |year=2002 |title=Mechanistic study on the opposite migration order of the enantiomers of ketamine with α- and β-cyclodextrin in capillary electrophoresis |journal=Journal of Separation Science |volume=25 |issue=15–17 |pages=1155–1166 |doi=10.1002/1615-9314(20021101)25:15/17<1155::AID-JSSC1155>3.0.CO;2-M }}</ref>

=== Detection ===
Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized people, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma ketamine concentrations are usually in a range of 0.5–5.0&nbsp;mg/L in persons receiving the drug therapeutically (during general anesthesia), 1–2&nbsp;mg/L in those arrested for impaired driving, and 3–20&nbsp;mg/L in victims of acute fatal overdosage. Urine is often the preferred specimen for routine drug use monitoring purposes. The presence of norketamine, a pharmacologically active metabolite, is useful for confirmation of ketamine ingestion.<ref>Feng N, Vollenweider FX, Minder EI, Rentsch K, Grampp T, Vonderschmitt DJ. Development of a gas chromatography-mass spectrometry method for determination of ketamine in plasma and its application to human samples. Ther. Drug Monit. 17: 95–100, 1995.</ref><ref>Parkin MC, Turfus SC, Smith NW, Halket JM, Braithwaite RA, Elliott SP, Osselton MD, Cowan DA, Kicman AT. Detection of ketamine and its metabolites in urine by ultra-high-pressure liquid chromatography-tandem mass spectrometry. J. Chrom. B 876: 137–142, 2008.</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 806–808.</ref>

== History ==
Ketamine was first synthesized in 1962 by ],<ref name="Sachdeva_2023" /> a professor of chemistry at ] and a ] consultant. It was known by the developmental code name ''CI-581''.<ref name="Sachdeva_2023" /> After promising preclinical research in animals, ketamine was tested in ] in 1964.<ref name="pmid20693870">{{cite journal |vauthors=Domino EF |title=Taming the ketamine tiger. 1965 |journal=Anesthesiology |volume=113 |issue=3 |pages=678–84 |date=September 2010 |pmid=20693870 |doi=10.1097/ALN.0b013e3181ed09a2 | doi-access = free | title-link = doi }}</ref> These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over ] (PCP) as an anesthetic.<ref>{{cite journal | vauthors = Corssen G, Domino EF | title = Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581 | journal = Anesthesia and Analgesia | volume = 45 | issue = 1 | pages = 29–40 | date = January–February 1966 | pmid = 5325977 | doi = 10.1213/00000539-196601000-00007 | s2cid = 29516392 }}<!-- full text pdf available free at url given --></ref> The researchers wanted to call the state of ketamine anesthesia "dreaming", but Parke-Davis did not approve of the name. Hearing about this problem and the "disconnected" appearance of treated people, Mrs. Edward F. Domino,<ref name="pmid27965560">{{cite journal | vauthors = Li L, Vlisides PE | title = Ketamine: 50 Years of Modulating the Mind | journal = Frontiers in Human Neuroscience | volume = 10 | issue = | pages = 612 | date = 2016 | pmid = 27965560 | pmc = 5126726 | doi = 10.3389/fnhum.2016.00612 | url = | doi-access = free | title-link = doi }}</ref> the wife of one of the pharmacologists working on ketamine, suggested "dissociative anesthesia".<ref name="pmid20693870" /> Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the ].<ref name="CESAR" />

