Ketamine

Ketamine
(S)-Ketamine ball-and-stick model
Names
Trade namesKetalar, others
Other namesCI-581; CL-369; CM-52372-2[1]
IUPAC name
  • (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Clinical data
Drug classNMDA receptor antagonists; General anesthetics; Dissociative hallucinogens; Analgesics; Antidepressants
Addiction riskLow–moderate[2]
                                                      
Pregnancy
category
  • AU: B3[3]
  • US: N (Not classified yet)[3]
    Routes of
    use    		Any[4][5][6][7]
    Onset of action
    • Intravenous: seconds[8]
    • Intramuscular: 1–5 min[8][9]
    • Subcutaneous: 15–30 min[9]
    • Insufflation: 5–10 min[8]
    • By mouth: 15–30 min[8][9]
    Duration of action
    • Intramuscular: 0.5–2 hours[9]
    • Insufflation: 45–60 min[8]
    • By mouth: 1–6+ hours[8][9]
    Defined daily doseNot established[10]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability
    Protein binding12–47% (low)[12][8][18]
    MetabolismLiver (N-demethylation):[6][19]
    Metabolites
    Elimination half-life
    • Ketamine: 2.5–3 hours[8][6]
    • Norketamine: 12 hours[9]
    Excretion
    Chemical and physical data
    FormulaC13H16ClNO
    Molar mass237.725 g·mol−1
    3D model (JSmol)
    ChiralityRacemic mixture:[8]
    Melting point258 to 261 °C (496 to 502 °F)
    SMILES
    • Clc1ccccc1C2(NC)CCCCC2=O
    InChI
    • InChI=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 checkY
    • Key:YQEZLKZALYSWHR-UHFFFAOYSA-N checkY

    Ketamine is a medication mainly used for starting and maintaining anesthesia.[21] It induces a trance-like state while providing pain relief, sedation, and memory loss.[22] Other uses include sedation in intensive care and treatment of pain and depression.[23][24][16][25][26] Heart function, breathing, and airway reflexes generally remain functional.[22] Effects typically begin within five minutes when given by injection, and last up to approximately 25 minutes.[21][27]

    Common side effects include agitation, confusion, or hallucinations as the medication wears off.[21][28][29] Elevated blood pressure and muscle tremors are relatively common.[21][29] Spasms of the larynx may rarely occur.[21] Ketamine is an NMDA receptor antagonist, but it may also have other actions.[30]

    Ketamine was discovered in 1962, first tested in humans in 1964, and approved for use in the United States in 1970.[27][31] It was extensively used for surgical anesthesia in the Vietnam War due to its safety.[31] It is on the World Health Organization's List of Essential Medicines.[32] It is available as a generic medication.[21] The wholesale price in the developing world is between US$0.84 and US$3.22 per vial.[33] Ketamine is also used as a recreational drug for its hallucinogenic and dissociative effects.[34]

    Medical uses

    Anesthesia

    Uses as an anesthetic:[35]

    Since it suppresses breathing much less than most other available anesthetics,[38] 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.[39] A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine.[22] It is the drug of choice for people in traumatic shock who are at risk of hypotension.[40] Low blood pressure is harmful in people with severe head injury[41] and ketamine is least likely to cause low blood pressure, often even able to prevent it.[42][43]

    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.[44] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways.[45] Ketamine is considered relatively safe because protective airway reflexes are preserved.[46]

    It has been successfully used to prevent postanesthetic shivering.[47]

    Asthma

    Ketamine is used as a bronchodilator in the treatment of severe asthma.[48] However, evidence of clinical benefit is limited.[48][49]

    Seizures

    Ketamine is sometimes used in the treatment of status epilepticus that has failed to adequately respond to standard treatments.[50]

    Pain

    Ketamine may be used for postoperative pain management. Low doses of ketamine may reduce morphine use, nausea, and vomiting after surgery.[51][52] It is especially useful in the prehospital setting, due to its effectiveness and low risk of respiratory depression.[53]

