GetWiki

{{Short description|Dissociative anesthetic and anti-depressant}}{{For|the functional group referred to as ketimine|Imine}}{{Use dmy dates|date=March 2023}}{{cs1 config|name-list-style=vanc|display-authors=6}}

factoids

| DailyMedID = Ketamine| licence_US = Ketamine| pregnancy_AU = B3 DATE=22 NOVEMBER 2019 ACCESS-DATE=18 MAY 2020 ARCHIVE-URL=HTTPS://WEB.ARCHIVE.ORG/WEB/20200626125239/HTTPS://WWW.DRUGS.COM/PREGNANCY/KETAMINE.HTML, live, PUBLISHER=US DEA ARCHIVE-DATE=8 APRIL 2024 URL-STATUS=LIVE, Ketamine is listed in Schedule III.Huang, MC., Lin, SK. (2020). Ketamine Abuse: Past and Present. In: Hashimoto, K., Ide, S., Ikeda, K. (eds) Ketamine. Springer, Singapore.weblink JOURNAL = THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS PAGES = CD003351 ISSUE = 9 PMC = 6481583 URL = HTTP://OPUS.BATH.AC.UK/57535/1/PUBLISHED_VERSION.PDF ARCHIVE-DATE = 12 JANUARY 2024 URL-STATUS = LIVE, MOYSE DW, KAYE AD, DIAZ JH, QADRI MY, LINDSAY D, PYATI S > TITLE = PERIOPERATIVE KETAMINE ADMINISTRATION FOR THORACOTOMY PAIN VOLUME = 20 PAGES = 173–184 PMID = 28339431, MATHEW SJ, ZARATE JR CA >TITLE=KETAMINE FOR TREATMENT-RESISTANT DEPRESSION: THE FIRST DECADE OF PROGRESS DATE=25 NOVEMBER 2016 ISBN=978-3-319-42925-0 URL-STATUS=LIVE ARCHIVE-DATE=8 SEPTEMBER 2017, KETAMINE HYDROCHLORIDE: MARTINDALE: THE COMPLETE DRUG REFERENCE>DATE=9 JANUARY 2017VEDITORS=BRAYFIELD AWEBSITE=MEDICINESCOMPLETELOCATION=LONDON, UKARCHIVE-URL=HTTPS://WEB.ARCHIVE.ORG/WEB/20210828134205/HTTPS://ABOUT.MEDICINESCOMPLETE.COM/WP-CONTENT/THEMES/MC-MARKETING/ASSETS/IMAGES/FAVICONS-TILES/FAVICON.ICO, live, | class = NMDA receptor antagonists; General anesthetics; Dissociative hallucinogens; Analgesics; Antidepressants| ATC_prefix = N01| ATC_suffix = AX03| legal_AU = S8| legal_BR = C1| legal_CA = Schedule I| legal_DE = Unscheduled| legal_UK = Class B| legal_US = Schedule III| legal_UN = Unscheduled| legal_status = Rx-onlyIntravenous therapy>Intravenous: 100%

• Intramuscular: 93%
• Epidural: 77%BOOK, Kintz P, Toxicological Aspects of Drug-Facilitated Crimes,weblink 22 March 2014, Elsevier Science, 978-0-12-416969-2, 87–, live,weblink 8 September 2017,
• Intranasal: 45–50%JOURNAL, Marland S, Ellerton J, Andolfatto G, Strapazzon G, Thomassen O, Brandner B, Weatherall A, Paal P, Ketamine: use in anesthesia, CNS Neurosci Ther, 19, 6, 381–9, June 2013, 23521979, 6493613, 10.1111/cns.12072,
• Sublingual: 24–30%JOURNAL, Hashimoto K, Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective, Psychiatry and Clinical Neurosciences, 73, 10, 613–627, October 2019, 31215725, 6851782, 10.1111/pcn.12902,
• Rectal: 25–30%
• By mouth: 16–20%

JOURNAL=EUR J CLIN PHARMACOL ISSUE=6 DATE=1983 DOI=10.1007/BF00607095, 807011, Liver, intestine (oral):HIJAZI Y, BOULIEU R JOURNAL = DRUG METABOLISM AND DISPOSITION ISSUE = 7 DATE = JULY 2002 DOI = 10.1124/DMD.30.7.853, 15787750,

• Major: CYP3A4, CYP2B6| metabolites = Norketamine
• Dehydronorketamine
• Hydroxynorketamine

TITLE= MODERN ANESTHETICS SERIES= HANDBOOK OF EXPERIMENTAL PHARMACOLOGY VOLUME= 182 PAGES= 313–33 DOI=10.1007/978-3-540-74806-9_15, 18175098,

• Intramuscular: 1–5 min
• Subcutaneous: 15–30 min
• Insufflation: 5–10 min
• By mouth: 15–30 min| elimination_half-life = Ketamine: 2.5–3 hours
• Norketamine: 12 hours| duration_of_action = Intramuscular: 0.5–2 hours
• Insufflation: 45–60 min
• By mouth: 1–6+ hours| excretion = Urine: 91%
• Feces: 3%

| index2_label = HCl| IUPHAR_ligand = 4233correct|??}}| CAS_number = 6740-88-1correct|??}}| CAS_number2 = 1867-66-9

• 33643-46-8 (esketamine)
• 33643-49-1 (arketamine)

correct|EBI}}| ChEBI = 6121| PubChem = 3821correct|drugbank}}| DrugBank = DB01221correct|chemspider}}| ChemSpiderID = 3689correct|FDA}}| UNII = 690G0D6V8Hcorrect|kegg}}| KEGG = D08098correct|kegg}}| KEGG2 = D00711correct|EBI}}| ChEMBL = 742URL=HTTPS://BOOKS.GOOGLE.COM/BOOKS?ID=TSJRCAAAQBAJ&PG=PA159 PUBLISHER=SPRINGER SCIENCE & BUSINESS MEDIA PAGES=159– ARCHIVE-URL=HTTPS://WEB.ARCHIVE.ORG/WEB/20170411144623/HTTPS://BOOKS.GOOGLE.COM/BOOKS?ID=TSJRCAAAQBAJ&PG=PA159, 11 April 2017, | IUPAC_name = (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone| C = 13| H = 16| Cl = 1| N = 1| O = 1| chirality = Racemic mixture:

• Esketamine (S(+)-isomer)
• Arketamine (R(−)-isomer)| SMILES = Clc1ccccc1C2(NC)CCCCC2=O

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,4-5,8-9H2,1H3correct|chemspider}}| StdInChIKey = YQEZLKZALYSWHR-UHFFFAOYSA-N| density = | density_notes = CHAPTER=KETAMINE VOLUME=6 PAGES=297–322 ISBN=9780122608063, | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management.JOURNAL, Sachdeva B, Sachdeva P, Ghosh S, Ahmad F, Sinha JK, March 2023, Ketamine as a therapeutic agent in major depressive disorder and posttraumatic stress disorder: Potential medicinal and deleterious effects, Ibrain, en, 9, 1, 90–101, 10.1002/ibra.12094, 37786516, 10528797, 257117630, 2769-2795, free, It is a novel compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.JOURNAL, Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI, Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy, Clinical Pharmacokinetics, 55, 9, 1059–77, September 2016, 27028535, 10.1007/s40262-016-0383-6, 5078489, At anesthetic doses, ketamine induces a state of dissociative anesthesia, a trance-like state providing pain relief, sedation and amnesia. Its distinguishing features as anesthesia are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation.JOURNAL, Green SM, Roback MG, Kennedy RM, Krauss B, Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update, Annals of Emergency Medicine, 57, 5, 449–461, May 2011, 21256625, 10.1016/j.annemergmed.2010.11.030, free, At lower, sub-anesthetic doses, it is a promising agent for pain and treatment-resistant depression.JOURNAL, Zhang K, Hashimoto K, An update on ketamine and its two enantiomers as rapid-acting antidepressants, Expert Review of Neurotherapeutics, 19, 1, 83–92, January 2019, 30513009, 10.1080/14737175.2019.1554434, 54628949, As with many antidepressants, the results of a single administration wane with time.JOURNAL, Hibicke M, Landry AN, Kramer HM, Talman ZK, Nichols CD, Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression, ACS Chemical Neuroscience, 11, 6, 864–871, March 2020, 32133835, 10.1021/acschemneuro.9b00493, 212418003, free, The long-term effects of repeated use are largely unknown, and are an area of active investigation.Liver and urinary toxicity have been reported among regular users of high doses of ketamine for recreational purposes.BOOK, Orhurhu VJ, Vashisht R, Claus LE, Cohen SP, StatPearls, Treasure Island (FL), StatPearls Publishing, Ketamine toxicity, April 2022, 31082131,weblink 18 August 2022, 16 May 2022,weblink live, Ketamine is an NMDA receptor antagonist, accounting for most of its psychoactive effects.Ketamine was first synthesized in 1962 and approved for use in the United States in 1970. It has been regularly used in veterinary medicine and was extensively used for surgical anesthesia in the Vietnam War. Along with other psychotropic drugs, it is on the World Health Organization's List of Essential Medicines.BOOK, ((World Health Organization)), World Health Organization model list of essential medicines: 22nd list (2021), 2021, 10665/345533, World Health Organization, World Health Organization, Geneva, WHO/MHP/HPS/EML/2021.02, free, It is available as a generic medication.WEB, Ketamine Injection,weblink Drugs.com, 1 December 2014, live,weblink" title="web.archive.org/web/20141210181630weblink">weblink 10 December 2014, When used as a recreational drug, it is found both in crystalline powder and liquid form, and is often referred to by recreational users as "Special K" or simply "K". It is used as a recreational drug for its hallucinogenic and dissociative effects.JOURNAL, Morgan CJ, Curran HV, January 2012, Ketamine use: a review, Addiction, 107, 1, 27–38, 10.1111/j.1360-0443.2011.03576.x, 21777321, 11064759, {{TOC limit}}

