Ketamine Explained

Watchedfields:changed
Verifiedrevid:477168837
Width:150
Width2:175
Alt2:(S)-Ketamine ball-and-stick model
Tradename:Ketalar, others
Dailymedid:Ketamine
Licence Us:Ketamine
Pregnancy Au:B3
Pregnancy Au Comment:[1]
Addiction Liability:Moderate–high[2] [3]
Routes Of Administration:Any[4] [5] [6] [7]
Class:NMDA receptor antagonists
General anesthetics; Dissociative hallucinogens; Analgesics; Antidepressants
Atc Prefix:N01
Atc Suffix:AX03
Legal Au:S8
Legal Br:C1
Legal Ca:Schedule I
Legal De:Anlage III
Legal Uk:Class B
Legal Us:Schedule III
Legal Un:Unscheduled
Legal Status:In general Rx-only
Bioavailability:
Protein Bound:23 to 47%.[11]
Metabolism:Liver, intestine (oral):[12]
Metabolites:
Onset:
  • Intravenous: seconds[13]
  • Intramuscular: 1–5 min
  • Subcutaneous: 15–30 min
  • Insufflation: 5–10 min
  • By mouth: 15–30 min
Elimination Half-Life:
  • Ketamine: 2.5–3 hours
  • Norketamine: 12 hours
Duration Of Action:
  • Intramuscular: 0.5–2 hours
  • Insufflation: 45–60 min
  • By mouth: 1–6+ hours
Excretion:
Index2 Label:HCl
Iuphar Ligand:4233
Cas Number:6740-88-1
Cas Number2:1867-66-9
Cas Supplemental:
Chebi:6121
Pubchem:3821
Drugbank:DB01221
Chemspiderid:3689
Unii:690G0D6V8H
Kegg:D08098
Kegg2:D00711
Chembl:742
Synonyms:CI-581; CL-369; CM-52372-2[14]
Iupac Name:(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
C:13
H:16
Cl:1
N:1
O:1
Chirality:Racemic mixture
Smiles:Clc1ccccc1C2(NC)CCCCC2=O
Stdinchi:1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3
Stdinchikey:YQEZLKZALYSWHR-UHFFFAOYSA-N
Melting Point:92 [15]

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management.[16] It is a compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.[17]

At anesthetic doses, ketamine induces a state of dissociative anesthesia, a trance-like state providing pain relief, sedation and amnesia. Its distinguishing features as anesthesia are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation.[18] At lower, sub-anesthetic doses, it is a promising agent for pain and treatment-resistant depression.[19] As with many antidepressants, the results of a single administration wane with time.[20] 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.[21] Ketamine is an NMDA receptor antagonist, accounting for most of its psychoactive effects.

Ketamine was first synthesized in 1962 and 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. Along with other psychotropic drugs, it is on the World Health Organization's List of Essential Medicines.[22] It is available as a generic medication.[23] When used as a recreational drug, it is found both in crystalline powder and liquid form, and is often referred to by recreational users as "Special K" or simply "K". It is used as a recreational drug for its hallucinogenic and dissociative effects.[24]

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.[25] The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. It suppresses breathing much less than most other available anesthetics.[26] When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system.[27] Protective airway reflexes are preserved[28] and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways.[25] Psychotomimetic effects limit the acceptance of ketamine; however, lamotrigine and nimodipine decrease psychotomimetic effects and can be counteracted also by benzodiazepines 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.[29] It has been widely used for emergency surgery in field conditions in war zones, for example, during the Vietnam War.[30] 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.[31] Ketamine is unlikely to lower blood pressure, which is dangerous for people with severe head injury;[32] in fact, it can raise blood pressure, often making it useful in treating such injuries.[33] [34]

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[35] In particular, children with cyanotic heart disease and neuromuscular disorders are good candidates for ketamine anesthesia.[36] [37]

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.[35] [36] [38]

Pain

Ketamine infusions are used for acute pain treatment in emergency departments and in the perioperative period for individuals with refractory pain. The doses are lower than those used for anesthesia; they are usually referred to as sub-anesthetic doses. Adjunctive to morphine or on its own, ketamine reduces morphine use, pain level, nausea, and vomiting after surgery. Ketamine is likely to be most beneficial for surgical patients when severe post-operative pain is expected, and for opioid-tolerant patients.[39] [40]

Ketamine is especially useful in the pre-hospital setting, due to its effectiveness and low risk of respiratory depression.[41] Ketamine has similar efficacy to opioids in a hospital emergency department setting for management of acute pain and for control of procedural pain.[42] It may also prevent opioid-induced hyperalgesia[43] [44] and postanesthetic shivering.[45]

For chronic pain, ketamine is used as an intravenous analgesic, particularly if the pain is neuropathic.[46] It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain.[47] In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after traumatic spine injury, fibromyalgia, and complex regional pain syndrome (CRPS).[46] 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.[46]

Depression

Ketamine is a rapid-acting antidepressant, although its effect is transient.[48] Intravenous ketamine infusion in treatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours.[49] 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 there are only a few pilot studies studying the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome.[50] The antidepressant effect of ketamine is diminished at 7 days, and most people relapse within 10 days, although for a significant minority the improvement may last 30 days or more.[51] [52] [53]

One of the main challenges with ketamine treatment can be the length of time that the antidepressant effects lasts 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.[49] [51] [54] Ketamine may decrease suicidal thoughts for up to three days after the injection.[55]

An enantiomer of ketamine esketamine commercially sold as Spravato was approved as an antidepressant by the European Medicines Agency in 2019.[56] Esketamine was approved as a nasal spray for treatment-resistant depression in the United States[57] and elsewhere in 2019 (see Esketamine and Depression). The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends esketamine as a third-line treatment for depression.[51]

A Cochrane review of randomized controlled trials in adults with unipolar 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.[58] 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, 2.1% (2.5 to 24.4%) more encountered some relief at 24 hours and 10.3% (4.5 to 18.2%) more had few or no symptoms. These effects did not persist beyond one week, although higher dropout rate in some studies mean that the duration of benefit remains unclear.[58]

Ketamine may partially improve depressive symptoms among people with bipolar depression, at 24 hours after treatment, but not 3 or more days.[59] Potentially, 10 more people with bipolar depression per 1000 may experience brief improvement, but not cessation of symptoms, one day following treatment. These estimates are based on limited available research.[59]

In February 2022, the US Food and Drug Administration issued an alert to health care professionals concerning compounded nasal spray products containing ketamine intended to treat depression.[60]

Near-death experience

Most people who were able to remember their dreams during ketamine anesthesia report near-death experiences (NDEs) when the widest possible definition of an NDE is used.[61] Ketamine can reproduce features that commonly have been associated with NDEs.[62] 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.[63]

Seizures

Ketamine is used to treat status epilepticus[64] that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use.[65] [66]

Asthma

Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment.[67] 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:[46] [39]

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.[68] Psychotomimetic effects decrease 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.

