At anesthetic doses, ketamine induces a state of dissociative anesthesia, atrance-like state providing pain relief,sedation, andamnesia.[21] Its distinguishing features as an anesthestic are preserved breathing and airway reflexes, stimulated heart function with increasedblood pressure, and moderatebronchodilation.[21] As an anesthetic, it is used especially in trauma,emergency, andpediatric cases. At lower, sub-anesthetic doses, it is used as a treatment forpain andtreatment-resistant depression.
Ketamine is legally used in medicine but is also tightly controlled, as it is used as a recreational drug for itshallucinogenic anddissociative effects.[22] When used recreationally, it is found both in crystalline powder and liquid form, and is often referred to by users as "Ket", "Special K" or simply "K". The long-term effects of repeated use are largely unknown and are an area of active investigation.[23][24][25] Liver and urinary toxicity have been reported among regular users of high doses of ketamine for recreational purposes.[26] Ketamine can causedissociation and nausea, and other adverse effects, and iscontraindicated in severeheart orliver disease, and uncontrolledpsychosis. Ketamine’s clinical and antidepressant effects can be influenced by co-administration of other drugs, though these interactions are variable and not yet fully understood.
Ketamine was first synthesized in 1962; it is derived fromphencyclidine in pursuit of a safer anesthetic with fewer hallucinogenic effects.[27][28] It was approved for use in the United States in 1970.[20] It has been regularly used inveterinary medicine and was extensively used forsurgical anesthesia in theVietnam War.[29] It later gained prominence for its rapid antidepressant effects discovered in 2000, marking a major breakthrough in depression treatment. Racemic ketamine, especially at higher doses, may be more effective and longer-lasting than esketamine in reducing depression severity.[30] It is on theWorld Health Organization's List of Essential Medicines.[31] It is available as ageneric medication.[32]
The use of ketamine in anesthesia reflects its characteristics. It is a drug of choice for short-term procedures whenmuscle relaxation is not required.[33] The effect of ketamine on therespiratory andcirculatory systems is different from that of other anesthetics. It suppresses breathing much less than most other available anesthetics.[34] When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system.[35] Protective airway reflexes are preserved,[36] and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways.[33]Psychotomimetic effects limit the acceptance of ketamine; however,lamotrigine[37] andnimodipine[38] decrease psychotomimetic effects and can also be counteracted bybenzodiazepines orpropofol administration.[39]Ketofol is a combination of ketamine andpropofol.
Ketamine is frequently used in severely injured people and appears to be safe in this group.[40] It has been widely used for emergency surgery in field conditions in war zones,[41] for example, during theVietnam War.[42] A 2011clinical practice guideline supports the use of ketamine as asedative inemergency medicine, including during physically painful procedures.[21] It is the drug of choice for people intraumatic shock who are at risk ofhypotension.[43] 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.[44][45][46]
Ketamine infusions are used for acute pain treatment in emergency departments and in the perioperative period for individuals with refractory orintractable pain. The doses are lower than those used for anesthesia, usually referred to as sub-anesthetic doses. Adjunctive tomorphine 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.[49][50]
Ketamine is especially useful in the pre-hospital setting due to its effectiveness and low risk of respiratory depression.[51]Ketamine has similar efficacy to opioids in a hospital emergency department setting for the management of acute pain and the control of procedural pain.[52] It may also preventopioid-induced hyperalgesia[53][54] andpostanesthetic shivering.[55]
For chronic pain, ketamine is used as an intravenous analgesic, mainly if the pain isneuropathic.[28] It has the added benefit of counteractingspinal sensitization orwind-up phenomena experienced withchronic pain.[56] In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after a traumatic spine injury,fibromyalgia, andcomplex regional pain syndrome (CRPS).[28] 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, andcancer pain. In particular, only for CRPS, there is evidence of medium to longer-term pain relief.[28]
This section needs to beupdated. The reason given is: Recent (2022–2025) systematic reviews and guideline updates on ketamine and esketamine for depression have not been incorporated.. Please help update this article to reflect recent events or newly available information.(October 2025)
Ketamine is a rapid-actingantidepressant,[20] but its effect is transient.[57] Intravenous ketamine infusion intreatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours.[58][23] 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.[59] 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.[60] 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.[23][24][59][61]
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 every two weeks.[23][24][25] Ketamine may decreasesuicidal thoughts for up to three days after the injection.[62]
Anenantiomer of ketamine –esketamine – was approved as an antidepressant by theEuropean Medicines Agency in 2019.[63] Esketamine was approved as a nasal spray for treatment-resistant depression in the United States[64] and elsewhere in 2019. The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends esketamine as a third-line treatment for depression.[24]