Medical uses

Anesthesia

The use of ketamine in anesthesia reflects its characteristics. It is a drug of choice for short-term procedures when muscle relaxation is not required.BOOK, Rosenbaum SB, Gupta V, Palacios JL, Ketamine, 2020,weblink StatPearls, StatPearls Publishing, 29262083, 5 March 2020, 12 November 2020,weblink live, The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. It suppresses breathing much less than most other available anesthetics.JOURNAL, Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A, Use of ketamine in severe status asthmaticus in intensive care unit, Iranian Journal of Allergy, Asthma, and Immunology, 2, 4, 175–80, December 2003, 17301376,weblink live,weblink" title="web.archive.org/web/20141006100116weblink">weblink 6 October 2014, When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system.JOURNAL, Adams HA, [S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation], DE, Der Anaesthesist, 46, 12, 1081–7, December 1997, 9451493, 10.1007/s001010050510, 36323023, S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation, Protective airway reflexes are preservedJOURNAL, Wong JJ, Lee JH, Turner DA, Rehder KJ, A review of the use of adjunctive therapies in severe acute asthma exacerbation in critically ill children, Expert Review of Respiratory Medicine, 8, 4, 423–41, August 2014, 24993063, 10.1586/17476348.2014.915752, 31435021, and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways. Psychotomimetic effects limit the acceptance of ketamine; however, lamotrigine and nimodipine decrease psychotomimetic effects and can be counteracted also by benzodiazepines or propofol administration. Ketofol is a combination of ketamine and propofol.Ketamine is frequently used in severely injured people and appears to be safe in this group.JOURNAL, Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM, The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review, Annals of Emergency Medicine, 65, 1, 43–51.e2, January 2015, 25064742, 10.1016/j.annemergmed.2014.06.018, It has been widely used for emergency surgery in field conditions in war zones, for example, during the Vietnam War.JOURNAL, Mion G, History of anaesthesia: The ketamine story - past, present and future, Eur J Anaesthesiol, 34, 9, 571–575, September 2017, 28731926, 10.1097/EJA.0000000000000638, 27536846, A 2011 clinical practice guideline supports the use of ketamine as a sedative in emergency medicine, including during physically painful procedures. It is the drug of choice for people in traumatic shock who are at risk of hypotension.WEB, Nickson C,weblink Intubation, Hypotension and Shock, Critical Care Compendium, Life in the Fastlane, 7 August 2013, 10 April 2014, blog, dead,weblink" title="web.archive.org/web/20140209161412weblink">weblink 9 February 2014, {{unreliable medical source|date=July 2014}} Ketamine is unlikely to lower blood pressure, which is dangerous for people with severe head injury;JOURNAL, Manley G, Knudson MM, Morabito D, Damron S, Erickson V, Pitts L, Hypotension, hypoxia, and head injury: frequency, duration, and consequences, Archives of Surgery, 136, 10, 1118–23, October 2001, 11585502, 10.1001/archsurg.136.10.1118, free, in fact, it can raise blood pressure, often making it useful in treating such injuries.JOURNAL, Hemmingsen C, Nielsen JE, Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia, Acta Anaesthesiologica Scandinavica, 35, 8, 755–7, November 1991, 1763596, 10.1111/j.1399-6576.1991.tb03385.x, 1324453, JOURNAL, Wong DH, Jenkins LC, The cardiovascular effects of ketamine in hypotensive states, Canadian Anaesthetists' Society Journal, 22, 3, 339–48, May 1975, 1139377, 10.1007/BF03004843, free, Ketamine is an option in children as the sole anesthetic for minor procedures or as an induction agent followed by neuromuscular blocker and tracheal intubationJOURNAL, Kurdi MS, Theerth KA, Deva RS, Ketamine: Current applications in anesthesia, pain, and critical care, Anesthesia: Essays and Researches, 8, 3, 283–90, September 2014, 25886322, 4258981, 10.4103/0259-1162.143110, free, In particular, children with cyanotic heart disease and neuromuscular disorders are good candidates for ketamine anesthesia.JOURNAL, Barrett W, Buxhoeveden M, Dhillon S, Ketamine: a versatile tool for anesthesia and analgesia, Current Opinion in Anesthesiology, 33, 5, 633–638, October 2020, 32826629, 10.1097/ACO.0000000000000916, 221236545, WEB, 2024-04-24, Clinical Uses of Ketamine in Children: A Narrative Review - PMC,weblink 2024-04-24, web.archive.org, 24 April 2024,weblink bot: unknown, Due to the bronchodilating properties of ketamine it can be used for anesthesia in people with asthma, chronic obstructive airway disease, and with severe reactive airway disease including active bronchospasm.JOURNAL, Goyal S, Agrawal A, Ketamine in status asthmaticus: A review, Indian Journal of Critical Care Medicine, 17, 3, 154–61, May 2013, 24082612, 3777369, 10.4103/0972-5229.117048, free,

Pain

Ketamine infusions are used for acute pain treatment in emergency departments and in the perioperative period for individuals with refractory pain. The doses are lower than those used for anesthesia; they are usually referred to as sub-anesthetic doses. Adjunctive to morphine or on its own, ketamine reduces morphine use, pain level, nausea, and vomiting after surgery. Ketamine is likely to be most beneficial for surgical patients when severe post-operative pain is expected, and for opioid-tolerant patients.JOURNAL, Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP, Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists, Reg Anesth Pain Med, 43, 5, 456–466, July 2018, 29870457, 6023582, 10.1097/AAP.0000000000000806, JOURNAL, Sin B, Ternas T, Motov SM, The use of subdissociative-dose ketamine for acute pain in the emergency department, Academic Emergency Medicine, 22, 3, 251–7, March 2015, 25716117, 10.1111/acem.12604, 24658476, free, Ketamine is especially useful in the prehospital setting, due to its effectiveness and low risk of respiratory depression.JOURNAL, Svenson J, Biedermann M, Ketamine: a unique drug with several potential uses in the prehospital setting, Journal of Paramedic Practice, 3, 10, 2011, 552–556, 10.12968/jpar.2011.3.10.552, Ketamine has similar efficacy to opioids in a hospital emergency department setting for management of acute pain and for control of procedural pain.JOURNAL, Karlow N, Schlaepfer CH, Stoll CR, Doering M, Carpenter CR, Colditz GA, Motov S, Miller J, Schwarz ES, A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department, Academic Emergency Medicine, 25, 10, 1086–1097, October 2018, 30019434, 10.1111/acem.13502, free, It may also prevent opioid-induced hyperalgesiaJOURNAL, Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD, Role of ketamine in acute postoperative pain management: a narrative review, BioMed Research International, 2015, 749837, 2015, 26495312, 4606413, 10.1155/2015/749837, free, JOURNAL, Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L, A comprehensive review of opioid-induced hyperalgesia, Pain Physician, 14, 2, 145–61, 2011, 10.36076/ppj.2011/14/145, 21412369, free, and postanesthetic shivering.JOURNAL, Zhou Y, Mannan A, Han Y, Liu H, Guan HL, Gao X, Dai MS, Cao JL, Efficacy and safety of prophylactic use of ketamine for prevention of postanesthetic shivering: a systematic review and meta analysis, BMC Anesthesiology, 19, 1, 245, December 2019, 31888509, 6937868, 10.1186/s12871-019-0910-8, free, For chronic pain, ketamine is used as an intravenous analgesic, particularly if the pain is neuropathic.JOURNAL, Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM, Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists, Reg Anesth Pain Med, 43, 5, 521–546, July 2018, 29870458, 6023575, 10.1097/AAP.0000000000000808, It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain.JOURNAL, Elia N, Tramèr MR, Ketamine and postoperative pain—a quantitative systematic review of randomised trials, Pain, 113, 1–2, 61–70, January 2005, 15621365, 10.1016/j.pain.2004.09.036, 25925720, In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after traumatic spine injury, fibromyalgia, and complex regional pain syndrome (CRPS). However, the 2018 consensus guidelines on chronic pain concluded that, overall, there is only weak evidence in favor of ketamine use in spinal injury pain, moderate evidence in favor of ketamine for CRPS, and weak or no evidence for ketamine in mixed neuropathic pain, fibromyalgia, and cancer pain. In particular, only for CRPS there is evidence of medium to longer term pain relief.

