「Ketamine」の版間の差分

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細 (ケタミンへの転送ページ)
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{{For|the functional group referred to as ketimine|imine}}
#転送 [[ケタミン]]
{{short description|Dissociative medication}}
{{Use dmy dates|date=February 2020}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 477168837
| IUPAC_name = (''RS'')-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
| image = Ketamine2DCSD.svg
| width = 150px
| image2 = S-ketamine-from-HCl-xtal-3D-balls.png
| width2 = 175px
| alt2 = (''S'')-Ketamine ball-and-stick model
 
<!--Clinical data-->
| tradename = Ketalar, others
| Drugs.com = {{drugs.com|monograph|ketamine-hydrochloride}}
| DailyMedID = Ketamine
| licence_US = Ketamine
| pregnancy_AU = B3
| 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}}</ref>
| pregnancy_US = N
| pregnancy_US_comment = <ref name="Drugs.com pregnancy" />
| legal_status = Rx-only
| legal_AU = S8
| legal_CA = Schedule I
| legal_UK = Class B
| legal_US = Schedule III
| legal_UN = Unscheduled
| routes_of_administration = Any<ref>{{cite journal |last1=Bell |first1=RF |last2=Eccleston |first2=C |last3=Kalso |first3=EA |title=Ketamine as an adjuvant to opioids for cancer pain |journal=[[Cochrane Database of Systematic Reviews]] |date=28 June 2017 |volume=6 |pages=CD003351 |doi=10.1002/14651858.CD003351.pub3 |pmid=28657160 |pmc=6481583 |url=http://opus.bath.ac.uk/57535/1/Published_Version.pdf}}</ref><ref>{{cite journal |last1=Moyse |first1=DW |last2=Kaye |first2=AD |last3=Diaz |first3=JH |last4=Qadri |first4=MY |last5=Lindsay |first5=D |last6=Pyati |first6=S |title=Perioperative Ketamine Administration for Thoracotomy Pain |journal=Pain Physician |date=March 2017 |volume=20 |issue=3 |pages=173–184 |pmid=28339431}}</ref><ref name="MathewZarate2016" /><ref name="MD" />
| addiction_liability = Low–moderate<ref name="NHM-PCP and ketamine">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 | pages=374–375 |edition=2nd |chapter=Chapter 15: Reinforcement and Addictive Disorders |quote=Phencyclidine (PCP or angel dust) and ketamine (also known as special K) are structurally related drugs... their reinforcing properties and risks related to compulsive abuse}}</ref><!--Start widen drugbox--><br />&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;<!--End widen drugbox-->
| class = [[NMDA receptor antagonists]]; [[General anesthetics]]; [[Dissociative hallucinogen]]s; [[Analgesic]]s; [[Antidepressant]]s
 
<!--Pharmacokinetic data-->
| bioavailability =
* [[Intravenous therapy|Intravenous]]: 100%<ref name="MathewZarate2016" />
* [[Intramuscular injection|Intramuscular]]: 93%<ref name="MathewZarate2016" />
* [[Subcutaneous injection|Subcutaneous]]: high<ref name="Mao2016">{{cite book |author=Jianren Mao |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 |archiveurl=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127 |archivedate=8 September 2017 }}</ref>
* [[Epidural administration|Epidural]]: 77%<ref name="Kintz2014">{{cite book |author=Pascal Kintz |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 |archiveurl=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=YgnUAgAAQBAJ&pg=PA87 |archivedate=8 September 2017 }}</ref>
* [[Intranasal administration|Intranasal]]: 8–50%<ref name="MathewZarate2016" /><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 |url= }}</ref><ref name="sinner" />
* [[Sublingual administration|Sublingual]]: 24–30%<ref name="MathewZarate2016" /><ref name="Hashimoto2019">{{cite journal|last1=Hashimoto|first1=Kenji|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|year=2019|pages=613–627|issn=1323-1316|doi=10.1111/pcn.12902|pmid=31215725|pmc=6851782}}</ref>
* [[Rectal administration|Rectal]]: 11–30%<ref name="Nemeroff2017">{{cite book |author1=Alan F. Schatzberg |author2=Charles B. Nemeroff |title=The American Psychiatric Association Publishing Textbook of Psychopharmacology, Fifth Edition |url=https://books.google.com/books?id=KfHEDgAAQBAJ&pg=PA550 |year=2017 |publisher=American Psychiatric Pub |isbn=978-1-58562-523-9 |pages=550– |url-status=live |archiveurl=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=KfHEDgAAQBAJ&pg=PA550 |archivedate=8 September 2017 }}</ref><ref name=Zhang2018 />
* [[Oral administration|By mouth]]: 16–29%<ref name="Kintz2014" /><ref name="DickmanSchneider2016">{{cite book |author1=Andrew Dickman |author2=Jennifer Schneider |title=The Syringe Driver: Continuous Subcutaneous Infusions in Palliative Care |url=https://books.google.com/books?id=jbUSDQAAQBAJ&pg=PA114 |date=22 September 2016 |publisher=[[Oxford University Press]] |isbn=978-0-19-873372-0 |pages=114– |url-status=live |archiveurl=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=jbUSDQAAQBAJ&pg=PA114 |archivedate=8 September 2017 }}</ref><ref name=Zhang2018 />
| protein_bound = 12–47% (low)<ref name="Kintz2014" /><ref name="sinner" /><ref name="DowdJohnson2016" />
| metabolism = [[Liver]] ([[demethylation|''N''-demethylation]]):<ref name="MathewZarate2016" /><ref>{{cite journal |last1=Hijazi |first1=Y |last2=Boulieu |first2=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|url=https://semanticscholar.org/paper/935c35b819e091b777788d99379fbb33bcc9e24f }}</ref>
* Major: [[CYP3A4]]
* Minor: [[CYP2B6]], [[CYP2C9]]
| metabolites =
* [[Norketamine]]
* [[Dehydronorketamine]]
* [[Hydroxynorketamine]]
* [[Conjugation (biochemistry)|Conjugates]]<ref name="Levine2003">{{cite book |author=Barry Levine |title=Principles of Forensic Toxicology |url=https://books.google.com/books?id=k7BInEQ-iqgC&pg=PA282 |year=2003 |publisher=[[American Association for Clinical Chemistry]] |isbn=978-1-890883-87-4 |pages=282– |url-status=live |archiveurl=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=k7BInEQ-iqgC&pg=PA282 |archivedate=8 September 2017 }}</ref>
| onset =
* Intravenous: seconds<ref name="sinner" />
* 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 =
* [[Urine]]: 91%<ref name="MathewZarate2016" />
* [[Feces]]: 1–3%<ref name="MathewZarate2016" />
 
<!--Identifiers-->
| IUPHAR_ligand = 4233
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 6740-88-1
| CAS_supplemental = {{plainlist|
* 1867-66-9 ([[hydrochloride]])
* 33643-46-8 ([[esketamine]])
* 33643-49-1 ([[arketamine]])}}
| ATC_prefix = N01
| ATC_suffix = AX03
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 6121
| PubChem = 3821
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01221
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3689
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 690G0D6V8H
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08098
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 742
| synonyms = CI-581; CL-369; CM-52372-2<ref name="MortonHall2012" />
 
<!--Chemical data-->
| C=13 | H=16 | Cl=1 | N=1 | O=1
| molecular_weight = 237.725
| chirality = [[Racemic mixture]]:<ref name="sinner" />
* [[Esketamine]] (''S''(+)-isomer)
* [[Arketamine]] (''R''(−)-isomer)
| SMILES = Clc1ccccc1C2(NC)CCCCC2=O
| 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YQEZLKZALYSWHR-UHFFFAOYSA-N
 
<!--Physical data-->
| melting_point = 258
| melting_high = 261
 
<!--Empty-->
| alt=|caption=|type=|MedlinePlus=|licence_EU=|pregnancy_category=
}}
 
<!-- Definition and medical uses -->
'''Ketamine''' is a [[medication]] mainly used for starting and maintaining [[anesthesia]].<ref name=KetPres2013 /> It induces a [[trance]]-like state while providing [[analgesia|pain relief]], [[sedation]], and [[amnesia|memory loss]].<ref name="GreenRoback2011" /> Other uses include sedation in [[intensive care]] and treatment of [[pain]] and [[depression (mood)|depression]].<ref>{{cite journal |last1=Zgaia |first1=AO |last2=Irimie |first2=A |last3=Sandesc |first3=D |last4=Vlad |first4=C |last5=Lisencu |first5=C |last6=Rogobete |first6=A |last7=Achimas-Cadariu |first7=P |title=The role of ketamine in the treatment of chronic cancer pain |journal=Clujul Medical |date=2015 |volume=88 |issue=4 |pages=457–61 |pmid=26733743 |doi=10.15386/cjmed-500 |pmc=4689236}}</ref><ref>{{cite journal |last1=Zapantis |first1=A |last2=Leung |first2=S |title=Tolerance and withdrawal issues with sedation |journal=Critical Care Nursing Clinics of North America |date=September 2005 |volume=17 |issue=3 |pages=211–23 |pmid=16115529 |doi=10.1016/j.ccell.2005.04.011}}</ref><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=December 2018 |pmid=30513009 |doi=10.1080/14737175.2019.1554434 |url= }}</ref><ref>{{cite journal |last1=Kraus |first1=Christoph |last2=Rabl |first2=Ulrich |last3=Vanicek |first3=Thomas |last4=Carlberg |first4=Laura |last5=Popovic |first5=Ana |last6=Spies |first6=Marie |last7=Bartova |first7=Lucie |last8=Gryglewski |first8=Gregor |last9=Papageorgiou |first9=Konstantinos |last10=Lanzenberger |first10=Rupert |last11=Willeit |first11=Matthäus |last12=Winkler |first12=Dietmar |last13=Rybakowski |first13=Janusz K. |last14=Kasper |first14=Siegfried |title=Administration of ketamine for unipolar and bipolar depression |journal=International Journal of Psychiatry in Clinical Practice |date=18 January 2017 |volume=21 |issue=1 |pages=2–12 |doi=10.1080/13651501.2016.1254802 |pmid=28097909}}</ref><ref name=RD9/> Heart function, breathing, and airway reflexes generally remain functional.<ref name="GreenRoback2011">{{cite journal |last1=Green |first1=Steven M. |last2=Roback |first2=Mark G. |last3=Kennedy |first3=Robert M. |last4=Krauss |first4=Baruch |title=Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update |journal=Annals of Emergency Medicine |date=May 2011 |volume=57 |issue=5 |pages=449–461 |doi=10.1016/j.annemergmed.2010.11.030 |pmid=21256625}}</ref> Effects typically begin within five minutes when given by injection, and last up to approximately 25 minutes.<ref name=KetPres2013 /><ref name=Mary2014 />
 
<!-- Adverse effects and mechanism -->
Common side effects include [[psychomotor agitation|agitation]], confusion, or [[hallucinations]] as the medication wears off.<ref name=KetPres2013>{{cite web |title=Ketamine Injection |url=https://www.drugs.com/pro/ketamine-injection.html |website=[[Drugs.com]] |accessdate=1 December 2014 |url-status=live |archiveurl=https://web.archive.org/web/20141210181630/http://www.drugs.com/pro/ketamine-injection.html |archivedate=10 December 2014 }}</ref><ref name="StrayerNelson2008">{{cite journal |last1=Strayer |first1=RJ |last2=Nelson |first2=LS |year=2008 |title=Adverse events associated with ketamine for procedural sedation in adults |journal=[[American Journal of Emergency Medicine]] |volume=26 |issue=9 |pages=985–1028 |doi=10.1016/j.ajem.2007.12.005 |pmid=19091264 |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0026626/ |url-status=live |archiveurl=https://web.archive.org/web/20170908185727/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0026626/ |archivedate=8 September 2017 }}</ref><ref name=KetSide2014 /> Elevated [[blood pressure]] and muscle tremors are relatively common.<ref name=KetPres2013 /><ref name=KetSide2014>{{cite web |title=Ketamine Side Effects |url=https://www.drugs.com/sfx/ketamine-side-effects.html |website=drugs.com |accessdate=1 December 2014 |url-status=live |archiveurl=https://web.archive.org/web/20141210173330/http://www.drugs.com/sfx/ketamine-side-effects.html |archivedate=10 December 2014 }}</ref> [[Laryngospasms|Spasms of the larynx]] may rarely occur.<ref name=KetPres2013 /> Ketamine is an [[NMDA receptor antagonist]], but it may also have other actions.<ref name=ACS2017>{{cite journal |last1=Tyler |first1=Marshall W. |last2=Yourish |first2=Harmony B. |last3=Ionescu |first3=Dawn F. |last4=Haggarty |first4=Stephen J. |title=Classics in Chemical Neuroscience: Ketamine |journal=[[ACS Chemical Neuroscience]] |date=21 April 2017 |volume=8 |issue=6 |pages=1122–1134 |doi=10.1021/acschemneuro.7b00074 |pmid=28418641}}</ref>
 
<!-- Society and culture / Legal status -->
Ketamine was discovered in 1962, first tested in humans in 1964, and approved for use in the United States in 1970.<ref name=Mary2014>{{cite web |title=Ketamine – CESAR |url=http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |website=Center for Substance Abuse Research |publisher=[[University of Maryland]] |accessdate=26 September 2014 |url-status=live |archiveurl=https://web.archive.org/web/20131112080924/http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |archivedate=12 November 2013 }}</ref><ref name=Domino2010 /> It was extensively used for surgical anesthesia in the [[Vietnam War]] due to its safety.<ref name="Domino2010" /> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=KetPres2013 /> The wholesale price in the [[developing world]] is between US$0.84 and US$3.22 per vial.<ref>{{cite web |title=Ketamine |url=http://mshpriceguide.org/en/single-drug-information/?DMFId=454&searchYear=2014 |accessdate=12 January 2016 |url-status=live |archiveurl=https://web.archive.org/web/20170823163821/http://mshpriceguide.org/en/single-drug-information/?DMFId=454&searchYear=2014 |archivedate=23 August 2017 }}</ref> Ketamine is also used as a [[recreational drug]] for its [[hallucinogenic]] and [[dissociative]] effects.<ref>{{cite journal |last1=Morgan |first1=CJA |last2=Curran |first2=HV |title=Ketamine use: a review |journal=[[Addiction (journal)|Addiction]] |date=January 2012 |volume=107 |issue=1 |pages=27–38 |doi=10.1111/j.1360-0443.2011.03576.x |pmid=21777321|url=https://semanticscholar.org/paper/bbfba0ebcd72ce21fd1ee3e3813bca775eebaf62 }}</ref>
{{TOC limit}}
 
== Medical uses ==
 
=== Anesthesia ===
Uses as an anesthetic:<ref>{{cite journal|title=Ketamine: Current applications in anesthesia, pain, and critical care|author1=Madhuri S. Kurdi |author2=Kaushic A. Theerth |author3=Radhika S. Deva|journal=Anesthesia: Essays and Researches|date=September 2014|pmc=4258981|pmid=25886322|doi=10.4103/0259-1162.143110|volume=8|issue=3 |pages=283–90}}</ref>
{{flowlist|
* Anesthesia in children, as the sole anesthetic for minor procedures or as an induction agent followed by [[neuromuscular blocker]] and [[tracheal intubation]]
* [[Asthma]]tics or people with [[chronic obstructive airway disease]]
* As a [[sedative]] for physically painful procedures in [[emergency department]]s<ref name="GreenRoback2011" />
* Emergency surgery in field conditions in war zones
* To supplement [[Spinal anesthesia|spinal]] or [[epidural]] anesthesia/[[analgesia]] using low doses}}
* To prevent [[opioid-induced hyperalgesia]] <ref name="pmid26495312">{{cite journal| author1=Radvansky BM |author2=Shah K |author3=Parikh A |author4=Sifonios AN |author5=Le V |author6=Eloy JD| title=Role of ketamine in acute postoperative pain management: a narrative review. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 749837 | pmid=26495312 | doi=10.1155/2015/749837 | pmc=4606413 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26495312  }}</ref><ref name="pmid21412369">{{cite journal| author1=Lee M |author2=Silverman SM |author3=Hansen H |author4=Patel VB |author5=Manchikanti L| title=A comprehensive review of opioid-induced hyperalgesia. | journal=Pain Physician | year= 2011 | volume= 14 | issue= 2 | pages= 145–61 | pmid=21412369 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21412369  }}</ref>
 
Since it suppresses breathing much less than most other available anesthetics,<ref name="heshmati">{{cite journal |last1=Heshmati |first1=F |last2=Zeinali |first2=MB |last3=Noroozinia |first3=H |last4=Abbacivash |first4=R |last5=Mahoori |first5=A |displayauthors=4 |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 |doi= |url-status=live |archiveurl=https://web.archive.org/web/20141006100116/http://ijaai.tums.ac.ir/index.php/ijaai/article/view/52/52 |archivedate=6 October 2014 }}</ref> ketamine is used in medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anesthetic of choice when reliable [[Mechanical ventilation|ventilation]] equipment is not available.
 