The discovery of antidepressive action of ketamine in 2000<ref name="pmid10686270">{{cite journal |vauthors=Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH |title=Antidepressant effects of ketamine in depressed patients |journal=Biol Psychiatry |volume=47 |issue=4 |pages=351–4 |date=February 2000 |pmid=10686270 |doi=10.1016/s0006-3223(99)00230-9 |s2cid=43438286 }}</ref> has been described as the single most important advance in the treatment of depression in more than 50 years.<ref name="pmid28395988" /><ref name="Hashimoto2019" /> It has sparked interest in NMDA receptor antagonists for depression,<ref>{{cite web | vauthors = Chaffrey J | url = https://www.nbcconnecticut.com/news/local/yale-researchers-study-potential-treatment-for-depression-in-patients-with-parkinsons-disease/2742209/ | title = Yale Researchers Study Potential Treatment for Depression in Patients With Parkinson's Disease | work = NBC Connecticut | date = 16 March 2022 | access-date = 19 March 2022 | archive-date = 19 March 2022 | archive-url = https://web.archive.org/web/20220319160153/https://www.nbcconnecticut.com/news/local/yale-researchers-study-potential-treatment-for-depression-in-patients-with-parkinsons-disease/2742209/ | url-status = live }}</ref> and has shifted the direction of antidepressant research and development.<ref name="pmid27960559">{{cite journal | vauthors = Dhir A | title = Investigational drugs for treating major depressive disorder | journal = Expert Opinion on Investigational Drugs | volume = 26 | issue = 1 | pages = 9–24 | date = January 2017 | pmid = 27960559 | doi = 10.1080/13543784.2017.1267727 | s2cid = 45232796 }}</ref>

== Society and culture ==
{{Main|Ketamine in society and culture}}

=== Legal status ===
While ketamine is marketed legally in many countries worldwide,<ref name="IndexNominum2000">{{cite book |title=Index Nominum 2000: International Drug Directory |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA584 |year=2000 |publisher=Taylor & Francis |isbn=978-3-88763-075-1 |pages=584–585}}</ref> it is also a ] in many countries.<ref name="MathewZarate2016" />