At lower sub-anesthetic doses, psychiatric side effects are prominent. Most people feel strange, spacey, woozy, or a sense of floating, or have visual distortions or numbness. Also very frequent (20–50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating. The symptoms of psychosis such as going into a hole, disappearing, feeling as if melting, experiencing colors, and hallucinations are described by 6–10% of people. Dizziness, blurred vision, dry mouth, hypertension, nausea, increased or decreased body temperature, or feeling flushed 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.[69]

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.[70] It includes a range of disorders from cystitis to hydronephrosis to kidney failure.[71] The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and blood in urine.[72] 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.[73]

Management of ketamine-induced cystitis involves ketamine cessation as the first step. This is followed by NSAIDs and anticholinergics and, if the response is insufficient, by tramadol. The second line treatments are epithelium-protective agents such as oral pentosan polysulfate or intravesical (intra-bladder) 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,[74] cachexia, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury.[75]

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, shaking, sweating, and palpitations, following the attempts to stop. Cognitive deficits as well as increased dissociation and delusion symptoms were observed in frequent recreational users of ketamine.[76]

Interactions

Ketamine potentiates the sedative effects of propofol[77] and midazolam.[78] Naltrexone potentiates psychotomimetic effects of a low dose of ketamine,[79] while lamotrigine[80] and nimodipine[81] decrease them. Clonidine reduces the increase of salivation, heart-rate and blood-pressure during ketamine anesthesia and decreases the incidence of nightmares.[82]

Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine.[83] 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 enantiomers: 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.[84] [85] 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.[86]

The mechanism of action of ketamine in alleviating depression is not well understood, and is an area of active investigation. Because of 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.[87] Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as (2R,6R)-hydroxynorketamine, the metabolite with negligible affinity for the NMDA receptor but potent alpha-7 nicotinic receptor antagonist activity, may have antidepressant action. This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine.[88] 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.[89] [90]

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.[91] [92] 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.[93] 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.[94] [95]

Molecular targets

Ketamine and biological targets (with Ki below 100 μM)
Site Value (μM) Type Action Species Ref
0.25–0.66 Ki Antagonist Human [96] [97]
42 Ki Antagonist Human [98]
12.1KiAntagonist Human [99]
28
25
Ki
Ki
Antagonist
Agonist
Human
[100]
26 Ki Rat [101]
0.5
>10
Ki
Ki
Agonist
Human [102]
[103]
45 Ki Human [104]
92 IC50 Antagonist Human [105]
29 IC50 Antagonist Human
50 IC50 Antagonist Human
9.5 IC50 Antagonist Human
72 IC50 Antagonist Human
18 IC50 Antagonist Human
3.1 IC50 Antagonist Rat [106]
0.34 KiHuman [107]
82–291 IC50 Inhibitor Human [108] [109]
63 Ki Inhibitor Rat
8–16 EC50 Inhibitor Mouse [110]
TRPV11-100KiAgonistRat[111]
The smaller the value, the stronger the interaction with the site.

Ketamine principally acts as a pore blocker of the NMDA receptor, an ionotropic glutamate receptor.[112] 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.[113]

Ketamine may interact with and inhibit the NMDAR via another allosteric site on the receptor.[114]

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).[115]

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 metabolites at concentrations of up to 10,000 nM.[112] Moreover, animal studies and at least three human case reports have found no interaction between ketamine and the monoamine oxidase inhibitor (MAOI) tranylcypromine, which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as serotonin syndrome or hypertensive crisis.[116] [117] 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 the potency similar to that of its NMDA receptor antagonism.[118] [119] However, later studies by different researchers found the affinity of ketamine of >10 μM for the regular human and rat D2 receptors,[120] Moreover, whereas D2 receptor agonists such as bromocriptine are able to rapidly and powerfully suppress prolactin secretion,[121] 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.[122] [123] Imaging studies have shown mixed results on inhibition of striatal [<sup>11</sup>C] raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect.[124] However, changes in [<sup>11</sup>C] raclopride 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 a rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60–110 μM.[125] [126] 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).[127] 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.[128]

Pharmacokinetics

Ketamine can be absorbed by many different routes due to both its water and lipid solubility. Intravenous ketamine bioavailability is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%, and epidural bioavailability is 77%. Subcutaneous bioavailability has never been measured, but is presumed to be high.[129] 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. It is biotransformed by CYP3A4 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.[130] This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.[131]

After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from the feces.[132] The medication is excreted mostly in the form of metabolites, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.

Chemistry

Synthesis

2-chlorobenzonitrile is reacted with the Grignard reagent cyclopentylmagnesium bromide to give (2-chlorophenyl)(cyclopentyl)methanone. This is then brominated using bromine to form the corresponding bromoketone, which is then reacted with methylamine in an aqueous solution to form the methylimino derivative, 1-(2-Chloro-N-methylbenzimidoyl)cyclopentanol, with hydrolysis of the tertiary bromine atom. This final intermediate is then heated in decalin or another suitable high-boiling solvent, upon which an Alpha-ketol rearrangement occurs resulting in a ring-expansion, and the formation of racemic ketamine.

Structure

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,[133] 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.[134]

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 to 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.[135] [136] [137]

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.[138] These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as an anesthetic.[139] 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 about the "disconnected" appearance of treated people, Mrs. Edward F. Domino,[140] 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 discovery of antidepressive action of ketamine in 2000[141] 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,[142] and has shifted the direction of antidepressant research and development.[143]

Society and culture

See main article: Ketamine in society and culture.

Legal status

While ketamine is marketed legally in many countries worldwide,[144] 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.[151] At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucination.[152] John C. Lilly, Marcia Moore, D. M. Turner, and David Woodard (among others) have written extensively about their own entheogenic and psychonautic experiences with ketamine.[153] Turner died prematurely due to drowning during presumed unsupervised ketamine use.[154] In 2006, the Russian edition of Adam Parfrey's Apocalypse Culture II 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.[155]

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.[156] The majority of deaths were among young people.[157] 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.[158] Because of its ability to cause confusion and amnesia, ketamine has been used for date rape.[159] [160]

Research

Ketamine is under investigation for its potential in treating treatment-resistant depression.[161] [162] [163] Ketamine is a known psychoplastogen, which refers to a compound capable of promoting rapid and sustained neuroplasticity.[164]

Ketamine has shown anthelmintic activity in rats, with an effect comparable to ivermectin and albendazole at extremely high concentrations.[165]

Veterinary medicine

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,[166] dogs,[167] rabbits, rats, and other small animals.[168] [169] 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.[170]

Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.[171]