Ketamine is frequently used in severely injured people and appears to be safe in this group.<ref>{{cite journal |last1=Cohen |first1=L |last2=Athaide |first2=V |last3=Wickham |first3=ME |last4=Doyle-Waters |first4=MM |last5=Rose |first5=NG |last6=Hohl |first6=CM |title=The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review |journal=Annals of Emergency Medicine |date=16 July 2014 |pmid=25064742 |doi=10.1016/j.annemergmed.2014.06.018 |volume=65 |issue=1 |pages=43–51.e2}}</ref> A 2011 [[Medical guideline|clinical practice guideline]] supports the use of ketamine as a [[dissociative]] sedative in [[emergency medicine]].<ref name="GreenRoback2011" /> <!-- Ketamine was called a "dissociative" anesthetic because of its effect on electroecephalography (EEG): it caused EEG dissociation between limbic and thalamoneocortical areas.
-->It is the drug of choice for people in traumatic shock who are at risk of [[hypotension]].<ref>{{cite web |first=Chris |last=Nickson |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 |accessdate=10 April 2014 |type=blog |url-status=dead |archiveurl=https://web.archive.org/web/20140209161412/http://lifeinthefastlane.com/education/ccc/rapid-sequence-induction-of-the-shock-patient/ |archivedate=9 February 2014 }}{{unreliable medical source|date=July 2014}}</ref> [[Hypotension|Low blood pressure]] is harmful in people with severe head injury<ref>{{cite journal |pmid=11585502 |year=2001 |last1=Manley |first1=G |title=Hypotension, hypoxia, and head injury: Frequency, duration, and consequences |journal=[[JAMA Surgery|Archives of Surgery]] |volume=136 |issue=10 |pages=1118–23 |last2=Knudson |first2=MM |last3=Morabito |first3=D |last4=Damron |first4=S |last5=Erickson |first5=V |last6=Pitts |first6=L |displayauthors=4 |doi=10.1001/archsurg.136.10.1118 |doi-access=free }}</ref> and ketamine is least likely to cause low blood pressure, often even able to prevent it.<ref>{{cite journal |pmid=1763596 |year=1991 |last1=Hemmingsen |first1=C |title=Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia |journal=[[Acta Anaesthesiologica Scandinavica]] |volume=35 |issue=8 |pages=755–7 |last2=Nielsen |first2=JE |doi=10.1111/j.1399-6576.1991.tb03385.x}}</ref><ref>{{cite journal |doi=10.1007/BF03004843 |title=The cardiovascular effects of ketamine in hypotensive states |journal=Canadian Anaesthetists' Society Journal |volume=22 |issue=3 |pages=339–48 |year=1975 |last1=Wong |first1=DHW |last2=Jenkins |first2=LC |pmid=1139377|doi-access=free }}</ref>
 
The effect of ketamine on the [[respiratory system|respiratory]] and [[circulatory system]]s is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system.<ref>{{cite journal |last=Adams |first=HA |trans-title=S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation |title=S-(+)-ketamin kreislaufinteraktionen bei totaler intravenöser anästhesie und analgosedierung |language=DE |journal=Der Anaesthesist |volume=46 |issue=12 |pages=1081–7 |date=December 1997 |pmid=9451493 |doi=10.1007/s001010050510}}</ref> It is sometimes possible to perform ketamine anesthesia without protective measures to the airways.<ref>{{Citation|last1=Rosenbaum|first1=Steven B.|title=Ketamine|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK470357/|work=StatPearls|publisher=StatPearls Publishing|pmid=29262083|access-date=2020-03-05|last2=Gupta|first2=Vikas|last3=Palacios|first3=Jorge L.}}</ref> Ketamine is considered relatively safe because protective airway reflexes are preserved.<ref name="WongLee2014">{{cite journal |last1=Wong |first1=JJM |last2=Lee |first2=JH |last3=Turner |first3=DA |last4=Rehder |first4=KJ |year=2014 |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 |doi=10.1586/17476348.2014.915752 |pmid=24993063}}</ref>
 
It has been successfully used to prevent [[postanesthetic shivering]].<ref>{{cite journal |last1=Zhou |first1=Y |last2=Mannan |first2=A |last3=Han |first3=Y |last4=Liu |first4=H |last5=Guan |first5=HL |last6=Gao |first6=X |last7=Dai |first7=MS |last8=Cao |first8=JL |title=Efficacy and safety of prophylactic use of ketamine for prevention of postanesthetic shivering: a systematic review and meta analysis. |journal=BMC Anesthesiology |date=30 December 2019 |volume=19 |issue=1 |pages=245 |doi=10.1186/s12871-019-0910-8 |pmid=31888509 |pmc=6937868}}</ref>
 
===Asthma===
Ketamine is used as a bronchodilator in the treatment of severe asthma.<ref name="Goyal">{{cite journal |last1=Agrawal |first1=Amit |last2=Goyal |first2=Shweta |title=Ketamine in status asthmaticus: A review |journal=Indian Journal of Critical Care Medicine |date=2013 |volume=17 |issue=3 |pages=154–161 |doi=10.4103/0972-5229.117048 |pmid=24082612 |pmc=3777369}}</ref> However, evidence of clinical benefit is limited.<ref name="Goyal" /><ref>{{cite journal |last1=Jat |first1=KR |last2=Chawla |first2=D |title=Ketamine for management of acute exacerbations of asthma in children |journal=Cochrane Database of Systematic Reviews |department=Airways Group |issue=11 |pages=CD009293 |nopp=yes |date=November 2012 |pmid=23152273 |pmc=6483733 |doi=10.1002/14651858.CD009293.pub2 |volume=11}}</ref>
 
===Seizures===
Ketamine is sometimes used in the treatment of [[status epilepticus]] that has failed to adequately respond to standard treatments.<ref>{{cite journal |last1=Gomes |first1=D |last2=Pimentel |first2=J |last3=Bentes |first3=C |last4=Aguiar de Sousa |first4=D |last5=Antunes |first5=AP |last6=Alvarez |first6=A |last7=Silva |first7=ZC |title=Consensus Protocol for the Treatment of Super-Refractory Status Epilepticus. |journal=Acta Medica Portuguesa |date=31 October 2018 |volume=31 |issue=10 |pages=598–605 |doi=10.20344/amp.9679 |pmid=30387431 |url=https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/9679|doi-access=free }}</ref>
 
=== Pain management ===
Ketamine may be used for postoperative pain management.<!-- A 2006 [[Cochrane Collaboration]] [[systematic review]] found --> Low doses of ketamine may reduce [[morphine]] use, nausea, and vomiting after surgery.<ref>{{cite journal |last1=Bell |first1=Rae F |last2=Dahl |first2=Jørgen B |last3=Moore |first3=R Andrew |last4=Kalso |first4=Eija A |title=Perioperative ketamine for acute postoperative pain |journal=Cochrane Database of Systematic Reviews |issue=7 |pages=CD004603 |date=2 July 2015 |doi=10.1002/14651858.cd004603.pub3|pmid=26133677 }}</ref><ref>{{cite journal |last1=Sin |first1=Billy |last2=Ternas |first2=Theologia |last3=Motov |first3=Sergey M. |last4=Zehtabchi |first4=Shahriar |title=The Use of Subdissociative-dose Ketamine for Acute Pain in the Emergency Department |journal=[[Academic Emergency Medicine]] |date=March 2015 |volume=22 |issue=3 |pages=251–257 |doi=10.1111/acem.12604 |pmid=25716117|url=https://semanticscholar.org/paper/a5d368cb3a31a25bae829eb9e9c94451e3793252 }}</ref> It is especially useful in the prehospital setting, due to its effectiveness and low risk of respiratory depression.<ref name="SvensonBiedermann2011">{{cite journal|last1=Svenson|first1=James|last2=Biedermann|first2=Marc|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|issn=1759-1376|doi=10.12968/jpar.2011.3.10.552}}</ref>
 
Ketamine has similar efficacy to opioids in a hospital emergency department setting for management of acute pain and for control of procedural pain.<ref>{{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 |url= |doi-access=free }}</ref> If given [[intrathecally]], its adverse cognitive effects are largely avoided at analgesic doses.<ref name = RD9>{{cite book |last1=Ritter |first1=JM |last2=Flower |first2=RJ |last3=Hendersen |first3=G |last4=Loke|first4=YK|last5=MacEwan|first5=D|last6=Rang|first6=HP|title=Rang and Dale's Pharmacology |date=2018 |publisher=Elsevier |isbn=9780702074462 |page=560 |edition=Ninth}}</ref>
 
It may also be used as an intravenous analgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic. It has the added benefit of counteracting [[spinal sensitization]] or [[Pain wind-up|wind-up phenomena]] experienced with [[chronic pain]]. At these doses, the [[psychoactive drug|psychotropic]] side effects are less apparent and well managed with [[benzodiazepine]]s.<ref name="elia">{{cite journal |last1=Elia |first1=N |last2=Tramèr |first2=MR |title=Ketamine and postoperative pain: A quantitative systematic review of randomised trials |journal=[[Pain (journal)|Pain]] |volume=113 |issue=1 |pages=61–70 |date=January 2005 |pmid=15621365 |doi=10.1016/j.pain.2004.09.036}}</ref> Ketamine is an analgesic that is most effective when used alongside a low-dose [[opioid]]; because, while it does have analgesic effects by itself, the doses required for adequate pain relief when it is used as the sole analgesic agent are considerably higher and far more likely to produce disorienting side effects.<ref name="elia" /> A review article in 2013 concluded, "despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain".<ref>{{cite journal |last1=Bredlau |first1=AL |last2=Thakur |first2=R |last3=Korones |first3=DN |last4=Dworkin |first4=RH |title=Ketamine for pain in adults and children with cancer: A systematic review and synthesis of the literature |journal=[[Pain Medicine (journal)|Pain Medicine]] |date=October 2013 |volume=14 |issue=10 |pages=1505–17 |pmid=23915253 |doi=10.1111/pme.12182|doi-access=free }}</ref>
 
Low-dose ketamine is sometimes used in the treatment of [[complex regional pain syndrome]] (CRPS).<ref>{{cite journal |last1=Correll |first1=GE |last2=Maleki |first2=J |last3=Gracely |first3=EJ |last4=Muir |first4=JJ |last5=Harbut |first5=RE |title=Subanesthetic ketamine infusion therapy: A retrospective analysis of a novel therapeutic approach to complex regional pain syndrome |journal=Pain Medicine |volume=5 |issue=3 |pages=263–75 |date=September 2004 |pmid=15367304 |doi=10.1111/j.1526-4637.2004.04043.x |doi-access=free }}</ref> A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.<ref name=OConnellWand2013>{{cite journal |last1=O'Connell |first1=NE |last2=Wand |first2=BM |last3=McAuley |first3=J |last4=Marston |first4=L |last5=Moseley |first5=GL |displayauthors=4 |title=Interventions for treating pain and disability in adults with complex regional pain syndrome |journal=Cochrane Database of Systematic Reviews |issue=4 |pages=CD009416 |nopp=yes |year=2013 |pmid=23633371 |pmc=6469537 |doi=10.1002/14651858.CD009416.pub2 |department=Pain, Palliative and Supportive Care Group |volume=4 }}</ref>
 
=== Depression ===
{{See also|Esketamine#Depression}}
 
Ketamine has been found to be a [[rapid-acting antidepressant]] in [[depression (mood)|depression]].<ref name=Zhang2018 /><ref name="pmid26415966">{{cite journal |vauthors=McCloud TL, Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, Brett D, Amit BH, McShane R, Hamadi L, Hawton K, Cipriani A |title=Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults |journal=Cochrane Database of Systematic Reviews |volume= |issue=9 |pages=CD011611 |date=September 2015 |pmid=26415966 |doi=10.1002/14651858.CD011611.pub2 |quote=ketamine (administered intravenously) proved to be more efficacious than placebo, though the quality of evidence was limited by risk of bias and small sample sizes.}}</ref><ref name="pmid25341010">{{cite journal|last1=Abdallah|first1=CG|authorlink2=Gerard Sanacora|last2=Sanacora|first2=G|last3=Duman|first3=RS|last4=Krystal|first4=JH|title=Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics|journal=Annual Review of Medicine|date=2015|volume=66|pages=509–23|pmid=25341010 |doi=10.1146/annurev-med-053013-062946|pmc=4428310}}</ref><ref name="pmid25426012">{{cite journal |last1=Serafini |first1=Gianluca |last2=Howland |first2=Robert |last3=Rovedi |first3=Fabiana |last4=Girardi |first4=Paolo |last5=Amore |first5=Mario |title=The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review |journal=Current Neuropharmacology |date=12 November 2014 |volume=12 |issue=5 |pages=444–461 |doi=10.2174/1570159X12666140619204251 |pmc=4243034 |pmid=25426012 }}</ref><ref name="pmid24688759">{{cite journal |last1=Caddy |first1=Caroline |last2=Giaroli |first2=Giovanni |last3=White |first3=Thomas P. |last4=Shergill |first4=Sukhwinder S. |last5=Tracy |first5=Derek K. |title=Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy |journal=Therapeutic Advances in Psychopharmacology |date=22 October 2013 |volume=4 |issue=2 |pages=75–99 |doi=10.1177/2045125313507739 |pmid=24688759 |pmc=3952483 }}</ref> It also may be effective in decreasing [[suicidal ideation]], although based on lower quality evidence.<ref name="pmid28342764">{{cite journal |vauthors=Bartoli F, Riboldi I, Crocamo C, Di Brita C, Clerici M, Carrà G |title=Ketamine as a rapid-acting agent for suicidal ideation: A meta-analysis |journal=Neurosci Biobehav Rev |volume=77 |issue=|pages=232–236 |date=June 2017 |pmid=28342764 |doi=10.1016/j.neubiorev.2017.03.010 |url=}}</ref><ref name="pmid28969441">{{cite journal |vauthors=Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, Sos P, Wang G, Zarate CA, Sanacora G |title=The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis |journal=Am J Psychiatry |volume=175 |issue=2 |pages=150–158 |date=February 2018 |pmid=28969441 |pmc=5794524 |doi=10.1176/appi.ajp.2017.17040472 |url=}}</ref><ref name="pmid29085082">{{cite journal |vauthors=Sathyanarayana Rao TS, Andrade C |title=A possible role for ketamine in suicide prevention in emergency and mainstream psychiatry |journal=Indian J Psychiatry |volume=59 |issue=3 |pages=259–261 |date=2017 |pmid=29085082 |pmc=5659073 |doi=10.4103/psychiatry.IndianJPsychiatry_345_17 |url=}}</ref> The antidepressant effects of ketamine were first shown in small studies in 2000 and 2006.<ref name="pmid29736744" /> They have since been demonstrated and characterized in subsequent studies.<ref name="pmid29736744" /> A single low, sub-anesthetic dose of ketamine given via intravenous infusion may produce antidepressant effects within four hours in people with depression.<ref name="pmid29736744" /> These antidepressant effects may persist for up to several weeks following a single infusion.<ref name="pmid29736744" /><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=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=10871/30208 |hdl-access=free }}</ref> This is in contrast to conventional antidepressants like [[selective serotonin reuptake inhibitor]]s (SSRIs) and [[tricyclic antidepressant]]s (TCAs), which generally require at least several weeks for their benefits to occur and become maximal.<ref name="pmid29736744"/> Moreover, based on the available preliminary evidence, the magnitude of the antidepressant effects of ketamine appears to be more than double that of conventional antidepressants.<ref name="pmid29736744" /> On the basis of these findings, ketamine has been described as the single most important advance in the treatment of depression in over 50 years.<ref name="pmid28395988" /><ref name="Hashimoto2019" /> It has sparked interest in NMDA receptor antagonists for depression, 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 Opin Investig Drugs |volume=26 |issue=1 |pages=9–24 |date=January 2017 |pmid=27960559 |doi=10.1080/13543784.2017.1267727 |url=}}</ref>
 
Ketamine has not been approved for use as an antidepressant, but its [[enantiomer]], [[esketamine]], was developed as a [[nasal spray]] for [[treatment-resistant depression]] and was approved for this indication in the United States in March 2019.<ref name="pmid27960559" /><ref name="pmid29736744" /> The effectiveness of esketamine is limited however, with significant effectiveness for treatment-resistant depression seen in only two of five [[clinical trial]]s.<ref name="Hashimoto2019" /> Although there is evidence to support the effectiveness of ketamine and esketamine in treating depression, there is a lack of consensus on dosing and the effects and safety of long-term therapy.<ref name="pmid24688759" /><ref name="pmid28249076">{{cite journal|last1=Sanacora|first1=G|last2=Frye|first2=MA|last3=McDonald|first3=W|last4=Mathew|first4=SJ|last5=Turner|first5=MS|last6=Schatzberg|first6=AF|last7=Summergrad|first7=P|last8=Nemeroff|first8=CB|last9=American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and|first9=Treatments.|title=A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders|journal=[[JAMA Psychiatry]]|date=1 April 2017|volume=74|issue=4|pages=399–405|pmid=28249076|doi=10.1001/jamapsychiatry.2017.0080}}</ref> Ketamine can produce [[euphoria]] and [[dissociative]] [[hallucinogen]] effects at higher doses, and thus has an [[abuse potential]].<ref name="pmid29736744" /><ref name="pmid28757132">{{cite journal |vauthors=Short B, Fong J, Galvez V, Shelker W, Loo CK |title=Side-effects associated with ketamine use in depression: a systematic review |journal=Lancet Psychiatry |volume=5 |issue=1 |pages=65–78 |date=January 2018 |pmid=28757132 |doi=10.1016/S2215-0366(17)30272-9 |url=}}</ref> Moreover, ketamine has been associated with [[cognitive deficit]]s, [[urotoxicity]], [[hepatotoxicity]], and other complications in some individuals with long-term use.<ref name="pmid29736744" /><ref name="pmid28757132" /> These undesirable effects may serve to limit the use of ketamine and esketamine for depression.<ref name="pmid29736744" /><ref name="pmid28757132" />
 
===Available forms===
Ketamine is available in the form of [[solution]] for [[intravenous infusion]].{{Citation needed|date=November 2019}}
 
<gallery>
File:Home Anesthetic.jpg|A 1000&nbsp;mg/10 mL vial of ketamine.
File:Two doses of iv ketamine.jpg|Two doses of intravenous ketamine, 100&nbsp;mg/2 ml and 20&nbsp;mg /2 ml
</gallery>
 
== Contraindications ==
The use of ketamine is cautioned against in cases of:<ref name="AMH">{{cite web|title=Ketamine – Australian Medicines Handbook|publisher=Australian Medicines Handbook Pty Ltd|date=July 2017|website=AMH Online|location=Adelaide, Australia|editor=Rossi, S|url=https://amhonline.amh.net.au/chapters/chap-02/general-anaesthetics/anaesthetic-general-iv/ketamine?menu=vertical|accessdate=24 August 2017}}</ref><ref name="MD">{{cite web|title=Ketamine Hydrochloride: Martindale: The Complete Drug Reference|date=9 January 2017|accessdate=24 August 2017|editor=Brayfield, A|publisher=Pharmaceutical Press|website=MedicinesComplete|url=https://www.medicinescomplete.com/mc/martindale/current/ms-3114-h.htm|location=London, UK}}</ref>
* Conditions worsened by an increase in blood pressure or heart rate, such as [[angina]], [[stroke]], poorly controlled [[hypertension|high blood pressure]]. Ketamine increases both heart rate and blood pressure.
* Psychiatric disorders: Ketamine can cause hallucinations, and therefore may exacerbate the symptoms of certain psychiatric disorders.
* Ketamine was once thought to cause [[Intracranial pressure#Increased ICP|increased intracranial pressure]] (IICP): as of 2014, this is believed not to be the case.<ref>{{cite journal |last1=Zeiler |first1=FA |last2=Teitelbaum |first2=J |last3=West |first3=M |last4=Gillman |first4=LM |title=The ketamine effect on ICP in traumatic brain injury |journal=Neurocritical Care |date=August 2014 |volume=21 |issue=1 |pages=163–73 |doi=10.1007/s12028-013-9950-y |pmid=24515638}}</ref>
* Raised [[intraocular pressure]] (IOP): Ketamine can further increase IOP.
* Penetrating [[eye injury]]: Can increase risk of loss of eye contents, due to increased IOP.
* [[Acute porphyria]]: Ketamine is considered porphyrinogenic, that is, it may provoke an attack of acute porphyria, a disease of the nervous system, in susceptible people.
 