* In Australia, ketamine is listed as a Schedule 8 controlled drug under the ] (October 2015).<ref name="Poisons Standard">Poisons Standard October 2015 {{cite web |url=https://www.comlaw.gov.au/Details/F2015L01534 |title=Poisons Standard | date = October 2015 | publisher = Australian Government |access-date=6 January 2016 |url-status=live |archive-url=https://web.archive.org/web/20160119074606/https://www.comlaw.gov.au/Details/F2015L01534/ |archive-date=19 January 2016 }}</ref>
* In Canada, ketamine has been classified as a Schedule I narcotic, since 2005.<ref name="CanadianLegalStatus">Legal status of ketamine in Canada references:
* {{cite web |url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-24.html#h-28 |title=Statutes of Canada (S.C.) Controlled Drugs and Substances Act (S.C. 1996 c.19) Schedule I §&nbsp;14 |date=12 June 2014 |website=Justice Laws Website |publisher=] |url-status=dead |archive-url=https://web.archive.org/web/20131122143804/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-24.html#h-28 |archive-date=22 November 2013 }}
* {{cite news |url=http://napra.ca/Content_Files/Files/CDSA-Ketamine.pdf |title=Order Amending Schedule I to the Controlled Drugs and Substances Act |date=21 September 2005 |newspaper=] ] |issue=19 |volume=139 |page=2130 |access-date=2 August 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140808053346/http://napra.ca/Content_Files/Files/CDSA-Ketamine.pdf |archive-date=8 August 2014 }}
* {{cite web |url=http://cscb.ca/node/94386 |title=Status of ketamine under CDSA |date=2 May 2005 |publisher=Canadian Society of Customs Brokers |access-date=2 August 2014 |url-status=live |archive-url=https://web.archive.org/web/20140810002143/http://cscb.ca/node/94386 |archive-date=10 August 2014 }}</ref>
* In December 2013, the ], in response to rising recreational use and the use of ketamine as a date rape drug, added it to ] of the ] requiring a special license for sale and maintenance of records of all sales for two years.<ref>{{cite news |title= Ketamine drug brought under 'Schedule X' to curb abuse |url= http://timesofindia.indiatimes.com/city/goa/Ketamine-drug-brought-under-Schedule-X-to-curb-abuse/articleshow/28486002.cms |newspaper= ] |date= 7 January 2014 |access-date= 2 August 2014 |url-status=live |archive-url= https://web.archive.org/web/20140414064604/http://timesofindia.indiatimes.com/city/goa/Ketamine-drug-brought-under-Schedule-X-to-curb-abuse/articleshow/28486002.cms |archive-date= 14 April 2014 |df= dmy-all }}</ref><ref>{{cite news| vauthors = Sumitra DR |newspaper=] |date=30 December 2013 |url=http://timesofindia.indiatimes.com/india/Govt-makes-notorious-date-rape-drug-ketamine-harder-to-buy-or-sell/articleshow/28116453.cms |title=Govt makes notorious 'date rape' drug ketamine harder to buy or sell |archive-url=https://web.archive.org/web/20131230025440/http://timesofindia.indiatimes.com/india/Govt-makes-notorious-date-rape-drug-ketamine-harder-to-buy-or-sell/articleshow/28116453.cms |archive-date=30 December 2013 |url-status=live }}</ref>
* In the United Kingdom, it became labeled a ] on 12 February 2014.<ref name="reclassify response">{{citation |url=https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/279186/ResponseACMDketamineReclassification.pdf |title=Response to ACMD recommendation on ketamine |access-date=21 February 2014 |date=12 February 2014 | vauthors = Baker N |author-link1=Norman Baker |type=Correspondence to Les Iverson ; ] |publisher=]; ] |postscript=. |url-status=live |archive-url=https://web.archive.org/web/20140228195318/https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/279186/ResponseACMDketamineReclassification.pdf |archive-date=28 February 2014 }}</ref><ref>{{cite news | vauthors = Dixon H |date=12 February 2014 |title=Party drug ketamine to be upgraded to Class B |url=https://www.telegraph.co.uk/news/uknews/law-and-order/10633800/Party-drug-ketamine-to-be-upgraded-to-Class-B.html |newspaper=] |access-date=2 August 2014 |url-status=live |archive-url=https://web.archive.org/web/20140609232635/http://www.telegraph.co.uk/news/uknews/law-and-order/10633800/Party-drug-ketamine-to-be-upgraded-to-Class-B.html |archive-date=9 June 2014 }}</ref>
* The increase in recreational use prompted ketamine to be placed in Schedule III of the United States ] in August 1999.<ref name="FedReg1999">{{cite journal | vauthors = Marshall DR |author-link1=Donnie R. Marshall |date=13 July 1999 |title=Schedules of Controlled Substances: Placement of Ketamine into Schedule III |journal=] |volume=64 |issue=133 |pages=37673–5 |url=http://www.gpo.gov/fdsys/pkg/FR-1999-07-13/pdf/99-17803.pdf |department=Rules and Regulations |author-link3=Drug Enforcement Administration |author-link4=United States Department of Justice |url-status=live |archive-url=https://web.archive.org/web/20150505060507/http://www.gpo.gov/fdsys/pkg/FR-1999-07-13/pdf/99-17803.pdf |archive-date=5 May 2015 }}</ref>

=== Recreational use ===
{{Main|Ketamine in society and culture#Recreational use}}

