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Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for
anesthesia Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...
, depression, and pain management. Ketamine exists as its S- (esketamine) and R- (arketamine) two
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
s 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 Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...
. Its distinguishing features as an anesthestic are preserved breathing and airway reflexes, stimulated heart function with increased
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
, and moderate bronchodilation. 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 Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...
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. 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 contraindicated in severe
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
or
liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
, uncontrolled
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
, pregnancy, and infants under 3 months. Ketamine’s effects are enhanced by propofol,
midazolam Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia, premedication before surgical anesthesia, and procedural sedation, and to treat psychomotor agitation, severe agitation. It induces ...
, and naltrexone; reduced by lamotrigine, nimodipine, and clonidine; and
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s 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. It was approved for use in the United States in 1970. It has been regularly used in
veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, medical diagnosis, diagnosis, and treatment of disease, disorder, and injury in non-human animals. The scope of veterinary medicine is wide, covering all a ...
and was extensively used for surgical anesthesia in the
Vietnam War The Vietnam War (1 November 1955 – 30 April 1975) was an armed conflict in Vietnam, Laos, and Cambodia fought between North Vietnam (Democratic Republic of Vietnam) and South Vietnam (Republic of Vietnam) and their allies. North Vietnam w ...
. 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. It is available as a generic medication.


Medical uses


Anesthesia

The use of ketamine in anesthesia reflects its characteristics. It is a drug of choice for short-term procedures when muscle relaxation is not required. The effect of ketamine on the respiratory and
circulatory system In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart ...
s is different from that of other anesthetics. It suppresses breathing much less than most other available anesthetics. When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system. Protective airway reflexes are preserved, and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways. Psychotomimetic effects limit the acceptance of ketamine; however, lamotrigine and nimodipine decrease psychotomimetic effects and can also be counteracted by
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s or propofol administration. Ketofol is a combination of ketamine and propofol. Ketamine is frequently used in severely injured people and appears to be safe in this group. It has been widely used for emergency surgery in field conditions in war zones, for example, during the
Vietnam War The Vietnam War (1 November 1955 – 30 April 1975) was an armed conflict in Vietnam, Laos, and Cambodia fought between North Vietnam (Democratic Republic of Vietnam) and South Vietnam (Republic of Vietnam) and their allies. North Vietnam w ...
. A 2011 clinical practice guideline supports the use of ketamine as a
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...
in
emergency medicine Emergency medicine is the medical specialty concerned with the care of illnesses or injuries requiring immediate medical attention. Emergency physicians (or "ER doctors") specialize in providing care for unscheduled and undifferentiated pa ...
, including during physically painful procedures. It is the drug of choice for people in traumatic shock who are at risk of
hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
. 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 Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic catheter, tube into the vertebrate trachea, trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer c ...
. 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 Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
, chronic obstructive airway disease, and with severe reactive airway disease including active bronchospasm.


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 Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
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. 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. It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with
chronic pain Chronic pain is pain that persists or recurs for longer than 3 months.https://icd.who.int/browse/2025-01/mms/en#1581976053 It is also known as gradual burning pain, electrical pain, throbbing pain, and nauseating pain. This type of pain is in cont ...
. 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.


Depression

Ketamine is a rapid-acting
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
, but its effect is transient. Intravenous ketamine infusion in treatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours. A single dose of intravenous ketamine has been shown to result in a response rate greater than 60% as early as 4.5 hours after the dose (with a sustained effect after 24 hours) and greater than 40% after 7 days. Although only a few pilot studies have sought to determine the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome. 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. 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. Ketamine may decrease suicidal thoughts for up to three days after the injection. An
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
of ketamine
esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...
was approved as an antidepressant by the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
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 trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
s in adults with
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) issued an alert to healthcare professionals concerning compounded nasal spray products containing ketamine intended to treat depression.