== Side effects ==
When administered by trained medical professionals, ketamine is generally safe for those people who are critically ill.<ref>{{cite journal|last1=Cohen|first1=L|last2=Athaide|first2=V|last3=Wickham|first3=ME|last4=Doyle-Waters|first4=MM|last5=Rose|first5=NG|last6=Hohl|first6=CM|title=The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review|journal=Annals of Emergency Medicine|date=January 2015|volume=65|issue=1|pages=43–51.e2|pmid=25064742|doi=10.1016/j.annemergmed.2014.06.018}}</ref> Even in these cases, there are known side effects that include one or more of the following:<ref name="MerckManual">Merck Manual; Drug Information Provided by Lexi-Comp. Last full review/revision May 2014 [http://www.merckmanuals.com/professional/lexicomp/ketamine.html Ketamine] {{webarchive|url=https://web.archive.org/web/20110309060707/http://www.merckmanuals.com/professional/lexicomp/ketamine.html |date=9 March 2011 }}</ref>
* Cardiovascular: [[Heart arrhythmia|abnormal heart rhythms]], [[bradycardia|slow heart rate]] or [[tachycardia|fast heart rate]], [[hypertension|high blood pressure]] or [[hypotension|low blood pressure]]
* Central nervous system: Ketamine is traditionally avoided in people with or at risk of [[intracranial hypertension]] (ICP) due to concerns about ketamine causing increased intracranial pressure. It does not increase ICP more than opioids.<ref>{{cite journal|last1=Wang|first1=X|last2=Ding|first2=X|last3=Tong|first3=Y|last4=Zong|first4=J|last5=Zhao|first5=X|last6=Ren|first6=H|last7=Li|first7=Q|title=Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials|journal=Journal of Anesthesia|date=24 May 2014|pages=821–827|doi=10.1007/s00540-014-1845-3|pmid=24859931|volume=28|issue=6}}</ref>
* Dermatologic: Transient [[erythema|reddening of the skin]], transient [[morbilliform|measles-like]] rash
* Gastrointestinal: reduced appetite, nausea, increased salivation, vomiting
* Local: Pain, [[exanthema|eruptions or rashes]] at the injection site
* Neuromuscular and skeletal: Increased skeletal muscle tone (tonic-clonic movements)
* Ocular: [[Diplopia|Double vision]], increased [[intraocular pressure]], [[nystagmus|involuntary eye movements]], [[tunnel vision]]
* Respiratory: Airway obstruction, [[apnea|cessation of breathing]], increased [[bronchus|bronchial]] secretions, [[respiratory depression|reduced effort to breathe]], spasm of the vocal cords (larynx)
* Other: [[Anaphylaxis]], dependence, [[Emergence delirium|emergence reaction]]
 
<!--PLEASE DO NOT DRAW FAR REACHING MEDICAL CONCLUSIONS THAT HAVE POSSIBLE CULTURAL INTERPRETATIONS BASED ON A SINGLE MEDICAL REFERENCE, ESP. WHEN IT IS DATED (HERE MORE THAN A HALF-DECADE OLD). The observation of lower frequency emergence events below age 15 and above age 65 was generalized and downgraded to "may" for this reason.-->
At anesthetic doses, 10–20% of people experience adverse reactions that occur during emergence from anesthesia, reactions that can manifest as seriously as hallucinations and delirium.<ref name="StrayerNelson2008" /> These reactions may be less common in some subpopulations, and when administered intramuscularly, and can occur up to 24&nbsp;hours postoperatively; the chance of this occurring can be reduced by minimizing stimulation to the person during recovery and pretreating with a [[benzodiazepine]], alongside a lower dose of ketamine.<ref name="StrayerNelson2008" /> People who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting [[barbiturate]].<ref name="MerckManual" />
 
[[Tonic (physiology)|Tonic]]-[[clonic]] movements are reported at higher anesthetic doses in greater than 10% of people.<ref name="Quibell2011" />
 
=== Neurological ===
[[File:Zebrafish Make a Splash in FDA Research (8614532586).jpg|thumb|Effects of ketamine on Zebrafish development. Green areas indicate neurons, and increasing doses of ketamine reduced growth of neurons from the spinal cord.]]
In 1989, psychiatry professor [[John Olney]] reported ketamine caused irreversible changes, known as [[Olney's lesions]], in two small areas of the rat brain. However, the rat brain has significant differences in metabolism from the human brain; therefore such changes may not occur in humans.<ref name="NeurologicalEffects">Neurological effects of ketamine introduction references:
* {{cite journal |last1= Olney |first1= JW |authorlink1= John Olney |last2= Labruyere |first2= J |last3= Price |first3= MT |title= Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs |journal= [[Science (journal)|Science]] |volume= 244 |issue= 4910 |pages= 1360–2 |date= June 1989 |pmid= 2660263 |doi= 10.1126/science.2660263|bibcode= 1989Sci...244.1360O }}
* {{cite web |last= Anderson |first= Cliff |title= The Bad News Isn't In: A Look at Evidence for Specific Mechanisms of Dissociative-Induced Brain Damage and Cognitive Impairment |url= http://www.erowid.org/chemicals/dxm/dxm_health2.shtml |publisher= [[Erowid]] |date= June 2003 |url-status=live |archiveurl= https://web.archive.org/web/20081217110632/http://www.erowid.org/chemicals/dxm/dxm_health2.shtml |archivedate= 17 December 2008 |df= dmy-all }}{{Unreliable medical source|date=July 2014}}
* {{cite journal |last1= Tryba |first1= M |last2= Gehling |first2= M |title= Clonidine – A potent analgesic adjuvant |journal= [[Current Opinion in Anesthesiology]] |volume= 15 |issue= 5 |pages= 511–7 |date= October 2002 |pmid= 17019247 |doi= 10.1097/00001503-200210000-00007}}
* {{cite journal |last1=Dong |first1= C |last2= Anand |first2= KJS |title= Developmental neurotoxicity of ketamine in pediatric clinical use |journal= [[Toxicology Letters]] |volume= 220 |issue= 1 |pages= 53–60 |date= June 2013 |pmid= 23566897 |doi= 10.1016/j.toxlet.2013.03.030 |url=}}</ref>
 
The first large-scale, longitudinal study of ketamine users found current frequent (averaging 20&nbsp;days/month) ketamine users had increased depression and impaired memory by several measures, including verbal, short-term memory, and visual memory. Current infrequent (averaging 3.25&nbsp;days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention, and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.<ref name="Morgan2009">{{cite journal |doi=10.1111/j.1360-0443.2009.02761.x |pmid=19919593 |title=Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: A 1-year longitudinal study |year=2009 |last1=Morgan |first1=CJA |last2=Muetzelfeldt |first2=L |last3=Curran |first3=HV |journal=Addiction |volume=105 |issue=1 |pages=121–33}}</ref>
 
Short-term exposure of cultures of [[GABAergic]] [[neuron]]s to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and noncell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal maintenance and development.<ref>{{cite journal |pmid= 17418473 |doi= 10.1016/j.tox.2007.03.004 |volume= 234 |issue= 3 |title= Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture |date= May 2007 |journal= [[Toxicology (journal)|Toxicology]] |pages= 216–26 |last1= Vutskits |first1= L |last2= Gascon |first2= E |last3= Potter |first3= G |last4= Tassonyi |first4= E |last5= Kiss |first5= JZ |displayauthors= 4}}</ref><ref>{{cite book |last1=Hargreaves|first1=RJ|last2=Hill|first2=RG|last3=Iversen|first3=LL |chapter=Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology |editor1-last=Ito |editor1-first=U. |display-editors=et al. |title=Brain Edema IX |journal=[[Acta Neurochirurgica. Supplementum]]|series=Acta Neurochirurgica |date=1994 |volume=60 |pages=15–9 |pmid=7976530 |doi=10.1007/978-3-7091-9334-1_4 |isbn=978-3-7091-9336-5}}</ref>
 
More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1&nbsp;mg/kg IV) to adolescent [[cynomolgus]] monkeys for varying periods of time.<ref name="SunLi2012">{{cite journal |last1=Sun |first1=L |last2=Li |first2=Q |last3=Li |first3=Q |first4=Y |last4=Zhang |first5=D |last5=Liu |first6=H |last6=Jiang |first7=F |last7=Pan |first8=DT |last8=Yew |displayauthors=4 |title=Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys |journal=[[Addiction Biology]] |date=November 2012 |doi=10.1111/adb.12004 |pmid=23145560 |pages=185–94 |volume=19 |issue=2}}</ref> Decreased locomotor activity and indicators of increased cell death in the [[prefrontal cortex]] were detected in monkeys given daily injections for six months, but not those given daily injections for one month.<ref name="SunLi2012" /> A study conducted on [[rhesus monkey]]s found a 24-hour [[intravenous]] infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals.<ref>{{cite journal |last1=Slikker |first1=W |last2=Zou |first2=X |last3=Hotchkiss |first3=CE |last4=Divine |first4=RL |last5=Sadovova |first5=N |last6=Twaddle |first6=NC |last7=Doerge |first7=DR |last8=Scallet |first8=AC |last9=Patterson |first9=TA |last10=Hanig |first10=JP |last11=Paule |first11=MG |last12=Wang |first12=C |displayauthors=4 |doi=10.1093/toxsci/kfm084 |title=Ketamine-induced neuronal cell death in the perinatal rhesus monkey |journal=[[Toxicological Sciences]] |volume=98 |issue=1 |pages=145–58 |year=2007 |pmid=17426105 |pmc= |url=http://toxsci.oxfordjournals.org/content/98/1/145.full|doi-access=free }}</ref><!-- There is a long list of medicines that could counteract these potential toxic effects {{dubious|date=December 2010}}, including [[clonidine]], [[anticholinergics]], [[benzodiazepines]], [[barbiturates]] and [[risperidone]]<ref name="Erowid" /><ref name="Tryba2002" /><ref name="Giannini2000" />{{Verify source|date=December 2009}} -->
 
Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects it may have on the developing brain. These neurodegenerative changes in early development have been seen with other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.<ref>{{cite journal |last1= Patel |first1= P |last2= Sun |first2= L |title= Update on neonatal anesthetic neurotoxicity: Insight into molecular mechanisms and relevance to humans |journal= [[Anesthesiology (journal)|Anesthesiology]] |date= April 2009 |volume= 110 |issue= 4 |pages= 703–8 |doi=10.1097/ALN.0b013e31819c42a4 |pmid= 19276968 |pmc= 2737718 |type= commentary}}</ref>
 
The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.<ref>{{cite journal |last1= Krystal |first1= JH |last2= Karper |first2= LP |last3= Seibyl |first3= JP |last4= Freeman |first4= GK |last5= Delaney |first5= R |last6= Bremner |first6= JD |last7= Heninger |first7= GR |last8= Bowers |first8= MB, Jr |last9= Charney |first9= DS |displayauthors= 4 |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 |url=}}</ref>
 
=== Urinary tract ===
A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine recreational use.<ref name="Middela2011">{{cite journal |last1= Middela |first1= S |last2= Pearce |first2= I |title= Ketamine-induced vesicopathy: A literature review |journal= International Journal of Clinical Practice |date= January 2011 |volume= 65 |issue= 1 |pages= 27–30 |doi= 10.1111/j.1742-1241.2010.02502.x |pmid= 21155941|url= https://hal.archives-ouvertes.fr/hal-00600043 }}</ref> Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge [[Urinary incontinence|incontinence]], decreased [[bladder]] compliance, decreased bladder volume, [[detrusor]] overactivity, and painful [[hematuria|blood in urine]]. [[Hydronephrosis|Bilateral hydronephrosis]] and [[renal papillary necrosis]] have also been reported in some cases.<ref name="Middela2011" /><ref name=morgan11>{{cite journal |last1= Morgan |first1= CJA |last2= Curran |first2= HV |last3= Independent Scientific Committee on Drugs (ISCD) |title= Ketamine use: A review |journal= [[Addiction (journal)|Addiction]] |date= January 2012 |volume= 107 |issue= 1 |pages= 27–38 |doi= 10.1111/j.1360-0443.2011.03576.x |pmid= 21777321|url= https://semanticscholar.org/paper/bbfba0ebcd72ce21fd1ee3e3813bca775eebaf62 }}</ref> The [[pathogenesis]] of papillary necrosis has been investigated in mice, and mononuclear [[inflammation|inflammatory]] infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.<ref>{{cite journal |last1= Yeung |first= LY |last2= Rudd |first2= JA |last3= Lam |first3= WP |last4= Mak |first4= YT |last5= Yew |first5= DT |displayauthors= 4 |title= Mice are prone to kidney pathology after prolonged ketamine addiction |journal= [[Toxicology Letters]] |date= December 2009 |volume= 191 |issue= 2–3 |pages= 275–8 |pmid= 19766175 |doi= 10.1016/j.toxlet.2009.09.006}}</ref>
 
The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use correspond linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5&nbsp;g/day reported symptoms of the lower urinary tract.<ref name="Middela2011" /> Urinary tract symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of time.<ref name="morgan11" /> These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.<ref name="morgan11" />
 
Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including [[antibiotics]], [[NSAID]]s, [[steroid]]s, [[anticholinergic]]s, and cystodistension.<ref name="Middela2011" /> Both [[hyaluronic acid]] instillation and combined [[pentosan polysulfate]] and ketamine cessation have been shown to provide relief in some people, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.<ref name="Middela2011" />
 
=== Liver ===
In case reports of three people treated with [[esketamine]] for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.<ref>{{cite journal|last1=Bell|first1=RF|title=Ketamine for chronic noncancer pain: concerns regarding toxicity|journal=Current Opinion in Supportive and Palliative Care|date=June 2012|volume=6|issue=2|pages=183–7|pmid=22436323|doi=10.1097/SPC.0b013e328352812c|url=https://semanticscholar.org/paper/793ce9284f50f9d2e78e38a49f743a8d63151212}}</ref>
 
=== Dependence ===
[[File:Rational harm assessment of drugs radar plot.svg|thumb|right|Radar plot showing relative physical harm, social harm, and dependence of ketamine<ref>{{cite journal |vauthors=Nutt D, King LA, Saulsbury W, Blakemore C |title=Development of a rational scale to assess the harm of drugs of potential misuse |journal=Lancet |volume=369 |issue=9566 |pages=1047–53 |year=2007 |pmid=17382831 |doi=10.1016/S0140-6736(07)60464-4}}</ref>]]
 
Ketamine's potential for dependence has been established in various [[operant conditioning]] paradigms, including [[conditioned place preference]] and [[self-administration]]; further, rats demonstrate locomotor [[sensitization]] following repeated exposure to ketamine.<ref name=morgan11 /> Increased subjective feelings of 'high' have been observed in healthy human volunteers exposed to ketamine.<ref name=morgan11 /> Additionally, the rapid onset of effects following smoking, [[insufflation (medicine)|insufflation]], and/or [[intramuscular injection]] is thought to increase the drug's recreational use potential. The short duration of effects promotes [[Drug binge|bingeing]]; [[Drug tolerance|tolerance]] can develop; and [[Drug withdrawal|withdrawal]] symptoms, including anxiety, shaking, and palpitations, may be present in some daily users following cessation of use.<ref name=morgan11 />
 
Ketamine can cause a variety of urinary tract problems that are more likely to occur with heavier and/or higher dosed use, especially in those not watching for a healthy lifestyle, according to a UK study.<ref>{{cite web |url=http://www.medicaldaily.com/articles/9445/20120405/ketamine-special-k-drug-use-urinary-tract-problems.htm |title=Club Drug Ketamine Linked to Urinary and Bladder Problems |date=5 April 2012}}</ref><ref>{{cite web |url=http://www.bbc.co.uk/newsbeat/10003110 |title=Doctors' warning on ketamine risk |date=23 November 2009}}</ref>
 
== Interactions ==
Plasma concentrations of ketamine are increased by [[CYP3A4#CYP3A4 ligands|CYP3A4 inhibitors]] (e.g., [[diazepam]]) and [[CYP2B6#CYP2B6 ligands|CYP2B6 inhibitors]] (e.g., [[orphenadrine]]) due to inhibition of its metabolism.<ref name="Quibell2011" /><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 |year=2017 |pmid=28858450 |doi=10.4088/JCP.17f11802 |url= |doi-access=free }}</ref> CYP2B6 and CYP3A4 inducers like [[carbamazepine]], [[phenobarbital]], [[phenytoin]], and [[rifampicin]] may reduce plasma levels of ketamine.<ref name="pmid28858450" />
 
Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI antidepressants, and MAOIs. Increase blood pressure and heart rate, palpitations, and arrhythmias may be potential effects.
 
Ketamine may increase the effects of other [[sedative]]s in a dose-dependent manner, including, but not limited to [[ethanol|alcohol]],<ref name="propofol">{{cite journal |title=Additive interactions between propofol and ketamine when used for anesthesia induction in female patients |last1=Hui |first1=TW |last2=Short |first2=TG |last3=Hong |first3=W |last4=Suen |first4=T |last5=Gin |first5=T |last6=Plummer |first6=J |displayauthors=4 |journal=Anesthesiology |date=March 1995 |volume=82 |issue=3 |pages=641–8 |pmid=7879932 |doi=10.1097/00000542-199503000-00005 }}</ref> [[benzodiazepine]]s,<ref name="midazolam">{{cite journal |title=Hypnotic and anesthetic interactions between ketamine and midazolam in female patients |last1=Hong |first1=W |last2=Short |first2=TG |last3=Hui |first3=TW |journal=Anesthesiology |date=December 1993 |volume=79 |issue=6 |pages=1227–32 |pmid=8267198 |doi=10.1097/00000542-199312000-00013 }}<!-- full text pdf available at url given --></ref> [[opioid]]s,<ref name="Akhavanakbari2014">{{cite journal |last1=Mohamadian |first1=Ali |last2=Akhavanakbari |first2=Godrat |last3=Entezariasl |first3=Masood |title=Evaluation the effects of adding ketamine to morphine in intravenous patient-controlled analgesia after orthopedic surgery |journal=Perspectives in Clinical Research |date=2014 |volume=5 |issue=2 |pages=85–7 |doi=10.4103/2229-3485.128028 |pmid=24741486 |pmc=3980550}}</ref> [[quinazolinone]]s, [[phenothiazine]]s, [[anticholinergic]]s, and [[barbiturate]]s.<ref name="EkerYalcin2011">{{cite journal |last1=Eker |first1=HE |last2=Yalcin Cok |first2=O |last3=Aribogan |first3=A |last4=Arslan |first4=G |title=Children on phenobarbital monotherapy requires more sedatives during MRI |journal=[[Pediatric Anesthesia]] |volume=21 |issue=10 |pages=998–1002 |date=October 2011 |pmid=21564387 |doi=10.1111/j.1460-9592.2011.03606.x |url= https://zenodo.org/record/889567}}</ref>
 
Benzodiazepines may diminish the antidepressant effects of ketamine.<ref name="pmid28858450" /> Most conventional antidepressants can likely be combined with ketamine without diminished antidepressant effectiveness or increased side effects.<ref name="pmid28858450" />
 