    Ketamine has similar efficacy to opioids in a hospital emergency department setting for management of acute pain and for control of procedural pain.[54] If given intrathecally, its adverse cognitive effects are largely avoided at analgesic doses.[26]

    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.[55] 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.[55] 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".[56]

    Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS).[57] A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.[58]

    Depression

    See also: Esketamine § Depression

    Ketamine is a rapid-acting antidepressant in depression.[16][59][60][61][62] It also may be effective in decreasing suicidal ideation, although based on lower quality evidence.[63][64][65] The antidepressant effects of ketamine were first shown in small studies in 2000 and 2006.[13] They have since been demonstrated and characterized in subsequent studies.[13] A single low, sub-anesthetic dose of ketamine given via intravenous infusion may produce antidepressant effects within four hours in people with depression.[13] These antidepressant effects may persist for up to several weeks following a single infusion.[13][66] This is in contrast to conventional antidepressants like selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), which generally require at least several weeks for their benefits to occur and become maximal.[13] Moreover, based on the available preliminary evidence, the magnitude of the antidepressant effects of ketamine appears to be more than double that of conventional antidepressants.[13] On the basis of these findings, some have described ketamine as the single most important advance in the treatment of depression in over 50 years.[66][14] It has sparked interest in NMDA receptor antagonists for depression, and has shifted the direction of antidepressant research and development.[67]

    Ketamine has not been approved for use as an antidepressant, but its enantiomer, esketamine, was developed as a nasal spray for treatment-resistant depression and was approved for this indication in the United States in March 2019.[67][13] The effectiveness of esketamine is limited however, with significant effectiveness for treatment-resistant depression seen in only two of five clinical trials.[14] Prescrire has described the harm / benefit balance in treatment resistant depression as "not acceptable" as of 2021.[68] There is also a lack of consensus on dosing and the effects and safety of long-term therapy.[62][69] Ketamine can produce euphoria and dissociative hallucinogen effects at higher doses, and thus has an abuse potential.[13][70] Moreover, ketamine has been associated with cognitive deficits, urotoxicity, hepatotoxicity, and other complications in some individuals with long-term use.[13][70] These undesirable effects may serve to limit the use of ketamine and esketamine for depression.[13][70]

    Dosage

    For rapid sequence intubation a dose of 1 to 3 mg per kg intravenously or 3 to 4 mg per kg injected into a muscle may be used.[71] Following intubation a dose of 1 to 6 mg per kg per hour may be used.[72]

    For procedural sedation 1 to 2 mg per kg intravenously followed by additional doses of 0.5 to 1 mg per kg may be used.[72] Intramuscular injections of 4 to 5 mg / kg may also be used.[72] In young children 3 to 6 mg per kg may be sprayed in the nose.[72]

    For pain management a dose of 0.1 to 0.3 mg per kg intravenously over 15 minutes is used.[72] For exited delirium a dose of 4 to 6 mg per kg by injection into a muscle or 1 mg per kg intravenously may be used.[72]

    • A 1000 mg/10 mL vial of ketamine.
      A 1000 mg/10 mL vial of ketamine.
    • Two doses of intravenous ketamine, 100 mg/2 ml and 20 mg /2 ml
      Two doses of intravenous ketamine, 100 mg/2 ml and 20 mg /2 ml

    Side effects

    When administered by medical professionals, ketamine is generally safe for those people who are critically ill.[73] Even in these cases, there are known side effects that include one or more of the following:[74]

    Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of people.[9]

    Laryngospasm

    Laryngospasm occurs in about 0.3% of people.[72] It is more common with large doses or when the medication is given by rapid intravenous push.[72] Treatment of laryngospasm due to ketamine may include: jaw thrust, bag valve mask with PEEP, further sedation with propofol, or paralysis and intubation.[72]

