Ketamine#Depression

File:Two doses of iv ketamine.jpg

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.{{cite book|vauthors=Rosenbaum SB, Gupta V, Palacios JL|chapter=Ketamine|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK470357/|title=StatPearls|publisher=StatPearls Publishing|pmid=29262083|access-date=5 March 2020|archive-date=12 November 2020|archive-url=https://web.archive.org/web/20201112215028/https://www.ncbi.nlm.nih.gov/books/NBK470357/|url-status=live}} 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.{{cite journal | vauthors = Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A | title = Use of ketamine in severe status asthmaticus in intensive care unit | journal = Iranian Journal of Allergy, Asthma, and Immunology | volume = 2 | issue = 4 | pages = 175–80 | date = December 2003 | pmid = 17301376 | url = http://ijaai.tums.ac.ir/index.php/ijaai/article/view/52/52 | url-status = live | archive-url = https://web.archive.org/web/20141006100116/http://ijaai.tums.ac.ir/index.php/ijaai/article/view/52/52 | archive-date = 6 October 2014 }} When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system.{{cite journal | vauthors = Adams HA | title = [S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation] | language = DE | journal = Der Anaesthesist | volume = 46 | issue = 12 | pages = 1081–7 | date = December 1997 | pmid = 9451493 | doi = 10.1007/s001010050510 | s2cid = 36323023 | trans-title = S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation }} Protective airway reflexes are preserved,{{cite journal | vauthors = Wong JJ, Lee JH, Turner DA, Rehder KJ | title = A review of the use of adjunctive therapies in severe acute asthma exacerbation in critically ill children | journal = Expert Review of Respiratory Medicine | volume = 8 | issue = 4 | pages = 423–41 | date = August 2014 | pmid = 24993063 | doi = 10.1586/17476348.2014.915752 | s2cid = 31435021 }} 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 also be counteracted 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.{{cite journal | vauthors = Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM | title = The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review | journal = Annals of Emergency Medicine | volume = 65 | issue = 1 | pages = 43–51.e2 | date = January 2015 | pmid = 25064742 | doi = 10.1016/j.annemergmed.2014.06.018 }} It has been widely used for emergency surgery in field conditions in war zones, for example, during the Vietnam War.{{cite journal |vauthors=Mion G |title=History of anaesthesia: The ketamine story – past, present and future |journal=Eur J Anaesthesiol |volume=34 |issue=9 |pages=571–575 |date=September 2017 |pmid=28731926 |doi=10.1097/EJA.0000000000000638 |s2cid=27536846 }} 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.{{cite web | vauthors = Nickson C |url=http://lifeinthefastlane.com/education/ccc/rapid-sequence-induction-of-the-shock-patient/ |title=Intubation, Hypotension and Shock |publisher=Critical Care Compendium |website=Life in the Fastlane |date=7 August 2013 |access-date=10 April 2014 |type=blog |url-status=dead |archive-url=https://web.archive.org/web/20140209161412/http://lifeinthefastlane.com/education/ccc/rapid-sequence-induction-of-the-shock-patient/ |archive-date=9 February 2014 }}{{unreliable medical source|date=July 2014}} Ketamine often raises blood pressure upon administration and is unlikely to lower blood pressure in most patients, making it useful in treating severe head injuries for which low blood pressure can be dangerous.{{cite journal |vauthors=Manley G, Knudson MM, Morabito D, Damron S, Erickson V, Pitts L |date=October 2001 |title=Hypotension, hypoxia, and head injury: frequency, duration, and consequences |journal=Archives of Surgery |volume=136 |issue=10 |pages=1118–23 |doi=10.1001/archsurg.136.10.1118 |pmid=11585502 |doi-access=free |title-link=doi}}{{cite journal | vauthors = Hemmingsen C, Nielsen JE | title = Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia | journal = Acta Anaesthesiologica Scandinavica | volume = 35 | issue = 8 | pages = 755–7 | date = November 1991 | pmid = 1763596 | doi = 10.1111/j.1399-6576.1991.tb03385.x | s2cid = 1324453 }}{{cite journal | vauthors = Wong DH, Jenkins LC | title = The cardiovascular effects of ketamine in hypotensive states | journal = Canadian Anaesthetists' Society Journal | volume = 22 | issue = 3 | pages = 339–48 | date = May 1975 | pmid = 1139377 | doi = 10.1007/BF03004843 | doi-access = free | title-link = doi }}

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

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.{{cite journal | vauthors = Goyal S, Agrawal A | title = Ketamine in status asthmaticus: A review | journal = Indian Journal of Critical Care Medicine | volume = 17 | issue = 3 | pages = 154–61 | date = May 2013 | pmid = 24082612 | pmc = 3777369 | doi = 10.4103/0972-5229.117048 | doi-access = free | title-link = doi }}

Ketamine infusions are used for acute pain treatment in emergency departments and in the perioperative period for individuals with refractory or intractable pain. The doses are lower than those used for anesthesia, 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.{{cite journal |vauthors=Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP |title=Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists |journal=Reg Anesth Pain Med |volume=43 |issue=5 |pages=456–466 |date=July 2018 |pmid=29870457 |pmc=6023582 |doi=10.1097/AAP.0000000000000806 }}{{cite journal | vauthors = Sin B, Ternas T, Motov SM | title = The use of subdissociative-dose ketamine for acute pain in the emergency department | journal = Academic Emergency Medicine | volume = 22 | issue = 3 | pages = 251–7 | date = March 2015 | pmid = 25716117 | doi = 10.1111/acem.12604 | s2cid = 24658476 | doi-access = free | title-link = doi }}

Ketamine is especially useful in the pre-hospital setting due to its effectiveness and low risk of respiratory depression.{{cite journal| vauthors = Svenson J, Biedermann M |title=Ketamine: a unique drug with several potential uses in the prehospital setting|journal=Journal of Paramedic Practice|volume=3|issue=10|year=2011|pages=552–556|doi=10.12968/jpar.2011.3.10.552}}

