Ketamine

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• Esketamine (S(+)-isomer)
• Arketamine (R(−)-isomer)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,4-5,8-9H2,1H3YQEZLKZALYSWHR-UHFFFAOYSA-NTemplate:StdinchiciteTemplate:Stdinchicite92<ref>Template:Cite book</ref>

| _combo_data= | _physiological_data= | _clinical_data=Template:Drugs.comModerate–high<ref>{{#invoke:citation/CS1|citation |CitationClass=web }} Ketamine is listed in Schedule III.</ref><ref>Huang, MC., Lin, SK. (2020). "Ketamine Abuse: Past and Present". In: Hashimoto, K., Ide, S., Ikeda, K. (eds.) Ketamine. Springer, Singapore. {{#invoke:doi|main}}.</ref>Ketamine <ref name="Drugs.com pregnancy">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>B3Any<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="MathewZarate2016">Template:Cite book</ref><ref name="MD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Ketalar, othersNMDA receptor antagonist; general anesthetic; dissociative hallucinogen; analgesic; antidepressantN01 | _legal_data=S8C1Schedule IAnlage IIIClass BUnscheduledSchedule IIIIn general Rx-only

| _other_data=(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone

| _image_0_or_2 = Ketamine enantiomers labelled.svg | _image_LR = Esketamine ball-and-stick model from xtal 2002.pngArketamine ball-and-stick model from xtal 2002.png

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Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Sachdeva_2023">Template:Cite journal</ref> Ketamine has S- (esketamine) and R- (arketamine) enamtiomers and has antidepressant action likely involving additional mechanisms than NMDA antagonism.

At anesthetic doses, ketamine induces a state of dissociative anesthesia, a trance-like state providing pain relief, sedation, and amnesia.<ref name="GreenRoback2011" /> Its distinguishing features as an anesthestic are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation.<ref name="GreenRoback2011">Template:Cite journal</ref> As an anesthetic, it is used especially in trauma, emergency, and pediatric cases. At lower, sub-anesthetic doses, it is used as a treatment for pain and treatment-resistant depression.

Ketamine is legally used in medicine but is also tightly controlled due to its potential for recreational use and dissociative effects. Ketamine is used as a recreational drug for its hallucinogenic and dissociative effects.<ref name="morgan11">Template:Cite journal</ref> When used recreationally, it is found both in crystalline powder and liquid form, and is often referred to by users as "Special K" or simply "K". The long-term effects of repeated use are largely unknown and are an area of active investigation.<ref name="pmid33065824" /><ref name="pmid33174760" /><ref name="pmid33162856" /> Liver and urinary toxicity have been reported among regular users of high doses of ketamine for recreational purposes.<ref name="Or">Template:Cite book</ref> Ketamine can cause dissociation and nausea, and other adverse effects, and is contraindicated in severe heart or liver disease, uncontrolled psychosis, pregnancy, and infants under 3 months. Ketamine’s effects are enhanced by propofol, midazolam, and naltrexone; reduced by lamotrigine, nimodipine, and clonidine; and benzodiazepines may blunt its antidepressant action.

Ketamine was first synthesized in 1962; it is derived from phencyclidine in pursuit of a safer anesthetic with fewer hallucinogenic effects.<ref>Template:Cite journal</ref><ref name="pmid29870458" /> It was approved for use in the United States in 1970.<ref name="Sachdeva_2023" /> It has been regularly used in veterinary medicine and was extensively used for surgical anesthesia in the Vietnam War.<ref name="pmid20693870" /> It later gained prominence for its rapid antidepressant effects discovered in 2000, marking a major breakthrough in depression treatment. A 2023 meta-analysis concluded that racemic ketamine, especially at higher doses, is more effective and longer-lasting than esketamine in reducing depression severity. It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> It is available as a generic medication.<ref name="KetPres2013">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

File:Two doses of iv ketamine.jpg

Two doses of injectable ketamine, 50mg/ml and 10mg/ml

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.<ref name="Ketamine">Template:Cite book</ref> 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.<ref name="heshmati">Template:Cite journal</ref> When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system.<ref>Template:Cite journal</ref> Protective airway reflexes are preserved,<ref name="WongLee2014">Template:Cite journal</ref> and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways.<ref name="Ketamine"/> Psychotomimetic effects limit the acceptance of ketamine; however, lamotrigine<ref name="pmid10711913" /> and nimodipine<ref name="pmid11750186" /> decrease psychotomimetic effects and can also be counteracted by benzodiazepines or propofol administration.<ref name="pmid32826629" /> Ketofol is a combination of ketamine and propofol.