    Cautions

    The use of ketamine is cautioned against in cases of:[76][7]

    • Conditions worsened by an increase in blood pressure or heart rate, such as angina, stroke, poorly controlled high blood pressure. Ketamine increases both heart rate and blood pressure.
    • Psychiatric disorders: Ketamine can cause hallucinations, and therefore may exacerbate the symptoms of certain psychiatric disorders.
    • Ketamine was once thought to cause increased intracranial pressure (IICP): as of 2014, this is believed not to be the case.[77]
    • Raised intraocular pressure (IOP): Ketamine can further 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, a disease of the nervous system, in susceptible people.

    Neurological

    Effects of ketamine on Zebrafish development. Green areas indicate neurons, and increasing doses of ketamine reduced growth of neurons from the spinal cord.

    At anesthetic doses, 10–20% of people experience adverse reactions that occur during emergence from anesthesia, reactions that can manifest as hallucinations and delirium.[28] These reactions may be less common in some spopulations, 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.[28] People who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.[74]

    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.[78]

    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.[79]

    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.[80][81]

    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.[82] 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.[82] 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.[83]

    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.[84]

    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.[85]

    Urinary tract

    A 2011 review found reports of irritative urinary tract symptoms from recreational use.[86] 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.[86][87] 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.[88]

    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 correspond 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.[86] Urinary tract symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of time.[87] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.[87]

    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.[86] 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.[86]

    Liver

    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.[89]

    Dependence

    Radar plot showing relative physical harm, social harm, and dependence of ketamine[90]

    Ketamine's potential for dependence has been established in various operant conditioning paradigms, including conditioned place preference and self-administration; further, rats demonstrate locomotor sensitization following repeated exposure to ketamine.[87] Increased subjective feelings of 'high' have been observed in healthy human volunteers exposed to ketamine.[87] Additionally, the rapid onset of effects following smoking, insufflation, and/or intramuscular injection is thought to increase the drug's recreational use potential. The short duration of effects promotes bingeing; tolerance can develop; and withdrawal symptoms, including anxiety, shaking, and palpitations, may be present in some daily users following cessation of use.[87]

    Ketamine can cause a variety of urinary tract problems that are more likely to occur with heavier and/or higher dosed use, especially in those not watching for a healthy lifestyle, according to a UK study.[91][92]

    Interactions

    Plasma concentrations of ketamine are increased by CYP3A4 inhibitors (e.g., diazepam) and CYP2B6 inhibitors (e.g., orphenadrine) due to inhibition of its metabolism.[9][93] CYP2B6 and CYP3A4 inducers like carbamazepine, phenobarbital, phenytoin, and rifampicin may reduce plasma levels of ketamine.[93]

    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,[94] benzodiazepines,[95] opioids,[96] quinazolinones, phenothiazines, anticholinergics, and barbiturates.[97]

    Benzodiazepines may diminish the antidepressant effects of ketamine.[93] Most conventional antidepressants can likely be combined with ketamine without diminished antidepressant effectiveness or increased side effects.[93]

