Ketamine, sold under the brand name Ketalar among others, is a medication mainly used for starting and maintaining anesthesia. It induces a trance-like state while providing pain relief, sedation, and memory loss. Other uses include for chronic pain and for sedation in intensive care. Heart function, breathing, and airway reflexes generally remain functional. Effects typically begin within five minutes when given by injection with the main effects lasting up to 25 minutes.
Common side effects include psychological reactions as the medication wears off. These reactions may include agitation, confusion, or hallucinations. Elevated blood pressure and muscle tremors are relatively common, while low blood pressure and a decrease in breathing are less so. Spasms of the larynx may rarely occur. Ketamine has been classified as an NMDA receptor antagonist but its mechanism are not well understood as of 2017.
Ketamine was discovered in 1962, first tested in humans in 1964, and was approved for use in the United States in 1970. Shortly after its US approval it was extensively used for surgical anesthesia in the Vietnam War, due to its safety. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world is between US$0.08 and US$0.32 per dose. Ketamine is also used as a recreational drug.
Uses as an anesthetic:
- Anesthesia in children, as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and tracheal intubation
- Asthmatics or people with chronic obstructive airway disease
- As a sedative for physically painful procedures in emergency departments
- Emergency surgery in field conditions in war zones
- To supplement spinal or epidural anesthesia/analgesia using low doses
Since it suppresses breathing much less than most other available anesthetics, ketamine is used in medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anesthetic of choice when reliable ventilation equipment is not available.
Ketamine is frequently used in severely injured people and appears to be safe in this group. A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine. It is the drug of choice for people in traumatic shock who are at risk of hypotension. Low blood pressure is harmful in people with severe head injury and ketamine is least likely to cause low blood pressure, often even able to prevent it.
The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system. It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is considered relatively safe because protective airway reflexes are preserved.
It may also be used as an intravenous analgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic. It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines. Ketamine is an analgesic that is most effective when used alongside a low-dose opioid; because, while it does have analgesic effects by itself, the doses required for adequate pain relief when it is used as the sole analgesic agent are considerably higher and far more likely to produce disorienting side effects. A review article in 2013 concluded, "despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain".
Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS). A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.
Ketamine has been tested as a rapid-acting antidepressant for treatment-resistant depression in bipolar disorder, and major depressive disorder. Ketamine's antidepressant effect has a short duration of action. The quality of the evidence supporting its use as an antidepressant is generally low. Currently, ketamine is not approved for the treatment of depression, and so this is an off-label use. As of June 2017, esketamine, the S(+) enantiomer of ketamine, is in phase III clinical trials for intranasal treatment of depression.
Ketamine is given by a single intravenous infusion at doses less than those used in anesthesia, and preliminary data indicate it produces a rapid (within 2 hours) and relatively sustained (about 1–2 weeks long) reduction in symptoms in some people. Initial studies have resulted in interest due to its rapid onset, and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.
- Conditions worsened by an increase in blood pressure or heart rate, such as angina, stroke, poorly controlled high blood pressure, etc. as ketamine increases both heart rate and blood pressure.
- Psychiatric disorders. Ketamine can cause hallucinations, so it can exacerbate the symptoms of certain psychiatric disorders.
- Raised intracranial pressure (ICP). Ketamine can further increase ICP.
- Raised intraocular pressure (IOP). Ketamine can also increase IOP.
- Penetrating eye injury. Can increase risk of loss of eye contents, due to increased IOP.
- Acute porphyria. Ketamine is considered porphyrinogenic, that is, it may provoke an attack of acute porphyria in susceptible persons.
Ketamine is generally safe for those critically ill, when administered by trained medical professionals. Even in these cases, there are known side effects that include one or more of the following:
- Cardiovascular: abnormal heart rhythms, slow heart rate or fast heart rate, high blood pressure or low blood pressure
- Central nervous system: Ketamine is traditionally avoided in people with or at risk of intracranial hypertension (ICP) due to concerns about ketamine causing increased intracranial pressure. It does not increase ICP more than opioids.