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

For chronic pain, ketamine is used as an intravenous analgesic, mainly if the pain is neuropathic.{{cite journal |vauthors=Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM |title=Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists |journal=Reg Anesth Pain Med |volume=43 |issue=5 |pages=521–546 |date=July 2018 |pmid=29870458 |pmc=6023575 |doi=10.1097/AAP.0000000000000808 }} It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain.{{cite journal | vauthors = Elia N, Tramèr MR | title = Ketamine and postoperative pain—a quantitative systematic review of randomised trials | journal = Pain | volume = 113 | issue = 1–2 | pages = 61–70 | date = January 2005 | pmid = 15621365 | doi = 10.1016/j.pain.2004.09.036 | s2cid = 25925720 }} In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after a 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.

{{See also|Esketamine#Depression|Ketamine-assisted psychotherapy}}

Ketamine is a rapid-acting antidepressant, but its effect is transient.{{cite journal | vauthors = Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB | title = A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | journal = JAMA Psychiatry | volume = 74 | issue = 4 | pages = 399–405 | date = April 2017 | pmid = 28249076 | doi = 10.1001/jamapsychiatry.2017.0080 | s2cid = 28320520 }} Intravenous ketamine infusion in treatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours.{{cite journal |vauthors=Zhang K, Hashimoto K |date=January 2019 |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 |doi=10.1080/14737175.2019.1554434 |pmid=30513009 |s2cid=54628949}}{{cite journal |vauthors=Marcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H, Richard-Devantoy S, Beauchamp S |title=A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 – January 2019 |journal=J Affect Disord |volume=277 |pages=831–841 |date=December 2020 |pmid=33065824 |doi=10.1016/j.jad.2020.09.007 |s2cid=223557698 }} 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 only a few pilot studies have sought to determine the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome.{{cite journal | vauthors = Sanacora G, Katz R | title = Ketamine: A Review for Clinicians | journal = Focus | volume = 16 | issue = 3 | pages = 243–250 | date = July 2018 | pmid = 31975918 | pmc = 6493090 | doi = 10.1176/appi.focus.20180012 | publisher = American Psychiatric Association Publishing }} The antidepressant effect of ketamine is diminished at 7 days, and most people relapse within 10 days. However, for a significant minority, the improvement may last 30 days or more.{{cite journal |vauthors=Swainson J, McGirr A, Blier P, Brietzke E, Richard-Devantoy S, Ravindran N, Blier J, Beaulieu S, Frey BN, Kennedy SH, McIntyre RS, Milev RV, Parikh SV, Schaffer A, Taylor VH, Tourjman V, van Ameringen M, Yatham LN, Ravindran AV, Lam RW |title=The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur |journal=Can J Psychiatry |pages=113–125 |date=November 2020 |volume=66 |issue=2 |pmid=33174760 |doi=10.1177/0706743720970860 |pmc=7918868 }}{{cite journal | vauthors = Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sánchez E, Gutiérrez-Rojas L, Meana JJ | title = Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review | journal = CNS Drugs | volume = 32 | issue = 5 | pages = 411–420 | date = May 2018 | pmid = 29736744 | doi = 10.1007/s40263-018-0519-3 | s2cid = 13679905 }}{{cite journal | vauthors = Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane R | title = Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight | journal = The Lancet. Psychiatry | volume = 4 | issue = 5 | pages = 419–426 | date = May 2017 | pmid = 28395988 | doi = 10.1016/S2215-0366(17)30102-5 | url = http://discovery.ucl.ac.uk/1552865/ | hdl-access = free | hdl = 10871/30208 | s2cid = 28186580 | access-date = 10 September 2018 | archive-date = 9 March 2019 | archive-url = https://web.archive.org/web/20190309081101/http://discovery.ucl.ac.uk/1552865/ | url-status = live }}

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

An enantiomer of ketamine {{ndash}} esketamine {{ndash}} was approved as an antidepressant by the European Medicines Agency in 2019.{{cite web|title=Spravato (esketamine)|publisher=European Medicines Agency|date=8 July 2022|accessdate=20 July 2022|url=https://www.ema.europa.eu/en/medicines/human/EPAR/spravato|archive-date=23 November 2020|archive-url=https://web.archive.org/web/20201123231245/https://www.ema.europa.eu/en/medicines/human/EPAR/spravato|url-status=live}} Esketamine was approved as a nasal spray for treatment-resistant depression in the United States{{cite web |title=FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic |url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified |publisher=US Food and Drug Administration |access-date=29 July 2022 |date=5 March 2019 |archive-date=23 July 2021 |archive-url=https://web.archive.org/web/20210723022112/https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified |url-status=dead }} and elsewhere in 2019. 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 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.{{cite journal | vauthors = Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A| title = Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder | journal = The Cochrane Database of Systematic Reviews | volume = 9 | pages = CD011612 | date = September 2021 | issue = 11 | pmid = 34510411 | pmc = 8434915 | doi = 10.1002/14651858.CD011612.pub3 }} 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, 12.1% (2.5 to 24.4%) encountered some relief at 24 hours, and 10.3% (4.5 to 18.2%) had few or no symptoms. These effects did not persist beyond one week, although a higher dropout rate in some studies means that the benefit duration remains unclear.

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

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

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

Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment.{{cite journal | vauthors = Jat KR, Chawla D | title = Ketamine for management of acute exacerbations of asthma in children | journal = The Cochrane Database of Systematic Reviews | volume = 11 | issue = 11 | pages = CD009293 | date = November 2012 | pmid = 23152273 | pmc = 6483733 | doi = 10.1002/14651858.CD009293.pub2 | collaboration = Cochrane Airways Group }} 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.