Depression

{{See also|Esketamine#Depression}}Ketamine is a rapid-acting antidepressant, although its effect is transient.JOURNAL, Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB, A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders, JAMA Psychiatry, 74, 4, 399–405, April 2017, 28249076, 10.1001/jamapsychiatry.2017.0080, 28320520, Intravenous ketamine infusion in treatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours.JOURNAL, Marcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H, Richard-Devantoy S, Beauchamp S, A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 - January 2019, J Affect Disord, 277, 831–841, December 2020, 33065824, 10.1016/j.jad.2020.09.007, 223557698, A single dose of intravenous ketamine has been shown to result in a response rate greater than 60% as early as 4.5 hours after the dose (with a sustained effect after 24 hours) and greater than 40% after 7 days. Although there are only a few pilot studies studying the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome.JOURNAL, Sanacora G, Katz R, Ketamine: A Review for Clinicians, Focus, 16, 3, 243–250, July 2018, 31975918, 6493090, 10.1176/appi.focus.20180012, American Psychiatric Association Publishing, The antidepressant effect of ketamine is diminished at 7 days, and most people relapse within 10 days, although for a significant minority the improvement may last 30 days or more.JOURNAL, Swainson J, McGirr A, Blier P, Brietzke E, Richard-Devantoy S, Ravindran N, Blier J, Beaulieu S, Frey BN, Kennedy SH, McIntyre RS, Milev RV, Parikh SV, Schaffer A, Taylor VH, Tourjman V, van Ameringen M, Yatham LN, Ravindran AV, Lam RW, The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur, Can J Psychiatry, 113–125, November 2020, 66, 2, 33174760, 10.1177/0706743720970860, 7918868, JOURNAL, Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sánchez E, Gutiérrez-Rojas L, Meana JJ, Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review, CNS Drugs, 32, 5, 411–420, May 2018, 29736744, 10.1007/s40263-018-0519-3, 13679905, JOURNAL, Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane R, Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight, The Lancet. Psychiatry, 4, 5, 419–426, May 2017, 28395988, 10.1016/S2215-0366(17)30102-5,weblink free, 10871/30208, 28186580, 10 September 2018, 9 March 2019,weblink" title="web.archive.org/web/20190309081101weblink">weblink live, One of the main challenges with ketamine treatment can be the length of time that the antidepressant effects lasts after finishing a course of treatment. A possible option may be maintenance therapy with ketamine which usually runs twice a week to once in two weeks.JOURNAL, Bobo WV, Riva-Posse P, Goes FS, Parikh SV, Next-Step Treatment Considerations for Patients With Treatment-Resistant Depression That Responds to Low-Dose Intravenous Ketamine, Focus (Am Psychiatr Publ), 18, 2, 181–192, April 2020, 33162856, 10.1176/appi.focus.20190048, 7587874, Ketamine may decrease suicidal thoughts for up to three days after the injection.JOURNAL, Witt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, Cipriani A, Hawton K, Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials, Aust N Z J Psychiatry, 54, 1, 29–45, January 2020, 31729893, 10.1177/0004867419883341, 208035394,weblink 18 January 2021, 2 July 2022,weblink live, An enantiomer of ketamine {{ndash}} esketamine commercially sold as Spravato {{ndash}} was approved as an antidepressant by the European Medicines Agency in 2019.WEB, Spravato (esketamine), European Medicines Agency, 8 July 2022, 20 July 2022,weblink 23 November 2020,weblink live, Esketamine was approved as a nasal spray for treatment-resistant depression in the United StatesWEB, FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic,weblink US Food and Drug Administration, 29 July 2022, 5 March 2019, 23 July 2021,weblink live, and elsewhere in 2019 (see Esketamine and Depression). The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends esketamine as a third-line treatment for depression.A Cochrane review of randomized controlled trials in adults with unipolar major depressive disorder, found that when compared with placebo, people treated with either ketamine or esketamine experienced reduction or remission of symptoms lasting 1 to 7 days.JOURNAL, Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A, Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder, The Cochrane Database of Systematic Reviews, 9, CD011612, September 2021, 11, 34510411, 8434915, 10.1002/14651858.CD011612.pub3, There were 18.7% (4.1 to 40.4%) more people reporting some benefit and 9.6% (0.2 to 39.4%) more who achieved remission within 24 hours of ketamine treatment. Among people receiving esketamine, 2.1% (2.5 to 24.4%) more encountered some relief at 24 hours and 10.3% (4.5 to 18.2%) more had few or no symptoms. These effects did not persist beyond one week, although higher dropout rate in some studies mean that the duration of benefit remains unclear.Ketamine may partially improve depressive symptoms among people with bipolar depression, at 24 hours after treatment, but not 3 or more days.JOURNAL, Dean RL, Marquardt T, Hurducas C, Spyridi S, Barnes A, Smith R, Cowen PJ, McShane R, Hawton K, Malhi GS, Geddes J, Cipriani A, Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder, The Cochrane Database of Systematic Reviews, 2021, CD011611, October 2021, 10, 34623633, 8499740, 10.1002/14651858.CD011611.pub3, Potentially, 10 more people with bipolar depression per 1000 may experience brief improvement, but not cessation of symptoms, one day following treatment. These estimates are based on limited available research.In February 2022, the US Food and Drug Administration issued an alert to health care professionals concerning compounded nasal spray products containing ketamine intended to treat depression: "There is no FDA-approved ketamine nasal spray product. Compounded drugs are not FDA-approved, which means FDA has not evaluated their safety, effectiveness, or quality prior to marketing."WEB, FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray,weblink US Food and Drug Administration, 29 July 2022, 16 February 2022, 31 August 2022,weblink live,

Near-death experience

Most people who were able to remember their dreams during ketamine anesthesia report near-death experiences (NDE) when the widest possible definition of an NDE is used.BOOK, Ketamine: Dreams and Realities, Jansen K, Multidisciplinary Association for Psychedelic Studies, 978-0-9660019-3-8, 2001, 122, Ketamine can reproduce features that commonly have been associated with NDEs.JOURNAL, Peinkhofer C, Dreier JP, Kondziella D, Semiology and Mechanisms of Near-Death Experiences, Current Neurology and Neuroscience Reports, 19, 9, 62, July 2019, 31352520, 10.1007/s11910-019-0983-2, 198965307, A 2019 large-scale study found that written reports of ketamine experiences had a high degree of similarity to written reports of NDE in comparison to other written reports of drug experiences.JOURNAL, Martial C, Cassol H, Charland-Verville V, Pallavicini C, Sanz C, Zamberlan F, Vivot RM, Erowid F, Erowid E, Laureys S, Greyson B, Tagliazucchi E, Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports, Consciousness and Cognition, 69, 52–69, March 2019, 30711788, 10.1016/j.concog.2019.01.011, 2268/231971, 73432875, free,

Seizures

Ketamine is used to treat status epilepticusJOURNAL, Ghosh S, Sinha JK, Khan T, Devaraju KS, Singh P, Vaibhav K, Gaur P, Pharmacological and Therapeutic Approaches in the Treatment of Epilepsy, Biomedicines, 9, 5, April 2021, 470, 33923061, 8146518, 10.3390/biomedicines9050470, free, that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use.JOURNAL, Gomes D, Pimentel J, Bentes C, Aguiar de Sousa D, Antunes AP, Alvarez A, Silva ZC, Consensus Protocol for the Treatment of Super-Refractory Status Epilepticus, Acta Médica Portuguesa, 31, 10, 598–605, October 2018, 30387431, 10.20344/amp.9679,weblink free, 11 February 2020, 29 August 2020,weblink live, JOURNAL, Rosati A, De Masi S, Guerrini R, Ketamine for Refractory Status Epilepticus: A Systematic Review, CNS Drugs, 32, 11, 997–1009, November 2018, 30232735, 10.1007/s40263-018-0569-6, 52302073,

Asthma

Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment.JOURNAL, Jat KR, Chawla D, Ketamine for management of acute exacerbations of asthma in children, The Cochrane Database of Systematic Reviews, 11, 11, CD009293, November 2012, 23152273, 6483733, 10.1002/14651858.CD009293.pub2, Cochrane Airways Group, This is due to its bronchodilator effects. A 2012 Cochrane review found there were minimal adverse effects reported, but the limited studies showed no significant benefit.