- Dermatologic: Transient reddening of the skin, transient measles-like rash
- Gastrointestinal: reduced appetite, nausea, increased salivation, vomiting
- Local: Pain, eruptions or rashes at the injection site
- Neuromuscular and skeletal: Increased skeletal muscle tone (tonic-clonic movements)
- Ocular: Double vision, increased intraocular pressure, involuntary eye movements, tunnel vision
- Respiratory: Airway obstruction, cessation of breathing, increased bronchial secretions, reduced effort to breathe, spasm of the vocal cords (larynx)
- Other: Anaphylaxis, dependence, emergence reaction
At anesthetic doses, 10-20% of people experience adverse reactions that occur during emergence from anesthesia, reactions that can manifest as seriously as hallucinations and delirium. These reactions may be less common in some people subpopulations, and when administered intramuscularly, and can occur up to 24 hours postoperatively; the chance of this occurring can be reduced by minimizing stimulation to the person during recovery and pretreating with a benzodiazepine, alongside a lower dose of ketamine. People who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.
In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes, known as Olney's lesions, in two small areas of the rat brain. However, the rat brain has significant differences in metabolism from the human brain, therefore such changes may not occur in humans.
The first large-scale, longitudinal study of ketamine users found current frequent (averaging 20 days/month) ketamine users had increased depression and impaired memory by several measures, including verbal, short-term memory, and visual memory. Current infrequent (averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention, and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.
Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and noncell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal maintenance and development.
More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time. Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month. A study conducted on rhesus monkeys found a 24-hour intravenous infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals.
Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects it may have on the developing brain. These neurodegenerative changes in early development have been seen with other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.
The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.
Urinary tract effectsEdit
A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine recreational use. Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful blood in urine. Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases. The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.
The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 g/day reported symptoms of the lower urinary tract. Urinary tract symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of time. These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.
Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension. Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some people, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.
In case reports of three people treated with esketamine for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.
Plasma concentrations of ketamine are increased by CYP3A4 inhibitors (e.g., diazepam) and CYP2B6 inhibitors (e.g., orphenadrine) due to inhibition of its metabolism. CYP2B6 and CYP3A4 inducers like carbamazepine, phenobarbital, phenytoin, and rifampicin may reduce plasma levels of ketamine.
Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI antidepressants, and MAOIs. Increase blood pressure and heart rate, palpitations, and arrhythmias may be potential effects.
Ketamine may increase the effects of other sedatives in a dose-dependent manner, including, but not limited to: alcohol, benzodiazepines, opioids, quinazolinones, phenothiazines, anticholinergics, and barbiturates.
Benzodiazepines may diminish the antidepressant effects of ketamine. Most conventional antidepressants can likely be combined with ketamine without diminished antidepressant effectiveness or increased side effects.
|Values are Ki (μM), unless otherwise noted. The smaller the
value, the more strongly the drug binds to the site.
Ketamine acts as a selective antagonist of the NMDA receptor, an ionotropic glutamate receptor. It binds specifically to the dizocilpine (MK-801) site of the NMDA receptor, near the channel pore, and is an uncompetitive antagonist. Ketamine may also interact with and inhibit the NMDAR via another allosteric site on the receptor. Its full mechanism of action is not well-understood as of 2017.
A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting the NMDA receptor, but rather by sustained indirect/downstream activation of another type of ionotropic glutamate receptor, the AMPA receptor, by a metabolite, (2R,6R)-hydroxynorketamine; as of 2017 it is unknown if this is the case in humans. Arketamine is also an indirect/downstream AMPA receptor activator.
Known actions of ketamine include:
- Uncompetitive antagonist (channel pore blocker) of the NMDA receptor
- Indirect/downstream activation of AMPA receptors
- Ligand of the μ-, κ-, and δ-opioid receptors
- Sigma σ1 and σ2 receptor agonist
- Partial agonist of the high-affinity state of the dopamine D2 receptor
- Ligand of the serotonin 5-HT2A receptor
- Potentiator of the serotonin 5-HT3 receptor
- Muscarinic acetylcholine receptor antagonist
- Negative allosteric modulator of nicotinic acetylcholine receptors (e.g., α7, α4β2)
- Inhibitor of cholinesterase
- Inhibitor of the reuptake of serotonin, norepinephrine, and dopamine
- Ligand of the PCP site 2
- Blocker of voltage-gated/dependent sodium and calcium channels
- Blocker of HCN1 cation channels
- Inhibitor of nitric oxide synthase
With the exception of partial agonism of the high-affinity state of the D2 receptor (and indirect/downstream activation of AMPA receptors), all of these actions are far weaker than ketamine's antagonism of the NMDA receptor (see table to the right; minimum of more than 10-fold selectivity for the NMDA receptor relative to the site with the next highest affinity). A binding study assessed ketamine at 56 sites including neurotransmitter receptors and transporters and found that ketamine had Ki values of >10,000 nM at all sites except the dizocilpine site of the NMDA receptor (Ki = 659 nM), indicating a minimum of 15-fold selectivity for the NMDA receptor over any other site.