Ketamine is frequently used in severely injured people and appears to be safe in this group.<ref name="The effect of ketamine on intracran">Template:Cite journal</ref> It has been widely used for emergency surgery in field conditions in war zones,<ref name="pmid25886322"/> for example, during the Vietnam War.<ref name="pmid28731926">Template:Cite journal</ref> A 2011 clinical practice guideline supports the use of ketamine as a sedative in emergency medicine, including during physically painful procedures.<ref name="GreenRoback2011" /> It is the drug of choice for people in traumatic shock who are at risk of hypotension.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Unreliable medical source</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="pmid25886322">Template:Cite journal</ref> In particular, children with cyanotic heart disease and neuromuscular disorders are good candidates for ketamine anesthesia.<ref name="pmid32826629">Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="pmid25886322"/><ref name="pmid32826629"/><ref name="Goyal">Template:Cite journal</ref>

Pain

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.<ref name="pmid29870457">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Ketamine is especially useful in the pre-hospital setting due to its effectiveness and low risk of respiratory depression.<ref name="SvensonBiedermann2011">Template:Cite journal</ref> Ketamine has similar efficacy to opioids in a hospital emergency department setting for the management of acute pain and the control of procedural pain.<ref name="pmid30019434">Template:Cite journal</ref> It may also prevent opioid-induced hyperalgesia<ref name="pmid26495312">Template:Cite journal</ref><ref name="pmid21412369">Template:Cite journal</ref> and postanesthetic shivering.<ref>Template:Cite journal</ref>

For chronic pain, ketamine is used as an intravenous analgesic, mainly if the pain is neuropathic.<ref name="pmid29870458">Template:Cite journal</ref> It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain.<ref name="elia">Template:Cite journal</ref> 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).<ref name="pmid29870458"/> However, the 2018 consensus guidelines on chronic pain concluded that, overall, there is only weak evidence in favor of ketamine use in spinal injury pain, moderate evidence in favor of ketamine for CRPS, and weak or no evidence for ketamine in mixed neuropathic pain, fibromyalgia, and cancer pain. In particular, only for CRPS, there is evidence of medium to longer-term pain relief.<ref name="pmid29870458"/>

Depression

Ketamine is a rapid-acting antidepressant,<ref name="Sachdeva_2023" /> but its effect is transient.<ref name="pmid28249076">Template:Cite journal</ref> Intravenous ketamine infusion in treatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours.<ref name="Zhang2018">Template:Cite journal</ref><ref name="pmid33065824">Template:Cite journal</ref> A single dose of intravenous ketamine has been shown to result in a response rate greater than 60% as early as 4.5 hours after the dose (with a sustained effect after 24 hours) and greater than 40% after 7 days.<ref name="pmid29736744"/> Although only a few pilot studies have sought to determine the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome.<ref name="Sanacora Katz 2018 pp. 243–250">Template:Cite journal</ref> The antidepressant effect of ketamine is diminished at 7 days, and most people relapse within 10 days. However, for a significant minority, the improvement may last 30 days or more.<ref name="pmid33065824" /><ref name="pmid33174760">Template:Cite journal</ref><ref name="pmid29736744">Template:Cite journal</ref><ref name="pmid28395988">Template:Cite journal</ref>

One of the main challenges with ketamine treatment can be the length of time that the antidepressant effects last after finishing a course of treatment. A possible option may be maintenance therapy with ketamine, which usually runs twice a week to once in two weeks.<ref name="pmid33065824"/><ref name="pmid33174760"/><ref name="pmid33162856">Template:Cite journal</ref> Ketamine may decrease suicidal thoughts for up to three days after the injection.<ref name="pmid31729893">Template:Cite journal</ref>