External links

Notes and References

  1. Web site: Ketamine (Ketalar) Use During Pregnancy . Drugs.com . 22 November 2019 . 18 May 2020 . 26 June 2020 . https://web.archive.org/web/20200626125239/https://www.drugs.com/pregnancy/ketamine.html . live .
  2. Web site: Drug Scheduling . US DEA . 29 December 2023 . 8 April 2024 . https://web.archive.org/web/20240408102758/https://www.dea.gov/drug-information/drug-scheduling . live . Ketamine is listed in Schedule III.
  3. Huang, MC., Lin, SK. (2020). Ketamine Abuse: Past and Present. In: Hashimoto, K., Ide, S., Ikeda, K. (eds) Ketamine. Springer, Singapore. https://doi.org/10.1007/978-981-15-2902-3_1
  4. Bell RF, Eccleston C, Kalso EA . Ketamine as an adjuvant to opioids for cancer pain . The Cochrane Database of Systematic Reviews . 6 . CD003351 . June 2017 . 9 . 28657160 . 6481583 . 10.1002/14651858.CD003351.pub3 . 10 September 2018 . 12 January 2024 . https://web.archive.org/web/20240112122726/http://opus.bath.ac.uk/57535/1/Published_Version.pdf . live .
  5. Moyse DW, Kaye AD, Diaz JH, Qadri MY, Lindsay D, Pyati S . Perioperative Ketamine Administration for Thoracotomy Pain . Pain Physician . 20 . 3 . 173–184 . March 2017 . 28339431 .
  6. Book: Mathew SJ, Zarate Jr CA . Ketamine for Treatment-Resistant Depression: The First Decade of Progress . 25 November 2016 . Springer . 978-3-319-42925-0 . 8–10, 14–22 . live . https://web.archive.org/web/20170908185726/https://books.google.com/books?id=QDOgDQAAQBAJ&pg=PA22 . 8 September 2017 .
  7. Web site: Ketamine Hydrochloride: Martindale: The Complete Drug Reference. 9 January 2017. 24 August 2017. Brayfield A. Pharmaceutical Press. MedicinesComplete. London, UK. 28 August 2021. https://web.archive.org/web/20210828134205/https://about.medicinescomplete.com/wp-content/themes/mc-marketing/assets/images/favicons-tiles/favicon.ico. live.
  8. Book: Kintz P . Toxicological Aspects of Drug-Facilitated Crimes . 22 March 2014 . Elsevier Science . 978-0-12-416969-2 . 87– . live . https://web.archive.org/web/20170908185726/https://books.google.com/books?id=YgnUAgAAQBAJ&pg=PA87 . 8 September 2017 .
  9. Marland S, Ellerton J, Andolfatto G, Strapazzon G, Thomassen O, Brandner B, Weatherall A, Paal P . Ketamine: use in anesthesia . CNS Neurosci Ther . 19 . 6 . 381–9 . June 2013 . 23521979 . 6493613 . 10.1111/cns.12072 .
  10. Hashimoto K . Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective . Psychiatry and Clinical Neurosciences . 73 . 10 . 613–627 . October 2019 . 31215725 . 6851782 . 10.1111/pcn.12902 .
  11. Dayton PG, Stiller RL, Cook DR, Perel JM . The binding of ketamine to plasma proteins: emphasis on human plasma . Eur J Clin Pharmacol . 24 . 6 . 825–31 . 1983 . 6884418 . 10.1007/BF00607095 . 807011 .
  12. Hijazi Y, Boulieu R . Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes . Drug Metabolism and Disposition . 30 . 7 . 853–8 . July 2002 . 12065445 . 10.1124/dmd.30.7.853 . 15787750 .
  13. Book: Sinner B, Graf BM . Ketamine . Modern Anesthetics . Schüttler J, Schwilden H . Handbook of Experimental Pharmacology . 2008 . 182 . 182 . 313–33 . 978-3-540-72813-9 . 10.1007/978-3-540-74806-9_15 . 18175098.
  14. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms . 6 December 2012 . Springer Science & Business Media . 978-94-011-4439-1 . 159– . live . https://web.archive.org/web/20170411144623/https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA159 . 11 April 2017 .
  15. Book: Sass W, Fusari S . 1977 . Ketamine . Analytical Profiles of Drug Substances . 6 . Academic Press . 297–322 . 10.1016/S0099-5428(08)60347-0 . 9780122608063 .
  16. Sachdeva B, Sachdeva P, Ghosh S, Ahmad F, Sinha JK . March 2023 . Ketamine as a therapeutic agent in major depressive disorder and posttraumatic stress disorder: Potential medicinal and deleterious effects . Ibrain . en . 9 . 1 . 90–101 . 10.1002/ibra.12094 . 37786516 . 10528797 . 257117630 . 2769-2795. free .
  17. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI . Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy . Clinical Pharmacokinetics . 55 . 9 . 1059–77 . September 2016 . 27028535 . 10.1007/s40262-016-0383-6 . 5078489 .
  18. Green SM, Roback MG, Kennedy RM, Krauss B . Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update . Annals of Emergency Medicine . 57 . 5 . 449–461 . May 2011 . 21256625 . 10.1016/j.annemergmed.2010.11.030 . free .
  19. Zhang K, Hashimoto K . An update on ketamine and its two enantiomers as rapid-acting antidepressants . Expert Review of Neurotherapeutics . 19 . 1 . 83–92 . January 2019 . 30513009 . 10.1080/14737175.2019.1554434 . 54628949 .
  20. Hibicke M, Landry AN, Kramer HM, Talman ZK, Nichols CD . Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression . ACS Chemical Neuroscience . 11 . 6 . 864–871 . March 2020 . 32133835 . 10.1021/acschemneuro.9b00493 . 212418003 . free .
  21. Book: Orhurhu VJ, Vashisht R, Claus LE, Cohen SP . StatPearls . Treasure Island (FL) . StatPearls Publishing . Ketamine toxicity . April 2022 . 31082131 . https://www.ncbi.nlm.nih.gov/books/NBK541087/ . 18 August 2022 . 16 May 2022 . https://web.archive.org/web/20220516231947/https://www.ncbi.nlm.nih.gov/books/NBK541087/ . live .
  22. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  23. Web site: Ketamine Injection . . 1 December 2014 . live . https://web.archive.org/web/20141210181630/http://www.drugs.com/pro/ketamine-injection.html . 10 December 2014 .
  24. Morgan CJ, Curran HV . January 2012 . Ketamine use: a review . Addiction . 107 . 1 . 27–38 . 10.1111/j.1360-0443.2011.03576.x . 21777321 . 11064759.
  25. Book: Rosenbaum SB, Gupta V, Palacios JL. Ketamine. 2020. StatPearls. StatPearls Publishing. 29262083. 5 March 2020. 12 November 2020. https://web.archive.org/web/20201112215028/https://www.ncbi.nlm.nih.gov/books/NBK470357/. live.
  26. Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A . Use of ketamine in severe status asthmaticus in intensive care unit . Iranian Journal of Allergy, Asthma, and Immunology . 2 . 4 . 175–80 . December 2003 . 17301376 . live . https://web.archive.org/web/20141006100116/http://ijaai.tums.ac.ir/index.php/ijaai/article/view/52/52 . 6 October 2014 .
  27. Adams HA . [S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation] . DE . Der Anaesthesist . 46 . 12 . 1081–7 . December 1997 . 9451493 . 10.1007/s001010050510 . 36323023 . S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation .
  28. Wong JJ, Lee JH, Turner DA, Rehder KJ . A review of the use of adjunctive therapies in severe acute asthma exacerbation in critically ill children . Expert Review of Respiratory Medicine . 8 . 4 . 423–41 . August 2014 . 24993063 . 10.1586/17476348.2014.915752 . 31435021 .
  29. Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM . The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review . Annals of Emergency Medicine . 65 . 1 . 43–51.e2 . January 2015 . 25064742 . 10.1016/j.annemergmed.2014.06.018 .
  30. Mion G . History of anaesthesia: The ketamine story – past, present and future . Eur J Anaesthesiol . 34 . 9 . 571–575 . September 2017 . 28731926 . 10.1097/EJA.0000000000000638 . 27536846 .