Seizures

Ketamine is used to treat
status epilepticus Status epilepticus (SE), or status seizure, is a medical condition with abnormally prolonged seizures. It can have long-term consequences, manifesting as a single seizure lasting more than a defined time (time point 1), or 2 or more seizures over ...
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 contraindications for ketamine are: * Severe
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
such as
unstable angina In dynamical systems instability means that some of the outputs or internal states increase with time, without bounds. Not all systems that are not stable are unstable; systems can also be marginally stable or exhibit limit cycle behavior ...
or poorly controlled
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
* Increased
intracranial The cranial cavity, also known as intracranial space, is the space within the skull that accommodates the brain. The skull is also known as the cranium. The cranial cavity is formed by eight cranial bones known as the neurocranium that in human ...
or intraocular pressure (however these remain controversial, with recent studies suggesting otherwise) * Poorly controlled
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
* Severe liver disease such as
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
*
Pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
* Active substance use disorder (for serial ketamine injections) * Age less than 3 months


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 Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...
to hallucinations and emergence delirium. Psychotomimetic effects decrease adding lamotrigine and nimodipine and can be counteracted by pretreatment with a
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
or propofol. Ketamine anesthesia commonly causes tonic- clonic movements (greater than 10% of people) and rarely hypertonia. Vomiting can be expected in 5–15% of the patients; pretreatment with propofol mitigates it as well. Laryngospasm occurs only rarely with ketamine. Ketamine, generally, stimulates breathing; however, in the first 2–3 minutes of a high-dose rapid intravenous injection, it may cause a transient respiratory depression. At lower sub-anesthetic doses, psychiatric side effects are prominent. The most common psychiatric side effects are dissociation, visual distortions, and
numbness Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to Sensory receptor, sensory stimuli. In everyday speech this is generally r ...
. Also very frequent (20–50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating.
hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s 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.


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 blood in urine. The damage to the bladder wall has similarities to both interstitial and eosinophilic cystitis. The wall is thickened and the functional bladder capacity is as low as 10–150 mL. Studies indicate that ketamine-induced cystitis is caused by ketamine and its metabolites directly interacting with urothelium, resulting in damage of the epithelial cells of the bladder lining and increased permeability of the urothelial barrier which results in clinical symptoms. Management of ketamine-induced cystitis involves ketamine cessation as the first step. This is followed by NSAIDs and
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...
s 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 Botulinum toxin, or botulinum neurotoxin (commonly called botox), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon en ...
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 Cachexia () is a syndrome that happens when people have certain illnesses, causing muscle loss that cannot be fully reversed with improved nutrition. It is most common in diseases like cancer, Heart failure, congestive heart failure, chronic o ...
, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury.


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. 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 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.


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. Destruction of dendrite trees is a consideration even with repeated low doses. Cognitive deficits as well as increased dissociation and
delusion A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...
s were observed in frequent recreational users of ketamine.


Interactions

Ketamine potentiates the sedative effects of propofol and
midazolam Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia, premedication before surgical anesthesia, and procedural sedation, and to treat psychomotor agitation, severe agitation. It induces ...
. 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. Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine. It appears most conventional antidepressants can be safely combined with ketamine.


Pharmacology


Pharmacodynamics


Mechanism of action

Ketamine is a mixture of equal amounts of two
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
s:
esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...
and arketamine. Esketamine is a far more potent NMDA receptor pore blocker than arketamine. Pore blocking of the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
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 The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
. 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 In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
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 Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...
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 Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
, 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 pathway In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...
s 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 Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...
(BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the
mammalian target of rapamycin The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''M ...
(mTOR) pathway, deactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of the
phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
of the eukaryotic elongation factor 2 (eEF2) kinase.


Molecular targets

Ketamine principally acts as a pore blocker of the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
, an ionotropic glutamate receptor. 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. 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 allosteric sites on the monoamine transporters to produce monoamine reuptake inhibition. However, no functional inhibition ( IC50) of the human monoamine transporters has been observed with ketamine or its
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s at concentrations of up to 10,000 nM. Moreover, animal studies and at least three human case reports have found no interaction between ketamine and the monoamine oxidase inhibitor (MAOI) tranylcypromine, which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as
serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...
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 Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...
secretion Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mec ...
, 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.
Imaging Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image). Imaging technology is the application of materials and methods to create, preserve, or duplicate images. ...
studies have shown mixed results on inhibition of striatal sup>11C raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect. However, changes in sup>11Craclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D2 receptor.