Contraindications

Some major contraindications for ketamine are:

• Severe cardiovascular disease such as unstable angina or poorly controlled hypertension
• Increased intracranial or intraocular pressure (however these remain controversial, with recent studies suggesting otherwise)
• Poorly controlled psychosis
• Severe liver disease such as cirrhosis
• Pregnancy
• Active substance use disorder (for serial ketamine injections)
• Age less than 3 months

Adverse effects

(File:HarmCausedByDrugsTable.svg|thumb|upright=1.35|Table from the 2010 ISCD study ranking various drugs (legal and illegal) based on statements by drug-harm experts. Ketamine was found to be the 11th overall most dangerous drug.JOURNAL, Nutt DJ, King LA, Phillips LD, Drug harms in the UK: a multicriteria decision analysis, Lancet, 376, 9752, 1558–1565, November 2010, 21036393, 10.1016/S0140-6736(10)61462-6, 5667719, 10.1.1.690.1283, )At anesthetic doses, 10–20% of adults and 1–2% of children experience adverse psychiatric reactions that occur during emergence from anesthesia, ranging from dreams and dysphoria to hallucinations and emergence delirium.JOURNAL, Strayer RJ, Nelson LS, Adverse events associated with ketamine for procedural sedation in adults, The American Journal of Emergency Medicine, 26, 9, 985–1028, November 2008, 19091264, 10.1016/j.ajem.2007.12.005,weblink live,weblink 8 September 2017, Psychotomimetic effects decrease adding lamotrigine and nimodipine and can be counteracted by pretreatment with a benzodiazepine or propofol. Ketamine anesthesia commonly causes tonic-clonic movements (greater than 10% of people) and rarely hypertonia. Vomiting can be expected in 5–15% of the patients; pretreatment with propofol mitigates it as well. Laryngospasm occurs only rarely with ketamine. Ketamine, generally, stimulates breathing; however, in the first 2–3 minutes of a high-dose rapid intravenous injection it may cause a transient respiratory depression.At lower sub-anesthetic doses, psychiatric side effects are prominent. Most people feel strange, spacey, woozy, or a sense of floating, or have visual distortions or numbness. Also very frequent (20–50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating.{{Citation needed|date=April 2024}} The symptoms of psychosis such as going into a hole, disappearing, feeling as if melting, experiencing colors, and hallucinations are described by 6–10% of people. Dizziness, blurred vision, dry mouth, hypertension, nausea, increased or decreased body temperature, or feeling flushed are the common (>10%) non-psychiatric side effects. All these adverse effects are most pronounced by the end of the injection, dramatically reduced 40 minutes afterward, and completely disappear within 4 hours after the injection.JOURNAL, Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA, Park LT, Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression, J Affect Disord, 263, 568–575, February 2020, 31791675, 10.1016/j.jad.2019.11.028, 8457026,

Urinary and liver toxicity

Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20–30% of frequent users having bladder complaints.JOURNAL, Smith HS, Ketamine-induced urologic insult (KIUI), Pain Physician, 13, 6, E343–6, 2010, 10.36076/ppj.2010/13/E343, 21102971, free, It includes a range of disorders from cystitis to hydronephrosis to kidney failure.JOURNAL, Castellani D, Pirola GM, Gubbiotti M, Rubilotta E, Gudaru K, Gregori A, Dellabella M, What urologists need to know about ketamine-induced uropathy: A systematic review, Neurourol Urodyn, 39, 4, 1049–1062, April 2020, 32212278, 10.1002/nau.24341, 214643776, The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and blood in urine.JOURNAL, Middela S, Pearce I, Ketamine-induced vesicopathy: a literature review, International Journal of Clinical Practice, 65, 1, 27–30, January 2011, 21155941, 10.1111/j.1742-1241.2010.02502.x, 25034266,weblink free, 10 September 2018, 19 September 2018,weblink live, The damage to the bladder wall has similarities to both interstitial and eosinophilic cystitis. The wall is thickened and the functional bladder capacity is as low as 10–150 mL. Studies indicate that ketamine-induced cystitis is caused by ketamine and its metabolites directly interacting with urothelium, resulting in damage of the epithelial cells of the bladder lining and increased permeability of the urothelial barrier which results in clinical symptoms.JOURNAL, Changes to the bladder epithelial barrier are associated with ketamine-induced cystitis, 28966667, 5615221, 10.3892/etm.2017.4913, Qixin D, Tianpeng W, Xiaochun Y, Lingqi L, Jiantao Y, Zhongjie L, Experimental and Therapeutic Medicine, 20 January 2017, 14, 4, 2757–2762, Management of ketamine-induced cystitis involves ketamine cessation as the first step. This is followed by NSAIDs and anticholinergics and, if the response is insufficient, by tramadol. The second line treatments are epithelium-protective agents such as oral pentosan polysulfate or intravesical (intra-bladder) instillation of hyaluronic acid. Intravesical botulinum toxin is also useful.Liver toxicity of ketamine involves higher doses and repeated administration. In a group of chronic high dose ketamine users, the frequency of liver injury was reported to be about 10%.{{Citation needed|date=April 2024}} There are case reports of increased liver enzymes involving ketamine treatment of chronic pain. Chronic ketamine abuse has also been associated with biliary colic,JOURNAL, 27330331, 4898409, Chronic biliary colic associated with ketamine abuse, Ahamed AN, Yahya AA, 2 June 2016, 135–137, International Medical Case Reports Journal, 9, 10.2147/IMCRJ.S100648, free, cachexia, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury.JOURNAL, 10.1080/08998280.2014.11929117, Joseph P, Binu R, Sebastian T, Fahmy H, Baylor University Medical Center Proceedings, 27, 3, 11 December 2017, 223–225, Multiorgan Dysfunction Related to Chronic Ketamine Abuse, 24982568, 4059572,

Dependence and tolerance

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

Interactions

Ketamine potentiates the sedative effects of propofolJOURNAL, Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J, Additive interactions between propofol and ketamine when used for anesthesia induction in female patients, Anesthesiology, 82, 3, 641–8, March 1995, 7879932, 10.1097/00000542-199503000-00005, 24005549, free, and midazolam.JOURNAL, Hong W, Short TG, Hui TW, Hypnotic and anesthetic interactions between ketamine and midazolam in female patients, Anesthesiology, 79, 6, 1227–32, December 1993, 8267198, 10.1097/00000542-199312000-00013, 12246068, free, Naltrexone potentiates psychotomimetic effects of a low dose of ketamine,JOURNAL, Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D'Souza DC, Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism, Neuropsychopharmacology, 31, 8, 1793–800, August 2006, 16395307, 10.1038/sj.npp.1300994, free, while lamotrigineJOURNAL, Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH, Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists, Arch Gen Psychiatry, 57, 3, 270–6, March 2000, 10711913, 10.1001/archpsyc.57.3.270, free, and nimodipineJOURNAL, Krupitsky EM, Burakov AM, Romanova TN, Grinenko NI, Grinenko AY, Fletcher J, Petrakis IL, Krystal JH, Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists, Neuropsychopharmacology, 25, 6, 936–47, December 2001, 11750186, 10.1016/S0893-133X(01)00346-3, free, decrease them. Clonidine reduces the increase of salivation, heart-rate and blood-pressure during ketamine anesthesia and decreases the incidence of nightmares.JOURNAL, Handa F, Tanaka M, Nishikawa T, Toyooka H, Effects of oral clonidine premedication on side effects of intravenous ketamine anesthesia: a randomized, double-blind, placebo-controlled study, J Clin Anesth, 12, 1, 19–24, February 2000, 10773503, 10.1016/s0952-8180(99)00131-2, Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine.JOURNAL, Andrade C, Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions, The Journal of Clinical Psychiatry, 78, 7, e858–e861, July 2017, 28858450, 10.4088/JCP.17f11802, free, It appears most conventional antidepressants can be safely combined with ketamine.