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

File:HarmCausedByDrugsTable.svg

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.{{cite journal |vauthors=Strayer RJ, Nelson LS |title=Adverse events associated with ketamine for procedural sedation in adults |journal=The American Journal of Emergency Medicine |volume=26 |issue=9 |pages=985–1028 |date=November 2008 |pmid=19091264 |doi=10.1016/j.ajem.2007.12.005 |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0026626/ |url-status=live |archive-url=https://web.archive.org/web/20170908185727/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0026626/ |archive-date=8 September 2017}} 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. The most common psychiatric side effects are dissociation, visual distortions, and numbness. Also very frequent (20–50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating. Hallucinations are described by 6–10% of people. Dizziness, blurred vision, dry mouth, hypertension, nausea, increased or decreased body temperature, or flushing 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.{{cite journal |vauthors=Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA, Park LT |title=Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression |journal=J Affect Disord |volume=263 |pages=568–575 |date=February 2020 |pmid=31791675 |doi=10.1016/j.jad.2019.11.028|pmc=8457026 }}

Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20–30% of frequent users having bladder complaints.{{cite journal |vauthors=Smith HS |title=Ketamine-induced urologic insult (KIUI) |journal=Pain Physician |volume=13 |issue=6 |pages=E343–6 |date=2010 |doi=10.36076/ppj.2010/13/E343 |pmid=21102971| doi-access = free | title-link = doi }} It includes a range of disorders from cystitis to hydronephrosis to kidney failure.{{cite journal |vauthors=Castellani D, Pirola GM, Gubbiotti M, Rubilotta E, Gudaru K, Gregori A, Dellabella M |title=What urologists need to know about ketamine-induced uropathy: A systematic review |journal=Neurourol Urodyn |volume=39 |issue=4 |pages=1049–1062 |date=April 2020 |pmid=32212278 |doi=10.1002/nau.24341|s2cid=214643776 }} The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and blood in urine.{{cite journal |vauthors=Middela S, Pearce I |title=Ketamine-induced vesicopathy: a literature review |journal=International Journal of Clinical Practice |volume=65 |issue=1 |pages=27–30 |date=January 2011 |pmid=21155941 |doi=10.1111/j.1742-1241.2010.02502.x |s2cid=25034266 |url=https://hal.archives-ouvertes.fr/hal-00600043 | doi-access = free | title-link = doi |access-date=10 September 2018 |archive-date=19 September 2018 |archive-url=https://web.archive.org/web/20180919123758/https://hal.archives-ouvertes.fr/hal-00600043 |url-status=live }} 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.{{cite journal | title = Changes to the bladder epithelial barrier are associated with ketamine-induced cystitis | pmid = 28966667 | pmc = 5615221 | doi = 10.3892/etm.2017.4913 | vauthors = Qixin D, Tianpeng W, Xiaochun Y, Lingqi L, Jiantao Y, Zhongjie L | journal = Experimental and Therapeutic Medicine | date = 20 January 2017 | volume = 14 | issue = 4 | pages = 2757–2762}}

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 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%.{{cite journal | vauthors = Wong GL, Tam YH, Ng CF, Chan AW, Choi PC, Chu WC, Lai PB, Chan HL, Wong VW | title = Liver injury is common among chronic abusers of ketamine | journal = Clinical Gastroenterology and Hepatology | volume = 12 | issue = 10 | pages = 1759–62.e1 | date = October 2014 | pmid = 24534547 | doi = 10.1016/j.cgh.2014.01.041 }} There are case reports of increased liver enzymes involving ketamine treatment of chronic pain. Chronic ketamine abuse has also been associated with biliary colic,{{cite journal | pmid = 27330331 | pmc = 4898409 | title = Chronic biliary colic associated with ketamine abuse | vauthors = Ahamed AN, Yahya AA | date = 2 June 2016 | pages = 135–137 | journal = International Medical Case Reports Journal | volume = 9 | doi = 10.2147/IMCRJ.S100648 | doi-access = free | title-link = doi }} cachexia, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury.{{cite journal | doi = 10.1080/08998280.2014.11929117 | vauthors = Joseph P, Binu R, Sebastian T, Fahmy H | journal = Baylor University Medical Center Proceedings | volume = 27 | issue = 3 | date = 11 December 2017 | pages = 223–225 | title = Multiorgan Dysfunction Related to Chronic Ketamine Abuse| pmid = 24982568 | pmc = 4059572 }}

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

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, tremor, sweating, and palpitations, following the attempts to stop.

Despite the balance of palliative benefits which planned course(s) of therapy can confer when patients face serious medical conditions, ongoing ketamine use is known to cause brain damage including reduction in both white and grey matter seen on MRI imaging and atrophy seen on CT scans.{{cite journal|date= October 2021 |title=Severe Encephalatrophy and Related Disorders From Long-Term Ketamine Abuse: A Case Report and Literature Review |publisher= National Institute of Health |pmc=8519172 |journal=Frontiers in Psychiatry |volume=12 |doi=10.3389/fpsyt.2021.707326 |doi-access=free |pmid=34658951 | vauthors = Liu L, Huang H, Li Y, Zhang R, Wei Y, Wu W }} Destruction of dendrite trees is a consideration even with repeated low doses.{{cite journal|date= May 2007 |title= Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture|url=https://www.sciencedirect.com/science/article/abs/pii/S0300483X07001138 |journal=Toxicology |doi= 10.1016/j.tox.2007.03.004|access-date=May 21, 2025|volume= 234|issue= 3|pages= 216–226|pmid= 17418473|bibcode= 2007Toxgy.234..216V| vauthors = Vutskits L, Gascon E, Potter G, Tassonyi E, Kiss JZ }} Cognitive deficits as well as increased dissociation and delusions were observed in frequent recreational users of ketamine.{{cite journal |vauthors=Morgan CJ, Muetzelfeldt L, Curran HV |title=Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study |journal=Addiction |volume=105 |issue=1 |pages=121–33 |date=January 2010 |pmid=19919593 |doi=10.1111/j.1360-0443.2009.02761.x}}