At sub-anesthetic doses, ketamine produces a ], characterised by a sense of detachment from one's physical body and the external world that is known as ] and ].<ref name="Giannini2000">{{cite journal | vauthors = Giannini AJ, Underwood NA, Condon M | title = Acute ketamine intoxication treated by haloperidol: a preliminary study | journal = American Journal of Therapeutics | volume = 7 | issue = 6 | pages = 389–91 | date = November 2000 | pmid = 11304647 | doi = 10.1097/00045391-200007060-00008 }}</ref> At sufficiently high doses, users may experience what is called the "]", a state of dissociation with visual and auditory hallucination.<ref>{{Cite book | vauthors = Giannini AJ |title=Drug Abuse |publisher=Health Information Press |location=Los Angeles |year=1999 |page= |isbn=978-1-885987-11-2 |url=https://archive.org/details/drugabuse00ajam |url-access=registration }}</ref> ], ], ], and ] (among others) have written extensively about their own ]ic and ] experiences with ketamine.<ref name="RecreationalLiterature">References for recreational use in literature:
* {{Cite book | vauthors = Lilly JC |author-link=John C. Lilly |title=The Scientist: A Metaphysical Autobiography |publisher=] |location=Berkeley, CA |year=1997 |pages= |isbn=978-0-914171-72-0 |url=https://archive.org/details/scientist00lill/page/144 }}
* {{cite book | vauthors = Kelly K |title=The Little Book of Ketamine |year=2001 |publisher=] |isbn=978-1-57951-121-0 |pages=, , , ibid }}
* {{Cite book | vauthors = Alltounian HS, Moore M |author-link2=Marcia Moore |title=Journeys Into the Bright World |publisher=Para Research |location=Rockport, MA |year=1978 |isbn=978-0-914918-12-7 |ref={{sfnref|Alltounian & Moore|1978}}}}
* {{cite book | vauthors = Palmer C, Horowitz M |author-link2=Fitz Hugh Ludlow Memorial Library|title=Sisters of the Extreme: Women Writing on the Drug Experience |year=2000|publisher=] |isbn=978-0-89281-757-3|pages=, ibid |ref={{sfnref|Palmer & Horowitz|2000}}}}
* {{Cite book | vauthors = Turner DM |author-link=D. M. Turner |title=The Essential Psychedelic Guide |publisher=Panther Press |location=San Francisco |year=1994 |isbn=978-0-9642636-1-1}}</ref> Turner died prematurely due to drowning during presumed unsupervised ketamine use.<ref name="Jansen2001">{{Cite book |title=Ketamine: Dreams and Realities | vauthors = Jansen K |publisher=Multidisciplinary Association for Psychedelic Studies |isbn=978-0-9660019-3-8 |year=2001 |pages=50, 89}}</ref> In 2006, the Russian edition of ]'s ''Apocalypse Culture'' was banned and destroyed by authorities owing to its inclusion of an essay by Woodard about the entheogenic use of, and psychonautic experiences with, ketamine.<ref>{{cite book | vauthors = Woodard D | chapter-url = https://tranxcend.tumblr.com/post/29813278762/ketamine | chapter = The Ketamine Necromance | veditors = Parfrey A | title = Apocalypse Culture II | location = ] | publisher = ] | date = 2000 | pages = 288–295 | access-date = 18 May 2020 | archive-date = 24 June 2021 | archive-url = https://web.archive.org/web/20210624204236/https://tranxcend.tumblr.com/post/29813278762/ketamine | url-status = live }}</ref>{{rp|288–295}}

Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005–2013.<ref name=DalyVice14 /> They include accidental poisonings, drownings, traffic accidents, and ].<ref name=DalyVice14>See Max Daly, 2014, "The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties," at ''Vice'' (online), 23 July 2014, see {{cite web |url=https://www.vice.com/en_uk/read/ketamine-slowly-ruins-your-bladder-and-kills-you-863 |title=The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties |access-date=7 June 2015 |url-status=live |archive-url=https://web.archive.org/web/20150607022331/http://www.vice.com/en_uk/read/ketamine-slowly-ruins-your-bladder-and-kills-you-863 |archive-date=7 June 2015 |date=23 July 2014 }}, accessed 7 June 2015.</ref> The majority of deaths were among young people.<ref name=TheCrownONS13>{{cite web | date = 2013 | title = Drug related deaths involving ketamine in England and Wales | work = A report of the Mortality team, Life Events and Population Sources Division, Office for National Statistics | publisher = Government of the United Kingdom | url = http://www.ons.gov.uk/ons/about-ons/business-transparency/freedom-of-information/what-can-i-request/published-ad-hoc-data/health/october-2013/drug-related-deaths-involving-ketamine-by-age-group.xls |access-date=7 June 2015 |url-status=live |archive-url=https://web.archive.org/web/20150607212436/http://www.ons.gov.uk/ons/about-ons/business-transparency/freedom-of-information/what-can-i-request/published-ad-hoc-data/health/october-2013/drug-related-deaths-involving-ketamine-by-age-group.xls |archive-date=7 June 2015 }} and {{cite web |url=https://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drug-poisoning/2012/stb---deaths-related-to-drug-poisoning-2012.html |title=Deaths Related to Drug Poisoning in England and Wales – Office for National Statistics |access-date=7 June 2015 |url-status=live |archive-url=https://web.archive.org/web/20150619235310/http://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drug-poisoning/2012/stb---deaths-related-to-drug-poisoning-2012.html |archive-date=19 June 2015 }}, accessed 7 June 2015.</ref> Several months after being found dead in his hot tub, actor ]'s October 2023 apparent drowning death was revealed to have been caused by a ketamine overdose, and while other factors were present, the acute effects of ketamine were ruled to be the primary cause of death.<ref>{{cite web |url=https://www.npr.org/2023/12/15/1219759019/matthew-perry-cause-of-death |title=Matthew Perry died from the 'acute effects of ketamine,' autopsy finds |website=NPR |vauthors=Bowman E |access-date=28 December 2023 |date=15 December 2023 |archive-date=28 December 2023 |archive-url=https://web.archive.org/web/20231228225746/https://www.npr.org/2023/12/15/1219759019/matthew-perry-cause-of-death |url-status=live }}</ref> Due to its ability to cause confusion and ], ketamine has been used for ].<ref name="CAMHDYK">{{cite web |url=https://knowledgex.camh.net/amhspecialists/resources_families/Pages/ketamine_dyk.aspx |title=Do you know... Ketamine |website=Knowledge Exchange |location= Toronto |publisher=] |access-date=27 July 2014 |year=2003 |archive-url=https://web.archive.org/web/20140407061143/https://knowledgex.camh.net/amhspecialists/resources_families/Pages/ketamine_dyk.aspx |archive-date= 7 April 2014 |url-status=dead |df= dmy-all}}</ref><ref name="CESAR">{{cite web |url=http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |title=Ketamine |access-date=27 July 2014 |date=29 October 2013 |publisher=Center for Substance Abuse Research (CESAR); ] |archive-url=https://web.archive.org/web/20131112080924/http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |archive-date=12 November 2013 |url-status=live}}</ref>