Pharmacology

Pharmacodynamics

Mechanism of action

Ketamine is a mixture of equal amounts of two enantiomers: esketamine and arketamine. Esketamine is a far more potent NMDA receptor pore blocker than arketamine. Pore blocking of the NMDA receptor is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine.JOURNAL, Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EF, Albuquerque EX, Thomas CJ, Zarate CA, Gould TD, Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms, Pharmacol Rev, 70, 3, 621–660, July 2018, 29945898, 6020109, 10.1124/pr.117.015198, JOURNAL, Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI, Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy, Clin Pharmacokinet, 55, 9, 1059–77, September 2016, 27028535, 10.1007/s40262-016-0383-6, 5078489, Blocking of the NMDA receptor results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord.JOURNAL, Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A, Ketamine*, Journal of Pain and Symptom Management, 41, 3, 640–9, March 2011, 21419322, 10.1016/j.jpainsymman.2011.01.001,weblink Therapeutic Review, free, 28 July 2014, 16 September 2018,weblink live, The mechanism of action of ketamine in alleviating depression is not well understood, and is an area of active investigation. Because of the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant. However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, have thus far failed to demonstrate significant effectiveness for depression.JOURNAL, Garay R, Zarate CA, Cavero I, Kim YK, Charpeaud T, Skolnick P, The development of glutamate-based antidepressants is taking longer than expected, Drug Discovery Today, 23, 10, 1689–1692, October 2018, 29501913, 6211562, 10.1016/j.drudis.2018.02.006, Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as (2R,6R)-hydroxynorketamine, the metabolite with negligible affinity for the NMDA receptor but potent alpha-7 nicotinic receptor antagonist activity, may have antidepressant action. This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine.WEB,weblink Arketamine – Jiangsu Hengrui Medicine – AdisInsight, 13 November 2019, 13 April 2021,weblink live, Acute inhibition of the lateral habenula, a part of the brain responsible for inhibiting the mesolimbic reward pathway and referred to as the "anti-reward center", is another possible mechanism for ketamine's antidepressant effects.JOURNAL, Kim D, Cheong E, Shin HS, Overcoming Depression by Inhibition of Neural Burst Firing, Neuron, 98, 5, 878–879, June 2018, 29879390, 10.1016/j.neuron.2018.05.032, free, JOURNAL, Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H, Ketamine blocks bursting in the lateral habenula to rapidly relieve depression, Nature, 554, 7692, 317–322, February 2018, 29446381, 10.1038/nature25509, 3334820, 2018Natur.554..317Y, Possible biochemical mechanisms of ketamine's antidepressant action include direct action on the NMDA receptor and downstream effects on regulators such as BDNF and mTOR. It is not clear whether ketamine alone is sufficient for antidepressant action or its metabolites are also important; the active metabolite of ketamine, hydroxynorketamine, which does not significantly interact with the NMDA receptor but nonetheless indirectly activates AMPA receptors, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.JOURNAL, Zanos P, Gould TD, Mechanisms of ketamine action as an antidepressant, Molecular Psychiatry, 23, 4, 801–811, April 2018, 29532791, 5999402, 10.1038/mp.2017.255, JOURNAL, Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD, Convergent Mechanisms Underlying Rapid Antidepressant Action, CNS Drugs, 32, 3, 197–227, March 2018, 29516301, 6005380, 10.1007/s40263-018-0492-x, In NMDA receptor antagonism, acute blockade of NMDA receptors in the brain results in an increase in the release of glutamate, which leads to an activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors), which in turn modulate a variety of downstream signaling pathways to influence neurotransmission in the limbic system and mediate antidepressant effects.JOURNAL, Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA, Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling, The International Journal of Neuropsychopharmacology, 21, 8, 740–747, August 2018, 29668918, 6070027, 10.1093/ijnp/pyy041, Such downstream actions of the activation of AMPA receptors include upregulation of brain-derived neurotrophic factor (BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the mammalian target of rapamycin (mTOR) pathway, deactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase.JOURNAL, Björkholm C, Monteggia LM, Lisa Monteggia, BDNF - a key transducer of antidepressant effects, Neuropharmacology, 102, 72–79, March 2016, 26519901, 4763983, 10.1016/j.neuropharm.2015.10.034, JOURNAL, Castrén E, Kojima M, Brain-derived neurotrophic factor in mood disorders and antidepressant treatments, Neurobiology of Disease, 97, Pt B, 119–126, January 2017, 27425886, 10.1016/j.nbd.2016.07.010, free, 644350, 10138/311483,

Molecular targets{| class"wikitable floatright" style"font-size:small;"|+ Ketamine and biological targets (with Ki below 100 μM)