  31. Web site: Nickson C . Intubation, Hypotension and Shock . Critical Care Compendium . Life in the Fastlane . 7 August 2013 . 10 April 2014 . blog . dead . https://web.archive.org/web/20140209161412/http://lifeinthefastlane.com/education/ccc/rapid-sequence-induction-of-the-shock-patient/ . 9 February 2014 .
  32. Manley G, Knudson MM, Morabito D, Damron S, Erickson V, Pitts L . Hypotension, hypoxia, and head injury: frequency, duration, and consequences . Archives of Surgery . 136 . 10 . 1118–23 . October 2001 . 11585502 . 10.1001/archsurg.136.10.1118 . free .
  33. Hemmingsen C, Nielsen JE . Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia . Acta Anaesthesiologica Scandinavica . 35 . 8 . 755–7 . November 1991 . 1763596 . 10.1111/j.1399-6576.1991.tb03385.x . 1324453 .
  34. Wong DH, Jenkins LC . The cardiovascular effects of ketamine in hypotensive states . Canadian Anaesthetists' Society Journal . 22 . 3 . 339–48 . May 1975 . 1139377 . 10.1007/BF03004843 . free .
  35. Kurdi MS, Theerth KA, Deva RS . Ketamine: Current applications in anesthesia, pain, and critical care . Anesthesia: Essays and Researches . 8 . 3 . 283–90 . September 2014 . 25886322 . 4258981 . 10.4103/0259-1162.143110 . free .
  36. Barrett W, Buxhoeveden M, Dhillon S . Ketamine: a versatile tool for anesthesia and analgesia . Current Opinion in Anesthesiology . 33 . 5 . 633–638 . October 2020 . 32826629 . 10.1097/ACO.0000000000000916 . 221236545 .
  37. 2024-04-24 . Clinical Uses of Ketamine in Children: A Narrative Review - PMC . 9389002 . Cureus . 14 . 7 . e27065 . 10.7759/cureus.27065 . free . 35989801 . Bali A, Dang AK, Gonzalez DA, Kumar R, Asif S .
  38. Goyal S, Agrawal A . Ketamine in status asthmaticus: A review . Indian Journal of Critical Care Medicine . 17 . 3 . 154–61 . May 2013 . 24082612 . 3777369 . 10.4103/0972-5229.117048 . free .
  39. Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP . Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists . Reg Anesth Pain Med . 43 . 5 . 456–466 . July 2018 . 29870457 . 6023582 . 10.1097/AAP.0000000000000806 .
  40. Sin B, Ternas T, Motov SM . The use of subdissociative-dose ketamine for acute pain in the emergency department . Academic Emergency Medicine . 22 . 3 . 251–7 . March 2015 . 25716117 . 10.1111/acem.12604 . 24658476 . free .
  41. Svenson J, Biedermann M . Ketamine: a unique drug with several potential uses in the prehospital setting. Journal of Paramedic Practice. 3. 10. 2011. 552–556. 10.12968/jpar.2011.3.10.552.
  42. Karlow N, Schlaepfer CH, Stoll CR, Doering M, Carpenter CR, Colditz GA, Motov S, Miller J, Schwarz ES . A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department . Academic Emergency Medicine . 25 . 10 . 1086–1097 . October 2018 . 30019434 . 10.1111/acem.13502 . free .
  43. Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD . Role of ketamine in acute postoperative pain management: a narrative review . BioMed Research International . 2015 . 749837 . 2015 . 26495312 . 4606413 . 10.1155/2015/749837 . free .
  44. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L . A comprehensive review of opioid-induced hyperalgesia . Pain Physician . 14 . 2 . 145–61 . 2011 . 10.36076/ppj.2011/14/145 . 21412369 . free .
  45. Zhou Y, Mannan A, Han Y, Liu H, Guan HL, Gao X, Dai MS, Cao JL . Efficacy and safety of prophylactic use of ketamine for prevention of postanesthetic shivering: a systematic review and meta analysis . BMC Anesthesiology . 19 . 1 . 245 . December 2019 . 31888509 . 6937868 . 10.1186/s12871-019-0910-8 . free .
  46. Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM . Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists . Reg Anesth Pain Med . 43 . 5 . 521–546 . July 2018 . 29870458 . 6023575 . 10.1097/AAP.0000000000000808 .
  47. Elia N, Tramèr MR . Ketamine and postoperative pain—a quantitative systematic review of randomised trials . Pain . 113 . 1–2 . 61–70 . January 2005 . 15621365 . 10.1016/j.pain.2004.09.036 . 25925720 .
  48. Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB . A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders . JAMA Psychiatry . 74 . 4 . 399–405 . April 2017 . 28249076 . 10.1001/jamapsychiatry.2017.0080 . 28320520 .
  49. Marcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H, Richard-Devantoy S, Beauchamp S . A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 – January 2019 . J Affect Disord . 277 . 831–841 . December 2020 . 33065824 . 10.1016/j.jad.2020.09.007 . 223557698 .
  50. Sanacora G, Katz R . Ketamine: A Review for Clinicians . Focus . 16 . 3 . 243–250 . July 2018 . 31975918 . 6493090 . 10.1176/appi.focus.20180012 . American Psychiatric Association Publishing .
  51. Swainson J, McGirr A, Blier P, Brietzke E, Richard-Devantoy S, Ravindran N, Blier J, Beaulieu S, Frey BN, Kennedy SH, McIntyre RS, Milev RV, Parikh SV, Schaffer A, Taylor VH, Tourjman V, van Ameringen M, Yatham LN, Ravindran AV, Lam RW . The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur . Can J Psychiatry . 113–125 . November 2020 . 66 . 2 . 33174760 . 10.1177/0706743720970860 . 7918868 .
  52. Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sánchez E, Gutiérrez-Rojas L, Meana JJ . Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review . CNS Drugs . 32 . 5 . 411–420 . May 2018 . 29736744 . 10.1007/s40263-018-0519-3 . 13679905 .
  53. Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane R . Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight . The Lancet. Psychiatry . 4 . 5 . 419–426 . May 2017 . 28395988 . 10.1016/S2215-0366(17)30102-5 . free . 10871/30208 . 28186580 . 10 September 2018 . 9 March 2019 . https://web.archive.org/web/20190309081101/http://discovery.ucl.ac.uk/1552865/ . live .
  54. Bobo WV, Riva-Posse P, Goes FS, Parikh SV . Next-Step Treatment Considerations for Patients With Treatment-Resistant Depression That Responds to Low-Dose Intravenous Ketamine . Focus (Am Psychiatr Publ) . 18 . 2 . 181–192 . April 2020 . 33162856 . 10.1176/appi.focus.20190048 . 7587874 .
  55. Witt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, Cipriani A, Hawton K . Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials . Aust N Z J Psychiatry . 54 . 1 . 29–45 . January 2020 . 31729893 . 10.1177/0004867419883341 . 208035394 . 18 January 2021 . 2 July 2022 . https://web.archive.org/web/20220702024708/https://ora.ox.ac.uk/objects/uuid:25219d6c-5c8f-4842-91d9-41a9fd7fb1bd . live .
  56. Web site: Spravato (esketamine). European Medicines Agency. 8 July 2022. 20 July 2022. 23 November 2020. https://web.archive.org/web/20201123231245/https://www.ema.europa.eu/en/medicines/human/EPAR/spravato. live.
  57. Web site: FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic . US Food and Drug Administration . 29 July 2022 . 5 March 2019 . 23 July 2021 . https://web.archive.org/web/20210723022112/https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified . live .
  58. Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder . The Cochrane Database of Systematic Reviews . 9 . CD011612 . September 2021 . 11 . 34510411 . 8434915 . 10.1002/14651858.CD011612.pub3 .