ACochrane review ofrandomized controlled trials in adults withmajor depressive disorder[20] found that when compared with placebo, people treated with either ketamine or esketamine experienced reduction or remission of symptoms lasting 1 to 7 days.[65] 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.[65]
Ketamine may partially improve depressive symptoms[20] among people withbipolar depression at 24 hours after treatment, but not three or more days.[66] 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.[66]
In February 2022, the USFood and Drug Administration (FDA) issued an alert to healthcare professionals concerningcompounded nasal spray products containing ketamine intended to treat depression.[67]
Ketamine is used to treatstatus epilepticus[68] that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use.[69][70]
Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment.[71] This is due to itsbronchodilator effects.[71] A 2012 Cochrane review found there were minimal adverse effects reported, but the limited studies showed no significant benefit.[71]
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.[72]
At anesthetic doses, 10–20% of adults and 1–2% of children[10] experience adverse psychiatric reactions that occur during emergence from anesthesia, ranging from dreams anddysphoria to hallucinations andemergence delirium.[73] Psychotomimetic effects decrease when addinglamotrigine[37] andnimodipine[38] and can be counteracted by pretreatment with abenzodiazepine orpropofol.[73][39] Ketamine anesthesia commonly causestonic-clonic movements (greater than 10% of people) and rarelyhypertonia.[14][73] Vomiting can be expected in 5–15% of the patients; pretreatment with propofol mitigates it as well.[10][73]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.[73]
At lower sub-anesthetic doses, psychiatric side effects are prominent. The most common psychiatric side effects aredissociation, visual distortions, andnumbness. Also common (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.[74]
Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20–30% of frequent users having bladder complaints.[28][75] It includes a range of disorders fromcystitis tohydronephrosis tokidney failure.[76] The typical symptoms of ketamine-induced cystitis arefrequent urination,dysuria, andurinary urgency sometimes accompanied by pain during urination andblood in urine.[77] The damage to the bladder wall has similarities to bothinterstitial andeosinophilic cystitis. The wall is thickened and the functional bladder capacity is as low as 10–150 mL.[76] Studies indicate that ketamine-induced cystitis is caused by ketamine and its metabolites directly interacting withurothelium, resulting in damage of theepithelial cells of the bladder lining and increased permeability of the urothelial barrier which results in clinical symptoms.[78]
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%.[79] There are case reports of increased liver enzymes involving ketamine treatment of chronic pain.[76] Chronic ketamine abuse has also been associated withbiliary colic,[80]cachexia,gastrointestinal diseases,hepatobiliary disorder, andacute kidney injury.[81]
Most people who were able to remember their dreams during ketamine anesthesia reportnear-death experiences (NDEs) when the broadest possible definition of an NDE is used.[82] Ketamine can reproduce features that commonly have been associated with NDEs.[83] 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.[84]
Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketaminedependence. Animal experiments also confirm the risk of misuse.[22] Additionally, the rapid onset of effects followinginsufflation may increase potential use as a recreational drug. The short duration of effects promotesbingeing. Ketaminetolerance rapidly develops, even with repeated medical use, prompting the use of higher doses. Some daily users reportedwithdrawal symptoms, primarily anxiety, tremor, sweating, and palpitations, following the attempts to stop.[22]
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.[85] Cognitive deficits as well as increased dissociation anddelusions were observed in frequent recreational users of ketamine.[86]
Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine.[91] It appears most conventional antidepressants can be safely combined with ketamine.[91]
Ketamine is a mixture of equal amounts of twoenantiomers:esketamine andarketamine. Esketamine is a far morepotent NMDA receptor pore blocker than arketamine.[11] Pore blocking of theNMDA receptor is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine.[92][93] Blocking of the NMDA receptor results in analgesia by preventingcentral sensitization indorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in thespinal cord.[14]
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.[11] However, multiple otherNMDA receptor antagonists, includingmemantine,lanicemine,rislenemdaz,rapastinel, and4-chlorokynurenine, have thus far failed to demonstrate significant effectiveness for depression.[11][94] Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as(2R,6R)-hydroxynorketamine, themetabolite with negligible affinity for the NMDA receptor but potentalpha-7 nicotinic receptor antagonist activity, may have antidepressant action.[11][95] This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine.[11][96][94] Acute inhibition of thelateral habenula, a part of the brain responsible for inhibiting themesolimbic reward pathway and referred to as the "anti-reward center", is another possible mechanism for ketamine's antidepressant effects.[97][98][99]
The smaller the value, the stronger the interaction with the site.