== Pharmacology ==
 
=== Pharmacodynamics ===
 
====Molecular interactions====
{| class="wikitable floatright" style="font-size:small;"
|+ Ketamine and biological targets<ref name="PDSP">{{cite web |title=PDSP K<sub>i</sub> Database |website=Psychoactive Drug Screening Program (PDSP) |author1=Roth, BL |author2=Driscol, J |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |accessdate=14 August 2017 |url=https://kidbdev.med.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=ketamine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref><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=[[Pharmacological Reviews]] |volume=70 |issue=3 |pages=621–660 |date=July 2018 |pmid=29945898 |pmc=6020109 |doi=10.1124/pr.117.015198 |url= }}</ref><ref name="MathewZarate2016" /><ref name="pmid24257811">{{cite journal |vauthors=Frohlich J, Van Horn JD |title=Reviewing the ketamine model for schizophrenia |journal=[[Journal of Psychopharmacology]] |volume=28 |issue=4 |pages=287–302 |year=2014 |pmid=24257811 |pmc=4133098 |doi=10.1177/0269881113512909 |url= }}</ref>
|-
! Site !! Value ([[Micromolar|μM]]) !! Type !! Action !! Species !! Ref
|-
| {{abbrlink|NMDA|N-Methyl-D-aspartate receptor}}<br />({{abbr|PCP|Phencyclidine site}}) || 0.25–0.66<br />0.35 || K<sub>i</sub><br />IC<sub>50</sub> || Antagonist || Human || <ref name="pmid28829612">{{cite journal |vauthors=Morris PJ, Moaddel R, Zanos P, Moore CE, Gould T, 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 |year=2017 |pmid=28829612 |doi=10.1021/acs.orglett.7b02177 |pmc=5641405}}</ref><ref name="pmid23527166">{{cite journal |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 |url= |bibcode=2013PLoSO...859334R}}</ref><br /><ref name="pmid28829612" />
|-
| {{abbrlink|GABA<sub>A</sub>|γ-Aminobutyric acid A receptor}} || 600–1,800 || EC<sub>50</sub>|| Agonist || Human ||<ref name="pmid24257811" /><ref name=":0">{{Cite journal|last1=Zanos|first1=Panos|last2=Moaddel|first2=Ruin|last3=Morris|first3=Patrick J.|last4=Riggs|first4=Lace M.|last5=Highland|first5=Jaclyn N.|last6=Georgiou|first6=Polymnia|last7=Pereira|first7=Edna F. R.|last8=Albuquerque|first8=Edson X.|last9=Thomas|first9=Craig J.|last10=Zarate|first10=Carlos A.|last11=Gould|first11=Todd D.|date=July 2018|title=Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms|journal=Pharmacological Reviews|volume=70|issue=3|pages=621–660|doi=10.1124/pr.117.015198|issn=0031-6997|pmc=6020109|pmid=29945898}}</ref>
|-
| {{abbrlink|MOR|μ-Opioid receptor}} || 26–42.1 || K<sub>i</sub> || Agonist || Various || <ref name="MathewZarate2016" /><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 |year=1999 |pmid=9915326 |doi=10.1097/00000542-199901000-00023 |url= }}</ref><ref name=":0" />
|-
| {{abbrlink|MOR<sub>2</sub>|μ-Opioid receptor}} || 12.1<br />700
| K<sub>i</sub><br />IC<sub>50</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 |url= }}</ref>
|-
| {{abbrlink|DOR|δ-Opioid receptor}} || 205–286 || K<sub>i</sub> || Agonist || Human ||<ref name=":0" />
|-
| {{abbrlink|KOR|κ-Opioid receptor}} || 23.1–60.0<br />29.0
| K<sub>i</sub><br />EC<sub>50</sub>
| Agonist || Human ||<ref name=":0" />
|-
| {{abbrlink|NOP|Nociceptin receptor}} || {{abbr|IA|Inactive}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || Human || <ref name="pmid9915326" />
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]] || 66–140 || K<sub>i</sub> || Agonist || 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=[[European Neuropsychopharmacology]] |volume=22 |issue=4 |pages=308–17 |year=2012 |pmid=21911285 |doi=10.1016/j.euroneuro.2011.08.002 |url= }}</ref><ref name="pmid24257811" /><ref name="pmid23527166" />
|-
| [[Sigma-2 receptor|σ<sub>2</sub>]] || 26.3 || K<sub>i</sub> || Agonist || Rat || <ref name="pmid21911285" /><ref name="pmid23527166" />
|-
| [[D2 receptor|D<sub>2</sub>]] || 0.05–0.5<br />0.4–0.9
| K<sub>i</sub><br />EC<sub>50</sub>|| Agonist || Human || <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|year=2016|title=Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters|url=|journal=Journal of Pharmacology and Experimental Therapeutics|volume=359|issue=1|pages=159–70|doi=10.1124/jpet.116.235838|pmc=5034706|pmid=27469513}}</ref><ref name=":0" />
|-
| [[D2 receptor|D<sub>2</sub><sup>High</sup>]] || 0.5<br />1.03 || K<sub>i</sub><br />EC<sub>50</sub> || Agonist || Human<br />Rat || <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 |url= |doi-access=free }}</ref><ref name="pmid18720422" /><br /><ref name="pmid19391150" />
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || >10 || K<sub>i</sub> || {{abbr|ND|No data}} || Human || <ref name="pmid23527166" />
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub><sup>{{abbr|Hi|High}}</sup>]] || ≥15 || K<sub>i</sub> || Agonist? || Rat || <ref name="pmid12232776" /><ref name="pmid11343613">{{cite journal |vauthors=Rabin RA, Doat M, Winter JC |title=Role of serotonergic 5-HT2A receptors in the psychotomimetic actions of phencyclidine |journal=[[The International Journal of Neuropsychopharmacology]] |volume=3 |issue=4 |pages=333–338 |year=2000 |pmid=11343613 |doi=10.1017/S1461145700002091 |url= |doi-access=free }}</ref>
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || 420<br />97<br />910
| K<sub>i</sub><br />K<sub>i</sub><br />IC<sub>50</sub>
| Antagonist || Human<br />Mouse<br />Human
|<ref name=":0" />
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 45 || K<sub>i</sub> || Antagonist || Human || <ref name="MathewZarate2016" /><ref name="pmid8942324" />
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || 294 || K<sub>i</sub> || Antagonist || Human || <ref name="MathewZarate2016" /><ref name="pmid8942324" />
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] || 246 || K<sub>i</sub> || Antagonist || Human || <ref name="MathewZarate2016" /><ref name="pmid8942324" />
|-
| [[Alpha-7 nicotinic receptor|α<sub>7</sub>]] || 20 || IC<sub>50</sub> || Antagonist || Human || <ref name="MathewZarate2016" />
|-
| [[alpha-4 beta-2 nicotinic receptor|α<sub>4</sub>β<sub>2</sub>]] || 50 || IC<sub>50</sub> || Antagonist || Human || <ref name="MathewZarate2016" />
|-
| {{abbrlink|ERα|Estrogen receptor alpha}} || 0.345<br />2.31 || K<sub>D</sub><br />IC<sub>50</sub> || {{abbr|ND|No data}} || Human<br />Human || <ref name="pmid29621538" /><br /><ref name="pmid29621538" />
|-
| {{abbrlink|ChE|Cholinesterase}} || 494 || K<sub>i</sub> || Inhibitor || Human || <ref name="MathewZarate2016" />
|-
| {{abbrlink|SERT|Serotonin transporter}} || >10<br />162<br />126 || K<sub>i</sub><br />K<sub>i</sub><br />IC<sub>50</sub> || Inhibitor || Human<br />Rat<br />Human || <ref name="pmid23527166" /><br /><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 | year = 1998 | pmid = 9523822 | doi = 10.1097/00000542-199803000-00029| url = }}</ref><ref name="pmid10553955">{{cite journal | vauthors = Nishimura M, Sato K | title = Ketamine stereoselectively inhibits rat dopamine transporter | journal = Neuroscience Letters | volume = 274 | issue = 2 | pages = 131–4 | year = 1999 | pmid = 10553955 | doi = 10.1016/s0304-3940(99)00688-6| url = }}</ref><br /><ref name=":0" />
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 66.8<br/>291 || K<sub>i</sub><br />IC<sub>50</sub> || Inhibitor || Human<br />Human || <ref name="pmid9523822" /><ref name="pmid10553955" /><ref name="pmid23527166" /><br /><ref name=":0" />
|-
| {{abbrlink|DAT|Dopamine transporter}} || >10<br />63<br/> >10 || K<sub>i</sub><br />K<sub>i</sub><br />IC<sub>50</sub> || Inhibitor || Human<br />Rat<br />Human || <ref name="pmid23527166" /><br /><ref name="pmid9523822" /><ref name="pmid10553955" /><br /><ref name="pmid27469513" />
|-
| [[Phencyclidine site 2|{{abbr|PCP|Phencyclidine}}<sub>2</sub>]] || 59.4 || K<sub>i</sub> || {{abbr|ND|No data}} || Human || <ref name="pmid7968938">{{cite journal | vauthors = Rothman RB | title = PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site | journal = Neurotoxicology and Teratology | volume = 16 | issue = 4 | pages = 343–53 | year = 1994 | pmid = 7968938 | doi = 10.1016/0892-0362(94)90022-1 | url = https://zenodo.org/record/1258623 }}</ref>
|-
| {{abbrlink|VGSC|Voltage-gated sodium channel}} || 11.5<br />222<br />1,100
| K<sub>i</sub><br />IC<sub>50</sub><br />ED<sub>50</sub>
| Antagonist || Rat<br />Rat<br />Human
|<ref name=":0" />
|-
| {{abbrlink|VDCC|Voltage-dependent calcium channel}} || 209 || IC<sub>50</sub> || Inhibitor || Human || <ref name="pmid8942324" />
|-
| {{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 | year = 2009 | pmid = 19158287 | pmc = 2744993 | doi = 10.1523/JNEUROSCI.3481-08.2009 | url = }}</ref>
|-
|[[D-serine]]
|0.46–0.57
|EC<sub>50</sub>
|Inhibitor
|Human
|<ref name=":0" />
|-
|{{Abbrlink|NOS|Nitric oxide synthase}}
|>100
|K<sub>i</sub>
|Inhibitor
|Rat
|<ref>{{Cite journal|last1=Li|first1=Chi-Yuan|last2=Chou|first2=Tz-Chong|last3=Wong|first3=Chih-Shung|last4=Ho|first4=Shung-Tai|last5=Wu|first5=Chin-Chen|last6=Yen|first6=Mao-Hsiung|last7=Ding|first7=Yu-An|date=September 1997|title=Ketamine inhibits nitric oxide synthase in lipopolysaccharide-treated rat alveolar macrophages|journal=Canadian Journal of Anaesthesia|language=en|volume=44|issue=9|pages=989–995|doi=10.1007/BF03011971|pmid=9305563|issn=0832-610X|doi-access=free}}</ref>
|- class="sortbottom"
| colspan="6" style="width: 1px;" | The smaller the value, the stronger the interaction with the site. 0.12–0.84 μM: Drowsiness, dissociative, and psychotic-like effects. 0.42–0.84 μM: Analgesia. 8.41–12.62 μM: Anaesthesia.
|}
 
''[[In vitro]]'', ketamine acts as an [[receptor antagonist|antagonist]] of the [[NMDA receptor]], an [[ionotropic glutamate receptor]].<ref name=ACS2017 /> It binds specifically to the [[dizocilpine]] (MK-801) site of the NMDA receptor, near the channel pore, and is an [[uncompetitive antagonist]].<ref name="pmid23527166" /> The ''S''(+) and ''R''(–) [[stereoisomer]]s of ketamine bind to the dizocilpine site of the NMDA receptor with different [[Binding affinity|affinities]], the former showing approximately 2- to 3-fold greater affinity for the receptor than the latter.<ref name="pmid8942324">{{cite journal |last1= Hirota |first1= K |last2= Lambert |first2= DG |title= Ketamine: Its mechanism(s) of action and unusual clinical uses |journal= British Journal of Anaesthesia |date= October 1996 |volume= 77 |issue= 4 |pages= 441–4 |pmid= 8942324 |doi= 10.1093/bja/77.4.441 |url= http://bja.oxfordjournals.org/content/77/4/441.long |url-status=live |archiveurl= https://web.archive.org/web/20151020232725/http://bja.oxfordjournals.org/content/77/4/441.long |archivedate= 20 October 2015 |df= dmy-all }}</ref> Ketamine may also interact with and inhibit the NMDAR via another [[allosteric site]] on the receptor.<ref name=Orser>{{cite journal |last1= Orser |first1= BA |last2= Pennefather |first2= PS |last3= MacDonald |first3= JF |year= 1997 |title= Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors |journal= Anesthesiology |volume= 86 |issue= 4 |pages= 903–17 |pmid= 9105235 |url= |doi=10.1097/00000542-199704000-00021}}</ref> Its full [[mechanism of action]] is not well-understood {{As of|2017||df=|lc=y}}.<ref name=ACS2017 /> Because of its complex mechanism of action, interacting with numerous receptors and subreceptor systems, it is often referred to as 'a pharmacologist's nightmare'.<ref name="pmiddoi.org/10.1111/cns.12111">{{cite journal| author1=Schmoldt A |author2=Benthe HF |author3=Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639–41 | pmid= 10| doi=10.1016/0006-2952(75)90094-5 | pmc=5922622 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }}</ref><ref name="pmid25224017">{{cite journal| author=Potter DE, Choudhury M| title=Ketamine: repurposing and redefining a multifaceted drug. | journal=Drug Discov Today | year= 2014 | volume= 19 | issue= 12 | pages= 1848–54 | pmid=25224017 | doi=10.1016/j.drudis.2014.08.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25224017  }}</ref>
 
Besides NMDA receptor antagonism, other actions of ketamine under laboratory research include:<ref name="PDSP" /><ref name="MathewZarate2016">{{cite book |author1=Sanjay J. Mathew |author2=Carlos A. Zarate, Jr. |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 |archiveurl=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=QDOgDQAAQBAJ&pg=PA22 |archivedate=8 September 2017 }}</ref><ref name="pmid24257811" />
 
* [[Ligand (biochemistry)|Ligand]] of the [[mu opioid receptor|μ-]], [[kappa-opioid receptor|κ-]], and [[delta-opioid receptor|δ-opioid receptors]]<ref name="pmid9806706">{{cite journal |last1=Kohrs |first1=R |last2=Durieux |first2=ME |title=Ketamine: Teaching an old drug new tricks |journal=[[Anesthesia & Analgesia]] |volume=87 |issue=5 |pages=1186–93 |date=November 1998 |pmid=9806706 |doi=10.1213/00000539-199811000-00039 }}</ref>
* [[Sigma receptor|Sigma]] [[sigma-1 receptor|σ<sub>1</sub>]] and [[sigma-2 receptor|σ<sub>2</sub> receptor]] [[agonist]]<ref name="pmid9806706" /><ref name="ReferenceA">{{cite journal |last1=Narita |first1=M |last2=Yoshizawa |first2=K |last3=Aoki |first3=K |last4=Takagi |first4=M |last5=Miyatake |first5=M |last6=Suzuki |first6=T |displayauthors=4 |title=A putative sigma1 receptor antagonist NE-100 attenuates the discriminative stimulus effects of ketamine in rats |journal=[[Addiction Biology]] |volume=6 |issue=4 |pages=373–6 |date=September 2001 |pmid=11900615 |doi=10.1080/13556210020077091}}</ref><ref>{{cite journal |journal=European Neuropsychopharmacology |date=22 April 2012 |pmid=21911285 |title=Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo |vauthors=Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR |doi=10.1016/j.euroneuro.2011.08.002 |volume=22 |issue=4 |pages=308–17}}</ref>
* [[Partial agonist]] of the high-affinity state of the [[dopamine]] [[D2 receptor|D<sub>2</sub> receptor]]<ref name="pmid12232776" /><ref name="pmid19391150">{{cite journal |last1=Seeman |first1=P |last2=Guan |first2=HC |last3=Hirbec |first3=H |title=Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil |journal=[[Synapse (journal)|Synapse]] |volume=63 |issue=8 |pages=698–704 |date=August 2009 |pmid=19391150 |doi=10.1002/syn.20647 |url= https://semanticscholar.org/paper/c119108f7ce0d841a2b88846108eece9ee0ac9ed}}</ref>
* Ligand of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]]<ref name="pmid12232776" />
* [[Positive allosteric modulator|Potentiator]] of the serotonin [[5-HT3 receptor|5-HT<sub>3</sub> receptor]]<ref name="pmid8777109">{{cite journal|vauthors=Appadu BL, Lambert DG|year=1996|title=Interaction of i.v. anaesthetic agents with 5-HT3 receptors|url=|journal=[[British Journal of Anaesthesia]]|volume=76|issue=2|pages=271–3|doi=10.1093/bja/76.2.271|pmid=8777109}}</ref><ref name="pmid1718520">{{cite journal|vauthors=Peters JA, Malone HM, Lambert JJ|year=1991|title=Ketamine potentiates 5-HT3 receptor-mediated currents in rabbit nodose ganglion neurones|url=|journal=[[British Journal of Pharmacology]]|volume=103|issue=3|pages=1623–5|doi=10.1111/j.1476-5381.1991.tb09837.x|pmc=1907797|pmid=1718520}}</ref>
* [[Muscarinic acetylcholine receptor]] antagonist<ref name="MathewZarate2016" /><ref name="pmid9806706" />
* [[Negative allosteric modulator]] of [[nicotinic acetylcholine receptor]]s (e.g., [[Alpha-7 nicotinic receptor|α<sub>7</sub>]], [[alpha-4 beta-2 nicotinic receptor|α<sub>4</sub>β<sub>2</sub>]])<ref name="MathewZarate2016" /><ref name="pmid9806706" />
* Ligand of [[Estrogen receptor alpha|estrogen receptor α]] (ERα)<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 (journal)|Biochemical Pharmacology]] | volume = 152 | issue = | pages = 279–292 | date = June 2018 | pmid = 29621538 | pmc = 5960634 | doi = 10.1016/j.bcp.2018.03.032 | url = }}</ref>
* [[Enzyme inhibitor|Inhibitor]] of [[cholinesterase]]<ref name="MathewZarate2016" />
* [[Reuptake inhibitor|Inhibitor]] of the [[reuptake]] of [[serotonin]], [[norepinephrine]], and [[dopamine]]<ref name="pmid9806706" />
* Ligand of the [[PCP site 2]]<ref name="pmid7968938" />
* [[Channel blocker|Blocker]] of [[voltage-gated sodium channel|voltage-gated/dependent sodium]] and [[voltage-dependent calcium channel|calcium channels]]<ref name="pmid9806706" /><ref>{{cite book |author1=Pharmaceutical Society of Australia |author2=The Royal Australian College of General Practitioners |author3=Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists |authorlink1=Pharmaceutical Society of Australia |authorlink2=Royal Australian College of General Practitioners |title=Australian Medicines Handbook 2011 |section=2.1.1 IV General Anaesthetics |sectionurl= |edition=12th |publisher=Australian Medicines Handbook Pty Ltd. |year=2011 |page=13 |isbn=978-0-9805790-4-8 |location=Adelaide |ref={{sfnref|Australian Medicines Handbook|2011}}}}</ref>
* Blocker of [[HCN1]] cation channels<ref name="pmid19158287" /><ref name="pmid28560710">{{cite journal |author1=Ku, SM |author2=Han, MH |title=HCN Channel Targets for Novel Antidepressant Treatment |journal=[[Neurotherapeutics]] |volume=14 |issue=3 |pages=698–715 |year=2017 |pmid=28560710 |doi=10.1007/s13311-017-0538-7 |pmc=5509632}}</ref>
*Decreasing extracellular levels of [[D-serine]], which is required for activation of the NMDA receptor complex, and increasing intracellular levels of the [[amino acid]]<ref name=":0" />
* Inhibitor of [[nitric oxide synthase]]<ref name="pmid9806706" /><ref name="ReferenceA" />
* Indirect agonist of the [[AMPA receptor]]<ref>{{cite journal |last1=Zanos |first1=Panos |last2=Moaddel |first2=Ruin |last3=Morris |first3=Patrick J. |last4=Georgiou |first4=Polymnia |last5=Fischell |first5=Jonathan |last6=Elmer |first6=Greg I. |last7=Alkondon |first7=Manickavasagom |last8=Yuan |first8=Peixiong |last9=Pribut |first9=Heather J. |last10=Singh |first10=Nagendra S. |last11=Dossou |first11=Katina S.S. |last12=Fang |first12=Yuhong |last13=Huang |first13=Xi-Ping |last14=Mayo |first14=Cheryl L. |last15=Wainer |first15=Irving W. |last16=Albuquerque |first16=Edson X. |last17=Thompson |first17=Scott M. |last18=Thomas |first18=Craig J. |last19=Zarate Jr |first19=Carlos A. |last20=Gould |first20=Todd D. |title=NMDAR inhibition-independent antidepressant actions of ketamine metabolites |journal=Nature |date=4 May 2016 |volume=533 |issue=7604 |pages=481–486 |doi=10.1038/nature17998 |pmid=27144355 |pmc=4922311 |bibcode=2016Natur.533..481Z}}</ref>
 
With a few exceptions (including interactions with the D<sub>2</sub> and D<sub>2</sub><sup>high</sup> receptor, nicotinic acetylcholine receptors by metabolites, and ERα) however, these actions 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 |year=2015 |pmid=26075331 |pmc=4556466 |doi=10.1111/bph.13222 |url= }}</ref> A binding study assessed ketamine at 56&nbsp;sites including [[neurotransmitter receptor]]s and [[neurotransmitter transporter|transporters]] and found that it had [[Ligand (biochemistry)#Receptor/ligand binding affinity|K<sub>i</sub>]] (binding affinity) values of >10,000&nbsp;[[Nanomolar|nM]] at all sites except the dizocilpine site of the NMDA receptor (K<sub>i</sub> = 659&nbsp;nM), indicating a minimum of 15-fold [[Binding selectivity|selectivity]] for the NMDA receptor over any other site assessed in this study.<ref name="pmid23527166" />
 