! Site !! Value (μM) !! Type !! Action !! Species !! RefNMDA JOURNAL = ORGANIC LETTERS ISSUE = 17 DATE = SEPTEMBER 2017 PMC = 5641405 TITLE = THE KETAMINE ANALOGUE METHOXETAMINE AND 3- AND 4-METHOXY ANALOGUES OF PHENCYCLIDINE ARE HIGH AFFINITY AND SELECTIVE LIGANDS FOR THE GLUTAMATE NMDA RECEPTOR VOLUME = 8 PAGES = E59334 PMID = 23527166 DOI = 10.1371/JOURNAL.PONE.0059334 DOI-ACCESS = FREE, MOR JOURNAL = ANESTHESIOLOGY ISSUE = 1 DATE = JANUARY 1999 DOI = 10.1097/00000542-199901000-00023, free, MOR2| 12.1| Ki JOURNAL = JOURNAL OF ANESTHESIA ISSUE = 2 YEAR = 1999 DOI = 10.1007/S005400050035, 9322174, KOR| 2825| KiKiJOURNAL=PSYCHOPHARMACOLOGY (BERL) ISSUE=2 DATE=JUNE 2010 PMC=2869248, 10.1007/s00213-010-1834-7, Sigma-2 receptor>σ2 26 Ki {{abbrNo data}} Rat 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 VOLUME=22 PAGES=308–17 PMID=21911285 S2CID=24494428, D2 receptor>D2 0.5>10 KiKi Agonist{{abbrNo data}} Human 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 VOLUME = 7 PAGES = 837–44 PMID = 12232776 DOI-ACCESS = FREE, CAN A, ZANOS P, MOADDEL R, KANG HJ, DOSSOU KS, WAINER IW, CHEER JF, FROST DO, HUANG XP, GOULD TD > TITLE = EFFECTS OF KETAMINE AND KETAMINE METABOLITES ON EVOKED STRIATAL DOPAMINE RELEASE, DOPAMINE RECEPTORS, AND MONOAMINE TRANSPORTERS VOLUME = 359 PAGES = 159–70 PMID = 27469513 DOI = 10.1124/JPET.116.235838, Muscarinic acetylcholine receptor M1>M1 45 Ki {{abbrNo data}} Human HIROTA K, HASHIMOTO Y, LAMBERT DG >TITLE=INTERACTION OF INTRAVENOUS ANESTHETICS WITH RECOMBINANT HUMAN M1-M3 MUSCARINIC RECEPTORS EXPRESSED IN CHINESE HAMSTER OVARY CELLS VOLUME=95 PAGES=1607–10, TABLE OF CONTENTS PMID=12456425 S2CID=25643394, free, α2β2JOURNAL=ANESTHESIOLOGY ISSUE=4 DATE=APRIL 2000 DOI=10.1097/00000542-200004000-00033 DOI-ACCESS=FREE, α2β4| alpha-3 beta-2 nicotinic receptor>α3β2 50 IC50 Antagonist Human alpha-3 beta-4 nicotinic receptor>α3β4 9.5 IC50 Antagonist Human alpha-4 beta-2 nicotinic receptor>α4β2 72 IC50 Antagonist Human alpha-4 beta-4 nicotinic receptor>α4β4 18 IC50 Antagonist Human Alpha-7 nicotinic receptor>α7 3.1 IC50 Antagonist Rat 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 VOLUME=698 PAGES=228–34 PMID=23183107 DOI=10.1016/J.EJPHAR.2012.11.023, ERαND JOURNAL = BIOCHEMICAL PHARMACOLOGY PAGES = 279–292 PMID = 29621538 DOI = 10.1016/J.BCP.2018.03.032, NETJOURNAL=ANESTHESIOLOGY ISSUE=3 DATE=MARCH 1998 DOI=10.1097/00000542-199803000-00029 DOI-ACCESS=FREE, ZHAO Y, SUN L >TITLE=ANTIDEPRESSANTS MODULATE THE IN VITRO INHIBITORY EFFECTS OF PROPOFOL AND KETAMINE ON NOREPINEPHRINE AND SEROTONIN TRANSPORTER FUNCTION VOLUME=15 PAGES=1264–9 PMID=18815045 DOI=10.1016/J.JOCN.2007.11.007, DAT| HCN1 JOURNAL = THE JOURNAL OF NEUROSCIENCE ISSUE = 3 DATE = JANUARY 2009 PMC = 2744993, 10.1523/JNEUROSCI.3481-08.2009, |TRPV1|1-100|Ki|Agonist|Rat JOURNAL = BIOCHEMICAL PHARMACOLOGY PAGES = 114210 PMID = 32882205 S2CID = 221497233, class="sortbottom" The smaller the value, the stronger the interaction with the site.Ketamine principally acts as a pore blocker of the NMDA receptor, an ionotropic glutamate receptor.JOURNAL, Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ, Classics in Chemical Neuroscience: Ketamine, ACS Chemical Neuroscience, 8, 6, 1122–1134, June 2017, 28418641, 10.1021/acschemneuro.7b00074, The S-(+) and R-(–) stereoisomers of ketamine bind to the dizocilpine site of the NMDA receptor with different affinities, the former showing approximately 3- to 4-fold greater affinity for the receptor than the latter. As a result, the S isomer is a more potent anesthetic and analgesic than its R counterpart.JOURNAL, Hirota K, Lambert DG, Ketamine: its mechanism(s) of action and unusual clinical uses, British Journal of Anaesthesia, 77, 4, 441–4, October 1996, 8942324, 10.1093/bja/77.4.441, dmy-all, free, Ketamine may interact with and inhibit the NMDAR via another allosteric site on the receptor.JOURNAL, Orser BA, Pennefather PS, MacDonald JF, Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors, Anesthesiology, 86, 4, 903–17, April 1997, 9105235, 10.1097/00000542-199704000-00021, 2164198, free, With a couple of exceptions, ketamine actions at other receptors are far weaker than ketamine's antagonism of the NMDA receptor (see the activity table to the right).JOURNAL, Lodge D, Mercier MS, Ketamine and phencyclidine: the good, the bad, and the unexpected, British Journal of Pharmacology, 172, 17, 4254–76, September 2015, 26075331, 4556466, 10.1111/bph.13222, Although ketamine is a very weak ligand of the monoamine transporters (Ki > 60 Î¼M), it has been suggested that it may interact with allosteric sites on the monoamine transporters to produce monoamine reuptake inhibition. However, no functional inhibition (IC50) of the human monoamine transporters has been observed with ketamine or its metabolites at concentrations of up to 10,000 nM. Moreover, animal studies and at least three human case reports 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.JOURNAL, Kraus C, Rabl U, Vanicek T, Carlberg L, Popovic A, Spies M, Bartova L, Gryglewski G, Papageorgiou K, Lanzenberger R, Willeit M, Winkler D, Rybakowski JK, Kasper S, Administration of ketamine for unipolar and bipolar depression, International Journal of Psychiatry in Clinical Practice, 21, 1, 2–12, March 2017, 28097909, 10.1080/13651501.2016.1254802, 35626369, JOURNAL, Bartova L, Vogl SE, Stamenkovic M, Praschak-Rieder N, Naderi-Heiden A, Kasper S, Willeit M, Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases, European Neuropsychopharmacology, 25, 11, 2183–4, November 2015, 26302763, 10.1016/j.euroneuro.2015.07.021, 39039021, Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans. Ketamine has been found to increase dopaminergic neurotransmission in the brain, but instead of being due to dopamine reuptake inhibition, this may be via indirect/downstream mechanisms, namely through antagonism of the NMDA receptor.Whether ketamine is an agonist of D2 receptors is controversial. Early research by the Philip Seeman group found ketamine to be a D2 partial agonist with the potency similar to that of its NMDA receptor antagonism.JOURNAL, Seeman P, Guan HC, Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia, Synapse, 62, 11, 819–28, November 2008, 18720422, 10.1002/syn.20561, 206519749, JOURNAL, Seeman P, Guan HC, Hirbec H, Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil, Synapse, 63, 8, 698–704, August 2009, 19391150, 10.1002/syn.20647, 17758902, However, later studies by different researchers found the affinity of ketamine of >10 Î¼M for the regular human and rat D2 receptors,JOURNAL, Jordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, Tadori Y, Kitagawa H, Kikuchi T, In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors, European Journal of Pharmacology, 540, 1–3, 53–6, July 2006, 16730695, 10.1016/j.ejphar.2006.04.026, Moreover, whereas D2 receptor agonists such as bromocriptine are able to rapidly and powerfully suppress prolactin secretion,BOOK, The Role of Brain Dopamine,weblink 6 December 2012, Springer Science & Business Media, 978-3-642-73897-5, 23–, 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.JOURNAL, Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS, Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses, Archives of General Psychiatry, 51, 3, 199–214, March 1994, 8122957, 10.1001/archpsyc.1994.03950030035004, JOURNAL, Hergovich N, Singer E, Agneter E, Eichler HG, Graselli U, Simhandl C, Jilma B, Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial, Neuropsychopharmacology, 24, 5, 590–3, May 2001, 11282259, 10.1016/S0893-133X(00)00194-9, free, Imaging studies have shown mixed results on inhibition of striatal [11C] raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect.JOURNAL, Rabiner EA, Imaging of striatal dopamine release elicited with NMDA antagonists: is there anything there to be seen?, Journal of Psychopharmacology, 21, 3, 253–8, May 2007, 17591653, 10.1177/0269881107077767, 23776189, However, changes in [11C] raclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D2 receptor.

Relationships between levels and effects

Dissociation and psychotomimetic effects are reported in people treated with ketamine at plasma concentrations of approximately 100 to 250 ng/mL (0.42–1.1 Î¼M). The typical intravenous antidepressant dosage of ketamine used to treat depression is low and results in maximal plasma concentrations of 70 to 200 ng/mL (0.29–0.84 Î¼M). At similar plasma concentrations (70 to 160 ng/mL; 0.29–0.67 Î¼M) it also shows analgesic effects. In 1–5 minutes after inducing anesthesia by a rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60–110 Î¼M.JOURNAL, Idvall J, Ahlgren I, Aronsen KR, Stenberg P, Ketamine infusions: pharmacokinetics and clinical effects, Br J Anaesth, 51, 12, 1167–73, December 1979, 526385, 10.1093/bja/51.12.1167, free, JOURNAL, Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE, Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay, Anesth Analg, 61, 2, 87–92, February 1982, 10.1213/00000539-198202000-00004, 7198883, 27596215, free, When the anesthesia was maintained using nitrous oxide together with continuous injection of ketamine, the ketamine concentration stabilized at approximately 9.3 μM. In an experiment with purely ketamine anesthesia, people began to awaken once the plasma level of ketamine decreased to about 2,600 ng/mL (11 Î¼M) and became oriented in place and time when the level was down to 1,000 ng/mL (4 Î¼M).JOURNAL, White PF, Schüttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ, Comparative pharmacology of the ketamine isomers. Studies in volunteers, Br J Anaesth, 57, 2, 197–203, February 1985, 3970799, 10.1093/bja/57.2.197, free, In a single-case study, the concentration of ketamine in cerebrospinal fluid, a proxy for the brain concentration, during anesthesia varied between 2.8 and 6.5 Î¼M and was approximately 40% lower than in plasma.JOURNAL, Stenberg P, Idvall J, Does ketamine metabolite II exist in vivo?, Br J Anaesth, 53, 7, 778, July 1981, 7248132, 10.1093/bja/53.7.778, free,

Pharmacokinetics

Ketamine can be absorbed by many different routes due to both its water and lipid solubility. Intravenous ketamine bioavailability is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%, and epidural bioavailability is 77%. Subcutaneous bioavailability has never been measured, but is presumed to be high.BOOK, Mao J, Opioid-Induced Hyperalgesia,weblink 19 April 2016, CRC Press, 978-1-4200-8900-4, 127–, live,weblink 8 September 2017, Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%) and oral â€“ the lowest (16–20%). Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%.After absorption ketamine is rapidly distributed into the brain and other tissues. The plasma protein binding of ketamine is variable at 23–47%.(File:Ketamine metabolites2.png|thumb|upright=1.7|Major routes of ketamine metabolism)In the body ketamine undergoes extensive metabolism. It is biotransformed by CYP3A4 and CYP2B6 isoenzymes into norketamine, which, in turn, is converted by CYP2A6 and CYP2B6 into hydroxynorketamine and dehydronorketamine. Low oral bioavailability of ketamine is due to the first-pass effect and, possibly, ketamine intestinal metabolism by CYP3A4. As a result, norketamine plasma levels are several-fold higher than ketamine following oral administration, and norketamine may play a role in anesthetic and analgesic action of oral ketamine.JOURNAL, Rao LK, Flaker AM, Friedel CC, Kharasch ED, Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance, Anesthesiology, 125, 6, 1103–1112, December 2016, 27763887, 10.1097/ALN.0000000000001392, 41380105, This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.JOURNAL, Li Y, Jackson KA, Slon B, Hardy JR, Franco M, William L, Poon P, Coller JK, Hutchinson MR, Currow DC, Somogyi AA, CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects, Br J Clin Pharmacol, 80, 2, 276–84, August 2015, 25702819, 4541975, 10.1111/bcp.12614, After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from the feces.JOURNAL, Chang T, Glazko AJ, Biotransformation and disposition of ketamine, Int Anesthesiol Clin, 12, 2, 157–77, 1974, 4603048, 10.1097/00004311-197412020-00018, 30723730, The medication is excreted mostly in the form of metabolites, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.