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

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

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.{{cite journal |vauthors=Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EF, Albuquerque EX, Thomas CJ, Zarate CA, Gould TD |title=Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms |journal=Pharmacol Rev |volume=70 |issue=3 |pages=621–660 |date=July 2018 |pmid=29945898 |pmc=6020109 |doi=10.1124/pr.117.015198 }}{{cite journal |vauthors=Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI |title=Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy |journal=Clin Pharmacokinet |volume=55 |issue=9 |pages=1059–77 |date=September 2016 |pmid=27028535 |doi=10.1007/s40262-016-0383-6 |s2cid=5078489 }} 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.{{cite journal | vauthors = Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A | title = Ketamine* | journal = Journal of Pain and Symptom Management | volume = 41 | issue = 3 | pages = 640–9 | date = March 2011 | pmid = 21419322 | doi = 10.1016/j.jpainsymman.2011.01.001 | url = http://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext | type = Therapeutic Review | doi-access = free | title-link = doi | access-date = 28 July 2014 | archive-date = 16 September 2018 | archive-url = https://web.archive.org/web/20180916035324/https://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext | url-status = live }}

The mechanism of action of ketamine in alleviating depression is not well understood, but it is an area of active investigation. Due to the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant. However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, have thus far failed to demonstrate significant effectiveness for depression.{{cite journal | vauthors = Garay R, Zarate CA, Cavero I, Kim YK, Charpeaud T, Skolnick P | title = The development of glutamate-based antidepressants is taking longer than expected | journal = Drug Discovery Today | volume = 23 | issue = 10 | pages = 1689–1692 | date = October 2018 | pmid = 29501913 | pmc = 6211562 | doi = 10.1016/j.drudis.2018.02.006 }} 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.{{cite web | url=https://adisinsight.springer.com/drugs/800056158 | title=Arketamine – Jiangsu Hengrui Medicine – AdisInsight | access-date=13 November 2019 | archive-date=13 April 2021 | archive-url=https://web.archive.org/web/20210413141717/https://adisinsight.springer.com/drugs/800056158 | url-status=live }} 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.{{cite journal | vauthors = Kim D, Cheong E, Shin HS | title = Overcoming Depression by Inhibition of Neural Burst Firing | journal = Neuron | volume = 98 | issue = 5 | pages = 878–879 | date = June 2018 | pmid = 29879390 | doi = 10.1016/j.neuron.2018.05.032 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H | title = Ketamine blocks bursting in the lateral habenula to rapidly relieve depression | journal = Nature | volume = 554 | issue = 7692 | pages = 317–322 | date = February 2018 | pmid = 29446381 | doi = 10.1038/nature25509 | s2cid = 3334820 | bibcode = 2018Natur.554..317Y }}

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.{{cite journal | vauthors = Zanos P, Gould TD | title = Mechanisms of ketamine action as an antidepressant | journal = Molecular Psychiatry | volume = 23 | issue = 4 | pages = 801–811 | date = April 2018 | pmid = 29532791 | pmc = 5999402 | doi = 10.1038/mp.2017.255 }}{{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 }} 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.{{cite journal |vauthors=Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA |title=Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling |journal=The International Journal of Neuropsychopharmacology |volume=21 |issue=8 |pages=740–747 |date=August 2018 |pmid=29668918 |pmc=6070027 |doi=10.1093/ijnp/pyy041}} 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.{{cite journal | vauthors = Björkholm C, Monteggia LM | author-link2 = Lisa Monteggia | title = BDNF – a key transducer of antidepressant effects | journal = Neuropharmacology | volume = 102 | pages = 72–79 | date = March 2016 | pmid = 26519901 | pmc = 4763983 | doi = 10.1016/j.neuropharm.2015.10.034 }}{{cite journal | vauthors = Castrén E, Kojima M | title = Brain-derived neurotrophic factor in mood disorders and antidepressant treatments | journal = Neurobiology of Disease | volume = 97 | issue = Pt B | pages = 119–126 | date = January 2017 | pmid = 27425886 | doi = 10.1016/j.nbd.2016.07.010 | hdl-access = free | s2cid = 644350 | hdl = 10138/311483 | url = https://doaj.org/article/13b03a41fdac43c0b6772f0d7be22ccb }}

Ketamine principally acts as a pore blocker of the NMDA receptor, an ionotropic glutamate receptor.{{cite journal | vauthors = Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ | title = Classics in Chemical Neuroscience: Ketamine | journal = ACS Chemical Neuroscience | volume = 8 | issue = 6 | pages = 1122–1134 | date = June 2017 | pmid = 28418641 | doi = 10.1021/acschemneuro.7b00074 }} 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.{{cite journal | vauthors = Hirota K, Lambert DG | title = Ketamine: its mechanism(s) of action and unusual clinical uses | journal = British Journal of Anaesthesia | volume = 77 | issue = 4 | pages = 441–4 | date = October 1996 | pmid = 8942324 | doi = 10.1093/bja/77.4.441 | df = dmy-all | doi-access = free | title-link = doi }}

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

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).{{cite journal | vauthors = Lodge D, Mercier MS | title = Ketamine and phencyclidine: the good, the bad, and the unexpected | journal = British Journal of Pharmacology | volume = 172 | issue = 17 | pages = 4254–76 | date = September 2015 | pmid = 26075331 | pmc = 4556466 | doi = 10.1111/bph.13222 }}