Although ketamine is a very weak ligand of the [[monoamine transporter]]s (K<sub>i</sub> > 60,000&nbsp;nM), it has been suggested that it may interact with [[allosteric site]]s on the monoamine transporters to produce [[monoamine reuptake inhibition]].<ref name="pmid23527166" /> However, no functional inhibition ([[IC50|IC<sub>50</sub>]]) of the human monoamine transporters has been observed with ketamine or its [[metabolite]]s at concentrations of up to 10,000&nbsp;nM.<ref name="pmid27469513" /><ref name="pmid28418641">{{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 |year=2017 |pmid=28418641 |doi=10.1021/acschemneuro.7b00074 |url=}}</ref> Moreover, [[preclinical research|animal studies]] and at least three human [[case report]]s have found no interaction between ketamine and the [[monoamine oxidase inhibitor]] (MAOI) [[tranylcypromine]], which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as [[serotonin syndrome]] or [[hypertensive crisis]].<ref name="pmid28097909">{{cite journal |vauthors=Kraus C, Rabl U, Vanicek T, et al. |title=Administration of ketamine for unipolar and bipolar depression |journal=International Journal of Psychiatry in Clinical Practice |volume=21 |issue=1 |pages=2–12 |year=2017 |pmid=28097909 |doi=10.1080/13651501.2016.1254802 |url=}}</ref><ref name="pmid26302763">{{cite journal |vauthors=Bartova L, Vogl SE, Stamenkovic M, et al. |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 |year=2015 |pmid=26302763 |doi=10.1016/j.euroneuro.2015.07.021 |url=}}</ref> Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans.<ref name="pmid28097909" /><ref name="pmid28418641" /><ref name="pmid27469513" /><ref name="pmid26302763" /> Ketamine has been found to increase [[Dopaminergic pathways|dopaminergic neurotransmission]] in the brain, but instead of being due to dopamine reuptake inhibition, this may be via [[upstream and downstream (transduction)|indirect/downstream]] mechanisms, namely through antagonism of the NMDA receptor.<ref name="pmid28418641" /><ref name="pmid27469513" />
 
[[Active metabolite]]s of ketamine including [[dehydronorketamine]], [[hydroxynorketamine]], and [[norketamine]] have been found to act as negative [[allosteric modulator]]s of the α<sub>7</sub> nicotinic acetylcholine receptor in the KXa7R1 [[cell line]] ([[HEK293]] cells [[transfection|transfected]] with rat nicotinic acetylcholine receptor genes) with subanesthetic and nanomolar potencies (e.g., IC<sub>50</sub> = 55&nbsp;nM for dehydronorketamine), whereas ketamine itself was inactive at the same concentrations (< 1&nbsp;μM).<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 = European Journal of Pharmacology | volume = 698 | issue = 1–3 | pages = 228–34 | year = 2013 | pmid = 23183107 | pmc = 3534778 | doi = 10.1016/j.ejphar.2012.11.023 | url = }}</ref> These findings suggest that metabolites may contribute importantly to the [[pharmacodynamics]] of ketamine by means other than NMDA receptor antagonism.<ref name="pmid23183107" />
 
Ketamine has been found to act as a potent partial agonist of the high-affinity state of the human and rat dopamine D<sub>2</sub> receptors in multiple studies.<ref name="pmid12232776" /><ref name="pmid18720422" /><ref name="pmid19391150" /> Its apparent potency for this action is similar to that of its NMDA receptor antagonism.<ref name="pmid12232776" /><ref name="pmid18720422" /><ref name="pmid19391150" /> However, there are also contradictory data, with studies finding an affinity of ketamine of >10,000&nbsp;nM 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 | year = 2006 | pmid = 16730695 | doi = 10.1016/j.ejphar.2006.04.026 | url = }}</ref> and direct interactions with the D<sub>2</sub> receptor are controversial.<ref name="pmid15247457">{{cite journal | vauthors = Seeman P | title = Comment on "Diverse psychotomimetics act through a common signaling pathway" | journal = Science | volume = 305 | issue = 5681 | pages = 180; author reply 180 | year = 2004 | pmid = 15247457 | doi = 10.1126/science.1096072 | url = | doi-access = free }}</ref> Moreover, whereas D<sub>2</sub> receptor agonists like [[bromocriptine]] are able to rapidly and powerfully suppress [[prolactin]] [[secretion]],<ref name="Springer2012">{{cite book|title=The Role of Brain Dopamine|url=https://books.google.com/books?id=yjHwCAAAQBAJ&pg=PA23|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73897-5|pages=23–}}</ref> subanesthetic doses of ketamine have not been found to do this in humans and in fact have been found to dose-dependently ''increase'' prolactin levels.<ref name="pmid8122957">{{cite journal | vauthors = Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS | title = Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses | journal = Archives of General Psychiatry | volume = 51 | issue = 3 | pages = 199–214 | year = 1994 | pmid = 8122957 | doi = 10.1001/archpsyc.1994.03950030035004| url = }}</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 | year = 2001 | pmid = 11282259 | doi = 10.1016/S0893-133X(00)00194-9 | url = | doi-access = free }}</ref> [[Medical imaging|Imaging]] studies have shown mixed results on inhibition of [[striatum|striatal]] [<sup>11</sup>C] [[raclopride]] binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect.<ref name="pmid17591653">{{cite journal | vauthors = Rabiner EA | title = Imaging of striatal dopamine release elicited with NMDA antagonists: is there anything there to be seen? | journal = Journal of Psychopharmacology | volume = 21 | issue = 3 | pages = 253–8 | year = 2007 | pmid = 17591653 | doi = 10.1177/0269881107077767 | url = }}</ref> However, changes in [<sup>11</sup>C] raclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D<sub>2</sub> receptor.<ref name="pmid17591653" />
 
Ketamine and certain metabolites have been found to act as agonists of the ERα, with affinities in the nanomolar to low micromolar range.<ref name="pmid29621538" /> The affinity of ketamine for the ERα was about 100-fold lower than that of [[estradiol (medication)|estradiol]].<ref name="pmid29621538" /> Ketamine and its metabolites may bind to a site on the ERα that is distinct from that of estradiol.<ref name="pmid29621538" />
 
==== Effects in the brain and the body ====
Antagonism of the NMDA receptor is thought to be responsible for the anesthetic, [[amnesic]], [[dissociative]], and [[hallucinogen]]ic effects of ketamine.<ref name="pmid9806706" /> The mechanism(s) of action for the [[antidepressant]] effects of ketamine at lower doses have yet to be fully elucidated.<ref name="pmid24409146">{{cite journal |last1= Browne |first1= CA |last2= Lucki |first2= I |title= Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants |journal= [[Frontiers in Pharmacology]] |volume= 4 |page= 161 |year= 2013 |pmid= 24409146 |pmc= 3873522 |doi= 10.3389/fphar.2013.00161 |df= dmy-all }}</ref> NMDA receptor antagonism results in analgesia by preventing [[central sensitization]] in [[posterior horn of spinal cord|dorsal horn]] neurons; in other words, ketamine's actions interfere with pain transmission in the [[spinal cord]].<ref name="Quibell2011">{{cite journal |last1= Quibell |first1= R |last2= Prommer |first2= EE |last3= Mihalyo |first3= M |last4= Twycross |first4= R |last5= Wilcock |first5= A |displayauthors= 4 |title= Ketamine* |journal= [[Journal of Pain and Symptom Management]] |date= March 2011 |volume= 41 |issue= 3 |pages= 640–9 |doi= 10.1016/j.jpainsymman.2011.01.001 |pmid= 21419322 |url= http://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext |type= Therapeutic Review|doi-access= free }}</ref> Inhibition of nitric oxide synthase lowers the production of [[nitric oxide]] – a [[gasotransmitter]] involved in [[pain perception]], hence further contributing to analgesia.<ref name=aroni>{{cite journal |last1= Aroni |first1= F |last2= Iacovidou |first2= N |last3= Dontas |first3= I |last4= Pourzitaki |first4= C |last5= Xanthos |first5= T |displayauthors= 4 |title= Pharmacological aspects and potential new clinical applications of ketamine: Reevaluation of an old drug |journal= The Journal of Clinical Pharmacology |date= August 2009 |volume= 49 |issue= 8 |pages= 957–64 |pmid= 19546251 |doi= 10.1177/0091270009337941|url= https://semanticscholar.org/paper/c40ec027e5e5e16f1a01c7c5589d888fa2fcde76 }}</ref>
 
Ketamine produces measurable changes in peripheral organ systems, including the [[cardiovascular]], [[gastrointestinal system|gastrointestinal]], and [[respiratory system]]s:<ref name=aroni />
* Cardiovascular: Ketamine stimulates the [[sympathetic nervous system]], resulting in cardiovascular changes.
* Gastrointestinal: Ketamine produces nausea and vomiting in 15 to 25% of individuals at anesthetic doses.<ref name="pmid9806706" /><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 | year = 2008 | pmid = 18720422 | doi = 10.1002/syn.20561 | url = }}</ref>
* Respiratory: Ketamine causes [[bronchodilation]].<ref name="pmid25417928">{{cite journal |vauthors=Xu J, Lei H |title=Ketamine-an update on its clinical uses and abuses |journal=CNS Neuroscience & Therapeutics |volume=20 |issue=12 |pages=1015–20 |year=2014 |pmid=25417928 |pmc=6493134 |doi=10.1111/cns.12363 |url=}}</ref> Several mechanisms have been hypothesized to explain this effect.<ref name="pmid25417928" />
 
The exact mechanisms of these effects are not fully understood.
 
==== Antidepressant effects ====
It has yet to be fully understood how ketamine mediates its robust and rapid-onset antidepressant effects.<ref name="pmid29736744" /><ref name="pmid29532791">{{cite journal | vauthors = Zanos P, Gould TD | title = Mechanisms of ketamine action as an antidepressant | journal = Mol. Psychiatry | volume = 23 | issue = 4 | pages = 801–811 | date = April 2018 | pmid = 29532791 | pmc = 5999402 | doi = 10.1038/mp.2017.255 | url = }}</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 | url = }}</ref> In any case, it has been elucidated that acute [[receptor antagonist|blockade]] of NMDA receptors in the brain results in an activation of [[α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor]]s (AMPA receptors), which in turn modulate a variety of downstream [[signaling pathway]]s to influence [[neurotransmission]] in the [[limbic system]] and mediate antidepressant effects of NMDA receptor antagonists like ketamine.<ref name="pmid29736744" /><ref name="pmid29532791" /> Such downstream actions of this activation of AMPA receptors include [[upregulation]] of [[brain-derived neurotrophic factor]] (BDNF) and activation of its signaling receptor [[tropomyosin receptor kinase B]] (TrkB), activation of the [[mammalian target of rapamycin]] (mTOR) pathway, deactivation of [[glycogen synthase kinase 3]] (GSK-3), and inhibition of the [[phosphorylation]] of the [[eukaryotic elongation factor 2]] (eEF2) [[kinase]].<ref name="pmid29736744" /><ref name="pmid29532791" /><ref name="pmid26519901">{{cite journal | vauthors = Björkholm C, Monteggia LM | title = BDNF – a key transducer of antidepressant effects | journal = Neuropharmacology | volume = 102 | issue = | pages = 72–9 | date = March 2016 | pmid = 26519901 | pmc = 4763983 | doi = 10.1016/j.neuropharm.2015.10.034 | url = }}</ref><ref name="pmid27425886">{{cite journal | vauthors = Castrén E, Kojima M | title = Brain-derived neurotrophic factor in mood disorders and antidepressant treatments | journal = Neurobiol. Dis. | volume = 97 | issue = Pt B | pages = 119–126 | date = January 2017 | pmid = 27425886 | doi = 10.1016/j.nbd.2016.07.010 | hdl = 10138/311483 | url = | hdl-access = free }}</ref> In addition to blockade of the NMDA receptor, the active metabolite of ketamine hydroxynorketamine, which does not interact importantly with the NMDA receptor but nonetheless indirectly activates AMPA receptors similarly, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.<ref name="pmid29532791" /><ref name="pmid29516301" /> Recent research has elucidated that an acute inhibition of the [[lateral habenula]], a part of the brain in the limbic system that has been referred to as the "anti-reward center" (projecting to and inhibiting the [[mesolimbic reward pathway]] and modulating other limbic areas), may be involved in the antidepressant effects of ketamine.<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 | url = | doi-access = free }}</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 | url = | bibcode = 2018Natur.554..317Y }}</ref>
 
[[Esketamine]] is a more [[potency (pharmacology)|potent]] NMDA receptor antagonist and dissociative hallucinogen than [[arketamine]], the other enantiomer of ketamine.<ref name="Hashimoto2019" /> Because NMDA receptor antagonism was thought to underlie the antidepressant effects of ketamine, esketamine was selected for clinical development as an antidepressant.<ref name="Hashimoto2019" /> However, [[preclinical research]] has since indicated that arketamine, as well as [[(2R,6R)-hydroxynorketamine|(2''R'',6''R'')-hydroxynorketamine]], a [[metabolite]] of arketamine with negligible affinity for the NMDA receptor, may be more effective antidepressants than esketamine.<ref name="Hashimoto2019" /> In addition, non-ketamine NMDA receptor antagonists in general are less effective antidepressants than ketamine.<ref name="Hashimoto2019" /> Indeed, non-ketamine NMDA receptor antagonists, including [[memantine]], [[lanicemine]], [[rislenemdaz]], [[rapastinel]], and [[4-chlorokynurenine]], have thus far failed to demonstrate sufficient effectiveness for depression.<ref name="Hashimoto2019" /><ref name="GarayZarate2018">{{cite journal|last1=Garay|first1=Ricardo|last2=Zarate|first2=Carlos A.|last3=Cavero|first3=Icilio|last4=Kim|first4=Yong-Ku|last5=Charpeaud|first5=Thomas|last6=Skolnick|first6=Phil|title=The development of glutamate-based antidepressants is taking longer than expected|journal=Drug Discovery Today|volume=23|issue=10|year=2018|pages=1689–1692|issn=1359-6446|doi=10.1016/j.drudis.2018.02.006|pmid=29501913|pmc=6211562}}</ref> It is now thought that NMDA receptor antagonism may not be responsible for the antidepressant effects of ketamine.<ref name="Hashimoto2019" /><ref name="GarayZarate2018" /> For these reasons, {{As of|2019||df=|lc=y}}, arketamine and (2''R'',6''R'')-hydroxynorketamine are both entering clinical trials for the treatment of depression.<ref name="Hashimoto2019" /><ref name="AdisInsight-HR-071603">{{Cite web | url=https://adisinsight.springer.com/drugs/800056158 | title=Arketamine - Jiangsu Hengrui Medicine - AdisInsight}}</ref>
 
==== Relationships between levels and effects ====
[[Drowsiness]], [[dissociative|dissociation]], and [[psychosis]]-like effects (e.g., [[hallucination]]s, [[delirium]]) are reported in patients treated with ketamine starting at circulating concentrations of around 50 to 200&nbsp;ng/mL (210–841&nbsp;nM), while analgesia begins at levels of approximately 100 to 200&nbsp;ng/mL (421–841&nbsp;nM).<ref name="SleighHarvey2014">{{cite journal |last1=Sleigh |first1=Jamie |last2=Harvey |first2=Martyn |last3=Voss |first3=Logan |last4=Denny |first4=Bill |title=Ketamine – More mechanisms of action than just NMDA blockade |journal=Trends in Anaesthesia and Critical Care |date=June 2014 |volume=4 |issue=2–3 |pages=76–81 |doi=10.1016/j.tacc.2014.03.002|doi-access=free }}</ref><ref name="sinner" /> 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 (294–841&nbsp;nM).<ref name="pmid28249076" /> Circulating concentrations of around 2,000 to 3,000&nbsp;ng/mL (8,413–12,620&nbsp;nM) are employed during anesthesia, and patients may start to awaken once levels of ketamine have decreased to about 500 to 1,000&nbsp;ng/mL (2,103–4,207&nbsp;nM).<ref name="SleighHarvey2014" /><ref name="sinner" /> There is wide variation in the peak concentrations of ketamine that have been reported in association with anesthesia in the literature, with values ranging from 2,211–3,447&nbsp;ng/mL (9,300–14,500&nbsp;nM) to as high as 22,370&nbsp;ng/mL (94,100&nbsp;nM).<ref name="pmid9915326" /><ref name="pmid12232776" /> [[Biological activity|Bioactive]] concentrations of ketamine are lower than total plasma levels due to [[plasma protein binding]],<ref name="pmid9915326" /> although plasma protein binding is relatively low with ketamine (approximately 12 to 47% protein-bound).<ref name="DowdJohnson2016">{{cite book|author1=Frank J. Dowd|author2=Bart Johnson|author3=Angelo Mariotti|title=Pharmacology and Therapeutics for Dentistry – E-Book|url=https://books.google.com/books?id=6xT7DAAAQBAJ&pg=PA235|date=3 September 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-44595-5|pages=235–}}</ref> Concentrations of ketamine in the [[brain]] have been reported to be several-fold higher than in plasma.<ref name="pmid12232776" />
 
=== Pharmacokinetics ===
 
====Absorption====
Ketamine can be absorbed by [[intravenous]], [[intramuscular]], [[oral administration|oral]], and [[topical]] routes due to both its water and lipid solubilities.<ref name=aroni /> In medical settings, ketamine is usually injected intravenously or intramuscularly.<ref name="lankenau">{{cite journal |last1=Lankenau |first1=Stephen E. |last2=Sanders |first2=Bill |last3=Bloom |first3=Jennifer Jackson |last4=Hathazi |first4=Dodi |last5=Alarcon |first5=Erica |last6=Tortu |first6=Stephanie |last7=Clatts |first7=Michael C. |title=First injection of ketamine among young injection drug users (IDUs) in three U.S. cities |journal=Drug and Alcohol Dependence |date=March 2007 |volume=87 |issue=2–3 |pages=183–193 |doi=10.1016/j.drugalcdep.2006.08.015 |pmid=16979848 |pmc=1852477 }}</ref> The medication can be started using the [[oral administration|oral route]], or people may be changed from a [[hypodermoclysis|subcutaneous infusion]] once pain is controlled. Oral ketamine is easily broken down by [[bile acid]]s, and hence has a low bioavailability. Often, [[lozenge]]s or "gummies" for [[sublingual administration|sublingual]] or [[buccal administration|buccal]] absorption prepared by a [[compounding pharmacy]] are used to combat this issue. Some specialists stop the subcutaneous infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.<ref>{{cite web |title= Ketamine in Palliative Care |url= http://www.palliativecareguidelines.scot.nhs.uk/documents/Ketaminefinal.pdf |date= August 2013 |origyear= August 2010 |website= Palliative Care Guidelines |publisher= [[NHS Lothian]], NHS Scotland, [[Health and Social Care Directorates]], Scotland |location= Edinburgh |archiveurl= https://web.archive.org/web/20131029203516/http://www.palliativecareguidelines.scot.nhs.uk/documents/Ketaminefinal.pdf |archivedate= 29 October 2013 |url-status=dead |df= dmy-all }}</ref>
 
Bioavailability through the oral route reaches 17 to 29%; bioavailability through other routes are: 93% intramuscularly, 8 to 50% intranasally, 24 to 30% sublingually, and 11 to 30% rectally.<ref name="Quibell2011" /><ref name=sinner>{{cite book |last1= Sinner |first1= B |last2 =Graf |first2= BM |chapter= Ketamine |title= Modern Anesthetics |editor-last1= Schüttler |editor-first1= J |editor-last2= Schwilden |editor-first2= 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><ref name="pmid29736744" /><ref name=Zhang2018 /><ref name="Hashimoto2019" /> The [[onset of action]] of ketamine is seconds intravenously, 1 to 5 minutes intramuscularly, 15 to 30 minutes subcutaneously, 5 to 10 minutes via insufflation, and 15 to 30 minutes orally.<ref name="sinner" /><ref name="Quibell2011" /> [[Tmax (pharmacology)|Maximal concentrations]] of ketamine are reached in 1 to 3 minutes intravenously, 5 to 15 minutes intramuscularly, 10 to 20 minutes intranasally, 30 minutes orally, 30 to 45 minutes rectally, and 30 to 45 minutes sublingually.<ref name=haas>{{cite journal |last1= Haas |first= DA |last2= Harper |first2= DG |title= Ketamine: A review of its pharmacologic properties and use in ambulatory anesthesia |journal= Anesthesia Progress |year= 1992 |volume= 39 |issue= 3 |pages= 61–8 |pmid= 1308374 |pmc= 2148758}}</ref><ref name=Zhang2018 /><ref name="Hashimoto2019" />
 