== Research ==
Ketamine is under investigation for its potential in treating treatment-resistant depression.<ref>{{Cite web |vauthors=Grinspoon P |date=9 August 2022 |title=Ketamine for treatment-resistant depression: When and where is it safe? |url=https://www.health.harvard.edu/blog/ketamine-for-treatment-resistant-depression-when-and-where-is-it-safe-202208092797 |access-date=6 September 2022 |website=Harvard Health |language=en |archive-date=31 August 2022 |archive-url=https://web.archive.org/web/20220831012716/https://www.health.harvard.edu/blog/ketamine-for-treatment-resistant-depression-when-and-where-is-it-safe-202208092797 |url-status=live }}</ref><ref>{{Cite web |title=New Hope for Treatment-Resistant Depression: Guessing Right on Ketamine |url=https://www.nimh.nih.gov/about/director/messages/2019/new-hope-for-treatment-resistant-depression-guessing-right-on-ketamine |access-date=6 September 2022 |website=National Institute of Mental Health (NIMH) |date=13 August 2019 |language=en |archive-date=10 September 2022 |archive-url=https://web.archive.org/web/20220910063011/https://www.nimh.nih.gov/about/director/messages/2019/new-hope-for-treatment-resistant-depression-guessing-right-on-ketamine |url-status=live }}</ref><ref>{{cite journal | vauthors = Pérez-Esparza R | title = Ketamine for Treatment-Resistant Depression: a New Advocate | journal = Revista de Investigacion Clinica | volume = 70 | issue = 2 | pages = 65–67 | date = 2018 | pmid = 29718013 | doi = 10.24875/RIC.18002501 | doi-access = free | title-link = doi }}</ref> Ketamine is a known ], which refers to a compound capable of promoting rapid and sustained ].<ref>{{cite journal |vauthors=Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS |date=August 2010 |title=mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists |url=https://www.neuroplasticitymd.com/ |journal=Science |volume=329 |issue=5994 |pages=959–964 |bibcode=2010Sci...329..959L |doi=10.1126/science.1190287 |pmc=3116441 |pmid=20724638}}</ref>