  59. Dean RL, Marquardt T, Hurducas C, Spyridi S, Barnes A, Smith R, Cowen PJ, McShane R, Hawton K, Malhi GS, Geddes J, Cipriani A . Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder . The Cochrane Database of Systematic Reviews . 2021 . CD011611 . October 2021 . 10 . 34623633 . 8499740 . 10.1002/14651858.CD011611.pub3 .
  60. Web site: FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray . US Food and Drug Administration . 29 July 2022 . 16 February 2022 . 31 August 2022 . https://web.archive.org/web/20220831210903/https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-professionals-potential-risks-associated-compounded-ketamine-nasal-spray . live .
  61. Book: Ketamine: Dreams and Realities . Jansen K . Multidisciplinary Association for Psychedelic Studies . 978-0-9660019-3-8 . 2001 . 122.
  62. Peinkhofer C, Dreier JP, Kondziella D . Semiology and Mechanisms of Near-Death Experiences . Current Neurology and Neuroscience Reports . 19 . 9 . 62 . July 2019 . 31352520 . 10.1007/s11910-019-0983-2 . 198965307 .
  63. Martial C, Cassol H, Charland-Verville V, Pallavicini C, Sanz C, Zamberlan F, Vivot RM, Erowid F, Erowid E, Laureys S, Greyson B, Tagliazucchi E . Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports . Consciousness and Cognition . 69 . 52–69 . March 2019 . 30711788 . 10.1016/j.concog.2019.01.011 . 2268/231971 . 73432875 . free .
  64. Ghosh S, Sinha JK, Khan T, Devaraju KS, Singh P, Vaibhav K, Gaur P . Pharmacological and Therapeutic Approaches in the Treatment of Epilepsy . Biomedicines . 9 . 5 . April 2021 . 470 . 33923061 . 8146518 . 10.3390/biomedicines9050470 . free .
  65. Gomes D, Pimentel J, Bentes C, Aguiar de Sousa D, Antunes AP, Alvarez A, Silva ZC . Consensus Protocol for the Treatment of Super-Refractory Status Epilepticus . Acta Médica Portuguesa . 31 . 10 . 598–605 . October 2018 . 30387431 . 10.20344/amp.9679 . free . 11 February 2020 . 29 August 2020 . https://web.archive.org/web/20200829074412/https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/9679 . live .
  66. Rosati A, De Masi S, Guerrini R . Ketamine for Refractory Status Epilepticus: A Systematic Review . CNS Drugs . 32 . 11 . 997–1009 . November 2018 . 30232735 . 10.1007/s40263-018-0569-6 . 52302073 .
  67. Jat KR, Chawla D . Ketamine for management of acute exacerbations of asthma in children . The Cochrane Database of Systematic Reviews . 11 . 11 . CD009293 . November 2012 . 23152273 . 6483733 . 10.1002/14651858.CD009293.pub2 . Cochrane Airways Group .
  68. Strayer RJ, Nelson LS . Adverse events associated with ketamine for procedural sedation in adults . The American Journal of Emergency Medicine . 26 . 9 . 985–1028 . November 2008 . 19091264 . 10.1016/j.ajem.2007.12.005 . live . https://web.archive.org/web/20170908185727/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0026626/ . 8 September 2017.
  69. Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA, Park LT . Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression . J Affect Disord . 263 . 568–575 . February 2020 . 31791675 . 10.1016/j.jad.2019.11.028. 8457026 .
  70. Smith HS . Ketamine-induced urologic insult (KIUI) . Pain Physician . 13 . 6 . E343–6 . 2010 . 10.36076/ppj.2010/13/E343 . 21102971. free .
  71. Castellani D, Pirola GM, Gubbiotti M, Rubilotta E, Gudaru K, Gregori A, Dellabella M . What urologists need to know about ketamine-induced uropathy: A systematic review . Neurourol Urodyn . 39 . 4 . 1049–1062 . April 2020 . 32212278 . 10.1002/nau.24341. 214643776 .
  72. Middela S, Pearce I . Ketamine-induced vesicopathy: a literature review . International Journal of Clinical Practice . 65 . 1 . 27–30 . January 2011 . 21155941 . 10.1111/j.1742-1241.2010.02502.x . 25034266 . free . 10 September 2018 . 19 September 2018 . https://web.archive.org/web/20180919123758/https://hal.archives-ouvertes.fr/hal-00600043 . live .
  73. Changes to the bladder epithelial barrier are associated with ketamine-induced cystitis . 28966667 . 5615221 . 10.3892/etm.2017.4913 . Qixin D, Tianpeng W, Xiaochun Y, Lingqi L, Jiantao Y, Zhongjie L . Experimental and Therapeutic Medicine . 20 January 2017 . 14 . 4 . 2757–2762.
  74. 27330331 . 4898409 . Chronic biliary colic associated with ketamine abuse . Ahamed AN, Yahya AA . 2 June 2016 . 135–137 . International Medical Case Reports Journal . 9 . 10.2147/IMCRJ.S100648 . free .
  75. 10.1080/08998280.2014.11929117 . Joseph P, Binu R, Sebastian T, Fahmy H . Baylor University Medical Center Proceedings . 27 . 3 . 11 December 2017 . 223–225 . Multiorgan Dysfunction Related to Chronic Ketamine Abuse. 24982568 . 4059572 .
  76. Morgan CJ, Muetzelfeldt L, Curran HV . Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study . Addiction . 105 . 1 . 121–33 . January 2010 . 19919593 . 10.1111/j.1360-0443.2009.02761.x.
  77. Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J . Additive interactions between propofol and ketamine when used for anesthesia induction in female patients . Anesthesiology . 82 . 3 . 641–8 . March 1995 . 7879932 . 10.1097/00000542-199503000-00005 . 24005549 . free .
  78. Hong W, Short TG, Hui TW . Hypnotic and anesthetic interactions between ketamine and midazolam in female patients . Anesthesiology . 79 . 6 . 1227–32 . December 1993 . 8267198 . 10.1097/00000542-199312000-00013 . 12246068 . free .
  79. Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D'Souza DC . Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism . Neuropsychopharmacology . 31 . 8 . 1793–800 . August 2006 . 16395307 . 10.1038/sj.npp.1300994 . free .
  80. Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH . Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists . Arch Gen Psychiatry . 57 . 3 . 270–6 . March 2000 . 10711913 . 10.1001/archpsyc.57.3.270 . free .
  81. Krupitsky EM, Burakov AM, Romanova TN, Grinenko NI, Grinenko AY, Fletcher J, Petrakis IL, Krystal JH . Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists . Neuropsychopharmacology . 25 . 6 . 936–47 . December 2001 . 11750186 . 10.1016/S0893-133X(01)00346-3 . free .
  82. Handa F, Tanaka M, Nishikawa T, Toyooka H . Effects of oral clonidine premedication on side effects of intravenous ketamine anesthesia: a randomized, double-blind, placebo-controlled study . J Clin Anesth . 12 . 1 . 19–24 . February 2000 . 10773503 . 10.1016/s0952-8180(99)00131-2 .
  83. Andrade C . Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions . The Journal of Clinical Psychiatry . 78 . 7 . e858–e861 . July 2017 . 28858450 . 10.4088/JCP.17f11802 . free .
  84. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EF, Albuquerque EX, Thomas CJ, Zarate CA, Gould TD . Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms . Pharmacol Rev . 70 . 3 . 621–660 . July 2018 . 29945898 . 6020109 . 10.1124/pr.117.015198 .
  85. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI . Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy . Clin Pharmacokinet . 55 . 9 . 1059–77 . September 2016 . 27028535 . 10.1007/s40262-016-0383-6 . 5078489 .