====Distribution====
Ketamine is rapidly [[distribution (pharmacology)|distributed]] and, due to its high [[lipophilicity]], rapidly crosses the [[blood–brain barrier]] into the [[central nervous system]].<ref name="Cromhout2003">{{cite journal|last1=Cromhout|first1=Andries|title=Ketamine: Its use in the emergency department|journal=Emergency Medicine Australasia|volume=15|issue=2|year=2003|pages=155–159|issn=1742-6731|doi=10.1046/j.1442-2026.2003.00433.x|pmid=12675625|url=https://semanticscholar.org/paper/57b7d345688ca3efc73512a9ae985c0b8d700c7f}}</ref> Its [[distribution half-life]] is about 7 to 11 minutes.<ref name="Cromhout2003" /> The [[plasma protein binding]] of ketamine is relatively low at 12 to 47%.<ref name="Kintz2014" /><ref name="sinner" /><ref name="DowdJohnson2016" />
 
====Metabolism====
When administered orally, ketamine undergoes [[first-pass metabolism]], where it is [[biotransformation|biotransformed]] in the [[liver]] by [[CYP3A4]] (major), [[CYP2B6]] (minor), and [[CYP2C9]] (minor) [[isoenzyme]]s into [[norketamine]] (through ''N''-[[demethylation]]) and ultimately [[dehydronorketamine]].<ref name=sinner /> Intermediate in the biotransformation of norketamine into dehydronorketamine is the [[hydroxylation]] of norketamine into [[hydroxynorketamine]] by CYP2B6 and [[CYP2A6]]. As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent as an anesthetic, and plasma levels of this metabolite are three times higher than ketamine following oral administration.<ref name=aroni /><ref name=haas /> Ketamine and its metabolites are also [[conjugation (biochemistry)|conjugated]].<ref name="Levine2003" />
 
The [[duration of action]] of ketamine in a clinical setting is 0.5 to 2 hours intramuscularly and 4 to 6 hours orally.<ref name="Quibell2011" />
 
====Elimination====
Ketamine is [[elimination (pharmacology)|eliminated]] about 90% in [[urine]] and about 1 to 5% in [[feces]].<ref name="MathewZarate2016" /> The medication is excreted mostly in the form of [[metabolite]]s, with only 2 to 4% remaining unchanged.<ref name="Cromhout2003" /> Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.<ref name=heng2011>{{cite journal |last1= Li |first1= JH |last2= Vicknasingam |first2= B |last3= Cheung |first3= YW |last4= Zhou |first4= W |last5= Nurhidayat |first5= AW |last6= Jarlais |first6= DC |last7= Schottenfeld |first7= R |displayauthors= 4 |title= To use or not to use: An update on licit and illicit ketamine use |journal= Substance Abuse and Rehabilitation |volume= 2 |issue= 1 |pages= 11–20 |year= 2011 |pmid= 24474851 |pmc= 3846302 |doi= 10.2147/SAR.S15458 |df= dmy-all }}</ref>
 
== 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 [[arylcyclohexylamine]] derivative. Ketamine is a [[chirality (chemistry)|chiral]] compound. Most pharmaceutical preparations of ketamine are [[racemic]]; however, some brands reportedly have (mostly undocumented) differences in their [[enantiomer]]ic proportions. The more active enantiomer, [[esketamine]] (''S''-ketamine), is also available for medical use under the brand name Ketanest S,<ref name="Kruger1998">{{cite journal |last= Krüger |first= AD |title= Current aspects of using ketamine in childhood |language= DE |journal= Anaesthesiologie und Reanimation |volume= 23 |issue= 3 |pages= 64–71 |year= 1998 |pmid= 9707751 |doi= |url=}}</ref> while the less active enantiomer, [[arketamine]] (''R''-ketamine), has never been marketed as an [[enantiopure drug]] for clinical use.
 
The [[optical rotation]] of a given enantiomer of ketamine can vary between its [[Salt (chemistry)|salts]] and [[free base]] form. The free base form of (''S'')‑ketamine exhibits [[Dextrorotation and levorotation|dextrorotation]] and is therefore labelled (''S'')‑(+)‑ketamine. However, its [[hydrochloride]] salt shows [[Dextrorotation and levorotation|levorotation]] and is thus labelled (''S'')‑(−)‑ketamine hydrochloride. The difference originates from the [[Cyclohexane conformation|conformation of the cyclohexanone ring]]. In both the free base and the hydrochloride, the cyclohexanone ring adopts a [[Cyclohexane conformation#Chair conformation|chair conformation]], but the orientation of the substituents varies. In the free base, the ''o''-chlorophenyl group adopts an equatorial position and the methylamino group adopts an axial position.<ref>{{cite journal|last2=Burjanadze|first2=N|last3=Breitkreutz|first3=J|last4=Bergander|first4=K|last5=Bergenthal|first5=D|last6=Kataeva|first6=O|last7=Fröhlich|first7=R|last8=Luftmann|first8=H|last9=Blaschke|first9=G|year=2002|title=Mechanistic study on the opposite migration order of the enantiomers of ketamine with α- and β-cyclodextrin in capillary electrophoresis|url=|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|first1=Bezhan|last1=C}}</ref> In the hydrochloride salt, the positions are reversed, with the ''o''-chlorophenyl group axial and the methylamino group equatorial.<ref>{{ cite journal | first1 = P | last1 = Hakey | first2 = W | last2 = Ouellette | first3 = J | last3 = Zubieta | first4 = T | last4 = Korter | title = (''S'')-(+)-Ketamine hydrochloride | journal = [[Acta Crystallographica Section E]] | year = 2008 | volume = 64 | issue = Pt 8 | page = o1487 | doi = 10.1107/S1600536808021053 | pmid = 21203199 | pmc = 2962251 }}</ref> Not all salts of ketamine show different optical rotation to the free base: (''S'')-ketamine (''R'',''R'')-[[tartrate]] is levorotatory, like (''S'')‑ketamine.<ref>{{ cite journal | first1 = E | last1 = Ratti-Mobery | first2 = P | last2 = Groth | first3 = AJ | last3 = Aasen | title = The Absolute Configuration of Ketamine – A General Anaesthetic. The Crystal Structure of the (''R'',''R'')-Tartrate Salt of (−)-(''S'')-Ketamine | journal = [[Acta Chemica Scandinavica]] | year = 1991 | volume = 45 | pages = 108–110 | doi = 10.3891/acta.chem.scand.45-0108 | doi-access = free }}</ref>
 
{|class=wikitable
|+ Conformational and optical-sign effects of amine-salt formation of ''(S)''-ketamine
!
! Free-base amine<br>(equatorial chlorophenyl)
! Hydrochloride salt<br>(axial chlorophenyl)
|-
! Skeletal<br>structure
| [[File:S-ketamine-2D-skeletal.png|upright=0.5|frameless]]
| [[File:S-(+)-ketamine-hydrochloride-2D-skeletal.png|upright=0.5|frameless]]
|-
! X-ray<br>structure
| [[File:S-ketamine-3D-balls.png|upright=0.5|frameless]]
| [[File:S-ketamine-from-HCl-xtal-3D-balls.png|upright=0.5|frameless]]
|}
 
=== Analogues ===
[[File:Arylcyclohexylamines.png|325px|thumb|right|Ketamine and other arylcyclohexylamines.]]
{{Main|Arylcyclohexylamine#List of arylcyclohexylamines}}
 
Other arylcyclohexylamines and [[structural analogue|analogues]] of ketamine include [[eticyclidine]] (PCE), [[3-MeO-PCE]], [[methoxetamine]] (MXE), [[tiletamine]], [[phencyclidine]] (PCP), [[tenocyclidine]] (TCP), and [[Arylcyclohexylamine#List of arylcyclohexylamines|many others]].<ref name="pmid24678061">{{cite journal | vauthors = Morris H, Wallach J | title = From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs | journal= Drug Testing and Analysis | volume = 6 | issue = 7–8 | pages = 614–32 | year = 2014 | pmid =24678061 |doi=10.1002/dta.1620 |url= https://semanticscholar.org/paper/14fa18fafa0cbf5d835cfce4bce18435f2ac4ec2}}</ref>
 
=== Detection ===
Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to 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 ==
 
=== Medical use ===
[[File:Ketamine Vials.jpg|thumb|Ketamine vials.]]
 
Ketamine was first synthesized in 1962 by [[Calvin L. Stevens]], a professor of Chemistry at [[Wayne State University]] and a [[Parke-Davis]] consultant conducting research on alpha-hydroxyimine rearrangements.<ref name="Clark">{{cite book |title=Chronic Pain and Addiction |url=https://archive.org/details/chronicpainaddic00clar |url-access=limited |last=Clark |first=Michael R. |publisher=Karger AG |year=2011 |isbn=978-3-8055-9725-8 |location=Basel, Switzerland |pages=[https://archive.org/details/chronicpainaddic00clar/page/n170 166]– |quote= |authorlink= }}</ref> It was known by the developmental code name ''CI-581''.<ref name="Hashimoto2019" /> After promising preclinical research in animals, ketamine was introduced to testing in [[Experimentation on prisoners|human prisoners]] in 1964.<ref name=Domino2010>{{cite journal |last=Domino |first=EF |title=Taming the ketamine tiger |journal=Anesthesiology |date=September 2010 |volume=113 |issue=3 |pages=678–84 |pmid=20693870 |doi=10.1097/ALN.0b013e3181ed09a2 |url=https://zenodo.org/record/896636 |doi-access=free }}</ref><ref name=Morris>{{cite journal |last1=Morris |first1=H |last2=Wallach |first2=J |title=From PCP to MXE: A comprehensive review of the non-medical use of dissociative drugs |journal=[[Drug Testing and Analysis]] |volume=6 |issue=7–8 |pages=614–32 |date=July 2014 |pmid=24678061 |doi=10.1002/dta.1620 |url= https://semanticscholar.org/paper/14fa18fafa0cbf5d835cfce4bce18435f2ac4ec2}}</ref> These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over [[phencyclidine]] (PCP) as a [[dissociative]] anesthetic.<ref>{{cite journal |last1=Corssen |first1=G |last2=Domino |first2=EF |title=Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581 |journal=Anesthesia & Analgesia |date=January–February 1966 |volume=45 |issue=1 |pages=29–40 |pmid=5325977 |doi=10.1213/00000539-196601000-00007 }}<!-- full text pdf available free at url given --></ref> Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the [[Vietnam War]].<ref name="CESAR" />
 
=== Nonmedical use ===
[[File:Just Say Neigh (7909762236).jpg|thumb|"Just Say Neigh" T-shirts making reference to ketamine became popular in the late 2000s, parodying the [[Just Say No]] campaign and ketamine's reputation as a drug for horses.<ref>{{cite web |title='Ketamine – Just Say Neigh' Shirts Gets The Message Out |url=https://www.trendhunter.com/trends/ketamin-just-say-neigh-drugs-messaging-t-shirts |website=Trendhunter |accessdate=19 August 2017 |date=15 April 2009 |url-status=live |archiveurl=https://web.archive.org/web/20170819104544/https://www.trendhunter.com/trends/ketamin-just-say-neigh-drugs-messaging-t-shirts |archivedate=19 August 2017 }}</ref>]]
 
Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.<ref name="CESAR" /> Early use was documented in underground literature such as ''[[The Fabulous Furry Freak Brothers]]''. It was used in [[psychiatry|psychiatric]] and other academic research through the 1970s, culminating in 1978 with the publishing of [[psychonautics|psychonaut]] [[John C. Lilly|John Lilly's]] ''The Scientist'', and [[Marcia Moore]] and Howard Alltounian's ''Journeys into the Bright World'', which documented the unusual phenomenology of ketamine intoxication.<ref name="HistoryLiterature">History of non-medical use in literature references:
* {{harvnb|Alltounian & Moore|1978}}
* {{harvnb|Palmer & Horowitz|2000}}
* {{harvnb|Kelly|2001}}</ref> The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of [[rave party|raves]] and other parties.<ref name="KetamineRave">Increased non-medical use references:
* {{cite journal |last=Awuonda |first=M |title=Swedes alarmed at ketamine misuse |journal=[[The Lancet]] |date=13 July 1996 |volume=348 |issue=9020 |page=122 |doi=10.1016/S0140-6736(05)64628-4}}
* {{cite journal |last1=Curran |first1=HV |last2=Morgan |first2=C |title=Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later |journal=[[Addiction (journal)|Addiction]] |date=April 2000 |volume=95 |issue=4 |pages=575–90 |pmid=10829333 |doi=10.1046/j.1360-0443.2000.9545759.x}}
* {{cite journal |last=Gahlinger |first=PM |title=Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine |journal=[[American Family Physician]] |date=1 June 2004 |volume=69 |issue=11 |pages=2619–26 |pmid=15202696 |url=http://www.aafp.org/afp/2004/0601/p2619.html |url-status=live |archiveurl=https://web.archive.org/web/20151117033142/http://www.aafp.org/afp/2004/0601/p2619.html |archivedate=17 November 2015 }}
* {{cite journal |last=Jansen |first=KL |title=Non-medical use of ketamine |journal=[[BMJ]] |date=6 March 1993 |volume=306 |issue=6878 |pages=601–2 |pmid=8461808 |pmc=1676978 |doi=10.1136/bmj.306.6878.601}}
* {{harvnb|Joe-Laider & Hunt|2008}}</ref> However, its emergence as a [[club drug]] differs from other club drugs (e.g., [[MDMA]]) due to its [[anesthetic]] properties (e.g., slurred speech, immobilization) at higher doses;<ref name=hongkong>{{cite journal |last1=Joe-Laidler |first1=K |last2=Hunt |first2=G |title=Sit down to float: The cultural meaning of ketamine use in Hong Kong |journal=Addiction Research & Theory |date=1 June 2008 |volume=16 |issue=3 |pages=259–71 |doi=10.1080/16066350801983673 |pmid=19759834 |pmc=2744071 |ref={{sfnref|Joe-Laider & Hunt|2008}}}}</ref> in addition, there are reports of ketamine being sold as "ecstasy".<ref name="KetamineAsEctstasy">Ketamine sold as "ecstasy" references:
* {{cite journal |last=Tanner-Smith |first=EE |title=Pharmacological content of tablets sold as "ecstasy": Results from an online testing service |journal=[[Drug and Alcohol Dependence (journal)|Drug and Alcohol Dependence]] |volume=83 |issue=3 |pages=247–54 |date=July 2006 |pmid=16364567 |doi=10.1016/j.drugalcdep.2005.11.016 |url=http://www.recoveryonpurpose.com/upload/Pharmacology%20of%20Ecstasy.pdf |url-status=live |archiveurl=https://web.archive.org/web/20160304044352/http://www.recoveryonpurpose.com/upload/Pharmacology%20of%20Ecstasy.pdf |archivedate=4 March 2016 |df= dmy-all}}
* {{cite journal |last1=Copeland |first1=J |last2=Dillon |first2=P |title=The health and psycho-social consequences of ketamine use |journal= International Journal of Drug Policy |volume=16 |issue=2 |year=2005 |pages=122–31 |doi=10.1016/j.drugpo.2004.12.003}}
* {{cite book|last1=Measham |first1=Fiona |last2=Parker |first2=Howard |first3=Judith |last3=Aldridge |title=Dancing on Drugs: Risk, Health and Hedonism in the British Club Scene |year=2001 |publisher=[[Free Association Books]] |location=London |isbn=978-1-85343-512-6 |pages= }}{{Verify source|date=August 2014}}{{page needed|date=December 2013}}</ref> The use of ketamine as part of a "postclubbing experience" has also been documented.<ref>{{cite journal |last1=Moore |first1=K |last2=Measham |first2=F |title=Ketamine use: Minimising problems and maximising pleasure |journal=Drugs and Alcohol Today |year=2006 |volume=6 |issue=3 |pages=29–32 |doi=10.1108/17459265200600047}}</ref> Ketamine's rise in the dance culture was rapid in [[Hong Kong]] by the end of the 1990s.<ref name="hongkong" /> Before becoming a federally controlled substance in the United States in 1999, ketamine was available as diverted pharmaceutical preparations and as a pure powder sold in bulk quantities from domestic chemical supply companies.<ref name=Morris /> Much of the current ketamine diverted for nonmedical use originates in China and India.<ref name=Morris />
 
== Society and culture ==
 
=== Generic names ===
''Ketamine'' is the [[English language|English]] [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while ''ketamine hydrochloride'' is its {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book |author=J. Elks |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA258 |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |pages=258– |url-status=live |archiveurl=https://web.archive.org/web/20170215024945/https://books.google.com/books?id=0vXTBwAAQBAJ |archivedate=15 February 2017 }}</ref><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><ref name="MortonHall2012">{{cite book |author1=I.K. Morton |author2=Judith M. Hall |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 |archiveurl=https://web.archive.org/web/20170411144623/https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA159 |archivedate=11 April 2017 }}</ref> Its generic name in [[Spanish language|Spanish]] and [[Italian language|Italian]] and its {{abbrlink|DCIT|Denominazione Comune Italiana}} are ''ketamina'', in [[French language|French]] and its {{abbrlink|DCF|Dénomination Commune Française}} are ''kétamine'', in [[German language|German]] is ''Ketamin'', and in [[Latin language|Latin]] is ''ketaminum''.<ref name="IndexNominum2000" />
 
The ''S''(+) [[stereoisomer]] of ketamine is known as ''[[esketamine]]'', and this is its {{abbrlink|BAN|British Approved Name}} while ''esketamine hydrochloride'' is its {{abbrlink|BANM|British Approved Name}}.<ref name="Drugs.com-Esketamine">{{cite web |url=https://www.drugs.com/international/esketamine.html |title=Esketamine |accessdate=28 August 2017 |url-status=live |archiveurl=https://web.archive.org/web/20170829040021/https://www.drugs.com/international/esketamine.html |archivedate=29 August 2017 }}</ref>
 
=== Brand names ===
Ketamine is primarily sold throughout the world under the brand name Ketalar.<ref name="IndexNominum2000" /><ref name="MortonHall2012" /> It is also marketed under a variety of other brand names, including Calypsol, Ketamin, Ketamina, Ketamine, Ketaminol, Ketanest, Ketaset, Tekam, and Vetalar among others.<ref name="IndexNominum2000" /><ref name="MortonHall2012" />
 
Esketamine is sold mainly under the brand names Ketanest and Ketanest-S.<ref name="Drugs.com-Esketamine" />
 