An enantiomer of ketamine Template:Ndash esketamine Template:Ndash was approved as an antidepressant by the European Medicines Agency in 2019.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Esketamine was approved as a nasal spray for treatment-resistant depression in the United States<ref name="fda-spravato">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and elsewhere in 2019. The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends esketamine as a third-line treatment for depression.<ref name="pmid33174760"/>

A Cochrane review of randomized controlled trials in adults with major depressive disorder<ref name="Sachdeva_2023" /> found that when compared with placebo, people treated with either ketamine or esketamine experienced reduction or remission of symptoms lasting 1 to 7 days.<ref name="dean2">Template:Cite journal</ref> There were 18.7% (4.1 to 40.4%) more people reporting some benefit and 9.6% (0.2 to 39.4%) more who achieved remission within 24 hours of ketamine treatment. Among people receiving esketamine, 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.<ref name=dean2/>

Ketamine may partially improve depressive symptoms<ref name="Sachdeva_2023" /> among people with bipolar depression at 24 hours after treatment, but not three or more days.<ref name="dean">Template:Cite journal</ref> Potentially, ten more people with bipolar depression per 1000 may experience brief improvement, but not the cessation of symptoms, one day following treatment. These estimates are based on limited available research.<ref name=dean/>

In February 2022, the US Food and Drug Administration (FDA) issued an alert to healthcare professionals concerning compounded nasal spray products containing ketamine intended to treat depression.<ref name="fda-2/22">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Seizures

Ketamine is used to treat status epilepticus<ref name="pmid33923061">Template:Cite journal</ref> that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use.<ref>Template:Cite journal</ref><ref name="pmid30232735">Template:Cite journal</ref>

Asthma

Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment.<ref name="Jat_2012">Template:Cite journal</ref> This is due to its bronchodilator effects.<ref name="Jat_2012" /> A 2012 Cochrane review found there were minimal adverse effects reported, but the limited studies showed no significant benefit.<ref name="Jat_2012" />

Contraindications

Some major contraindications for ketamine are:<ref name="pmid29870458" /><ref name="pmid29870457" />

• 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)<ref name="pmid29870457" />
• Poorly controlled psychosis
• Severe liver disease such as cirrhosis
• Pregnancy
• Active substance use disorder (for serial ketamine injections)
• Age less than 3 months<ref name="pmid23521979" />

Adverse effects

File:HarmCausedByDrugsTable.svg

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.<ref name="Nutt_2010">Template:Cite journal</ref>

At anesthetic doses, 10–20% of adults and 1–2% of children<ref name="pmid23521979" /> experience adverse psychiatric reactions that occur during emergence from anesthesia, ranging from dreams and dysphoria to hallucinations and emergence delirium.<ref name="StrayerNelson2008">Template:Cite journal</ref> Psychotomimetic effects decrease adding lamotrigine<ref name="pmid10711913" /> and nimodipine<ref name="pmid11750186" /> and can be counteracted by pretreatment with a benzodiazepine or propofol.<ref name="StrayerNelson2008" /><ref name="pmid32826629" /> Ketamine anesthesia commonly causes tonic-clonic movements (greater than 10% of people) and rarely hypertonia.<ref name="Quibell2011" /><ref name="StrayerNelson2008" /> Vomiting can be expected in 5–15% of the patients; pretreatment with propofol mitigates it as well.<ref name="pmid23521979" /><ref name="StrayerNelson2008" /> 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.<ref name="StrayerNelson2008" />

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.<ref name="pmid31791675">Template:Cite journal</ref>

Urinary and liver toxicity

Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20–30% of frequent users having bladder complaints.<ref name="pmid29870458" /><ref name="pmid21102971">Template:Cite journal</ref> It includes a range of disorders from cystitis to hydronephrosis to kidney failure.<ref name="pmid32212278">Template:Cite journal</ref> The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and blood in urine.<ref name="Middela2011">Template:Cite journal</ref> 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.<ref name="pmid32212278" /> 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.<ref>Template:Cite journal</ref>

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.<ref name="pmid32212278" />

Liver toxicity of ketamine involves higher doses and repeated administration. In a group of chronic high-dose ketamine users, the frequency of liver injury was reported to be about 10%.<ref>Template:Cite journal</ref> There are case reports of increased liver enzymes involving ketamine treatment of chronic pain.<ref name="pmid32212278" /> Chronic ketamine abuse has also been associated with biliary colic,<ref>Template:Cite journal</ref> cachexia, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury.<ref>Template:Cite journal</ref>