    Pharmacology

    Pharmacodynamics

    Molecular interactions

    Ketamine and biological targets[98][99][6][100]
    SiteValue (μM)TypeActionSpeciesRef
    NMDA
    (PCP)    		0.25–0.66
    0.35    		Ki
    IC50    		AntagonistHuman[101][102]
    [101]
    GABAA600–1,800EC50AgonistHuman[100][103]
    MOR26–42.1KiAgonistVarious[6][104][103]
    MOR212.1
    700    		 Ki
    IC50    		 AntagonistHuman[105]
    DOR205–286KiAgonistHuman[103]
    KOR23.1–60.0
    29.0    		 Ki
    EC50    		 AgonistHuman[103]
    NOPIANDNDHuman[104]
    σ166–140KiAgonistRat[106][100][102]
    σ226.3KiAgonistRat[106][102]
    D20.05–0.5
    0.4–0.9    		 Ki
    EC50    		AgonistHuman[102][107][103]
    D2High0.5
    1.03    		Ki
    EC50    		AgonistHuman
    Rat    		[108][109]
    [110]
    5-HT2A>10KiNDHuman[102]
    5-HT2AHi≥15KiAgonist?Rat[108][111]
    5-HT3420
    97
    910    		 Ki
    Ki
    IC50    		 AntagonistHuman
    Mouse
    Human    		 [103]
    M145KiAntagonistHuman[6][112]
    M2294KiAntagonistHuman[6][112]
    M3246KiAntagonistHuman[6][112]
    α720IC50AntagonistHuman[6]
    α4β250IC50AntagonistHuman[6]
    ERα0.345
    2.31    		KD
    IC50    		NDHuman
    Human    		[113]
    [113]
    ChE494KiInhibitorHuman[6]
    SERT>10
    162
    126    		Ki
    Ki
    IC50    		InhibitorHuman
    Rat
    Human    		[102]
    [114][115]
    [103]
    NET66.8
    291    		Ki
    IC50    		InhibitorHuman
    Human    		[114][115][102]
    [103]
    DAT>10
    63
    >10    		Ki
    Ki
    IC50    		InhibitorHuman
    Rat
    Human    		[102]
    [114][115]
    [107]
    PCP259.4KiNDHuman[116]
    VGSC11.5
    222
    1,100    		 Ki
    IC50
    ED50    		 AntagonistRat
    Rat
    Human    		 [103]
    VDCC209IC50InhibitorHuman[112]
    HCN18–16EC50InhibitorMouse[117]
    D-serine 0.46–0.57 EC50 Inhibitor Human [103]
    NOS >100 Ki Inhibitor Rat [118]
    The smaller the value, the stronger the interaction with the site. 0.12–0.84 μM: Drowsiness, dissociative, and psychotic-like effects. 0.42–0.84 μM: Analgesia. 8.41–12.62 μM: Anaesthesia.

    In vitro, ketamine acts as an antagonist of the NMDA receptor, an ionotropic glutamate receptor.[30] It binds specifically to the dizocilpine (MK-801) site of the NMDA receptor, near the channel pore, and is an uncompetitive antagonist.[102] The S(+) and R(–) stereoisomers of ketamine 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.[112] Ketamine may also interact with and inhibit the NMDAR via another allosteric site on the receptor.[119] Its full mechanism of action is not well-understood as of 2017.[30] Because of its complex mechanism of action, interacting with numerous receptors and subreceptor systems, it is often referred to as 'a pharmacologist's nightmare'.[120][121]

    Besides NMDA receptor antagonism, other actions of ketamine under laboratory research include:[98][6][100]

    With a few exceptions (including interactions with the D2 and D2high receptor, nicotinic acetylcholine receptors by metabolites, and ERα) however, these actions are far weaker than ketamine's antagonism of the NMDA receptor (see the activity table to the right).[6][130] A binding study assessed ketamine at 56 sites including neurotransmitter receptors and transporters and found that it had Ki (binding affinity) 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 assessed in this study.[102]

    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.[102] 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.[107][131] 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.[132][133] Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans.[132][131][107][133] 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.[131][107]

    Active 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).[134] These findings suggest that metabolites may contribute importantly to the pharmacodynamics of ketamine by means other than NMDA receptor antagonism.[134]

    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.[108][109][110] Its apparent potency for this action is similar to that of its NMDA receptor antagonism.[108][109][110] 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,[102][107][135] and direct interactions with the D2 receptor are controversial.[136] Moreover, whereas D2 receptor agonists like bromocriptine are able to rapidly and powerfully suppress prolactin secretion,[137] 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.[138][139] 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.[140] 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.[140]