Chemistry

Synthesis

2-chlorobenzonitrile is reacted with the Grignard reagent cyclopentylmagnesium bromide to give (2-chlorophenyl)(cyclopentyl)methanone. This is then brominated using bromine to form the corresponding bromoketone, which is then reacted with methylamine in an aqueous solution to form the methylimino derivative, 1-(2-Chloro-N-methylbenzimidoyl)cyclopentanol, with hydrolysis of the tertiary bromine atom. This final intermediate is then heated in decalin or another suitable high-boiling solvent, upon which an Alpha-ketol rearrangement occurs resulting in a ring-expansion, and the formation of racemic ketamine.File:Ketamine synthesis.svg|900px|thumb|center|Preparation of ketamineSynthesis of ketamine references:

• JOURNAL, 10.1021/jo01020a019, Amino ketone rearrangements. IV. Thermal rearrangements of α-amino methyl ketones, Journal of Organic Chemistry, 30, 9, 2967–72, 1965, Stevens CL, Klundt IL, Munk ME, Pillai MD,
• PATENT, US, 3254124, patent, Aminoketones and methods for their production, 31 May 1966, 29 June 1962, 1962-06-29, Stevens, Calvin L., Parke-Davis, Parke Davis & CoParke-Davis, Parke Davis & Co

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 chiral compound. The more active enantiomer, esketamine (S-ketamine), is also available for medical use under the brand name Ketanest S,JOURNAL, Krüger AD, [Current aspects of using ketamine in childhood], DE, Anaesthesiologie und Reanimation, 23, 3, 64–71, 1998, 9707751, while the less active enantiomer, arketamine (R-ketamine), has never been marketed as an enantiopure drug for clinical use. While S-ketamine is more effective as an analgesic and anesthetic through NMDA receptor antagonism, R-ketamine produces longer-lasting effects as an antidepressant.The optical rotation of a given enantiomer of ketamine can vary between its salts and free base form. The free base form of (S)‑ketamine exhibits dextrorotation and is therefore labelled (S)‑(+)‑ketamine. However, its hydrochloride salt shows levorotation and is thus labelled (S)‑(−)‑ketamine hydrochloride.JOURNAL, Chankvetadze B, Burjanadze N, Breitkreutz J, Bergander K, Bergenthal D, Kataeva O, Fröhlich R, Luftmann H, Blaschke G, 2002, Mechanistic study on the opposite migration order of the enantiomers of ketamine with α- and β-cyclodextrin in capillary electrophoresis, Journal of Separation Science, 25, 15–17, 1155–1166, 10.1002/1615-9314(20021101)25:15/173.0.CO;2-M,

Detection

Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized people, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma ketamine concentrations are usually in a range of 0.5–5.0 mg/L in persons receiving the drug therapeutically (during general anesthesia), 1–2 mg/L in those arrested for impaired driving and 3–20 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.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.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.R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 806–808.

History

Ketamine was first synthesized in 1962 by Calvin L. Stevens, a professor of chemistry at Wayne State University and a Parke-Davis consultant. It was known by the developmental code name CI-581. After promising preclinical research in animals, ketamine was tested in human prisoners in 1964.JOURNAL, Domino EF, Taming the ketamine tiger. 1965, Anesthesiology, 113, 3, 678–84, September 2010, 20693870, 10.1097/ALN.0b013e3181ed09a2, free, These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as an anesthetic.JOURNAL, Corssen G, Domino EF, Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581, Anesthesia and Analgesia, 45, 1, 29–40, January–February 1966, 5325977, 10.1213/00000539-196601000-00007, 29516392, The researchers wanted to call the state of ketamine anesthesia "dreaming", but Parke-Davis did not approve of the name. Hearing about this problem and about the "disconnected" appearance of treated people, Mrs. Edward F. Domino,JOURNAL, Li L, Vlisides PE, Ketamine: 50 Years of Modulating the Mind, Frontiers in Human Neuroscience, 10, 612, 2016, 27965560, 5126726, 10.3389/fnhum.2016.00612, free, the wife of one of the pharmacologists working on ketamine, suggested "dissociative anesthesia". Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.The discovery of antidepressive action of ketamine in 2000JOURNAL, Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH, Antidepressant effects of ketamine in depressed patients, Biol Psychiatry, 47, 4, 351–4, February 2000, 10686270, 10.1016/s0006-3223(99)00230-9, 43438286, has been described as the single most important advance in the treatment of depression in more than 50 years. It has sparked interest in NMDA receptor antagonists for depression,WEB, Chaffrey J,weblink Yale Researchers Study Potential Treatment for Depression in Patients With Parkinson's Disease, NBC Connecticut, 16 March 2022, 19 March 2022, 19 March 2022,weblink live, and has shifted the direction of antidepressant research and development.JOURNAL, Dhir A, Investigational drugs for treating major depressive disorder, Expert Opinion on Investigational Drugs, 26, 1, 9–24, January 2017, 27960559, 10.1080/13543784.2017.1267727, 45232796,

Society and culture

Legal status

While ketamine is marketed legally in many countries worldwide,BOOK, Index Nominum 2000: International Drug Directory,weblink 2000, Taylor & Francis, 978-3-88763-075-1, 584–585, it is also a controlled substance in many countries.

• In Australia, ketamine is listed as a schedule 8 controlled drug under the Poisons Standard (October 2015).Poisons Standard October 2015 WEB,weblink Poisons Standard, October 2015, Australian Government, 6 January 2016, live,weblink 19 January 2016,
• In Canada, ketamine is classified as a Schedule I narcotic, since 2005.Legal status of ketamine in Canada references:
• WEB,weblink Statutes of Canada (S.C.) Controlled Drugs and Substances Act (S.C. 1996 c.19) Schedule I § 14, 12 June 2014, Justice Laws Website, Government of Canada, dead,weblink" title="web.archive.org/web/20131122143804weblink">weblink 22 November 2013,
• NEWS,weblink Order Amending Schedule I to the Controlled Drugs and Substances Act, 21 September 2005, Canada Gazette Canada GazettePart II, Part II, 19, 139, 2130, 2 August 2014, dead,weblink" title="web.archive.org/web/20140808053346weblink">weblink 8 August 2014,
• WEB,weblink Status of ketamine under CDSA, 2 May 2005, Canadian Society of Customs Brokers, 2 August 2014, live,weblink" title="web.archive.org/web/20140810002143weblink">weblink 10 August 2014,
• 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 Drug and Cosmetics Act requiring a special license for sale and maintenance of records of all sales for two years.NEWS, Ketamine drug brought under 'Schedule X' to curb abuse,weblink The Times of India, 7 January 2014, 2 August 2014, live,weblink" title="web.archive.org/web/20140414064604weblink">weblink 14 April 2014, dmy-all, NEWS, Sumitra DR, The Times of India, 30 December 2013,weblink Govt makes notorious 'date rape' drug ketamine harder to buy or sell,weblink" title="web.archive.org/web/20131230025440weblink">weblink 30 December 2013, live,
• In the United Kingdom, it became labeled a Class B drug on 12 February 2014.{{citation |url=https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/279186/ResponseACMDketamineReclassification.pdf |title=Response to ACMD recommendation on ketamine |access-date=21 February 2014 |date=12 February 2014 | vauthors = Baker N |author-link1=Norman Baker |type=Correspondence to Les Iverson [chair of]; Advisory Council on the Misuse of Drugs |publisher=Crown copyright; Open Government Licence |postscript=. |url-status=live |archive-url=https://web.archive.org/web/20140228195318weblink |archive-date=28 February 2014 }}NEWS, Dixon H, 12 February 2014, Party drug ketamine to be upgraded to Class B,weblink The Daily Telegraph, 2 August 2014, live,weblink" title="web.archive.org/web/20140609232635weblink">weblink 9 June 2014,
• The increase in recreational use prompted ketamine to be placed in Schedule III of the United States Controlled Substances Act in August 1999.JOURNAL, Marshall DR, Donnie R. Marshall, 13 July 1999, Schedules of Controlled Substances: Placement of Ketamine into Schedule III [21 CFR Part 1308. Final Rule 99-17803], Federal Register, 64, 133, 37673–5,weblink Rules and Regulations, Drug Enforcement Administration, United States Department of Justice, live,weblink" title="web.archive.org/web/20150505060507weblink">weblink 5 May 2015,