  86. Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A . Ketamine* . Journal of Pain and Symptom Management . 41 . 3 . 640–9 . March 2011 . 21419322 . 10.1016/j.jpainsymman.2011.01.001 . Therapeutic Review . free . 28 July 2014 . 16 September 2018 . https://web.archive.org/web/20180916035324/https://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext . live .
  87. Garay R, Zarate CA, Cavero I, Kim YK, Charpeaud T, Skolnick P . The development of glutamate-based antidepressants is taking longer than expected . Drug Discovery Today . 23 . 10 . 1689–1692 . October 2018 . 29501913 . 6211562 . 10.1016/j.drudis.2018.02.006 .
  88. Web site: Arketamine – Jiangsu Hengrui Medicine – AdisInsight . 13 November 2019 . 13 April 2021 . https://web.archive.org/web/20210413141717/https://adisinsight.springer.com/drugs/800056158 . live .
  89. Kim D, Cheong E, Shin HS . Overcoming Depression by Inhibition of Neural Burst Firing . Neuron . 98 . 5 . 878–879 . June 2018 . 29879390 . 10.1016/j.neuron.2018.05.032 . free .
  90. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H . Ketamine blocks bursting in the lateral habenula to rapidly relieve depression . Nature . 554 . 7692 . 317–322 . February 2018 . 29446381 . 10.1038/nature25509 . 3334820 . 2018Natur.554..317Y .
  91. Zanos P, Gould TD . Mechanisms of ketamine action as an antidepressant . Molecular Psychiatry . 23 . 4 . 801–811 . April 2018 . 29532791 . 5999402 . 10.1038/mp.2017.255 .
  92. Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD . Convergent Mechanisms Underlying Rapid Antidepressant Action . CNS Drugs . 32 . 3 . 197–227 . March 2018 . 29516301 . 6005380 . 10.1007/s40263-018-0492-x .
  93. Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA . Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling . The International Journal of Neuropsychopharmacology . 21 . 8 . 740–747 . August 2018 . 29668918 . 6070027 . 10.1093/ijnp/pyy041.
  94. Björkholm C, Monteggia LM . Lisa Monteggia . BDNF – a key transducer of antidepressant effects . Neuropharmacology . 102 . 72–79 . March 2016 . 26519901 . 4763983 . 10.1016/j.neuropharm.2015.10.034 .
  95. Castrén E, Kojima M . Brain-derived neurotrophic factor in mood disorders and antidepressant treatments . Neurobiology of Disease . 97 . Pt B . 119–126 . January 2017 . 27425886 . 10.1016/j.nbd.2016.07.010 . free . 644350 . 10138/311483 .
  96. Morris PJ, Moaddel R, Zanos P, Moore CE, Gould TD, Zarate CA, Thomas CJ . Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites . Organic Letters . 19 . 17 . 4572–4575 . September 2017 . 28829612 . 5641405 . 10.1021/acs.orglett.7b02177 .
  97. Bryan Roth . Roth BL, Gibbons S, Arunotayanun W, Huang XP, Setola V, Treble R, Iversen L . The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor . PLOS ONE . 8 . 3 . e59334 . 2013 . 23527166 . 3602154 . 10.1371/journal.pone.0059334 . 2013PLoSO...859334R . free .
  98. Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG . Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells . Anesthesiology . 90 . 1 . 174–82 . January 1999 . 9915326 . 10.1097/00000542-199901000-00023 . free .
  99. Hirota K, Sikand KS, Lambert DG . Interaction of ketamine with mu2 opioid receptors in SH-SY5Y human neuroblastoma cells . Journal of Anesthesia . 13 . 2 . 107–9 . 1999 . 14530949 . 10.1007/s005400050035 . 9322174 .
  100. Nemeth CL, Paine TA, Rittiner JE, Béguin C, Carroll FI, Roth BL, Cohen BM, Carlezon WA . Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats . Psychopharmacology (Berl) . 210 . 2 . 263–74 . June 2010 . 20358363 . 2869248 . 10.1007/s00213-010-1834-7 .
  101. Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR . Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo . Eur Neuropsychopharmacol . 22 . 4 . 308–17 . April 2012 . 21911285 . 10.1016/j.euroneuro.2011.08.002 . 24494428 .
  102. Kapur S, Seeman P . NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia . Molecular Psychiatry . 7 . 8 . 837–44 . 2002 . 12232776 . 10.1038/sj.mp.4001093 . free .
  103. Can A, Zanos P, Moaddel R, Kang HJ, Dossou KS, Wainer IW, Cheer JF, Frost DO, Huang XP, Gould TD . Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters . The Journal of Pharmacology and Experimental Therapeutics . 359 . 1 . 159–70 . October 2016 . 27469513 . 5034706 . 10.1124/jpet.116.235838 .
  104. Hirota K, Hashimoto Y, Lambert DG . Interaction of intravenous anesthetics with recombinant human M1-M3 muscarinic receptors expressed in chinese hamster ovary cells . Anesth Analg . 95 . 6 . 1607–10, table of contents . December 2002 . 12456425 . 10.1097/00000539-200212000-00025 . 25643394 . free .
  105. Yamakura T, Chavez-Noriega LE, Harris RA . Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine . Anesthesiology . 92 . 4 . 1144–53 . April 2000 . 10754635 . 10.1097/00000542-200004000-00033 . 23651917 . free .
  106. Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, Rosenberg A, Tran T, Xiao Y, Zarate CA, Wainer IW . Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors . Eur J Pharmacol . 698 . 1–3 . 228–34 . January 2013 . 23183107 . 3534778 . 10.1016/j.ejphar.2012.11.023 .
  107. Ho MF, Correia C, Ingle JN, Kaddurah-Daouk R, Wang L, Kaufmann SH, Weinshilboum RM . Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression . Biochemical Pharmacology . 152 . 279–292 . June 2018 . 29621538 . 5960634 . 10.1016/j.bcp.2018.03.032 .
  108. Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, Tohyama M . Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells . Anesthesiology . 88 . 3 . 768–74 . March 1998 . 9523822 . 10.1097/00000542-199803000-00029 . 30159489 . free .
  109. Zhao Y, Sun L . Antidepressants modulate the in vitro inhibitory effects of propofol and ketamine on norepinephrine and serotonin transporter function . J Clin Neurosci . 15 . 11 . 1264–9 . November 2008 . 18815045 . 2605271 . 10.1016/j.jocn.2007.11.007 .
  110. Chen X, Shu S, Bayliss DA . HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine . The Journal of Neuroscience . 29 . 3 . 600–9 . January 2009 . 19158287 . 2744993 . 10.1523/JNEUROSCI.3481-08.2009 .
  111. da Costa FL, Pinto MC, Santos DC, Carobin NV, de Jesus IC, Ferreira LA, Guatimosim S, Silva JF, Castro Junior CJ . Ketamine potentiates TRPV1 receptor signaling in the peripheral nociceptive pathways . Biochemical Pharmacology . 182 . 114210 . December 2020 . 32882205 . 10.1016/j.bcp.2020.114210 . 221497233 .
  112. Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ . Classics in Chemical Neuroscience: Ketamine . ACS Chemical Neuroscience . 8 . 6 . 1122–1134 . June 2017 . 28418641 . 10.1021/acschemneuro.7b00074 .
  113. Hirota K, Lambert DG . Ketamine: its mechanism(s) of action and unusual clinical uses . British Journal of Anaesthesia . 77 . 4 . 441–4 . October 1996 . 8942324 . 10.1093/bja/77.4.441 . dmy-all . free .
  114. Orser BA, Pennefather PS, MacDonald JF . Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors . Anesthesiology . 86 . 4 . 903–17 . April 1997 . 9105235 . 10.1097/00000542-199704000-00021 . 2164198 . free .
  115. Lodge D, Mercier MS . Ketamine and phencyclidine: the good, the bad, and the unexpected . British Journal of Pharmacology . 172 . 17 . 4254–76 . September 2015 . 26075331 . 4556466 . 10.1111/bph.13222 .
