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Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and Hallucinogen properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its two enantiomers, Esketamine and Arketamine, 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. Its distinguishing features as an anesthestic are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation. As an anesthetic, it is used especially in trauma, emergency, and Pediatrics 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, as it is used as a recreational drug for its Hallucinogen and dissociative effects. 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. Liver and urinary toxicity have been reported among regular users of high doses of ketamine for recreational purposes. Ketamine can cause dissociation and nausea, and other adverse effects, and is Contraindication in severe heart or liver disease, and uncontrolled psychosis. 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 from phencyclidine in pursuit of a safer anesthetic with fewer hallucinogenic effects. It was approved for use in the United States in 1970. It has been regularly used in veterinary medicine and was extensively used for surgical anesthesia in the Vietnam War. 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. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.
Ketamine is frequently used in severely injured people and appears to be safe in this group. It has been widely used for emergency surgery in field conditions in war zones, for example, during the Vietnam War. 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. 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.
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. In particular, children with cyanotic heart disease and neuromuscular disorders are good candidates for ketamine anesthesia.
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.
Ketamine is especially useful in the pre-hospital setting due to its effectiveness and low risk of respiratory depression. Ketamine has similar efficacy to opioids in a hospital emergency department setting for the management of acute pain and the control of procedural pain. It may also prevent opioid-induced hyperalgesia and postanesthetic shivering.
For chronic pain, ketamine is used as an intravenous analgesic, mainly if the pain is Neuropathic pain. It has the added benefit of counteracting spinal sensitization or Pain wind-up experienced with chronic pain. 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.
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. Ketamine may decrease for up to three days after the injection.
An enantiomer of ketamine esketamine was approved as an antidepressant by the European Medicines Agency in 2019. Esketamine was approved as a nasal spray for treatment-resistant depression in the United States 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. 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. 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 compounding nasal spray products containing ketamine intended to treat depression.
At lower sub-anesthetic doses, psychiatric side effects are prominent. The most common psychiatric side effects are dissociation, visual distortions, and numbness. Also common (20–50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating. 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.
Management of ketamine-induced cystitis involves ketamine cessation as the first step. This is followed by and 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%. There are case reports of increased liver enzymes involving ketamine treatment of chronic pain. Chronic ketamine abuse has also been associated with biliary colic, cachexia, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury.
Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine. It appears most conventional antidepressants can be safely combined with ketamine.
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. Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as (2 R,6 R)-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. 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.
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. 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. 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.
Ketamine principally acts as a pore blocker of the NMDA receptor, an ionotropic glutamate receptor. The S-(+) and R-(–) of ketamine bind to the dizocilpine site of the NMDA receptor with different Binding affinity, 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.
Ketamine may interact with and inhibit the NMDAR via another allosteric site on the receptor.
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).
Although ketamine is a very weak ligand of the monoamine transporters (Ki > 60 μM), it has been suggested that it may interact with 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 at concentrations of up to 10,000 nM. Moreover, animal studies and at least three human 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. 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. However, later studies by different researchers found the affinity of ketamine of >10 μM for the regular human and rat D2 receptors, Moreover, whereas D2 receptor agonists such as bromocriptine can rapidly and powerfully suppress prolactin secretion, 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. Medical imaging studies have shown mixed results on inhibition of striatum 11C raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect. 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.
After absorption ketamine is rapidly distributed into the brain and other tissues. The plasma protein binding of ketamine is variable at 23–47%.
In the body, ketamine undergoes extensive metabolism. It is biotransformed by CYP3A4 and CYP2B6 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. This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.
After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces. The medication is excreted mostly in the form of , 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, 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.
The discovery of antidepressive action of ketamine in 2000 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, and has shifted the direction of antidepressant research and development.
Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in 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 , accessed 7 June 2015. The majority of deaths were among young people. and , 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. Due to its ability to cause confusion and amnesia, ketamine has been used for date rape.
Ketamine has shown potential for rapid and tolerable symptom relief in obsessive-compulsive disorder, but evidence is limited and inconsistent.
Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.
Seizures
Ketamine is used to treat status epilepticus that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use.
Asthma
Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment. This is due to its bronchodilator effects. A 2012 Cochrane review found there were minimal adverse effects reported, but the limited studies showed no significant benefit.
Contraindications
Some major for ketamine are:
Adverse effects
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. Psychotomimetic effects decrease when 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.
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. It includes a range of disorders from cystitis to hydronephrosis to kidney failure. The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and hematuria. 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 Epithelium of the bladder lining and increased permeability of the urothelial barrier which results in clinical symptoms.
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. (2025). 9780966001938, Multidisciplinary Association for Psychedelic Studies. ISBN 9780966001938 Ketamine can reproduce features that commonly have been associated with NDEs. 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.
Dependence and tolerance
Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketamine dependence. Animal experiments also confirm the risk of misuse. Additionally, the rapid onset of effects following insufflation may increase potential use as a recreational drug. The short duration of effects promotes Drug binge. Ketamine Drug tolerance rapidly develops, even with repeated medical use, prompting the use of higher doses. Some daily users reported Drug withdrawal symptoms, primarily anxiety, tremor, sweating, and palpitations, following the attempts to stop.
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. Cognitive deficits as well as increased dissociation and were observed in frequent recreational users of ketamine.
Interactions
Ketamine Potentiator the sedative effects of propofol and midazolam. Naltrexone potentiates psychotomimetic effects of a low dose of ketamine, while lamotrigine and nimodipine decrease them. Clonidine reduces the increase of salivation, heart rate, and blood pressure during ketamine anesthesia and decreases the incidence of nightmares.
Pharmacology
Pharmacodynamics
Mechanism of action
Ketamine is a mixture of equal amounts of two : 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. 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.
Molecular targets
+ Ketamine and biological targets (with Ki below 100 μM)
12.1 Ki 28
25Ki
Ki
TRPV1 1-100 Ki Agonist Rat The smaller the value, the stronger the interaction with the site.
Relationships between levels and effects
Dissociative 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. 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). 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.
Pharmacokinetics
Ketamine can be absorbed by many different routes due to 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. 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%.
Chemistry
Structure
Detection
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.Feng N, Vollenweider FX, Minder EI, Rentsch K, Grampp T, Vonderschmitt DJ. Development of a gas chromatography-mass spectrometry method for determination of ketamine in plasma and its application to human samples. Ther. Drug Monit. 17: 95–100, 1995.Parkin MC, Turfus SC, Smith NW, Halket JM, Braithwaite RA, Elliott SP, Osselton MD, Cowan DA, Kicman AT. Detection of ketamine and its metabolites in urine by ultra-high-pressure liquid chromatography-tandem mass spectrometry. J. Chrom. B 876: 137–142, 2008.R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 806–808.
History
Ketamine was first synthesized in 1962 by Calvin L. Stevens, a professor of chemistry at Wayne State University and a Parke-Davis consultant. It was known by the developmental code name CI-581. After promising preclinical research in animals, ketamine was tested in human prisoners in 1964. These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as an anesthetic. 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, 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.
Society and culture
Legal status
While ketamine is marketed legally in many countries worldwide, it is also a controlled substance in many countries.
Recreational use
At sub-anesthetic doses, ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world that is known as depersonalization and derealization. At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucination. John C. Lilly, Marcia Moore, and D. M. Turner (among others) have written extensively about their own and psychonautics experiences with ketamine.References for recreational use in literature:
Turner died prematurely due to drowning during presumed unsupervised ketamine use. (1978). 9780914918127, Para Research. ISBN 9780914918127
(2025). 9780892817573, Inner Traditions. ISBN 9780892817573
(1994). 9780964263611, Panther Press. ISBN 9780964263611 (2025). 9780966001938, Multidisciplinary Association for Psychedelic Studies. ISBN 9780966001938
Research
Ketamine is approved in the United States for treating treatment-resistant depression. 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. 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.
Veterinary uses
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, , , and other small animals. 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. 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.
External links
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