    Ketamine and certain metabolites have been found to act as agonists of the ERα, with affinities in the nanomolar to low micromolar range.[113] The affinity of ketamine for the ERα was about 100-fold lower than that of estradiol.[113] Ketamine and its metabolites may bind to a site on the ERα that is distinct from that of estradiol.[113]

    Effects in the brain and the body

    Antagonism of the NMDA receptor is thought to be responsible for the anesthetic, amnesic, dissociative, and hallucinogenic effects of ketamine.[122] The mechanism(s) of action for the antidepressant effects of ketamine at lower doses have yet to be fully elucidated.[141] 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.[9] Inhibition of nitric oxide synthase lowers the production of nitric oxide – a gasotransmitter involved in pain perception, hence further contributing to analgesia.[142]

    Ketamine produces measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[142]

    • Cardiovascular: Ketamine stimulates the sympathetic nervous system, resulting in cardiovascular changes.
    • Gastrointestinal: Ketamine produces nausea and vomiting in 15 to 25% of individuals at anesthetic doses.[122][109]
    • Respiratory: Ketamine causes bronchodilation.[143] Several mechanisms have been hypothesized to explain this effect.[143]

    The exact mechanisms of these effects are not fully understood.

    Antidepressant effects

    It has yet to be fully understood how ketamine mediates its robust and rapid-onset antidepressant effects.[13][144][145] In any case, it has been elucidated that acute blockade of NMDA receptors in the brain results in 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 of NMDA receptor antagonists like ketamine.[13][144] Such downstream actions of this 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.[13][144][146][147] In addition to blockade of the NMDA receptor, the active metabolite of ketamine hydroxynorketamine, which does not interact importantly with the NMDA receptor but nonetheless indirectly activates AMPA receptors similarly, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.[144][145] Recent research has elucidated that an acute inhibition of the lateral habenula, a part of the brain in the limbic system that has been referred to as the "anti-reward center" (projecting to and inhibiting the mesolimbic reward pathway and modulating other limbic areas), may be involved in the antidepressant effects of ketamine.[144][148][149]

    Esketamine is a more potent NMDA receptor antagonist and dissociative hallucinogen than arketamine, the other enantiomer of ketamine.[14] Because NMDA receptor antagonism was thought to underlie the antidepressant effects of ketamine, esketamine was selected for clinical development as an antidepressant.[14] However, preclinical research has since indicated that arketamine, as well as (2R,6R)-hydroxynorketamine, a metabolite of arketamine with negligible affinity for the NMDA receptor, may be more effective antidepressants than esketamine.[14] In addition, non-ketamine NMDA receptor antagonists in general are less effective antidepressants than ketamine.[14] Indeed, non-ketamine NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, have thus far failed to demonstrate sufficient effectiveness for depression.[14][150] It is now thought that NMDA receptor antagonism may not be responsible for the antidepressant effects of ketamine.[14][150] For these reasons, as of 2019, arketamine and (2R,6R)-hydroxynorketamine are both entering clinical trials for the treatment of depression.[14][151]

    Relationships between levels and effects

    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).[152][8] 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).[69] 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).[152][8] 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).[104][108] Bioactive concentrations of ketamine are lower than total plasma levels due to plasma protein binding,[104] although plasma protein binding is relatively low with ketamine (approximately 12 to 47% protein-bound).[18] Concentrations of ketamine in the brain have been reported to be several-fold higher than in plasma.[108]

    Pharmacokinetics

    Absorption

    Ketamine can be absorbed by intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.[142] In medical settings, ketamine is usually injected intravenously or intramuscularly.[153] The medication can be started using the oral route, or people may be changed from a subcutaneous infusion once pain is controlled. Oral ketamine is easily broken down by bile acids, and hence 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.[154]