Although ketamine is a very weak ligand of the monoamine transporters (Ki > 60,000 nM), it has been suggested that it may interact with allosteric sites on the monoamine transporters to produce monoamine reuptake inhibition. However, no functional inhibition (IC50) of the human monoamine transporters has been observed with ketamine or its metabolites at concentrations of up to 10,000 nM. Moreover, animal studies and at least three human case reports have found no interaction between ketamine and the monoamine oxidase inhibitor (MAOI) tranylcypromine. 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 via dopamine reuptake inhibition, this may be via indirect/downstream mechanisms, namely antagonism of the NMDA receptor.
Metabolites of ketamine including dehydronorketamine, hydroxynorketamine, and norketamine have been found to act as negative allosteric modulators of the α7 nicotinic acetylcholine receptor in the KXa7R1 cell line (HEK293 cells transfected with rat nicotinic acetylcholine receptor genes) with subanesthetic and nanomolar potencies (e.g., IC50 = 55 nM for dehydronorketamine), whereas ketamine itself was inactive at the same concentrations (< 1 µM). These findings suggest that metabolites may contribute importantly to the pharmacodynamics of ketamine.
Ketamine has been found to act as a potent partial agonist of the high-affinity state of the human and rat dopamine D2 receptors in multiple studies. Its apparent potency for this action is similar to that of its NMDA receptor antagonism. However, there are also contradictory data, with studies finding an affinity of ketamine of >10,000 nM for the regular human and rat D2 receptors, and direct interactions with the D2 receptor are controversial. Moreover, whereas D2 receptor agonists like bromocriptine are able to 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 significantly and dose-dependently increase prolactin levels. Imaging studies have shown mixed results on inhibition of striatal [11C]raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect. 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.
The S(+) and R(–) stereoisomers bind to the dizocilpine site of the NMDA receptor with different affinities, the former showing approximately 2- to 3-fold greater affinity for the receptor than the latter.
Relationship between concentrations and effectsEdit
Drowsiness, dissociation, and psychosis-like effects (e.g., hallucinations, delirium) are reported in patients treated with ketamine starting at circulating concentrations of around 50 to 200 ng/mL (210–841 nM), while analgesia begins at levels of approximately 100 to 200 ng/mL (421–841 nM). 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 (294–841 nM). Circulating concentrations of around 2,000 to 3,000 ng/mL (8,413–12,620 nM) are employed during anesthesia, and patients may start to awaken once levels of ketamine have decreased to about 500 to 1,000 ng/mL (2,103–4,207 nM). There is wide variation in the peak concentrations of ketamine that have been reported in association with anesthesia in the literature, with values ranging from 2,211–3,447 ng/mL (9,300–14,500 nM) to as high as 22,370 ng/mL (94,100 nM). Bioactive concentrations of ketamine are lower than total plasma levels due to plasma protein binding, although plasma protein binding is relatively low with ketamine (approximately 12 to 47% protein-bound). Concentrations of ketamine in the brain have been reported to be several-fold higher than in plasma.
Effects in central nervous systemEdit
Antagonism of the NMDA receptor is thought to be responsible for the anesthetic, amnesic, dissociative, and hallucinogenic effects of ketamine. The mechanism(s) of action for the antidepressant effects of ketamine at lower doses have yet to be elucidated. NMDA receptor antagonism 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. Inhibition of nitric oxide synthase lowers the production of nitric oxide – a gasotransmitter involved in pain perception, hence further contributing to analgesia.
Effects in peripheral systemsEdit
- Cardiovascular: Ketamine stimulates the sympathetic nervous system, resulting in cardiovascular changes.
- Gastrointestinal: Ketamine produces nausea and vomiting in 15 to 25% of individuals.
- Respiratory: Ketamine causes bronchodilation. Several mechanisms have been hypothesized to explain this effect.
The exact mechanisms of these effects are not fully understood.
Ketamine is absorbable by intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities. When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine. Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine. As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent as an anesthetic, and plasma levels of this metabolite are three times higher than ketamine following oral administration. Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally. Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally. Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.
- Oral ketamine is easily broken down by bile acids, thus has a low bioavailability. Often, lozenges or "gummies" for sublingual or buccal absorption prepared by a compounding pharmacy are used to combat this issue.
- Some specialists stop the subcutaneous infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.
In chemical structure, ketamine is an arylcyclohexylamine derivative. Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. 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.