  116. Kraus C, Rabl U, Vanicek T, Carlberg L, Popovic A, Spies M, Bartova L, Gryglewski G, Papageorgiou K, Lanzenberger R, Willeit M, Winkler D, Rybakowski JK, Kasper S . Administration of ketamine for unipolar and bipolar depression . International Journal of Psychiatry in Clinical Practice . 21 . 1 . 2–12 . March 2017 . 28097909 . 10.1080/13651501.2016.1254802 . 35626369 .
  117. Bartova L, Vogl SE, Stamenkovic M, Praschak-Rieder N, Naderi-Heiden A, Kasper S, Willeit M . Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases . European Neuropsychopharmacology . 25 . 11 . 2183–4 . November 2015 . 26302763 . 10.1016/j.euroneuro.2015.07.021 . 39039021 .
  118. Seeman P, Guan HC . Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia . Synapse . 62 . 11 . 819–28 . November 2008 . 18720422 . 10.1002/syn.20561 . 206519749 .
  119. Seeman P, Guan HC, Hirbec H . Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil . Synapse . 63 . 8 . 698–704 . August 2009 . 19391150 . 10.1002/syn.20647 . 17758902 .
  120. Jordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, Tadori Y, Kitagawa H, Kikuchi T . In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors . European Journal of Pharmacology . 540 . 1–3 . 53–6 . July 2006 . 16730695 . 10.1016/j.ejphar.2006.04.026 .
  121. Book: The Role of Brain Dopamine. 6 December 2012. Springer Science & Business Media. 978-3-642-73897-5. 23–.
  122. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS . Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses . Archives of General Psychiatry . 51 . 3 . 199–214 . March 1994 . 8122957 . 10.1001/archpsyc.1994.03950030035004 .
  123. Hergovich N, Singer E, Agneter E, Eichler HG, Graselli U, Simhandl C, Jilma B . Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial . Neuropsychopharmacology . 24 . 5 . 590–3 . May 2001 . 11282259 . 10.1016/S0893-133X(00)00194-9 . free .
  124. Rabiner EA . Imaging of striatal dopamine release elicited with NMDA antagonists: is there anything there to be seen? . Journal of Psychopharmacology . 21 . 3 . 253–8 . May 2007 . 17591653 . 10.1177/0269881107077767 . 23776189 .
  125. Idvall J, Ahlgren I, Aronsen KR, Stenberg P . Ketamine infusions: pharmacokinetics and clinical effects . Br J Anaesth . 51 . 12 . 1167–73 . December 1979 . 526385 . 10.1093/bja/51.12.1167 . free .
  126. Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE . Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay . Anesth Analg . 61 . 2 . 87–92 . February 1982 . 10.1213/00000539-198202000-00004 . 7198883 . 27596215 . free .
  127. White PF, Schüttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ . Comparative pharmacology of the ketamine isomers. Studies in volunteers . Br J Anaesth . 57 . 2 . 197–203 . February 1985 . 3970799 . 10.1093/bja/57.2.197 . free .
  128. Stenberg P, Idvall J . Does ketamine metabolite II exist in vivo? . Br J Anaesth . 53 . 7 . 778 . July 1981 . 7248132 . 10.1093/bja/53.7.778 . free .
  129. Book: Mao J . Opioid-Induced Hyperalgesia . 19 April 2016 . CRC Press . 978-1-4200-8900-4 . 127– . live . https://web.archive.org/web/20170908185726/https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127 . 8 September 2017 .
  130. Rao LK, Flaker AM, Friedel CC, Kharasch ED . Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance . Anesthesiology . 125 . 6 . 1103–1112 . December 2016 . 27763887 . 10.1097/ALN.0000000000001392 . 41380105 .
  131. Li Y, Jackson KA, Slon B, Hardy JR, Franco M, William L, Poon P, Coller JK, Hutchinson MR, Currow DC, Somogyi AA . CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects . Br J Clin Pharmacol . 80 . 2 . 276–84 . August 2015 . 25702819 . 4541975 . 10.1111/bcp.12614 .
  132. Chang T, Glazko AJ . Biotransformation and disposition of ketamine . Int Anesthesiol Clin . 12 . 2 . 157–77 . 1974 . 4603048 . 10.1097/00004311-197412020-00018 . 30723730 .
  133. Krüger AD . [Current aspects of using ketamine in childhood] . DE . Anaesthesiologie und Reanimation . 23 . 3 . 64–71 . 1998 . 9707751 .
  134. Chankvetadze B, Burjanadze N, Breitkreutz J, Bergander K, Bergenthal D, Kataeva O, Fröhlich R, Luftmann H, Blaschke G . 2002 . Mechanistic study on the opposite migration order of the enantiomers of ketamine with α- and β-cyclodextrin in capillary electrophoresis . Journal of Separation Science . 25 . 15–17 . 1155–1166 . 10.1002/1615-9314(20021101)25:15/17<1155::AID-JSSC1155>3.0.CO;2-M .
  135. 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.
  136. 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.
  137. R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 806–808.
  138. Domino EF . Taming the ketamine tiger. 1965 . Anesthesiology . 113 . 3 . 678–84 . September 2010 . 20693870 . 10.1097/ALN.0b013e3181ed09a2 . free .
  139. Corssen G, Domino EF . Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581 . Anesthesia and Analgesia . 45 . 1 . 29–40 . January–February 1966 . 5325977 . 10.1213/00000539-196601000-00007 . 29516392 .
  140. Li L, Vlisides PE . Ketamine: 50 Years of Modulating the Mind . Frontiers in Human Neuroscience . 10 . 612 . 2016 . 27965560 . 5126726 . 10.3389/fnhum.2016.00612 . free .
  141. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH . Antidepressant effects of ketamine in depressed patients . Biol Psychiatry . 47 . 4 . 351–4 . February 2000 . 10686270 . 10.1016/s0006-3223(99)00230-9 . 43438286 .
  142. Web site: Chaffrey J . Yale Researchers Study Potential Treatment for Depression in Patients With Parkinson's Disease . NBC Connecticut . 16 March 2022 . 19 March 2022 . 19 March 2022 . https://web.archive.org/web/20220319160153/https://www.nbcconnecticut.com/news/local/yale-researchers-study-potential-treatment-for-depression-in-patients-with-parkinsons-disease/2742209/ . live .
  143. Dhir A . Investigational drugs for treating major depressive disorder . Expert Opinion on Investigational Drugs . 26 . 1 . 9–24 . January 2017 . 27960559 . 10.1080/13543784.2017.1267727 . 45232796 .
  144. Book: Index Nominum 2000: International Drug Directory . 2000 . Taylor & Francis . 978-3-88763-075-1 . 584–585.
  145. Poisons Standard October 2015 Web site: Poisons Standard . October 2015 . Australian Government . 6 January 2016 . live . https://web.archive.org/web/20160119074606/https://www.comlaw.gov.au/Details/F2015L01534/ . 19 January 2016 .
  146. Legal status of ketamine in Canada references:
  147. News: Ketamine drug brought under 'Schedule X' to curb abuse . . 7 January 2014 . 2 August 2014 . live . https://web.archive.org/web/20140414064604/http://timesofindia.indiatimes.com/city/goa/Ketamine-drug-brought-under-Schedule-X-to-curb-abuse/articleshow/28486002.cms . 14 April 2014 . dmy-all .
  148. News: Sumitra DR . . 30 December 2013 . Govt makes notorious 'date rape' drug ketamine harder to buy or sell . https://web.archive.org/web/20131230025440/http://timesofindia.indiatimes.com/india/Govt-makes-notorious-date-rape-drug-ketamine-harder-to-buy-or-sell/articleshow/28116453.cms . 30 December 2013 . live .