Although ketamine is a very weak ligand of the monoamine transporters (K_i > 60 μM), 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.{{cite journal | vauthors = Kraus C, Rabl U, Vanicek T, Carlberg L, Popovic A, Spies M, Bartova L, Gryglewski G, Papageorgiou K, Lanzenberger R, Willeit M, Winkler D, Rybakowski JK, Kasper S | title = Administration of ketamine for unipolar and bipolar depression | journal = International Journal of Psychiatry in Clinical Practice | volume = 21 | issue = 1 | pages = 2–12 | date = March 2017 | pmid = 28097909 | doi = 10.1080/13651501.2016.1254802 | s2cid = 35626369 }}{{cite journal | vauthors = Bartova L, Vogl SE, Stamenkovic M, Praschak-Rieder N, Naderi-Heiden A, Kasper S, Willeit M | title = Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases | journal = European Neuropsychopharmacology | volume = 25 | issue = 11 | pages = 2183–4 | date = November 2015 | pmid = 26302763 | doi = 10.1016/j.euroneuro.2015.07.021 | s2cid = 39039021 }} 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 a potency similar to that of its NMDA receptor antagonism.{{cite journal | vauthors = Seeman P, Guan HC | title = Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia | journal = Synapse | volume = 62 | issue = 11 | pages = 819–28 | date = November 2008 | pmid = 18720422 | doi = 10.1002/syn.20561 | s2cid = 206519749 }}{{cite journal | vauthors = Seeman P, Guan HC, Hirbec H | title = Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil | journal = Synapse | volume = 63 | issue = 8 | pages = 698–704 | date = August 2009 | pmid = 19391150 | doi = 10.1002/syn.20647 | s2cid = 17758902 }} However, later studies by different researchers found the affinity of ketamine of >10 μM for the regular human and rat D₂ receptors,{{cite journal | vauthors = Jordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, Tadori Y, Kitagawa H, Kikuchi T | title = In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors | journal = European Journal of Pharmacology | volume = 540 | issue = 1–3 | pages = 53–6 | date = July 2006 | pmid = 16730695 | doi = 10.1016/j.ejphar.2006.04.026 }} Moreover, whereas D₂ receptor agonists such as bromocriptine can rapidly and powerfully suppress prolactin secretion,{{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–}} 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.{{cite journal | vauthors = Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS | title = Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses | journal = Archives of General Psychiatry | volume = 51 | issue = 3 | pages = 199–214 | date = March 1994 | pmid = 8122957 | doi = 10.1001/archpsyc.1994.03950030035004 }}{{cite journal | vauthors = Hergovich N, Singer E, Agneter E, Eichler HG, Graselli U, Simhandl C, Jilma B | title = Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial | journal = Neuropsychopharmacology | volume = 24 | issue = 5 | pages = 590–3 | date = May 2001 | pmid = 11282259 | doi = 10.1016/S0893-133X(00)00194-9 | doi-access = free | title-link = doi }} 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.{{cite journal | vauthors = Rabiner EA | title = Imaging of striatal dopamine release elicited with NMDA antagonists: is there anything there to be seen? | journal = Journal of Psychopharmacology | volume = 21 | issue = 3 | pages = 253–8 | date = May 2007 | pmid = 17591653 | doi = 10.1177/0269881107077767 | s2cid = 23776189 }} 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.

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 μM). 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 μM). At similar plasma concentrations (70 to 160 ng/mL; 0.29–0.67 μM) it also shows analgesic effects. In 1–5 minutes after inducing anesthesia by rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60–110 μM.{{cite journal |vauthors=Idvall J, Ahlgren I, Aronsen KR, Stenberg P |title=Ketamine infusions: pharmacokinetics and clinical effects |journal=Br J Anaesth |volume=51 |issue=12 |pages=1167–73 |date=December 1979 |pmid=526385 |doi=10.1093/bja/51.12.1167 | doi-access = free | title-link = doi }}{{cite journal |vauthors=Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE |title=Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay |journal=Anesth Analg |volume=61 |issue=2 |pages=87–92 |date=February 1982 |doi=10.1213/00000539-198202000-00004 |pmid=7198883 |s2cid=27596215 | doi-access = free | title-link = doi }} 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 μM) and became oriented in place and time when the level was down to 1,000 ng/mL (4 μM).{{cite journal |vauthors=White PF, Schüttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ |title=Comparative pharmacology of the ketamine isomers. Studies in volunteers |journal=Br J Anaesth |volume=57 |issue=2 |pages=197–203 |date=February 1985 |pmid=3970799 |doi=10.1093/bja/57.2.197 | doi-access = free | title-link = doi }} 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 μM and was approximately 40% lower than in plasma.{{cite journal |vauthors=Stenberg P, Idvall J |title=Does ketamine metabolite II exist in vivo? |journal=Br J Anaesth |volume=53 |issue=7 |page=778 |date=July 1981 |pmid=7248132 |doi=10.1093/bja/53.7.778 | doi-access = free | title-link = doi }}

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.{{cite book | vauthors = Mao J |title=Opioid-Induced Hyperalgesia |url=https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127|date=19 April 2016 |publisher=CRC Press |isbn=978-1-4200-8900-4 |pages=127– |url-status=live |archive-url=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127 |archive-date=8 September 2017 }} Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%) and oral – 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

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.{{cite journal |vauthors=Rao LK, Flaker AM, Friedel CC, Kharasch ED |title=Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance |journal=Anesthesiology |volume=125 |issue=6 |pages=1103–1112 |date=December 2016 |pmid=27763887 |doi=10.1097/ALN.0000000000001392 |s2cid=41380105 }} This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.{{cite journal |vauthors=Li Y, Jackson KA, Slon B, Hardy JR, Franco M, William L, Poon P, Coller JK, Hutchinson MR, Currow DC, Somogyi AA |title=CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects |journal=Br J Clin Pharmacol |volume=80 |issue=2 |pages=276–84 |date=August 2015 |pmid=25702819 |pmc=4541975 |doi=10.1111/bcp.12614 }}

After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces.{{cite journal |vauthors=Chang T, Glazko AJ |title=Biotransformation and disposition of ketamine |journal=Int Anesthesiol Clin |volume=12 |issue=2 |pages=157–77 |date=1974 |pmid=4603048 |doi=10.1097/00004311-197412020-00018 |s2cid=30723730 }} 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.