Ketamine principally acts as a pore blocker of theNMDA receptor, anionotropic glutamate receptor.[120] TheS-(+) andR-(–)stereoisomers of ketamine bind to the dizocilpine site of the NMDA receptor with differentaffinities, the former showing approximately 3- to 4-fold greater affinity for the receptor than the latter. As a result, theS isomer is a more potent anesthetic and analgesic than itsR counterpart.[121]
Ketamine may interact with and inhibit the NMDAR via anotherallosteric site on the receptor.[122]
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).[7][123]
Whether ketamine is an agonist of D2 receptors is controversial. Early research by thePhilip Seeman group found ketamine to be a D2 partial agonist with a potency similar to that of its NMDA receptor antagonism.[110][126][127] However, later studies by different researchers found the affinity of ketamine of >10 μM for the regular human and rat D2 receptors,[105][111][112] Moreover, whereas D2 receptor agonists such asbromocriptine can rapidly and powerfully suppressprolactinsecretion,[128] subanesthetic doses of ketamine have not been found to do this in humans and in fact, have been found to dose-dependentlyincrease prolactin levels.[129][130]Imaging studies have shown mixed results on inhibition ofstriatal [11C]raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect.[131] 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.[131]
Dissociation andpsychotomimetic effects are reported in people treated with ketamine at plasma concentrations of approximately 100 to 250 ng/mL (0.42–1.1 μM).[92] 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).[57] At similar plasma concentrations (70 to 160 ng/mL; 0.29–0.67 μM) it also shows analgesic effects.[57] In 1–5 minutes after inducing anesthesia by rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60–110 μM.[132][133] When the anesthesia was maintained usingnitrous oxide together with continuous injection of ketamine, the ketamine concentration stabilized at approximately 9.3 μM.[132] 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).[134] In a single-case study, the concentration of ketamine incerebrospinal 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.[135]
Ketamine can be absorbed by many different routes due to its water and lipid solubility.Intravenous ketaminebioavailability is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%,[7] andepidural bioavailability is 77%.[9] Subcutaneous bioavailability has never been measured but is presumed to be high.[136] Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%)[7][10] and oral – the lowest (16–20%).[7][10] Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%.[7][11][10]
In the body, ketamine undergoes extensivemetabolism. It isbiotransformed byCYP3A4 andCYP2B6isoenzymes intonorketamine, which, in turn, is converted byCYP2A6 and CYP2B6 intohydroxynorketamine anddehydronorketamine.[92] Low oral bioavailability of ketamine is due to thefirst-pass effect and, possibly, ketamine intestinal metabolism by CYP3A4.[17] 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.[7][17] This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.[17][137]
After an intravenous injection oftritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces.[15] The medication is excreted mostly in the form ofmetabolites, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.[29]
In chemical structure, ketamine is anarylcyclohexylamine derivative. Ketamine is achiral compound. The more active enantiomer,esketamine (S-ketamine), is also available for medical use under the brand name Ketanest S,[138] while the less active enantiomer,arketamine (R-ketamine), has never been marketed as anenantiopure 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.[20]
Theoptical rotation of a given enantiomer of ketamine can vary between itssalts andfree base form. The free base form of (S)‑ketamine exhibitsdextrorotation and is therefore labelled (S)‑(+)‑ketamine. However, itshydrochloride salt showslevorotation and is thus labelled (S)‑(−)‑ketamine hydrochloride.[139]
Ketamine may be quantified 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.[140][141][142]