Near-death experience

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.<ref name="Jansen2001b">Template:Cite book</ref> Ketamine can reproduce features that commonly have been associated with NDEs.<ref name="Peinkhofer">Template:Cite journal</ref> A 2019 large-scale study found that written reports of ketamine experiences had a high degree of similarity to written reports of NDEs in comparison to other written reports of drug experiences.<ref>Template:Cite journal</ref>

Dependence and tolerance

Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketamine dependence. Animal experiments also confirm the risk of misuse.<ref name=morgan11 /> Additionally, the rapid onset of effects following 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.<ref name=morgan11 />

Brain damage

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.<ref>Template:Cite journal</ref> Destruction of dendrite trees is a consideration even with repeated low doses.<ref>Template:Cite journal</ref> Cognitive deficits as well as increased dissociation and delusions were observed in frequent recreational users of ketamine.<ref name="Morgan2009">Template:Cite journal</ref>

Interactions

Ketamine potentiates the sedative effects of propofol<ref name="propofol">Template:Cite journal</ref> and midazolam.<ref name="midazolam">Template:Cite journal</ref> Naltrexone potentiates psychotomimetic effects of a low dose of ketamine,<ref name="pmid16395307">Template:Cite journal</ref> while lamotrigine<ref name="pmid10711913">Template:Cite journal</ref> and nimodipine<ref name="pmid11750186">Template:Cite journal</ref> decrease them. Clonidine reduces the increase of salivation, heart rate, and blood pressure during ketamine anesthesia and decreases the incidence of nightmares.<ref name="pmid10773503">Template:Cite journal</ref>

Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine.<ref name="pmid28858450">Template:Cite journal</ref> It appears most conventional antidepressants can be safely combined with ketamine.<ref name="pmid28858450" />

Pharmacology

Pharmacodynamics

Mechanism of action

Ketamine is a mixture of equal amounts of two enantiomers: esketamine and arketamine. Esketamine is a far more potent NMDA receptor pore blocker than arketamine.<ref name="Hashimoto2019" /> Pore blocking of the NMDA receptor is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine.<ref name="pmid29945898">Template:Cite journal</ref><ref name="pmid27028535">Template:Cite journal</ref> 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.<ref name="Quibell2011">Template:Cite journal</ref>

The mechanism of action of ketamine in alleviating depression is not well understood, but it is an area of active investigation. Due to the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant.<ref name="Hashimoto2019" /> However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, have thus far failed to demonstrate significant effectiveness for depression.<ref name="Hashimoto2019" /><ref name="GarayZarate2018">Template:Cite journal</ref> 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.<ref name="Hashimoto2019" /><ref name="pmid23183107"/> This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine.<ref name="Hashimoto2019" /><ref name="AdisInsight-HR-071603">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="GarayZarate2018" /> Acute inhibition of the lateral habenula, a part of the brain responsible for inhibiting the mesolimbic reward pathway and referred to as the "anti-reward center", is another possible mechanism for ketamine's antidepressant effects.<ref name="pmid29532791" /><ref name="pmid29879390">Template:Cite journal</ref><ref name="pmid29446381">Template:Cite journal</ref>

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.<ref name="pmid29532791"/> It is not clear whether ketamine alone is sufficient for antidepressant action or its metabolites are also important; the active metabolite of ketamine, hydroxynorketamine, which does not significantly interact with the NMDA receptor but nonetheless indirectly activates AMPA receptors, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.<ref name="pmid29945898" /><ref name="pmid29532791">Template:Cite journal</ref><ref name="pmid29516301">Template:Cite journal</ref> 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.<ref name="pmid29736744" /><ref name="pmid29532791" /><ref name="pmid29668918">Template:Cite journal</ref> Such downstream actions of the activation of AMPA receptors include upregulation of brain-derived neurotrophic factor (BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the mammalian target of rapamycin (mTOR) pathway, deactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase.<ref name="pmid29736744" /><ref name="pmid29532791" /><ref name="pmid26519901">Template:Cite journal</ref><ref name="pmid27425886">Template:Cite journal</ref>