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 difference originates from the conformation of the cyclohexanone ring. In both the free base and the hydrochloride, the cyclohexanone ring adopts a chair conformation, but the orientation of the substituents varies. In the free base, the o-chlorophenyl group adopts an equatorial position and the methylamino group adopts an axial position. In the hydrochloride salt, the positions are reversed, with the o-chlorophenyl group axial and the methylamino group equatorial. Not all salts of ketamine show different optical rotation to the free base: (S)-ketamine (R,R)-tartrate is levorotatory, like (S)‑ketamine.
Ketamine was first synthesized in 1962 by Calvin L. Stevens, a professor of Chemistry at Wayne State University and a Parke Davis consultant conducting research on alpha-hydroxyimine rearrangements. After promising preclinical research in animals, ketamine was introduced to testing 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 a dissociative anesthetic. Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.
See the foregoing discussion and citations regarding the increasing stringency of governmental regulation that has resulted from a number of deaths of youth and young adults by overdose, accident, and suicide in which nonmedical/recreational ketamine use is implicated (in the Recreational use section, above).
Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s. Early use was documented in underground literature such as The Fabulous Furry Freak Brothers. It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonaut John Lilly's The Scientist, and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication. The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties. However, its emergence as a club drug differs from other club drugs (e.g. MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses; in addition, there are reports of ketamine being sold as "ecstasy". The use of ketamine as part of a "postclubbing experience" has also been documented. Ketamine's rise in the dance culture was rapid in Hong Kong by the end of the 1990s. Before becoming a federally controlled substance in the United States in 1999, ketamine was available as diverted pharmaceutical preparations and as a pure powder sold in bulk quantities from domestic chemical supply companies. Much of the current ketamine diverted for nonmedical use originates in China and India.
Society and cultureEdit
Ketamine is the English generic name of the drug and its INN and BAN, while ketamine hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are ketamina, in French and its DCF are kétamine, in German is ketamin, and in Latin is ketaminum.
Ketamine is primarily sold throughout the world under the brand name Ketalar. It is also marketed under a variety of other brand names, including Calypsol, Ketamin, Ketamina, Ketamine, Ketaminol, Ketanest, Ketaset, Tekam, and Vetalar among others.
Esketamine is sold mainly under the brand names Ketanest and Ketanest-S.
While ketamine is legally marketed in many countries worldwide, it is also a widely controlled substance throughout the world.
In Australia Ketamine is listed as a schedule 8 controlled drug under the Poisons Standard (October 2015). A schedule 8 drug is outlined in the Poisons Act 1964 as "Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence." 
In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.
In December 2013, the government of India, in response to rising recreational use and the use of ketamine as a date rape drug, has 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 became labeled a Class C drug on 1 January 2006. On 10 December 2013 the UK Advisory Council on the Misuse of Drugs (ACMD) recommended that the government reclassify ketamine to become a Class B drug, and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".
The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice, said the issue of its recheduling for medical and veterinary use would be addressed "separately to allow for a period of consultation."
Ketamine use as a recreational drug 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. The majority of deaths were among young people. This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.).
Unlike the other well-known dissociatives phencyclidine (PCP) and dextromethorphan (DXM), ketamine is very short-acting. It takes effect within about 10 minutes, while its hallucinogenic effects last 60 minutes when insufflated or injected and up to two hours when ingested orally.
At anesthetic doses, under-dosaged from a medical point of view, ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization. At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations. John C. Lilly, Marcia Moore and D. M. Turner (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with ketamine. Both Moore and Turner died prematurely (due to hypothermia and drowning respectively) during presumed unsupervised ketamine use.
After the publication of the NIH-run antidepressant clinical trial, clinics began opening in which the medication is given. This practice is an off label use of ketamine in the United States. As of 2015 there were about 60 such clinics in the US, the procedure was not covered by insurance, and people paid between $400 and $1700 out of pocket for a treatment. A chain of such clinics in Australia run by Aura Medical Corporation was closed down by regulatory authorities in 2015, because the clinics' marketing was not supported by scientific research and because the clinic sent people home with ketamine and needles to administer infusions to themselves.
Russian doctor Evgeny Krupitsky has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques. Krupitsky and Kolp summarized their work to date in 2007.
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. It is highly used in induction and anesthetic maintenance in horses. It is an important part of the "rodent cocktail", a mixture of drugs used for anesthetizing 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 used to manage pain among large animals, though it has less effect on bovines. It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.
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