=== Clinics ===
After the publication of the NIH-run antidepressant clinical trial, clinics began opening in which the intravenous ketamine is given for depression.<ref name=bloomberg>{{cite news |last1=Winter |first1=Caroline |title=The Club Drug Cure: Ketamine's New Shot as a Depression Treatment |url=https://www.bloomberg.com/graphics/2015-ketamine-depression-treatment/ |work=Bloomberg BusinessWeek |date=19 August 2015 |url-status=live |archiveurl=https://web.archive.org/web/20170330201420/https://www.bloomberg.com/graphics/2015-ketamine-depression-treatment/ |archivedate=30 March 2017 }}</ref><ref name="Lawrence2015">{{cite journal |last1=Lawrence |first1=Janna |title=The secret life of ketamine |journal=Pharmaceutical Journal |date=19 March 2015 |url=https://www.pharmaceutical-journal.com/news-and-analysis/features/the-secret-life-of-ketamine/20068151.article?firstPass=false }}</ref> This practice is an [[off label]] use of ketamine in the United States.<ref name=bloomberg /> As of 2015 there were about 60 such clinics in the US; the procedure was not covered by insurance, and people paid between $400 and $1700 [[Out-of-pocket expense|out of pocket]] for a treatment.<ref>{{cite news |last1=Agres |first1=Ted |title=Anesthesiologists Take Lead As Ketamine Clinics Proliferate |url=http://www.anesthesiologynews.com/PRN-/Article/12-15/Anesthesiologists-Take-Lead-As-Ketamine-Clinics-Proliferate/34407/ses=ogst |work=Anesthesiology News |date=3 December 2015}}</ref> It was estimated in 2018 that there were approximately 300 of these clinics.<ref name="Hashimoto2019" /> With the approval of esketamine for depression, it is expected that this will change.<ref name="Hashimoto2019" />
 
A chain of such clinics in Australia run by Aura Medical Corporation was closed down by regulatory authorities in 2015, because the clinics' marketing was not supported by scientific research and because the clinic sent people home with ketamine and needles to administer infusions to themselves.<ref>{{cite news |last1=Nulley |first1=Dan |title=Australia Has Closed Its Most Controversial Ketamine Clinics |url=https://www.vice.com/en_se/article/a-look-at-australias-ketamine-clinic-closures |work=Vice |date=28 July 2015 |url-status=live |archiveurl=https://web.archive.org/web/20170325113346/https://www.vice.com/en_se/article/a-look-at-australias-ketamine-clinic-closures |archivedate=25 March 2017 }}</ref>
 
=== Legal status ===
While ketamine is legally marketed in many countries worldwide,<ref name="IndexNominum2000" /> it is also a [[controlled substance]] in many countries.<ref name="MathewZarate2016" />
 
==== Australia ====
In [[Australia]], ketamine is listed as a schedule 8 controlled drug under the [[Standard for the Uniform Scheduling of Medicines and Poisons|Poisons Standard]] (October 2015).<ref name="Poisons Standard">Poisons Standard October 2015 {{cite web |url=https://www.comlaw.gov.au/Details/F2015L01534 |title=Archived copy |accessdate=6 January 2016 |url-status=live |archiveurl=https://web.archive.org/web/20160119074606/https://www.comlaw.gov.au/Details/F2015L01534/ |archivedate=19 January 2016 }}</ref> Schedule 8 drugs are outlined in the Poisons Act 1964 as "Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence."<ref>Poisons Act 1964 http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument:26063P/$FILE/Poisons%20Act%201964%20-%20%5B09-f0-04%5D.pdf?OpenElement {{webarchive |url=https://web.archive.org/web/20151222191725/http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument%3A26063P/%24FILE/Poisons%20Act%201964%20-%20%5B09-f0-04%5D.pdf?OpenElement |date=22 December 2015}}</ref>
 
==== Canada ====
In [[Canada]], ketamine is 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 |last= |first= |date=12 June 2014 |website=Justice Laws Website |publisher=[[Government of Canada]] |access-date= |chapter= |chapter-url= |url-status=dead |archiveurl=https://web.archive.org/web/20131122143804/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-24.html#h-28 |archivedate=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=[[Canada Gazette]] [[Canada Gazette#Part II|Part II]] |issue=19 |volume=139 |page=2130 |accessdate=2 August 2014 |url-status=dead |archiveurl=https://web.archive.org/web/20140808053346/http://napra.ca/Content_Files/Files/CDSA-Ketamine.pdf |archivedate=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 |accessdate=2 August 2014 |url-status=live |archiveurl=https://web.archive.org/web/20140810002143/http://cscb.ca/node/94386 |archivedate=10 August 2014 }}</ref>
 
==== Hong Kong ====
In [[Hong Kong]], since 2000, ketamine has been regulated under Schedule 1 of Hong Kong Chapter 134 ''Dangerous Drugs Ordinance''. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.<ref>{{citation |title=Government to tighten control on Ketamine |url=http://www.info.gov.hk/gia/general/200011/22/1122170.htm |website=info.gov.hk |publisher=[[Government of Hong Kong|Government of the Hong Kong Special Administrative]] |date=22 November 2000 |type=press release |accessdate=2 August 2014 |archiveurl=https://web.archive.org/web/20130626183118/http://www.info.gov.hk/gia/general/200011/22/1122170.htm |archivedate=26 June 2013 |url-status=live}}</ref><ref name="Ho Wai-kin2011">{{cite book |last1=Ho Wai-kin |first1=Victor |title=Criminal Law in Hong Kong |year=2011 |publisher=Kluwer Law International |isbn=9789041133069 |page= [https://books.google.com/books?id=6kdaN0f4ab0C&pg=PA33 33]}}</ref>
 
==== Taiwan ====
By 2002, ketamine was classified as class III in [[Taiwan]]; given the recent rise in prevalence in East Asia, however, rescheduling into class I or II is being considered.<ref name=heng2011 /><ref name="Chang2012">{{cite news |last= Chang |first= Rich |date= 4 December 2012 |title= Ketamine to be made a class-two drug: Official |url= http://www.taipeitimes.com/News/taiwan/archives/2012/12/04/2003549327 |newspaper= [[Taipei Times]] |page= 3 |url-status=live |archiveurl= https://web.archive.org/web/20140808044631/http://www.taipeitimes.com/News/taiwan/archives/2012/12/04/2003549327 |archivedate= 8 August 2014 |df= dmy-all }}</ref>
 
==== India ====
In December 2013, the [[government of India]], in response to rising recreational use and the use of ketamine as a date rape drug, has added it to [[Schedule X]] of the [[Drugs and Cosmetics Rules, 1945|Drug and Cosmetics Act]] 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= [[The Times of India]] |date= 7 January 2014 |accessdate= 2 August 2014 |url-status=live |archiveurl= https://web.archive.org/web/20140414064604/http://timesofindia.indiatimes.com/city/goa/Ketamine-drug-brought-under-Schedule-X-to-curb-abuse/articleshow/28486002.cms |archivedate= 14 April 2014 |df= dmy-all }}</ref><ref>{{cite news|first=Sumitra |last=Deb Roy |newspaper=[[The Times of India]] |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 |archiveurl=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 |archivedate=30 December 2013 |url-status=live }}</ref>
 
==== United Kingdom ====
In the [[United Kingdom]], it became labeled a [[Misuse of Drugs Act 1971|Class C drug]] on 1 January 2006.<ref name=heng2011 /><ref>{{cite news |url=http://news.bbc.co.uk/2/hi/uk_news/4564606.stm |work=[[BBC News]] |title=Club 'horse' drug to be outlawed |date=28 December 2005 |accessdate=7 May 2010 |archiveurl=https://web.archive.org/web/20090903231015/http://news.bbc.co.uk/2/hi/uk_news/4564606.stm |archivedate=3 September 2009 |url-status=live}}</ref> On 10 December 2013, the UK [[Advisory Council on the Misuse of Drugs]] (ACMD) recommended that the government reclassify ketamine to become a Class B drug,<ref>{{citation |url=https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/264677/ACMD_ketamine_report_dec13.pdf |title=Ketamine: A review of use and harm |accessdate=22 January 2014 |author1=Advisory Council on the Misuse of Drugs (ACMD) |authorlink1=Advisory Council on the Misuse of Drugs |last2=Baker |first2=Norman |authorlink2=Norman Baker |date=10 December 2013 |type=Policy paper |publisher=[[Crown copyright#United Kingdom|Crown copyright]]; [[Open Government Licence]] |postscript=. |url-status=live |archiveurl=https://web.archive.org/web/20140228133801/https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/264677/ACMD_ketamine_report_dec13.pdf |archivedate= 28 February 2014 }}</ref> and on 12 February 2014 the [[Home Office]] announced it would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".<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 |accessdate=21 February 2014 |date=12 February 2014 |last1=Baker |first1=Norman |authorlink1=Norman Baker |author2=(Minister for Crime Prevention) |author3=Home Office |authorlink3=Home Office |authorlink4=Government of the United Kingdom |author4=United Kingdom |type=Correspondence to Les Iverson [chair of]; [[Advisory Council on the Misuse of Drugs]] |publisher=[[Crown copyright#United Kingdom|Crown copyright]]; [[Open Government Licence]] |postscript=. |url-status=live |archiveurl=https://web.archive.org/web/20140228195318/https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/279186/ResponseACMDketamineReclassification.pdf |archivedate=28 February 2014 }}</ref><ref>{{cite news |last=Dixon |first=Hayley |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=[[The Daily Telegraph]] |accessdate=2 August 2014 |url-status=live |archiveurl=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 |archivedate=9 June 2014 }}</ref>
 
The UK Minister of State for Crime Prevention, [[Norman Baker]], responding to the ACMD's advice, said the issue of its recheduling for medical and veterinary use would be addressed "separately to allow for a period of consultation".<ref name="reclassify response" />
 
==== United States ====
The increase in recreational use prompted ketamine to be placed in Schedule III of the [[United States]] [[Controlled Substance Act]] in August 1999.<ref name="FedReg1999">{{cite journal |last1=Marshall |first1=DR |author2=(Deputy Administrator) |authorlink1=Donnie R. Marshall |author3=Drug Enforcement Administration |author4=Department of Justice |date=13 July 1999 |title=Schedules of Controlled Substances: Placement of Ketamine into Schedule III [21 CFR Part 1308. Final Rule 99-17803] |journal=[[Federal Register]] |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 |authorlink3=Drug Enforcement Administration |authorlink4=United States Department of Justice |url-status=live |archiveurl=https://web.archive.org/web/20150505060507/http://www.gpo.gov/fdsys/pkg/FR-1999-07-13/pdf/99-17803.pdf |archivedate=5 May 2015 }}</ref>
 
=== Recreational use ===
{{redirect|K-hole|the trend forecasting group|K-HOLE (trend forecasting group)}}
[[File:Ketamine Crystals.jpg|thumb|right|Ketamine solution poured onto glass and left to dry.]]
 
Recreational use of ketamine was documented in the early 1970s in underground literature (e.g., ''[[The Fabulous Furry Freak Brothers]]'').<ref name=furryfreak>{{cite book |last=Shelton |first=Gilbert |title=The Freak Brothers Omnibus |year=2008 |publisher=Knockabout Comics |location=London |isbn=978-0-86166-159-6 |pages=144}}</ref> It was used in [[psychiatry|psychiatric]] and other academic research through the 1970s, culminating in 1978 with the publishing of [[psychonautics|psychonaut]] [[John C. Lilly|John Lilly]]'s ''The Scientist'', and [[Marcia Moore]] and Howard Alltounian's ''Journeys into the Bright World'', which documented the unusual phenomenology of ketamine intoxication.<ref>{{Cite book |author1=Alltounian, Howard Sunny |author2=Marcia Moore |title=Journeys into the Bright World |publisher=Para Research |location=Rockport, Mass. |year=1978 |pages= |isbn=978-0-914918-12-7}}{{Page needed |date=September 2010}}</ref> The incidence of non-medical ketamine use increased through the end of the century, especially in the context of [[rave party|raves]] and other parties.<ref>{{cite journal |last=Awuonda |first=Moussa |title=Swedes alarmed at ketamine misuse |journal=[[The Lancet]] |date=1 July 1996 |volume=348 |issue=9020 |pages=122 |doi=10.1016/S0140-6736(05)64628-4}}</ref><ref>{{cite journal |last=Curran |first=HV |author2=Morgan, C  |title=Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later |journal=Addiction |date=April 2000 |volume=95 |issue=4 |pages=575–90 |pmid=10829333 |doi=10.1046/j.1360-0443.2000.9545759.x}}</ref><ref>{{cite journal |last=Gahlinger |first=PM |title=Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine |journal=[[American Family Physician]] |date=1 June 2004 |volume=69 |issue=11 |pages=2619–26 |pmid=15202696}}</ref><ref>{{cite journal |last=Jansen |first=KL |title=Non-medical use of ketamine |journal=[[BMJ]] |edition=Clinical research |date=6 March 1993 |volume=306 |issue=6878 |pages=601–2 |pmid=8461808 |pmc=1676978 |doi=10.1136/bmj.306.6878.601}}</ref><ref name=hongkong /> Its emergence as a [[club drug]] differs from other club drugs (e.g., [[MDMA]]), however, due to its [[anesthetic]] properties (e.g., slurred speech, immobilization) at higher doses;<ref name=hongkong /> in addition, reports of ketamine being sold as "ecstasy" are common.<ref>{{cite book |last=Parker |first=Fiona Measham, Judith Aldridge, Howard |title=Dancing on drugs: risk, health and hedonism in the British club scene |year=2001 |publisher=Free Association |location=London |isbn=978-1-85343-512-6}}</ref>  In the 1993 book ''[[E for Ecstasy]]''<ref>{{Cite book|vauthors=Saunders N, Heron L |year=1993 |title=E for Ecstasy |publisher=N. Saunders |location=London |isbn=978-0-9501628-8-1}}{{Page needed|date=September 2010}}</ref> (about the uses of the street drug [[Methylenedioxymethamphetamine|Ecstasy]] in the UK),  the writer, activist, and Ecstasy advocate [[Nicholas Saunders (activist)|Nicholas Saunders]] highlighted test results showing that certain consignments of the drug also contained ketamine. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine, [[ephedrine]], and [[selegiline]]", as did a consignment of "Sitting Duck" Ecstasy tablets.<ref>See: [http://ecstasy.org/testing/pillstilJuly.html] for details online.</ref>
 
The use of ketamine as part of a "post-clubbing experience" has also been documented.<ref>{{cite journal |last=Moore |first=Karenza |author2=Measham, Fiona  |title=Ketamine use: minimising problems and maximising pleasure |journal=Drugs and Alcohol Today |date=1 January 2006 |volume=6 |issue=3 |pages=29–32 |doi=10.1108/17459265200600047}}</ref> Ketamine's rise in the dance culture was most rapid in [[Hong Kong]] by the end of the 1990s.<ref name="hongkong" />
 
Ketamine use as a recreational drug 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 suicides.<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 |accessdate=7 June 2015 |url-status=live |archiveurl=https://web.archive.org/web/20150607022331/http://www.vice.com/en_uk/read/ketamine-slowly-ruins-your-bladder-and-kills-you-863 |archivedate=7 June 2015  |date=23 July 2014 }}, accessed 7 June 2015.</ref> The majority of deaths were among young people.<ref name=TheCrownONS13>The Crown, 2013, "Drug related deaths involving ketamine in England and Wales," a report of the Mortality team, Life Events and Population Sources Division, Office for National Statistics, the Crown (U.K.), see {{cite web |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 |title=Archived copy |accessdate=7 June 2015 |url-status=live |archiveurl=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 |archivedate=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 |accessdate=7 June 2015 |url-status=live |archiveurl=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 |archivedate=19 June 2015 }}, accessed 7 June 2015.</ref> This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.).<ref name=DixonTelegraph14>{{cite news|last1=Dixon|first1=Hayley|title=Ketamine death of public schoolgirl an 'act of stupidity which destroyed family'|url=https://www.telegraph.co.uk/news/uknews/law-and-order/10633700/Ketamine-death-of-public-schoolgirl-an-act-of-stupidity-which-destroyed-family.html|work=Telegraph.co.uk|date=12 February 2014|url-status=live|archiveurl=https://web.archive.org/web/20170824233230/http://www.telegraph.co.uk/news/uknews/law-and-order/10633700/Ketamine-death-of-public-schoolgirl-an-act-of-stupidity-which-destroyed-family.html|archivedate=24 August 2017}}</ref>
 
Unlike the other well-known dissociatives [[phencyclidine]] (PCP) and [[dextromethorphan]] (DXM), ketamine is very short-acting. It takes effect within about 10 minutes,<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=[[Centre for Addiction and Mental Health]] |accessdate=27 July 2014 |year=2003 |archiveurl=https://web.archive.org/web/20140407061143/https://knowledgex.camh.net/amhspecialists/resources_families/Pages/ketamine_dyk.aspx |archivedate= 7 April 2014 |url-status=dead |df= dmy-all}}</ref> while its [[hallucinogenic]] effects last 60 minutes when [[insufflation (medicine)|insufflated]] or injected and up to two hours when ingested orally.<ref>{{Cite journal |last1=Giannini |first1=AJ |last2=Loiselle |first2=RH |last3=Giannini |first3=MC |last4=Price |first4=WA |title=Phencyclidine and the dissociative |journal=Psychiatric Medicine |volume=3 |issue=3 |pages=197–217 |year=1985 |pmid=2893430}}</ref>
 
At subanesthetic doses—under-dosaged from a medical point of view—ketamine produces a [[Dissociation (psychology)|dissociative state]], characterised by a sense of detachment from one's physical body and the external world which is known as [[depersonalization]] and [[derealization]].<ref name="Giannini2000">{{Cite journal |last1=Giannini |first1=AJ |last2=Underwood |first2=NA |last3=Condon |first3=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 "K-hole", a state of dissociation with visual and auditory hallucinations.<ref>{{Cite book |last=Giannini |first=AJ |title=Drug Abuse |publisher=Health Information Press |location=Los Angeles |year=1999 |page=[https://archive.org/details/drugabuse00ajam/page/104 104] |isbn=978-1-885987-11-2 |url=https://archive.org/details/drugabuse00ajam |url-access=registration }}</ref> [[John C. Lilly]], [[Marcia Moore]], [[D. M. Turner]] and [[David Woodard]] (amongst others) have written extensively about their own [[entheogen]]ic use of, and [[psychonautics|psychonautic]] experiences with, ketamine.<ref name="RecreationalLiterature">References for recreational use in literature:
* {{Cite book |last=Lilly |first=John Cunningham |authorlink=John C. Lilly |title=The Scientist: A Metaphysical Autobiography |publisher=[[Ronin Publishing|Ronin]] |location=Berkeley, CA |year=1997 |pages=[https://archive.org/details/scientist00lill/page/144 144–] |isbn=978-0-914171-72-0 |url=https://archive.org/details/scientist00lill/page/144 }}
* {{cite book |last=Kelly |first=Kit |title=The Little Book of Ketamine |year=2001 |publisher=[[Ronin Publishing|Ronin]] |isbn=978-1-57951-121-0 |pages=[https://books.google.com/books?id=KAabFIHLl7oC&pg=PA23 23], [https://books.google.com/books?id=KAabFIHLl7oC&pg=PA40 40–45], [https://books.google.com/books?id=KAabFIHLl7oC&pg=PA46 46–51], ibid |ref={{sfnref|Kelly|2001}}}}
* {{Cite book |last1=Alltounian |first1=Howard Sunny |first2=Marcia |last2=Moore |authorlink2=Marcia Moore |title=Journeys Into the Bright World |publisher=Para Research |location=Rockport, MA |year=1978 |pages=|isbn=978-0-914918-12-7 |ref={{sfnref|Alltounian & Moore|1978}}}}
* {{cite book |last1=Palmer |first1=Cynthia |last2=Horowitz |first2=Michael |authorlink2=Fitz Hugh Ludlow Memorial Library|title=Sisters of the Extreme: Women Writing on the Drug Experience |year=2000|publisher=[[Inner Traditions – Bear & Company|Inner Traditions]] |isbn=978-0-89281-757-3|pages=[https://books.google.com/books?id=RaCG6kbk2lIC&pg=PT254 254–258], ibid |ref={{sfnref|Palmer & Horowitz|2000}}}}
* {{Cite book |last=Turner |first=D.M. |authorlink=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 |last=Jansen |first=Karl |publisher=Multidisciplinary Association for Psychedelic Studies |isbn=978-0-9660019-3-8 |year=2001 |pages=50, 89}}</ref> In 2006 the Russian edition of [[Adam Parfrey]]'s ''Apocalypse Culture II'' 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>Woodard, D., [https://tranxcend.tumblr.com/post/29813278762/ketamine “The Ketamine Necromance”], in A. Parfrey, ''Apocalypse Culture II'' ([[Los Angeles]]: [[Feral House]], 2000), pp. 288–295.</ref>{{rp|288–295}}
 