Ketamine has shown ] activity in rats, with an effect comparable to ] and ] at extremely high concentrations.<ref>{{cite journal | vauthors = Ferreira SR, Machado AR, Furtado LF, Gomes JH, de Almeida RM, de Oliveira Mendes T, Maciel VN, Barbosa FS, Carvalho LM, Bueno LL, Bartholomeu DC, de Araújo JV, Rabelo EM, de Pádua RM, Pimenta LP, Fujiwara RT | title = Ketamine can be produced by Pochonia chlamydosporia: an old molecule and a new anthelmintic? | journal = Parasites & Vectors | volume = 13 | issue = 1 | pages = 527 | date = October 2020 | pmid = 33081837 | pmc = 7574484 | doi = 10.1186/s13071-020-04402-w | doi-access = free | title-link = doi }}</ref>

== Veterinary uses ==
In ], ketamine is often used for its anesthetic and analgesic effects on cats,<ref>{{cite journal | vauthors = Robertson SA, Taylor PM | title = Pain management in cats—past, present and future. Part 2. Treatment of pain—clinical pharmacology | journal = Journal of Feline Medicine and Surgery | volume = 6 | issue = 5 | pages = 321–33 | date = October 2004 | pmid = 15363764 | doi = 10.1016/j.jfms.2003.10.002 | s2cid = 25572412 | pmc = 10822209 }}</ref> dogs,<ref>{{cite journal | vauthors = Lamont LA | title = Adjunctive analgesic therapy in veterinary medicine | journal = The Veterinary Clinics of North America. Small Animal Practice | volume = 38 | issue = 6 | pages = 1187–203, v | date = November 2008 | pmid = 18954680 | doi = 10.1016/j.cvsm.2008.06.002 }}</ref> ]s, ]s, and other small animals.<ref>{{cite journal | vauthors = Stunkard JA, Miller JC | title = An outline guide to general anesthesia in exotic species | journal = Veterinary Medicine, Small Animal Clinician | volume = 69 | issue = 9 | pages = 1181–6 | date = September 1974 | pmid = 4604091 }}</ref><ref>{{cite book |publisher=John Wiley & Sons |isbn=978-1-118-68590-7 |vauthors=Riviere JE, Papich MG |title=Veterinary Pharmacology and Therapeutics |date=2009 |page=200 |url=https://books.google.com/books?id=xAPa4WDzAnQC&pg=PP1 |access-date=26 December 2021 |archive-date=8 February 2023 |archive-url=https://web.archive.org/web/20230208191902/https://books.google.com/books?id=xAPa4WDzAnQC&pg=PP1 |url-status=live }}</ref> It is frequently used in induction and anesthetic maintenance in horses. It is an important part of the "]", a mixture of drugs used for anesthetising ].<ref>{{citation |year=2012 |title=Standard Operating Procedure No. 1 Anesthesia and Analgesia in Rodents |publisher=Washington College |pages=1–2 |url=https://www.washcoll.edu/live/files/1227-no-1-anesthesia-sop-revised-1012pdf |access-date=27 November 2015 |url-status=dead |archive-url=https://web.archive.org/web/20130804040842/http://www.washcoll.edu/live/files/1227-no-1-anesthesia-sop-revised-1012pdf |archive-date=4 August 2013 }}</ref> Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent ]. Ketamine is also used to manage pain among large animals. It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with ] and ], or sometimes ].<ref name="pmid7212404">{{cite journal | vauthors = Hubbell JA, Muir WW, Sams RA | title = Guaifenesin: cardiopulmonary effects and plasma concentrations in horses | journal = American Journal of Veterinary Research | volume = 41 | issue = 11 | pages = 1751–5 | date = November 1980 | pmid = 7212404 | doi = | url = }}</ref>

Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.<ref>{{cite journal | vauthors = Woodall AJ, McCrohan CR | title = Excitatory actions of propofol and ketamine in the snail ''Lymnaea stagnalis'' | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology | volume = 127 | issue = 3 | pages = 297–305 | date = December 2000 | pmid = 11246501 | doi = 10.1016/S0742-8413(00)00155-9 }}</ref>

== References ==
{{reflist}}

==External links==
{{Commons category|Ketamine}}
* — from the United States DEA, via Archive.org

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