Molecular targets

Ketamine and biological targets (with K_i below 100 μM)

Site	Value (μM)	Type	Action	Species	Ref
Template:Abbrlink	0.25–0.66	Ki	Antagonist	Human	<ref name="pmid28829612">Template:Cite journal</ref><ref name="pmid23527166">Template:Cite journal</ref>
Template:Abbrlink	42	Ki	Antagonist	Human	<ref name="pmid9915326">Template:Cite journal</ref>
Template:Abbrlink	12.1	Ki	Antagonist	Human	<ref name="pmid14530949">Template:Cite journal</ref>
Template:Abbrlink	28 25	Ki Ki	Antagonist Agonist	Human	<ref name="pmid9915326"/> <ref name="pmid20358363">Template:Cite journal</ref>
σ2	26	Ki	Template:Abbr	Rat	<ref name="pmid21911285">Template:Cite journal</ref>
D2	0.5 >10	Ki Ki	Agonist Template:Abbr	Human	<ref name="pmid12232776">Template:Cite journal</ref> <ref name="pmid23527166" /><ref name="pmid27469513">Template:Cite journal</ref><ref name="pmid16730695" />
M1	45	Ki	Template:Abbr	Human	<ref name="pmid12456425">Template:Cite journal</ref>
Template:Abbrlink	92	IC50	Antagonist	Human	<ref name="pmid10754635">Template:Cite journal</ref>
Template:Abbrlink	29	IC50	Antagonist	Human	<ref name="pmid10754635" />
α3β2	50	IC50	Antagonist	Human	<ref name="pmid10754635" />
α3β4	9.5	IC50	Antagonist	Human	<ref name="pmid10754635" />
α4β2	72	IC50	Antagonist	Human	<ref name="pmid10754635" />
α4β4	18	IC50	Antagonist	Human	<ref name="pmid10754635" />
α7	3.1 (HNK)	IC50	NAM	Rat	<ref name="pmid23183107">Template:Cite journal</ref>
Template:Abbrlink	0.34	Ki	Template:Abbr	Human	<ref name="pmid29621538">Template:Cite journal</ref>
Template:Abbrlink	82–291	IC50	Inhibitor	Human	<ref name="pmid9523822">Template:Cite journal</ref><ref name="pmid18815045">Template:Cite journal</ref>
Template:Abbrlink	63	Ki	Inhibitor	Rat	<ref name="pmid9523822" />
Template:Abbrlink	8–16	EC50	Inhibitor	Mouse	<ref name="pmid19158287">Template:Cite journal</ref>
TRPV1	1-100	Ki	Agonist	Rat	<ref>Template:Cite journal</ref>
The smaller the value, the stronger the interaction with the site.

Ketamine principally acts as a pore blocker of the NMDA receptor, an ionotropic glutamate receptor.<ref name="pmid28418641">Template:Cite journal</ref> 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.<ref name="pmid8942324">Template:Cite journal</ref>

Ketamine may interact with and inhibit the NMDAR via another allosteric site on the receptor.<ref name="Orser">Template:Cite journal</ref>

With a couple of exceptions, ketamine actions at other receptors are far weaker than ketamine's antagonism of the NMDA receptor (see the activity table to the right).<ref name="MathewZarate2016" /><ref name="pmid26075331">Template:Cite journal</ref>

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.<ref name="pmid23527166" /> 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.<ref name="pmid27469513" /><ref name="pmid28418641"/> 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.<ref name="pmid28097909">Template:Cite journal</ref><ref name="pmid26302763">Template:Cite journal</ref> Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans.<ref name="pmid28097909" /><ref name="pmid28418641" /><ref name="pmid27469513" /><ref name="pmid26302763" /> Ketamine has been found to increase dopaminergic 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.<ref name="pmid28418641" /><ref name="pmid27469513" />