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,{{cite journal | vauthors = Krüger 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 }} 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.{{cite journal| vauthors = Chankvetadze B, Burjanadze N, Breitkreutz J, Bergander K, Bergenthal D, Kataeva O, Fröhlich R, Luftmann H, Blaschke G |year=2002 |title=Mechanistic study on the opposite migration order of the enantiomers of ketamine with α- and β-cyclodextrin in capillary electrophoresis |journal=Journal of Separation Science |volume=25 |issue=15–17 |pages=1155–1166 |doi=10.1002/1615-9314(20021101)25:15/17<1155::AID-JSSC1155>3.0.CO;2-M }}

Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized people, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma ketamine concentrations are usually in a range of 0.5–5.0 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.

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.{{cite journal |vauthors=Domino EF |title=Taming the ketamine tiger. 1965 |journal=Anesthesiology |volume=113 |issue=3 |pages=678–84 |date=September 2010 |pmid=20693870 |doi=10.1097/ALN.0b013e3181ed09a2 | doi-access = free | title-link = doi }} These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as an anesthetic.{{cite journal | vauthors = Corssen G, Domino EF | title = Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581 | journal = Anesthesia and Analgesia | volume = 45 | issue = 1 | pages = 29–40 | date = January–February 1966 | pmid = 5325977 | doi = 10.1213/00000539-196601000-00007 | s2cid = 29516392 }} The researchers wanted to call the state of ketamine anesthesia "dreaming", but Parke-Davis did not approve of the name. Hearing about this problem and the "disconnected" appearance of treated people, Mrs. Edward F. Domino,{{cite journal | vauthors = Li L, Vlisides PE | title = Ketamine: 50 Years of Modulating the Mind | journal = Frontiers in Human Neuroscience | volume = 10 | issue = | pages = 612 | date = 2016 | pmid = 27965560 | pmc = 5126726 | doi = 10.3389/fnhum.2016.00612 | url = | doi-access = free | title-link = doi }} 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 2000{{cite journal |vauthors=Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH |title=Antidepressant effects of ketamine in depressed patients |journal=Biol Psychiatry |volume=47 |issue=4 |pages=351–4 |date=February 2000 |pmid=10686270 |doi=10.1016/s0006-3223(99)00230-9 |s2cid=43438286 }} 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,{{cite web | vauthors = Chaffrey J | url = https://www.nbcconnecticut.com/news/local/yale-researchers-study-potential-treatment-for-depression-in-patients-with-parkinsons-disease/2742209/ | title = Yale Researchers Study Potential Treatment for Depression in Patients With Parkinson's Disease | work = NBC Connecticut | date = 16 March 2022 | access-date = 19 March 2022 | archive-date = 19 March 2022 | archive-url = https://web.archive.org/web/20220319160153/https://www.nbcconnecticut.com/news/local/yale-researchers-study-potential-treatment-for-depression-in-patients-with-parkinsons-disease/2742209/ | url-status = live }} and has shifted the direction of antidepressant research and development.{{cite journal | vauthors = Dhir A | title = Investigational drugs for treating major depressive disorder | journal = Expert Opinion on Investigational Drugs | volume = 26 | issue = 1 | pages = 9–24 | date = January 2017 | pmid = 27960559 | doi = 10.1080/13543784.2017.1267727 | s2cid = 45232796 }}