Recreational use

At sub-anesthetic doses ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world that is known as depersonalization and derealization.JOURNAL, Giannini AJ, Underwood NA, Condon M, Acute ketamine intoxication treated by haloperidol: a preliminary study, American Journal of Therapeutics, 7, 6, 389–91, November 2000, 11304647, 10.1097/00045391-200007060-00008, At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucination.BOOK, Giannini AJ, Drug Abuse, Health Information Press, Los Angeles, 1999, 104, 978-1-885987-11-2,weblink registration, John C. Lilly, Marcia Moore, D. M. Turner, and David Woodard (among others) have written extensively about their own entheogenic and psychonautic experiences with ketamine.References for recreational use in literature:

• BOOK, Lilly JC, John C. Lilly, The Scientist: A Metaphysical Autobiography, Ronin Publishing, Ronin, Berkeley, CA, 1997, 144–, 978-0-914171-72-0,weblink
• BOOK, Kelly K, The Little Book of Ketamine, 2001, Ronin Publishing, Ronin, 978-1-57951-121-0, 23, 40–45, 46–51, ibid,
• BOOK, Alltounian HS, Moore M, Marcia Moore, Journeys Into the Bright World, Para Research, Rockport, MA, 1978, 978-0-914918-12-7, {{sfnref, Alltounian & Moore, 1978, }}
• BOOK, Palmer C, Horowitz M, Fitz Hugh Ludlow Memorial Library, Sisters of the Extreme: Women Writing on the Drug Experience, 2000, Inner Traditions – Bear & Company, Inner Traditions, 978-0-89281-757-3, 254–258, ibid, {{sfnref, Palmer & Horowitz, 2000, }}
• BOOK, Turner DM, D. M. Turner, The Essential Psychedelic Guide, Panther Press, San Francisco, 1994, 978-0-9642636-1-1, Turner died prematurely due to drowning during presumed unsupervised ketamine use.BOOK, Ketamine: Dreams and Realities, Jansen K, Multidisciplinary Association for Psychedelic Studies, 978-0-9660019-3-8, 2001, 50, 89, 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.BOOK, Woodard D,weblink The Ketamine Necromance, Parfrey A, Apocalypse Culture II, Los Angeles, Feral House, 2000, 288–295, 18 May 2020, 24 June 2021,weblink live, {{rp|288–295}}

Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005–2013. They include accidental poisonings, drownings, traffic accidents, and suicides.See Max Daly, 2014, "The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties," at Vice (online), 23 July 2014, see WEB,weblink The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties, 7 June 2015, live,weblink" title="web.archive.org/web/20150607022331weblink">weblink 7 June 2015, 23 July 2014, , accessed 7 June 2015. The majority of deaths were among young people.WEB, 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, Government of the United Kingdom,weblink 7 June 2015, live,weblink" title="web.archive.org/web/20150607212436weblink">weblink 7 June 2015, and WEB,weblink Deaths Related to Drug Poisoning in England and Wales – Office for National Statistics, 7 June 2015, live,weblink" title="web.archive.org/web/20150619235310weblink">weblink 19 June 2015, , accessed 7 June 2015. Several months after being found dead in his hot tub, actor Matthew Perry's October 2023 apparent drowning death was revealed to have been caused by a ketamine overdose, and while other factors were present, the acute effects of ketamine were ruled to be the primary cause of death.WEB,weblink Matthew Perry died from the 'acute effects of ketamine,' autopsy finds, NPR, Bowman E, 28 December 2023, 15 December 2023, 28 December 2023,weblink live, Because of its ability to cause confusion and amnesia, ketamine has been used for date rape.WEB,weblink Do you know... Ketamine, Knowledge Exchange, Toronto, Centre for Addiction and Mental Health, 27 July 2014, 2003,weblink 7 April 2014, dead, dmy-all, WEB,weblink Ketamine, 27 July 2014, 29 October 2013, Center for Substance Abuse Research (CESAR); University of Maryland, College Park,weblink" title="web.archive.org/web/20131112080924weblink">weblink 12 November 2013, live,

Research

Ketamine is under investigation for its potential in treating treatment-resistant depression.WEB, Grinspoon P, 9 August 2022, Ketamine for treatment-resistant depression: When and where is it safe?,weblink 6 September 2022, Harvard Health, en, 31 August 2022,weblink live, WEB, New Hope for Treatment-Resistant Depression: Guessing Right on Ketamine,weblink 6 September 2022, National Institute of Mental Health (NIMH), 13 August 2019, en, 10 September 2022,weblink live, JOURNAL, Pérez-Esparza R, Ketamine for Treatment-Resistant Depression: a New Advocate, Revista de Investigacion Clinica, 70, 2, 65–67, 2018, 29718013, 10.24875/RIC.18002501, free, Ketamine is a known psychoplastogen, which refers to a compound capable of promoting rapid and sustained neuroplasticity.JOURNAL, Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS, mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists, Science, 329, 5994, 959–964, August 2010, 20724638, 3116441, 10.1126/science.1190287, 2010Sci...329..959L, Ketamine has shown anthelmintic activity in rats, with an effect comparable to ivermectin and albendazole at extremely high concentrations.JOURNAL, Ferreira SR, Machado AR, Furtado LF, Gomes JH, de Almeida RM, de Oliveira Mendes T, Maciel VN, Barbosa FS, Carvalho LM, Bueno LL, Bartholomeu DC, de Araújo JV, Rabelo EM, de Pádua RM, Pimenta LP, Fujiwara RT, Ketamine can be produced by Pochonia chlamydosporia: an old molecule and a new anthelmintic?, Parasites & Vectors, 13, 1, 527, October 2020, 33081837, 7574484, 10.1186/s13071-020-04402-w, free,

Veterinary medicine

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,JOURNAL, Robertson SA, Taylor PM, Pain management in cats—past, present and future. Part 2. Treatment of pain—clinical pharmacology, Journal of Feline Medicine and Surgery, 6, 5, 321–33, October 2004, 15363764, 10.1016/j.jfms.2003.10.002, 25572412, dogs,JOURNAL, Lamont LA, Adjunctive analgesic therapy in veterinary medicine, The Veterinary Clinics of North America. Small Animal Practice, 38, 6, 1187–203, v, November 2008, 18954680, 10.1016/j.cvsm.2008.06.002, rabbits, rats, and other small animals.JOURNAL, Stunkard JA, Miller JC, An outline guide to general anesthesia in exotic species, Veterinary Medicine, Small Animal Clinician, 69, 9, 1181–6, September 1974, 4604091, BOOK, John Wiley & Sons, 978-1-118-68590-7, Riviere JE, Papich MG, Veterinary Pharmacology and Therapeutics, 2009, 200,weblink 26 December 2021, 8 February 2023,weblink live, It is frequently used in induction and anesthetic maintenance in horses. It is an important part of the "rodent cocktail", a mixture of drugs used for anesthetising rodents.{{citation |year=2012 |title=Standard Operating Procedure No. 1 Anesthesia and Analgesia in Rodents |publisher=Washington College |pages=1–2 |url=https://www.washcoll.edu/live/files/1227-no-1-anesthesia-sop-revised-1012pdf |access-date=27 November 2015 |url-status=dead |archive-url=https://web.archive.org/web/20130804040842weblink |archive-date=4 August 2013 }} 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 also used to manage pain among large animals. It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.JOURNAL, Hubbell JA, Muir WW, Sams RA, Guaifenesin: cardiopulmonary effects and plasma concentrations in horses, American Journal of Veterinary Research, 41, 11, 1751–5, November 1980, 7212404, Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.JOURNAL, Woodall AJ, McCrohan CR, Excitatory actions of propofol and ketamine in the snail Lymnaea stagnalis, Comparative Biochemistry and Physiology. Toxicology & Pharmacology, 127, 3, 297–305, December 2000, 11246501, 10.1016/S0742-8413(00)00155-9,

References

{{reflist}}

External links

{{Commons category|Ketamine}}

• weblink" title="web.archive.org/web/20130512224948weblink">Ketamine fact sheet — from the United States DEA, via Archive.org

{{Navboxes|title= Pharmacodynamics|titlestyle= background:#ccccff|list1={{Acetylcholine receptor modulators}}{{Dopamine receptor modulators}}{{Ion channel modulators}}{{Ionotropic glutamate receptor modulators}}{{Monoamine reuptake inhibitors}}{{Opioid receptor modulators}}{{Sigma receptor modulators}}}}{{NavboxesMedicine>Medical uses|titlestyle= background:#ccccff|list1={{General anesthetics}}{{Analgesics}}{{Antidepressants}}}}{{NavboxesRecreational drug use>Recreational uses|titlestyle= background:#ccccff|list1={{Drug use}}{{Hallucinogens}}{{Euphoriants}}}}{{Authority control}}