Ketamine was first synthesized in 1962 byCalvin L. Stevens,[20] a professor of chemistry atWayne State University and aParke-Davis consultant. It was known by the developmental code nameCI-581.[20] After promising preclinical research in animals, ketamine was tested inhuman prisoners in 1964.[29] These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice overphencyclidine (PCP) as an anesthetic.[143] 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,[144] the wife of one of the pharmacologists working on ketamine, suggested "dissociative anesthesia".[29] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during theVietnam War.[145]
The discovery of antidepressive action of ketamine in 2000[146] has been described as the single most important advance in the treatment of depression in more than 50 years.[61][11] It has sparked interest in NMDA receptor antagonists for depression,[147] and has shifted the direction of antidepressant research and development.[148]
While ketamine is marketed legally in many countries worldwide,[149] it is also acontrolled substance in many countries.[7]
In Australia, ketamine is listed as a Schedule 8 controlled drug under thePoisons Standard (October 2015).[150]
In Canada, ketamine has been classified as a Schedule I narcotic since 2005.[151]
In December 2013, thegovernment of India, in response to rising recreational use and the use of ketamine as a date rape drug, added it toSchedule X of theDrug and Cosmetics Act requiring a special license for sale and maintenance of records of all sales for two years.[152][153]
In the United Kingdom, it was labeled aClass B drug on 12 February 2014.[154][155] 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.[156]
The increase in recreational use prompted ketamine to be placed in Schedule III of the United StatesControlled Substances Act in August 1999.[157][158]
A spiral line of ketamine prepared for insufflation
At sub-anesthetic doses, ketamine produces adissociative state, characterised by a sense of detachment from one's physical body and the external world that is known asdepersonalization andderealization.[159] At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucination.[160]John C. Lilly,Marcia Moore, andD. M. Turner (among others) have written extensively about their ownentheogenic andpsychonautic experiences with ketamine.[161] Turner died prematurely due to drowning during presumed unsupervised ketamine use.[162]
Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in 2005–2013.[163] They include accidental poisonings, drownings, traffic accidents, andsuicides.[163] The majority of deaths were among young people.[164] Several months after being found dead in his hot tub, actorMatthew 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.[165] Due to its ability to cause confusion andamnesia, ketamine has been used fordate rape.[166][145]
Ketamine, in the form ofesketamine, is approved in the United States for treatingtreatment-resistant depression.[167]In vivo, ketamine rapidly activates themTOR pathway, promotingsynaptogenesis and reversing stress-related synaptic deficits in theprefrontal cortex, which might underlie its fast-acting antidepressant effects in treatment-resistant depression.[168] 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.[30]
TheBritishcritical psychiatristJoanna Moncrieff has critiqued the use and study of ketamine and related drugs likepsychedelics for treatment of psychiatric disorders, highlighting concerns including excessive hype around these drugs, questionable biologically-based theories of benefit, blurred lines between medical and recreational use, flawed clinical trial findings, financial conflicts of interest, strong expectancy effects and large placebo responses, small and short-term benefits over placebo, and their potential for difficult experiences and adverse effects, among others.[171]
An empty vial of Ketamine used by veterinarians for injection
Inveterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,[172] dogs,[173]rabbits,rats, and other small animals.[174][175] 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 anesthetisingrodents.[176] Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help preventpain 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 withdetomidine andthiopental, or sometimesguaifenesin.[177]
Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.[178]
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