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.<ref name="pmid12232776" /><ref name="pmid18720422">Template:Cite journal</ref><ref name="pmid19391150">Template:Cite journal</ref> However, later studies by different researchers found the affinity of ketamine of >10 μM for the regular human and rat D₂ receptors,<ref name="pmid23527166" /><ref name="pmid27469513" /><ref name="pmid16730695">Template:Cite journal</ref> Moreover, whereas D₂ receptor agonists such as bromocriptine can rapidly and powerfully suppress prolactin secretion,<ref name="Springer2012">Template:Cite book</ref> subanesthetic doses of ketamine have not been found to do this in humans and in fact, have been found to dose-dependently increase prolactin levels.<ref name="pmid8122957">Template:Cite journal</ref><ref name="pmid11282259">Template:Cite journal</ref> 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.<ref name="pmid17591653">Template:Cite journal</ref> 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.<ref name="pmid17591653" />

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 μM).<ref name="pmid29945898" /> The typical intravenous antidepressant dosage of ketamine used to treat depression is low and results in maximal plasma concentrations of 70 to 200 ng/mL (0.29–0.84 μM).<ref name="pmid28249076" /> At similar plasma concentrations (70 to 160 ng/mL; 0.29–0.67 μM) it also shows analgesic effects.<ref name="pmid28249076" /> In 1–5 minutes after inducing anesthesia by rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60–110 μM.<ref name="pmid526385">Template:Cite journal</ref><ref name="pmid7198883">Template:Cite journal</ref> When the anesthesia was maintained using nitrous oxide together with continuous injection of ketamine, the ketamine concentration stabilized at approximately 9.3 μM.<ref name="pmid526385" /> In an experiment with purely ketamine anesthesia, people began to awaken once the plasma level of ketamine decreased to about 2,600 ng/mL (11 μM) and became oriented in place and time when the level was down to 1,000 ng/mL (4 μM).<ref name="pmid3970799">Template:Cite journal</ref> In a single-case study, the concentration of ketamine in cerebrospinal fluid, a proxy for the brain concentration, during anesthesia varied between 2.8 and 6.5 μM and was approximately 40% lower than in plasma.<ref name="pmid7248132">Template:Cite journal</ref>

Pharmacokinetics

Ketamine can be absorbed by many different routes due to both its water and lipid solubility. Intravenous ketamine bioavailability is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%,<ref name="MathewZarate2016" /> and epidural bioavailability is 77%.<ref name="Kintz2014" /> Subcutaneous bioavailability has never been measured but is presumed to be high.<ref name="Mao2016">Template:Cite book</ref> Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%)<ref name="MathewZarate2016" /><ref name="pmid23521979" /> and oral – the lowest (16–20%).<ref name="MathewZarate2016" /><ref name="pmid23521979" /> Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%.<ref name="MathewZarate2016" /><ref name="Hashimoto2019" /><ref name="pmid23521979" />

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

File:Ketamine metabolites2.png

Major routes of ketamine metabolism<ref name="pmid29945898" />

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.<ref name="pmid29945898" /> Low oral bioavailability of ketamine is due to the first-pass effect and, possibly, ketamine intestinal metabolism by CYP3A4.<ref name="pmid27763887" /> As a result, norketamine plasma levels are several-fold higher than ketamine following oral administration, and norketamine may play a role in anesthetic and analgesic action of oral ketamine.<ref name="MathewZarate2016" /><ref name="pmid27763887">Template:Cite journal</ref> This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.<ref name="pmid27763887" /><ref name="pmid25702819">Template:Cite journal</ref>

After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces.<ref name="pmid4603048">Template:Cite journal</ref> 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.<ref name="pmid20693870" />

Chemistry

Structure

Template:Multiple image

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,<ref name="Kruger1998">Template:Cite journal</ref> 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.<ref name="Sachdeva_2023" />

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.<ref>Template:Cite journal</ref>

Detection

Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized people, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma ketamine concentrations are usually in a range of 0.5–5.0 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.<ref>Feng N, Vollenweider FX, Minder EI, Rentsch K, Grampp T, Vonderschmitt DJ. Development of a gas chromatography-mass spectrometry method for determination of ketamine in plasma and its application to human samples. Ther. Drug Monit. 17: 95–100, 1995.</ref><ref>Parkin MC, Turfus SC, Smith NW, Halket JM, Braithwaite RA, Elliott SP, Osselton MD, Cowan DA, Kicman AT. Detection of ketamine and its metabolites in urine by ultra-high-pressure liquid chromatography-tandem mass spectrometry. J. Chrom. B 876: 137–142, 2008.</ref><ref>R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 806–808.</ref>