    Bioavailability through the oral route reaches 17 to 29%; bioavailability through other routes are: 93% intramuscularly, 8 to 50% intranasally, 24 to 30% sublingually, and 11 to 30% rectally.[9][8][13][16][14] The onset of action of ketamine is seconds intravenously, 1 to 5 minutes intramuscularly, 15 to 30 minutes subcutaneously, 5 to 10 minutes via insufflation, and 15 to 30 minutes orally.[8][9] Maximal concentrations of ketamine are reached in 1 to 3 minutes intravenously, 5 to 15 minutes intramuscularly, 10 to 20 minutes intranasally, 30 minutes orally, 30 to 45 minutes rectally, and 30 to 45 minutes sublingually.[155][16][14]

    Distribution

    Ketamine is rapidly distributed and, due to its high lipophilicity, rapidly crosses the blood–brain barrier into the central nervous system.[156] Its distribution half-life is about 7 to 11 minutes.[156] The plasma protein binding of ketamine is relatively low at 12 to 47%.[12][8][18]

    Metabolism

    When administered orally, ketamine 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 ultimately dehydronorketamine.[8] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into hydroxynorketamine by CYP2B6 and CYP2A6. 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.[142][155] Ketamine and its metabolites are also conjugated.[20]

    The duration of action of ketamine in a clinical setting is 0.5 to 2 hours intramuscularly and 4 to 6 hours orally.[9]

    Elimination

    Ketamine is eliminated about 90% in urine and about 1 to 5% in feces.[6] The medication is excreted mostly in the form of metabolites, with only 2 to 4% remaining unchanged.[156] Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.[157]

    Chemistry

    Structure

    (S)-ketamine
    (R)-ketamine

    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,[158] 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.[159] In the hydrochloride salt, the positions are reversed, with the o-chlorophenyl group axial and the methylamino group equatorial.[160] Not all salts of ketamine show different optical rotation to the free base: (S)-ketamine (R,R)-tartrate is levorotatory, like (S)‑ketamine.[161]

    Conformational and optical-sign effects of amine-salt formation of (S)-ketamine
    Free-base amine
    (equatorial chlorophenyl)    		 Hydrochloride salt
    (axial chlorophenyl)
    Skeletal
    structure
    X-ray
    structure

    Analogues

    Ketamine and other arylcyclohexylamines.
    Main article: Arylcyclohexylamine § List of arylcyclohexylamines

    Other arylcyclohexylamines and analogues of ketamine include eticyclidine (PCE), 3-MeO-PCE, methoxetamine (MXE), tiletamine, phencyclidine (PCP), tenocyclidine (TCP), and many others.[162]

    Detection

    Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, 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.[163][164][165]

    History

    Medical use

    Ketamine vials.

    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.[166] It was known by the developmental code name CI-581.[14] After promising preclinical research in animals, ketamine was introduced to testing in human prisoners in 1964.[31][167] 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.[168] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.[169]

    Nonmedical use

    "Just Say Neigh" T-shirts making reference to ketamine became popular in the late 2000s, parodying the Just Say No campaign and ketamine's reputation as a drug for horses.[170]

    Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.[169] 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.[171] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[172] 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;[173] in addition, there are reports of ketamine being sold as "ecstasy".[174] The use of ketamine as part of a "postclubbing experience" has also been documented.[175] Ketamine's rise in the dance culture was rapid in Hong Kong by the end of the 1990s.[173] 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.[167] Much of the current ketamine diverted for nonmedical use originates in China and India.[167]

    Society and culture

    Generic names

    Ketamine is the English generic name of the drug and its INN and BAN, while ketamine hydrochloride is its USAN, USP, BANM, and JAN.[176][177][1] 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.[177]

    The S(+) stereoisomer of ketamine is known as esketamine, and this is its BAN while esketamine hydrochloride is its BANM.[178]

    Brand names

    Ketamine is primarily sold throughout the world under the brand name Ketalar.[177][1] It is also marketed under a variety of other brand names, including Calypsol, Ketamin, Ketamina, Ketamine, Ketaminol, Ketanest, Ketaset, Tekam, and Vetalar among others.[177][1]