  149. News: Dixon H . 12 February 2014 . Party drug ketamine to be upgraded to Class B . . 2 August 2014 . live . https://web.archive.org/web/20140609232635/http://www.telegraph.co.uk/news/uknews/law-and-order/10633800/Party-drug-ketamine-to-be-upgraded-to-Class-B.html . 9 June 2014 .
  150. Marshall DR . Donnie R. Marshall . 13 July 1999 . Schedules of Controlled Substances: Placement of Ketamine into Schedule III [21 CFR Part 1308. Final Rule 99-17803] ]. . 64 . 133 . 37673–5 . Rules and Regulations . Drug Enforcement Administration . United States Department of Justice . live . https://web.archive.org/web/20150505060507/http://www.gpo.gov/fdsys/pkg/FR-1999-07-13/pdf/99-17803.pdf . 5 May 2015 .
  151. Giannini AJ, Underwood NA, Condon M . Acute ketamine intoxication treated by haloperidol: a preliminary study . American Journal of Therapeutics . 7 . 6 . 389–91 . November 2000 . 11304647 . 10.1097/00045391-200007060-00008 .
  152. Book: Giannini AJ . Drug Abuse . Health Information Press . Los Angeles . 1999 . 104 . 978-1-885987-11-2 . registration .
  153. References for recreational use in literature:
    • Book: Lilly JC . John C. Lilly . The Scientist: A Metaphysical Autobiography . . Berkeley, CA . 1997 . 144– . 978-0-914171-72-0 .
    • Book: Kelly K . The Little Book of Ketamine . 2001 . . 978-1-57951-121-0 . 23, 40–45, 46–51, ibid .
    • Book: Alltounian HS, Moore M . Marcia Moore . Journeys Into the Bright World . Para Research . Rockport, MA . 1978 . 978-0-914918-12-7 . .
    • Book: Palmer C, Horowitz M . Fitz Hugh Ludlow Memorial Library. Sisters of the Extreme: Women Writing on the Drug Experience . 2000. . 978-0-89281-757-3. 254–258, ibid . .
    • Book: Turner DM . D. M. Turner . The Essential Psychedelic Guide . Panther Press . San Francisco . 1994 . 978-0-9642636-1-1.
  154. Book: Ketamine: Dreams and Realities . Jansen K . Multidisciplinary Association for Psychedelic Studies . 978-0-9660019-3-8 . 2001 . 50, 89.
  155. Book: Woodard D . https://tranxcend.tumblr.com/post/29813278762/ketamine . The Ketamine Necromance . Parfrey A . Apocalypse Culture II . . . 2000 . 288–295 . 18 May 2020 . 24 June 2021 . https://web.archive.org/web/20210624204236/https://tranxcend.tumblr.com/post/29813278762/ketamine . live .
  156. See Max Daly, 2014, "The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties," at Vice (online), 23 July 2014, see Web site: The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties . 7 June 2015 . live . https://web.archive.org/web/20150607022331/http://www.vice.com/en_uk/read/ketamine-slowly-ruins-your-bladder-and-kills-you-863 . 7 June 2015 . 23 July 2014 ., accessed 7 June 2015.
  157. Web site: 2013 . Drug related deaths involving ketamine in England and Wales . A report of the Mortality team, Life Events and Population Sources Division, Office for National Statistics . Government of the United Kingdom . 7 June 2015 . live . https://web.archive.org/web/20150607212436/http://www.ons.gov.uk/ons/about-ons/business-transparency/freedom-of-information/what-can-i-request/published-ad-hoc-data/health/october-2013/drug-related-deaths-involving-ketamine-by-age-group.xls . 7 June 2015 . and Web site: Deaths Related to Drug Poisoning in England and Wales – Office for National Statistics . 7 June 2015 . live . https://web.archive.org/web/20150619235310/http://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drug-poisoning/2012/stb---deaths-related-to-drug-poisoning-2012.html . 19 June 2015 ., accessed 7 June 2015.
  158. Web site: Matthew Perry died from the 'acute effects of ketamine,' autopsy finds . NPR . Bowman E . 28 December 2023 . 15 December 2023 . 28 December 2023 . https://web.archive.org/web/20231228225746/https://www.npr.org/2023/12/15/1219759019/matthew-perry-cause-of-death . live .
  159. Web site: Do you know... Ketamine . Knowledge Exchange . Toronto . . 27 July 2014 . 2003 . https://web.archive.org/web/20140407061143/https://knowledgex.camh.net/amhspecialists/resources_families/Pages/ketamine_dyk.aspx . 7 April 2014 . dead . dmy-all.
  160. Web site: Ketamine . 27 July 2014 . 29 October 2013 . . https://web.archive.org/web/20131112080924/http://www.cesar.umd.edu/cesar/drugs/ketamine.asp . 12 November 2013 . live.
  161. Web site: Grinspoon P . 9 August 2022 . Ketamine for treatment-resistant depression: When and where is it safe? . 6 September 2022 . Harvard Health . en . 31 August 2022 . https://web.archive.org/web/20220831012716/https://www.health.harvard.edu/blog/ketamine-for-treatment-resistant-depression-when-and-where-is-it-safe-202208092797 . live .
  162. Web site: New Hope for Treatment-Resistant Depression: Guessing Right on Ketamine . 6 September 2022 . National Institute of Mental Health (NIMH) . 13 August 2019 . en . 10 September 2022 . https://web.archive.org/web/20220910063011/https://www.nimh.nih.gov/about/director/messages/2019/new-hope-for-treatment-resistant-depression-guessing-right-on-ketamine . live .
  163. Pérez-Esparza R . Ketamine for Treatment-Resistant Depression: a New Advocate . Revista de Investigacion Clinica . 70 . 2 . 65–67 . 2018 . 29718013 . 10.24875/RIC.18002501 . free .
  164. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS . mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists . Science . 329 . 5994 . 959–964 . August 2010 . 20724638 . 3116441 . 10.1126/science.1190287 . 2010Sci...329..959L .
  165. Ferreira SR, Machado AR, Furtado LF, Gomes JH, de Almeida RM, de Oliveira Mendes T, Maciel VN, Barbosa FS, Carvalho LM, Bueno LL, Bartholomeu DC, de Araújo JV, Rabelo EM, de Pádua RM, Pimenta LP, Fujiwara RT . Ketamine can be produced by Pochonia chlamydosporia: an old molecule and a new anthelmintic? . Parasites & Vectors . 13 . 1 . 527 . October 2020 . 33081837 . 7574484 . 10.1186/s13071-020-04402-w . free .
  166. Robertson SA, Taylor PM . Pain management in cats—past, present and future. Part 2. Treatment of pain—clinical pharmacology . Journal of Feline Medicine and Surgery . 6 . 5 . 321–33 . October 2004 . 15363764 . 10.1016/j.jfms.2003.10.002 . 25572412 .
  167. Lamont LA . Adjunctive analgesic therapy in veterinary medicine . The Veterinary Clinics of North America. Small Animal Practice . 38 . 6 . 1187–203, v . November 2008 . 18954680 . 10.1016/j.cvsm.2008.06.002 .
  168. Stunkard JA, Miller JC . An outline guide to general anesthesia in exotic species . Veterinary Medicine, Small Animal Clinician . 69 . 9 . 1181–6 . September 1974 . 4604091 .
  169. Book: John Wiley & Sons . 978-1-118-68590-7 . Riviere JE, Papich MG . Veterinary Pharmacology and Therapeutics . 2009 . 200 . 26 December 2021 . 8 February 2023 . https://web.archive.org/web/20230208191902/https://books.google.com/books?id=xAPa4WDzAnQC&pg=PP1 . live .
  170. Hubbell JA, Muir WW, Sams RA . Guaifenesin: cardiopulmonary effects and plasma concentrations in horses . American Journal of Veterinary Research . 41 . 11 . 1751–5 . November 1980 . 7212404 .
  171. Woodall AJ, McCrohan CR . Excitatory actions of propofol and ketamine in the snail Lymnaea stagnalis . Comparative Biochemistry and Physiology. Toxicology & Pharmacology . 127 . 3 . 297–305 . December 2000 . 11246501 . 10.1016/S0742-8413(00)00155-9 .