{{Main|Ketamine in society and culture}}

While ketamine is marketed legally in many countries worldwide,{{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}} 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 {{cite web |url=https://www.comlaw.gov.au/Details/F2015L01534 |title=Poisons Standard | date = October 2015 | publisher = Australian Government |access-date=6 January 2016 |url-status=live |archive-url=https://web.archive.org/web/20160119074606/https://www.comlaw.gov.au/Details/F2015L01534/ |archive-date=19 January 2016 }}
• In Canada, ketamine has been classified as a Schedule I narcotic, since 2005.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 § 14 |date=12 June 2014 |website=Justice Laws Website |publisher=Government of Canada |url-status=dead |archive-url=https://web.archive.org/web/20131122143804/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-24.html#h-28 |archive-date=22 November 2013 }}
• {{cite news |url=http://napra.ca/Content_Files/Files/CDSA-Ketamine.pdf |title=Order Amending Schedule I to the Controlled Drugs and Substances Act |date=21 September 2005 |newspaper=Canada Gazette Part II |issue=19 |volume=139 |page=2130 |access-date=2 August 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140808053346/http://napra.ca/Content_Files/Files/CDSA-Ketamine.pdf |archive-date=8 August 2014 }}
• {{cite web |url=http://cscb.ca/node/94386 |title=Status of ketamine under CDSA |date=2 May 2005 |publisher=Canadian Society of Customs Brokers |access-date=2 August 2014 |url-status=live |archive-url=https://web.archive.org/web/20140810002143/http://cscb.ca/node/94386 |archive-date=10 August 2014 }}
• In December 2013, the government of India, in response to rising recreational use and the use of ketamine as a date rape drug, 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.{{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 |access-date= 2 August 2014 |url-status=live |archive-url= https://web.archive.org/web/20140414064604/http://timesofindia.indiatimes.com/city/goa/Ketamine-drug-brought-under-Schedule-X-to-curb-abuse/articleshow/28486002.cms |archive-date= 14 April 2014 |df= dmy-all }}{{cite news| vauthors = Sumitra DR |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 |archive-url=https://web.archive.org/web/20131230025440/http://timesofindia.indiatimes.com/india/Govt-makes-notorious-date-rape-drug-ketamine-harder-to-buy-or-sell/articleshow/28116453.cms |archive-date=30 December 2013 |url-status=live }}
• In the United Kingdom, it was 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/20140228195318/https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/279186/ResponseACMDketamineReclassification.pdf |archive-date=28 February 2014 }}{{cite news | vauthors = Dixon H |date=12 February 2014 |title=Party drug ketamine to be upgraded to Class B |url=https://www.telegraph.co.uk/news/uknews/law-and-order/10633800/Party-drug-ketamine-to-be-upgraded-to-Class-B.html |newspaper=The Daily Telegraph |access-date=2 August 2014 |url-status=live |archive-url=https://web.archive.org/web/20140609232635/http://www.telegraph.co.uk/news/uknews/law-and-order/10633800/Party-drug-ketamine-to-be-upgraded-to-Class-B.html |archive-date=9 June 2014 }} In 2025, the Home Office requested a review of the classification with a view to changing it to Class A, based on an increase in recreational use and the negative health consequences.{{Cite web |title=Home Office requests review of ketamine classification |url=https://www.gov.uk/government/news/home-office-requests-review-of-ketamine-classification |access-date=2025-03-04 |website=GOV.UK |language=en}}
• The increase in recreational use prompted ketamine to be placed in Schedule III of the United States Controlled Substances Act in August 1999.{{cite journal | vauthors = Marshall DR |author-link1=Donnie R. Marshall |date=13 July 1999 |title=Schedules of Controlled Substances: Placement of Ketamine into Schedule III [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 |author-link3=Drug Enforcement Administration |author-link4=United States Department of Justice |url-status=live |archive-url=https://web.archive.org/web/20150505060507/http://www.gpo.gov/fdsys/pkg/FR-1999-07-13/pdf/99-17803.pdf |archive-date=5 May 2015 }}{{cite web |title=Ketamine could become Class A drug as ministers seek advice |url=https://www.bbc.com/news/articles/cp8306prgy6o |website=www.bbc.com|date=7 January 2025 }}

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

File:SpiRaL.jpg

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.{{cite journal | vauthors = Giannini AJ, Underwood NA, Condon M | title = Acute ketamine intoxication treated by haloperidol: a preliminary study | journal = American Journal of Therapeutics | volume = 7 | issue = 6 | pages = 389–91 | date = November 2000 | pmid = 11304647 | doi = 10.1097/00045391-200007060-00008 }} At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucination.{{Cite book | vauthors = Giannini 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 }} 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:

• {{Cite book | vauthors = Lilly JC |author-link=John C. Lilly |title=The Scientist: A Metaphysical Autobiography |publisher=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 | vauthors = Kelly K |title=The Little Book of Ketamine |year=2001 |publisher=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 }}
• {{Cite book | vauthors = Alltounian HS, Moore M |author-link2=Marcia Moore |title=Journeys Into the Bright World |publisher=Para Research |location=Rockport, MA |year=1978 |isbn=978-0-914918-12-7 |ref={{sfnref|Alltounian & Moore|1978}}}}
• {{cite book | vauthors = Palmer C, Horowitz M |author-link2=Fitz Hugh Ludlow Memorial Library|title=Sisters of the Extreme: Women Writing on the Drug Experience |year=2000|publisher=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 | vauthors = Turner DM |author-link=D. M. Turner |title=The Essential Psychedelic Guide |publisher=Panther Press |location=San Francisco |year=1994 |isbn=978-0-9642636-1-1}} Turner died prematurely due to drowning during presumed unsupervised ketamine use.{{Cite book |title=Ketamine: Dreams and Realities | vauthors = Jansen K |publisher=Multidisciplinary Association for Psychedelic Studies |isbn=978-0-9660019-3-8 |year=2001 |pages=50, 89}} In 2006, the Russian edition of Adam Parfrey's Apocalypse Culture was banned and destroyed by authorities owing to its inclusion of an essay by Woodard about the entheogenic use of, and psychonautic experiences with, ketamine.{{cite book | vauthors = Woodard D | chapter-url = https://tranxcend.tumblr.com/post/29813278762/ketamine | chapter = The Ketamine Necromance | veditors = Parfrey A | title = Apocalypse Culture II | location = Los Angeles | publisher = Feral House | date = 2000 | pages = 288–295 | access-date = 18 May 2020 | archive-date = 24 June 2021 | archive-url = https://web.archive.org/web/20210624204236/https://tranxcend.tumblr.com/post/29813278762/ketamine | url-status = live }}{{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 {{cite web |url=https://www.vice.com/en/article/ketamine-slowly-ruins-your-bladder-and-kills-you-863/ |title=The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties |access-date=7 June 2015 |url-status=live |archive-url=https://web.archive.org/web/20150607022331/http://www.vice.com/en_uk/read/ketamine-slowly-ruins-your-bladder-and-kills-you-863 |archive-date=7 June 2015 |date=23 July 2014 }}, accessed 7 June 2015. The majority of deaths were among young people.{{cite web | date = 2013 | title = Drug related deaths involving ketamine in England and Wales | work = A report of the Mortality team, Life Events and Population Sources Division, Office for National Statistics | publisher = Government of the United Kingdom | url = http://www.ons.gov.uk/ons/about-ons/business-transparency/freedom-of-information/what-can-i-request/published-ad-hoc-data/health/october-2013/drug-related-deaths-involving-ketamine-by-age-group.xls |access-date=7 June 2015 |url-status=live |archive-url=https://web.archive.org/web/20150607212436/http://www.ons.gov.uk/ons/about-ons/business-transparency/freedom-of-information/what-can-i-request/published-ad-hoc-data/health/october-2013/drug-related-deaths-involving-ketamine-by-age-group.xls |archive-date=7 June 2015 }} and {{cite web |url=https://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drug-poisoning/2012/stb---deaths-related-to-drug-poisoning-2012.html |title=Deaths Related to Drug Poisoning in England and Wales – Office for National Statistics |access-date=7 June 2015 |url-status=live |archive-url=https://web.archive.org/web/20150619235310/http://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drug-poisoning/2012/stb---deaths-related-to-drug-poisoning-2012.html |archive-date=19 June 2015 }}, accessed 7 June 2015. 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.{{cite web |url=https://www.npr.org/2023/12/15/1219759019/matthew-perry-cause-of-death |title=Matthew Perry died from the 'acute effects of ketamine,' autopsy finds |website=NPR |vauthors=Bowman E |access-date=28 December 2023 |date=15 December 2023 |archive-date=28 December 2023 |archive-url=https://web.archive.org/web/20231228225746/https://www.npr.org/2023/12/15/1219759019/matthew-perry-cause-of-death |url-status=live }} Due to its ability to cause confusion and amnesia, ketamine has been used for date rape.{{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 |access-date=27 July 2014 |year=2003 |archive-url=https://web.archive.org/web/20140407061143/https://knowledgex.camh.net/amhspecialists/resources_families/Pages/ketamine_dyk.aspx |archive-date= 7 April 2014 |url-status=dead |df= dmy-all}}{{cite web |url=http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |title=Ketamine |access-date=27 July 2014 |date=29 October 2013 |publisher=Center for Substance Abuse Research (CESAR); University of Maryland, College Park |archive-url=https://web.archive.org/web/20131112080924/http://www.cesar.umd.edu/cesar/drugs/ketamine.asp |archive-date=12 November 2013 |url-status=live}}