History

Ketamine was first synthesized in 1962 by Calvin L. Stevens,<ref name="Sachdeva_2023" /> a professor of chemistry at Wayne State University and a Parke-Davis consultant. It was known by the developmental code name CI-581.<ref name="Sachdeva_2023" /> After promising preclinical research in animals, ketamine was tested in human prisoners in 1964.<ref name="pmid20693870">Template:Cite journal</ref> These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as an anesthetic.<ref>Template:Cite journal</ref> The researchers wanted to call the state of ketamine anesthesia "dreaming", but Parke-Davis did not approve of the name. Hearing about this problem and the "disconnected" appearance of treated people, Mrs. Edward F. Domino,<ref name="pmid27965560">Template:Cite journal</ref> the wife of one of the pharmacologists working on ketamine, suggested "dissociative anesthesia".<ref name="pmid20693870" /> Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.<ref name="CESAR" />

The discovery of antidepressive action of ketamine in 2000<ref name="pmid10686270">Template:Cite journal</ref> has been described as the single most important advance in the treatment of depression in more than 50 years.<ref name="pmid28395988" /><ref name="Hashimoto2019" /> It has sparked interest in NMDA receptor antagonists for depression,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and has shifted the direction of antidepressant research and development.<ref name="pmid27960559">Template:Cite journal</ref>

Society and culture

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Legal status

While ketamine is marketed legally in many countries worldwide,<ref name="IndexNominum2000">Template:Cite book</ref> it is also a controlled substance in many countries.<ref name="MathewZarate2016" />

• In Australia, ketamine is listed as a Schedule 8 controlled drug under the Poisons Standard (October 2015).<ref name="Poisons Standard">Poisons Standard October 2015 {{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• In Canada, ketamine has been classified as a Schedule I narcotic, since 2005.<ref name="CanadianLegalStatus">Legal status of ketamine in Canada references:
• {{#invoke:citation/CS1|citation

|CitationClass=web }}

• Template:Cite news
• {{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• 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.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>
• In the United Kingdom, it was labeled a Class B drug on 12 February 2014.<ref name="reclassify response">Template:Citation</ref><ref>Template:Cite news</ref> 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.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• The increase in recreational use prompted ketamine to be placed in Schedule III of the United States Controlled Substances Act in August 1999.<ref name="FedReg1999">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Recreational use

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

File:SpiRaL.jpg

A spiral line of ketamine prepared for insufflation

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.<ref name="Giannini2000">Template:Cite journal</ref> At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucination.<ref>Template:Cite book</ref> 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.<ref name="RecreationalLiterature">References for recreational use in literature:

• Template:Cite book
• Template:Cite book
• Template:Cite book
• Template:Cite book
• Template:Cite book</ref> Turner died prematurely due to drowning during presumed unsupervised ketamine use.<ref name="Jansen2001">Template:Cite book</ref> 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.<ref>Template:Cite book</ref>Template:Rp

Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005–2013.<ref name=DalyVice14 /> They include accidental poisonings, drownings, traffic accidents, and suicides.<ref name=DalyVice14>See Max Daly, 2014, "The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties," at Vice (online), 23 July 2014, see {{#invoke:citation/CS1|citation |CitationClass=web }}, accessed 7 June 2015.</ref> The majority of deaths were among young people.<ref name=TheCrownONS13>{{#invoke:citation/CS1|citation |CitationClass=web }} and {{#invoke:citation/CS1|citation |CitationClass=web }}, accessed 7 June 2015.</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Due to its ability to cause confusion and amnesia, ketamine has been used for date rape.<ref name="CAMHDYK">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="CESAR">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

Ketamine is approved in the United States for treating treatment-resistant depression.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Veterinary uses

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

An empty vial of Ketamine used by veterinarians for injection

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,<ref>Template:Cite journal</ref> dogs,<ref>Template:Cite journal</ref> rabbits, rats, and other small animals.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> 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.<ref>Template:Citation</ref> Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up. Ketamine is 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.<ref name="pmid7212404">Template:Cite journal</ref>

Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.<ref>Template:Cite journal</ref>