    Esketamine is sold mainly under the brand names Ketanest and Ketanest-S.[178]

    Clinics

    After the publication of the NIH-run antidepressant clinical trial, clinics began opening in which the intravenous ketamine is given for depression.[179][180] This practice is an off label use of ketamine in the United States.[179] 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.[181] It was estimated in 2018 that there were approximately 300 of these clinics.[14] With the approval of esketamine for depression, it is expected that this will change.[14]

    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.[182]

    While ketamine is legally marketed in many countries worldwide,[177] it is also a controlled substance in many countries.[6]

    Australia

    In Australia, ketamine is listed as a schedule 8 controlled drug under the Poisons Standard (October 2015).[183] Schedule 8 drugs are 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."[184]

    Canada

    In Canada, ketamine is classified as a Schedule I narcotic, since 2005.[185]

    Hong Kong

    In Hong Kong, since 2000, ketamine has been 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.[186][187]

    Taiwan

    By 2002, ketamine was classified as class III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into class I or II is being considered.[157][188]

    India

    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.[189][190]

    United Kingdom

    In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[157][191] 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,[192] and on 12 February 2014 the Home Office announced it would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".[193][194]

    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".[193]

    United States

    The increase in recreational use prompted ketamine to be placed in Schedule III of the United States Controlled Substance Act in August 1999.[195]

    Recreational use

    Ketamine solution poured onto glass and left to dry.

    Recreational use of ketamine was documented in the early 1970s in underground literature (e.g., The Fabulous Furry Freak Brothers).[196] 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.[197] The incidence of non-medical ketamine use increased through the end of the century, especially in the context of raves and other parties.[198][199][200][201][173] Its emergence as a club drug differs from other club drugs (e.g., MDMA), however, due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses;[173] in addition, reports of ketamine being sold as "ecstasy" are common.[202] In the 1993 book E for Ecstasy[203] (about the uses of the street drug Ecstasy in the UK), the writer, activist, and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained ketamine. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine, ephedrine, and selegiline", as did a consignment of "Sitting Duck" Ecstasy tablets.[204]

    The use of ketamine as part of a "post-clubbing experience" has also been documented.[205] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[173]

    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.[206] They include accidental poisonings, drownings, traffic accidents, and suicides.[206] The majority of deaths were among young people.[207] This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.).[208]

    Unlike the other well-known dissociatives phencyclidine (PCP) and dextromethorphan (DXM), ketamine is very short-acting. It takes effect within about 10 minutes,[209] while its hallucinogenic effects last 60 minutes when insufflated or injected and up to two hours when ingested orally.[210]

    At subanesthetic 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.[211] At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucinations.[212] John C. Lilly, Marcia Moore, D. M. Turner and David Woodard (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine.[213] Turner died prematurely due to drowning during presumed unsupervised ketamine use.[214] 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.[215]: 288–295 

    Because of its ability to cause confusion and amnesia, ketamine has been used for date rape.[209][169]

    Slang terms

    Production for recreational use has been traced to 1967, when it was referred to as "mean green" and "rockmesc".[216] Recreational names for ketamine include "Special K",[217] "K",[218][217] "Kitty", "Ket",[219] "K2",[218] "Vitamin K",[217][219] "Super K",[217] "Honey oil",[217][220] "Jet",[217][221] "Super acid",[217] "Mauve",[217] "Special LA coke",[217] "Purple",[217] "Cat Valium",[221] "Knod-off", "Skittles", "Blind Squid",[222] "Keller",[222] "Kelly's Day",[222] "New ecstasy",[223] "Psychedelic heroin",[223] "bump",[220] "Majestic".[224] A mixture of ketamine with cocaine is called "Calvin Klein" or "CK1".[225] In Hong Kong, where illicit use of the drug is popular, ketamine is colloquially referred to as "kai-jai".[173]