Relationships between levels and effects

Dissociation and psychotomimetic effects are reported in people treated with ketamine at plasma concentrations of approximately 100 to 250 ng/mL (0.42–1.1 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 Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or factitious air, among others, is a chemical compound, an Nitrogen oxide, oxide of nitrogen with the Chemical formula, formula . At room te ...
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 both its water and lipid solubility.
Intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
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%. 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 Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
. It is biotransformed by
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
and CYP2B6 isoenzymes into norketamine, which, in turn, is converted by CYP2A6 and CYP2B6 into hydroxynorketamine and dehydronorketamine. Low oral bioavailability of ketamine is due to the first-pass effect and, possibly, ketamine intestinal metabolism by CYP3A4. As a result, norketamine plasma levels are several-fold higher than ketamine following oral administration, and norketamine may play a role in anesthetic and analgesic action of oral ketamine. This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels. After an intravenous injection of
tritium Tritium () or hydrogen-3 (symbol T or H) is a rare and radioactive isotope of hydrogen with a half-life of ~12.33 years. The tritium nucleus (t, sometimes called a ''triton'') contains one proton and two neutrons, whereas the nucleus of the ...
-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces. The medication is excreted mostly in the form of
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.


Chemistry


Structure

In chemical structure, ketamine is an arylcyclohexylamine derivative. Ketamine is a chiral compound. The more active enantiomer,
esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...
(''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 Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...
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.


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.


History

Ketamine was first synthesized in 1962 by Calvin L. Stevens, a professor of chemistry at
Wayne State University Wayne State University (WSU) is a public university, public research university in Detroit, Michigan, United States. Founded in 1868, Wayne State consists of 13 schools and colleges offering approximately 375 programs. It is Michigan's third-l ...
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 The Vietnam War (1 November 1955 – 30 April 1975) was an armed conflict in Vietnam, Laos, and Cambodia fought between North Vietnam (Democratic Republic of Vietnam) and South Vietnam (Republic of Vietnam) and their allies. North Vietnam w ...
. 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.


Society and culture


Legal status

While ketamine is marketed legally in many countries worldwide, it is also a controlled substance in many countries. * In Australia, ketamine is listed as a Schedule 8 controlled drug under the Poisons Standard (October 2015).Poisons Standard October 2015 * In Canada, ketamine has been classified as a Schedule I narcotic, since 2005.Legal status of ketamine in Canada references: * * * * In December 2013, the
government of India The Government of India (ISO 15919, ISO: Bhārata Sarakāra, legally the Union Government or Union of India or the Central Government) is the national authority of the Republic of India, located in South Asia, consisting of States and union t ...
, 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. * In the United Kingdom, it was labeled a Class B drug on 12 February 2014. In 2025, the Home Office requested a review of the classification with a view to changing it to Class A, based on an increase in recreational use and the negative health consequences. * The increase in recreational use prompted ketamine to be placed in Schedule III of the United States
Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...
in August 1999.


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 Depersonalization is a dissociative phenomenon characterized by a subjective feeling of detachment from oneself, manifesting as a sense of disconnection from one's thoughts, emotions, sensations, or actions, and often accompanied by a feeling of ...
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 Marcia Moore (May 22, 1928 – January 14, 1979) was an American writer, astrologer and yoga teacher brought to national attention in 1965 through Jess Stearn's book ''Yoga, Youth, and Reincarnation''. She was an advocate and researcher of th ...
, D. M. Turner, and David Woodard (among others) have written extensively about their own entheogenic and psychonautic experiences with ketamine.References for recreational use in literature: * * * * * Turner died prematurely due to drowning during presumed unsupervised ketamine use. 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. Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005–2013. They include accidental poisonings, drownings, traffic accidents, and
suicides Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...
.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 Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...
, ketamine has been used for date rape.


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 In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
, 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,
rabbit Rabbits are small mammals in the family Leporidae (which also includes the hares), which is in the order Lagomorpha (which also includes pikas). They are familiar throughout the world as a small herbivore, a prey animal, a domesticated ...
s, rats, 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. Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.


References


External links

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