Because of its ability to cause confusion and [[anterograde amnesia|amnesia]], ketamine has been used for [[date rape]].<ref name="CAMHDYK" /><ref name="CESAR">{{cite web |url=http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |title=Ketamine |accessdate=27 July 2014 |date=29 October 2013 |publisher=Center for Substance Abuse Research (CESAR); [[University of Maryland, College Park]] |archiveurl=https://web.archive.org/web/20131112080924/http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |archivedate=12 November 2013 |url-status=live}}</ref>
 
==== Slang terms ====
<!-- Please do not add names without a reliable source -->
Production for recreational use has been traced to 1967, when it was referred to as "mean green" and "rockmesc".<ref name="Jansen24">{{Cite book|title=Ketamine: Dreams and Realities|last=Jansen|first=Karl|publisher=Multidisciplinary Association for Psychedelic Studies|isbn=978-0-9660019-3-8|year=2001|page=24}}</ref> Recreational names for ketamine include "Special K",<ref name=cesar>{{cite web|title=Center for Substance Abuse Research: Ketamine Terminology|url=http://www.cesar.umd.edu/cesar/drugs/ketamine.asp#terminology|accessdate=3 January 2012}}</ref> "K",<ref name="Jansen26">{{Cite book|title=Ketamine: Dreams and Realities|last=Jansen|first=Karl|publisher=Multidisciplinary Association for Psychedelic Studies|isbn=978-0-9660019-3-8|year=2001|page=26}}</ref><ref name=cesar /> "Kitty", "Ket",<ref name="Jansen55">{{Cite book|title=Ketamine: Dreams and Realities|last=Jansen|first=Karl|publisher=Multidisciplinary Association for Psychedelic Studies|isbn=978-0-9660019-3-8|year=2001|page=55}}</ref> "K2",<ref name="Jansen26" />  "Vitamin K",<ref name=cesar /><ref name="Jansen55" /> "Super K",<ref name=cesar /> "Honey oil",<ref name=cesar /><ref name=nida /> "Jet",<ref name=cesar /><ref name=dea>{{cite web|title=DEA Office of Diversion Control: Ketamine|url=http://www.deadiversion.usdoj.gov/drugs_concern/ketamine/ketamine.htm|accessdate=3 January 2012|url-status=dead|archiveurl=https://web.archive.org/web/20111215081724/http://www.deadiversion.usdoj.gov/drugs_concern/ketamine/ketamine.htm|archivedate=15 December 2011}}</ref> "Super acid",<ref name=cesar /> "Mauve",<ref name=cesar /> "Special LA coke",<ref name=cesar /> "Purple",<ref name=cesar /> "Cat Valium",<ref name=dea /> "Knod-off", "Skittles", "Blind Squid",<ref name=factsheet>{{cite web|title=Ketamine: A fact sheet (National Clearinghouse for Alcohol and Drug Information)|url=http://www.regionsix.com/ResourceLibrary/Club%20Drugs%20and%20Hallucinogens/Ketamine.pdf|accessdate=3 January 2012|url-status=dead|archiveurl=https://web.archive.org/web/20120426090754/http://www.regionsix.com/ResourceLibrary/Club%20Drugs%20and%20Hallucinogens/Ketamine.pdf|archivedate=26 April 2012}}</ref> "Keller",<ref name=factsheet /> "Kelly's Day",<ref name=factsheet /> "New ecstasy",<ref name=tellier>{{cite journal|last=Tellier|first=PP|title=Club drugs: is it all ecstasy?|journal=Pediatric Annals|date=September 2002|volume=31|issue=9|pages=550–6|pmid=12271739|doi=10.3928/0090-4481-20020901-07}}</ref> "Psychedelic heroin",<ref name=tellier /> "bump",<ref name=nida>{{cite web|title=Research Report on Hallucinogens and Dissociatives|url=http://www.drugabuse.gov/sites/default/files/rrhalluc.pdf|publisher=NIDA|accessdate=11 January 2012}}</ref> "Majestic".<ref>{{cite book|title=Drugs – Without the Hot Air: Minimising the Harms of Legal and Illegal Drugs|last=Nutt|first=David|authorlink=David Nutt|publisher=UIT Cambridge|isbn=978-1-906860-16-5|year=2012}}</ref> A mixture of ketamine with [[cocaine]] is called "Calvin Klein" or "CK1".<ref>{{cite journal|last=Chakraborty|first=K|author2=Neogi, R |author3=Basu, D |title=Club drugs: review of the 'rave' with a note of concern for the Indian scenario|journal=The Indian Journal of Medical Research|date=June 2011|volume=133|issue=6|pages=594–604|pmid=21727657|pmc=3135986}}</ref> In Hong Kong, where illicit use of the drug is popular, ketamine is colloquially referred to as "kai-jai".<ref name=hongkong />
 
==== Usage ====
 
===== North America =====
According to the ongoing ''[[Monitoring the Future]]'' study conducted by [[University of Michigan]], prevalence rates of recreational ketamine use among American secondary school students (grades 8, 10, and 12) have varied between 0.8–2.5% since 1999, with recent rates at the lower end of this range.<ref>{{cite web|title=Trends in Use of Various Drugs, Table 2|url=http://monitoringthefuture.org/data/11data/pr11t2.pdf|website=[[Monitoring the Future]]|accessdate=17 January 2012}}</ref> The ''2006 [[National Survey on Drug Use and Health]]'' (NSDUH) reports a rate of 0.1% for persons ages 12 or older with the highest rate (0.2%) in those ages 18–25.<ref name=nsduh>{{cite web|title=Use of Specific Hallucinogens: 2006|url=http://www.samhsa.gov/data/2k8/hallucinogens/hallucinogens.htm|website=The NSDUH Report|publisher=Substance Abuse and Mental Health Services Administration|accessdate=17 January 2012}}</ref> Further, 203,000 people are estimated to have used ketamine in 2006, and an estimated 2.3 million people used ketamine at least once in their life.<ref name=nsduh /> A total of 529 emergency department visits in 2009 were ketamine-related.<ref>{{cite web|title=Drug Abuse Warning Network, 2009: National Estimates of Drug-Related Emergency Department Visits|url=http://www.samhsa.gov/data/2k11/DAWN/2k9DAWNED/PDF/DAWN2k9ED.pdf|website=HHS Publication No. (SMA) 11-4659, DAWN Series D-35|publisher=Substance Abuse and Mental Health Services Administration|accessdate=17 January 2012}}</ref>
 
In 2003, the U.S. [[Drug Enforcement Administration]] conducted [[Operation TKO]], a probe into the quality of ketamine being imported from [[Mexico]].<ref name="SI-TKO">{{Cite news| url=http://sportsillustrated.cnn.com/2007/more/07/18/steroids0424/1.html | work=CNN | title=SI.com – The Mexican Connection – Jul 18, 2007 | accessdate=7 May 2010}}</ref> As a result of operation TKO, U.S. and Mexican authorities shut down the Mexico City company Laboratorios Ttokkyo, which was the biggest producer of ketamine in Mexico. According to the DEA, over 80% of ketamine seized in the United States is of Mexican origin. As of 2011, it was mostly shipped from places like India as cheap as $5/gram.<ref name="SI-TKO" /> The [[World Health Organization]] Expert Committee on Drug Dependence, in its thirty-third report (2003),<ref>[http://whqlibdoc.who.int/trs/WHO_TRS_915.pdf Untitled-59<!-- Bot generated title -->]</ref> recommended research into its recreational use due to growing concerns about its rising popularity in Europe, Asia, and North America.
 
===== Europe =====
Cases of ketamine use in club venues have been observed in the Czech Republic, France, Italy, Hungary, The Netherlands and the United Kingdom.<ref name=kalsi>{{cite journal|last=Kalsi|first=Sarbjeet S.|author2=Wood, David M. |author3=Dargan, Paul I. |title=The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use|journal=Emerging Health Threats Journal|date=15 April 2011|volume=4|pages=7107|doi=10.3402/ehtj.v4i0.7107|pmid=24149025|pmc=3168228}}</ref> Additional reports of use and dependence have been reported in Poland and Portugal.<ref>{{cite journal|last=Błachut|first=M|author2=Sołowiów, K |author3=Janus, A |author4=Ruman, J |author5=Cekus, A |author6=Matysiakiewicz, J |author7=Hese, RT |title=[A case of ketamine dependence]|journal=Psychiatria Polska|date=Sep–Oct 2009|volume=43|issue=5|pages=593–9|pmid=20214100}}</ref><ref>{{cite web|last=Greenwald|first=Glenn|title=Drug Decriminalization in Portugal|url=http://www.cato.org/pubs/wtpapers/greenwald_whitepaper.pdf|publisher=CATO Institute|accessdate=12 January 2012}}</ref>
 
===== Australia =====
Australia's ''2010 National Drug Strategy Household Survey report'' shows a prevalence of recent ketamine use of 0.3% in 2004 and 0.2% in 2007 and 2010 in persons aged 14 or older.<ref>{{cite web|title=2010 National Drug Strategy Household Survey report|url=http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=10737419578&libID=10737419577|publisher=Australian Institute of Health and Welfare|accessdate=11 January 2012}}</ref>
 
===== Asia =====
In China, the small village of [[Boshe]] in eastern Guangdong was confirmed as a main production centre when it was raided in 2013.<ref>{{Cite web | url=https://www.bbc.co.uk/news/resources/idt-bc7d54e7-88f6-4026-9faa-2a36d3359bb0 |title = The Ketamine Connection}}</ref>
 
Established by the Hong Kong Narcotics Division of the [[Security Bureau (Hong Kong)|Security Bureau]], the Central Registry of Drug Abuse (CRDA) maintains a database of all the illicit drug users who have come into contact with law enforcement, treatment, health care, and social organizations. The compiled data are confidential under ''The Dangerous Drugs Ordinance'' of Hong Kong, and statistics are made freely available online on a quarterly basis.<ref>{{cite web|last=Cheung|first=Yuet|url=http://www.drugtext.org/pdf/International-national-drug-policy/drug-policy-and-harm-reduction-in-hong-kong.pdf|title=Drug Policy and Harm Reduction in Hong Kong: A Socio-Historical Examination*|accessdate=12 January 2012}}</ref><ref>{{cite web|url=http://www.nd.gov.hk/en/crda.htm|title=CRDA Drug Statistics|accessdate=12 January 2012}}</ref> Statistics from the CRDA show that the number of ketamine users (all ages) in Hong Kong has increased from 1605 (9.8% of total drug users) in 2000 to 5212 (37.6%) in 2009.<ref name=59th>{{cite web|url=http://www.nd.gov.hk/pdf/report/crda_59th/crda_59th_full_report.pdf|title=CRDA Fifty-ninth Report (2000–2009)|accessdate=12 January 2012}}</ref> Increasing trends of ketamine use among illicit drug users under the age of 21 were also reported, rising from 36.9% of young drug users in 2000 to 84.3% in 2009.<ref name=59th />
 
A survey conducted among school-attending Taiwanese adolescents reported prevalence rates of 0.15% in 2004, 0.18% in 2005, and 0.15% in 2006 in middle-school (grades 7 and 9) students; in Taiwanese high-school (grades 10 and 12) students, prevalence was 1.13% in 2004, 0.66% in 2005, and 0.44% in 2006.<ref name=wei09>{{cite journal |last=Chen |first=Wei J |author2=Fu, Tsung-Chieh |author3=Ting, Te-Tien |author4=Huang, Wei-Lun |author5=Tang, Guang-Mang |author6=Hsiao, Chuhsing |author7=Chen, Chuan-Yu |title=Use of ecstasy and other psychoactive substances among school-attending adolescents in Taiwan: national surveys 2004–2006 |journal=[[BioMed Central#Journals|BMC Public Health]] |date=1 January 2009 |volume=9 |issue=1 |pages=27 |doi=10.1186/1471-2458-9-27 |pmid=19159468 |pmc=2636802}}</ref> From the same survey, a large portion (42.8%) of those who reported ecstasy use also reported ketamine use.<ref name=wei09 /> Ketamine was the second-most used [[illicit drug]] (behind ecstasy) in absconding Taiwanese adolescents as reported by a multi-city street outreach survey.<ref>{{cite journal |last=Wang |first=Shi-Heng |author2=Wen-Chun Chen |author3=Chih-Yin Lew-Ting |author4=Chuan-Yu Chen |author5=Wei J Chen |title=Running away experience and psychoactive substance use among adolescents in Taiwan: multi-city street outreach survey |journal=BMC Public Health |date=1 January 2010 |volume=10 |issue=1 |pages=29 |doi=10.1186/1471-2458-10-29 |pmid=20089181 |pmc=2823700}}</ref> In a study comparing the reporting rates between web questionnaires and paper-and-pencil questionnaires, ketamine use was reported a higher rate in the web version.<ref>{{cite journal |last=Wang |first=Yi-Ching |author2=Ching-Mei Lee |author3=Chih-Yin Lew-Ting |author4=Chuhsing Kate Hsiao |author5=Duan-Rung Chen |author6=Wei J. Chen |title=Survey of substance use among high school students in Taipei: Web-based questionnaire versus paper-and-pencil questionnaire |journal=[[Journal of Adolescent Health]] |date=1 October 2005 |volume=37 |issue=4 |pages=289–295 |doi=10.1016/j.jadohealth.2005.03.017 |pmid=16182139}}</ref> Urine samples taken at a club in Taipei, Taiwan showed high rates of ketamine use at 47.0%; this prevalence was compared with that of detainees suspected of recreational drug use in the general public, of which 2.0% of the samples tested positive for ketamine use.<ref>{{cite journal |last=Lua |first=Ahai Chang |author2=Lin, Huei Ru |author3=Tseng, Yong Te |author4=Hu, An Ren |author5=Yeh, Pei Chi |title=Profiles of urine samples from participants at rave party in Taiwan: prevalence of ketamine and MDMA abuse |journal=[[Forensic Science International]] |date=1 September 2003 |volume=136 |issue=1–3 |pages=47–51 |doi=10.1016/S0379-0738(03)00261-5 |pmid=12969619}}</ref>
 
== Research ==
Russian doctor Evgeny Krupitsky has claimed to have obtained encouraging results by using ketamine as part of a treatment for [[alcohol addiction]] which combines [[psychedelic therapy|psychedelic]] and [[aversion therapy|aversive]] techniques.<ref name="KrupitskyGrineko1992">{{cite journal |last1=Krupitsky |first1=EM |last2=Grineko |first2=A Ya |last3=Berkaliev| first3=TN |last4=Paley |first4=AI |last5=Tetrov |first5=UN |last6=Mushkov |first6=KA |last7=Borodikin |first7=Yu S |displayauthors=4 |title=The combination of psychedelic and aversive approaches in alcoholism treatment |journal=[[Alcoholism Treatment Quarterly]] |volume=9 |issue=1 |year=1992 |pages=99–105 |doi=10.1300/J020V09N01_09}}</ref><ref name="Krupitsky1997">{{cite journal |last1=Krupitsky |first1=EM |last2=Grinenko |first2=AY |title=Ketamine psychedelic therapy (KPT): A review of the results of ten years of research |journal=[[Journal of Psychoactive Drugs]] |volume=29 |issue=2 |pages=165–83 |year=1997 |pmid=9250944 |doi=10.1080/02791072.1997.10400185 |url= }}</ref> Krupitsky and Kolp summarized their work to date in 2007.<ref>{{cite book |last1=Krupitsky |first1=Evgeny |last2=Kolp |first2=Eli |chapter=Ch. 6: Ketamine Psychedelic Psychotherapy |volume=2 |title=Psychedelic Medicine: New Evidence for Hallucinogens as Treatments |editor-first1=Michael J. |editor-last1=Winkelman |editor-first2=Thomas B. |editor-last2=Roberts |location=Westport, CT |publisher=[[Greenwood Publishing Group|Praeger]] |pages= |isbn=978-0-275-99023-7 |year=2007 |chapter-url-access=registration |chapter-url=https://archive.org/details/psychedelicmedic0000unse }}</ref>
 
== Veterinary medicine ==
In [[veterinary anesthesia]], ketamine is often used for its anesthetic and analgesic effects on cats,<ref>{{cite journal |last1=Robertson |first1=SA |last2=Taylor |first2=PM |title=Pain management in cats--past, present and future. Part 2. Treatment of pain--clinical pharmacology |journal=Journal of Feline Medicine and Surgery |date=October 2004 |volume=6 |issue=5 |pages=321–33 |doi=10.1016/j.jfms.2003.10.002 |pmid=15363764}}</ref> dogs,<ref>{{cite journal |last1=Lamont |first1=LA |title=Adjunctive analgesic therapy in veterinary medicine |journal=Veterinary Clinics of North America: Small Animal Practice |date=November 2008 |volume=38 |issue=6 |pages=1187–203, v |doi=10.1016/j.cvsm.2008.06.002 |pmid=18954680}}</ref> [[rabbit]]s, [[rat]]s, and other small animals.<ref>{{cite journal |last1=Stunkard |first1=JA |last2=Miller |first2=JC |title=An outline guide to general anesthesia in exotic species |journal=Veterinary Medicine, Small Animal Clinician |date=September 1974 |volume=69 |issue=9 |pages=1181–6 |pmid=4604091}}</ref><ref>{{cite book |publisher=John Wiley & Sons |isbn=978-1-118-68590-7 |last1=Riviere |first1=JE |last2=Papich |first2=MG |title=Veterinary Pharmacology and Therapeutics |date=2009 |page=200 |url=https://books.google.com/books?id=xAPa4WDzAnQC&lpg=PP1&dq=Ketamine%20AND%20veterinary%20medicine&pg=PA200#v=onepage |url-status=live |archiveurl=https://web.archive.org/web/20170824215637/https://books.google.com.au/books?id=xAPa4WDzAnQC&lpg=PP1&dq=Ketamine%20AND%20veterinary%20medicine&pg=PA200#v=onepage&q&f=true |archivedate=24 August 2017 }}</ref> It is highly used in induction and anesthetic maintenance in horses. It is an important part of the "[[rodent cocktail]]", a mixture of drugs used for anesthetizing [[rodents]].<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 |accessdate=27 November 2015 |url-status=live |archiveurl=https://web.archive.org/web/20130804040842/http://www.washcoll.edu/live/files/1227-no-1-anesthesia-sop-revised-1012pdf |archivedate=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 [[pain wind-up]]. Ketamine is used to manage pain among large animals, though it has less effect on [[bovine]]s.{{citation needed|date=March 2014}} It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with [[detomidine]] and [[thiopental]], or sometimes [[guanfacine]].
 
Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.<ref>{{cite journal |last1=Woodall |first1=AJ |last2=McCrohan |first2=CR |title=Excitatory actions of propofol and ketamine in the snail Lymnaea stagnalis |journal=Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology |date=December 2000 |volume=127 |issue=3 |pages=297–305 |doi=10.1016/S0742-8413(00)00155-9|pmid=11246501 }}</ref>
 
== References ==
{{Reflist}}
 
== External links ==
{{Commons category|Ketamine}}
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ketamine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ketamine }}
* [https://web.archive.org/web/20130512224948/http://www.justice.gov/dea/druginfo/drug_data_sheets/Ketamine.pdf DEA: Ketamine Fact Sheet]
 
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