    Usage

    North America

    According to the ongoing Monitoring the Future study conducted by University of Michigan, prevalence rates of recreational ketamine use among American secondary school students (grades 8, 10, and 12) have varied between 0.8–2.5% since 1999, with recent rates at the lower end of this range.[226] The 2006 National Survey on Drug Use and Health (NSDUH) reports a rate of 0.1% for persons ages 12 or older with the highest rate (0.2%) in those ages 18–25.[227] Further, 203,000 people are estimated to have used ketamine in 2006, and an estimated 2.3 million people used ketamine at least once in their life.[227] A total of 529 emergency department visits in 2009 were ketamine-related.[228]

    In 2003, the U.S. Drug Enforcement Administration conducted Operation TKO, a probe into the quality of ketamine being imported from Mexico.[229] As a result of operation TKO, U.S. and Mexican authorities shut down the Mexico City company Laboratorios Ttokkyo, which was the biggest producer of ketamine in Mexico. According to the DEA, over 80% of ketamine seized in the United States is of Mexican origin. As of 2011, it was mostly shipped from places like India as cheap as $5/gram.[229] The World Health Organization Expert Committee on Drug Dependence, in its thirty-third report (2003),[230] recommended research into its recreational use due to growing concerns about its rising popularity in Europe, Asia, and North America.

    Europe

    Cases of ketamine use in club venues have been observed in the Czech Republic, France, Italy, Hungary, The Netherlands and the United Kingdom.[231] Additional reports of use and dependence have been reported in Poland and Portugal.[232][233]

    Australia

    Australia's 2010 National Drug Strategy Household Survey report shows a prevalence of recent ketamine use of 0.3% in 2004 and 0.2% in 2007 and 2010 in persons aged 14 or older.[234]

    Asia

    In China, the small village of Boshe in eastern Guangdong was confirmed as a main production centre when it was raided in 2013.[235]

    Established by the Hong Kong Narcotics Division of the Security Bureau, the Central Registry of Drug Abuse (CRDA) maintains a database of all the illicit drug users who have come into contact with law enforcement, treatment, health care, and social organizations. The compiled data are confidential under The Dangerous Drugs Ordinance of Hong Kong, and statistics are made freely available online on a quarterly basis.[236][237] Statistics from the CRDA show that the number of ketamine users (all ages) in Hong Kong has increased from 1605 (9.8% of total drug users) in 2000 to 5212 (37.6%) in 2009.[238] Increasing trends of ketamine use among illicit drug users under the age of 21 were also reported, rising from 36.9% of young drug users in 2000 to 84.3% in 2009.[238]

    A survey conducted among school-attending Taiwanese adolescents reported prevalence rates of 0.15% in 2004, 0.18% in 2005, and 0.15% in 2006 in middle-school (grades 7 and 9) students; in Taiwanese high-school (grades 10 and 12) students, prevalence was 1.13% in 2004, 0.66% in 2005, and 0.44% in 2006.[239] From the same survey, a large portion (42.8%) of those who reported ecstasy use also reported ketamine use.[239] Ketamine was the second-most used illicit drug (behind ecstasy) in absconding Taiwanese adolescents as reported by a multi-city street outreach survey.[240] In a study comparing the reporting rates between web questionnaires and paper-and-pencil questionnaires, ketamine use was reported a higher rate in the web version.[241] Urine samples taken at a club in Taipei, Taiwan showed high rates of ketamine use at 47.0%; this prevalence was compared with that of detainees suspected of recreational drug use in the general public, of which 2.0% of the samples tested positive for ketamine use.[242]

    Research

    Russian doctor Evgeny Krupitsky has claimed to have obtained encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.[243][244] Krupitsky and Kolp summarized their work to date in 2007.[245]

    Veterinary medicine

    In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,[246] dogs,[247] rabbits, rats, and other small animals.[248][249] 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.[250] 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 guanfacine.

    Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect.[251]

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