Ketamine is approved in the United States for treating treatment-resistant depression.{{Cite web | vauthors = Grinspoon P | title = Ketamine for treatment-resistant depression: When and where is it safe? | date = 9 August 2022 | url = https://www.health.harvard.edu/blog/ketamine-for-treatment-resistant-depression-when-and-where-is-it-safe-202208092797 | access-date = 6 September 2022 | website = Harvard Health | language = en | archive-date = 31 August 2022 | archive-url = https://web.archive.org/web/20220831012716/https://www.health.harvard.edu/blog/ketamine-for-treatment-resistant-depression-when-and-where-is-it-safe-202208092797 | url-status = live }} In vivo, ketamine rapidly activates the mTOR pathway, promoting synaptogenesis and reversing stress-related synaptic deficits in the prefrontal cortex, which may underlie its fast-acting antidepressant effects in treatment-resistant depression.{{Cite journal | vauthors = Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS, Li N | title = mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists | journal = Science | location = New York, N.Y. | volume = 329 | issue = 5994 | pages = 959–964 | date = 2010-08-20 | pmid = 20724638 | pmc = 3116441 | doi = 10.1126/science.1190287 | bibcode = 2010Sci...329..959L | issn = 1095-9203 }} A 2023 meta-analysis found that racemic ketamine, particularly at higher doses, is more effective than esketamine in reducing depression severity, with more sustained benefits over time.{{Cite journal | vauthors = Rodgers A, Schwaab A, Bahji A, Zarate C, Vazquez G, Loo C, Nikolin S | title = Ketamine for the treatment of major depression: a systematic review and meta-analysis | journal = eClinicalMedicine | volume = 62 | pages = 102127 | date = 2023-08-01 | pmid = 37593223 | pmc = 10430179 | doi = 10.1016/j.eclinm.2023.102127 | language = English | issn = 2589-5370 }}

File:A vile of Ketamine for veterinary use, with a concentration of 10mg per mL.jpg

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,{{cite journal | vauthors = Robertson SA, Taylor PM | title = Pain management in cats—past, present and future. Part 2. Treatment of pain—clinical pharmacology | journal = Journal of Feline Medicine and Surgery | volume = 6 | issue = 5 | pages = 321–33 | date = October 2004 | pmid = 15363764 | doi = 10.1016/j.jfms.2003.10.002 | s2cid = 25572412 | pmc = 10822209 }} dogs,{{cite journal | vauthors = Lamont LA | title = Adjunctive analgesic therapy in veterinary medicine | journal = The Veterinary Clinics of North America. Small Animal Practice | volume = 38 | issue = 6 | pages = 1187–203, v | date = November 2008 | pmid = 18954680 | doi = 10.1016/j.cvsm.2008.06.002 }} rabbits, rats, and other small animals.{{cite journal | vauthors = Stunkard JA, Miller JC | title = An outline guide to general anesthesia in exotic species | journal = Veterinary Medicine, Small Animal Clinician | volume = 69 | issue = 9 | pages = 1181–6 | date = September 1974 | pmid = 4604091 }}{{cite book |publisher=John Wiley & Sons |isbn=978-1-118-68590-7 |vauthors=Riviere JE, Papich MG |title=Veterinary Pharmacology and Therapeutics |date=2009 |page=200 |url=https://books.google.com/books?id=xAPa4WDzAnQC&pg=PP1 |access-date=26 December 2021 |archive-date=8 February 2023 |archive-url=https://web.archive.org/web/20230208191902/https://books.google.com/books?id=xAPa4WDzAnQC&pg=PP1 |url-status=live }} 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/20130804040842/http://www.washcoll.edu/live/files/1227-no-1-anesthesia-sop-revised-1012pdf |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.{{cite journal | vauthors = Hubbell JA, Muir WW, Sams RA | title = Guaifenesin: cardiopulmonary effects and plasma concentrations in horses | journal = American Journal of Veterinary Research | volume = 41 | issue = 11 | pages = 1751–5 | date = November 1980 | pmid = 7212404 | doi = 10.2460/ajvr.1980.41.11.1751| url = }}

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

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