Ketamine

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Ketamine
Ketamine2DCSD.svg
S-ketamine-from-HCl-xtal-3D-balls.png
Clinical data
Trade names Ketalar, others
Other namesCI-581; CL-369; CM-52372-2 [1]
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Addiction
liability 		Moderate–high [3] [4]
Routes of
administration 		Any [5] [6] [7] [8]
Drug class NMDA receptor antagonist; general anesthetic; dissociative hallucinogen; analgesic; antidepressant
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability
Protein binding 23–47% [12]
Metabolism Liver, intestine (oral):
Metabolites
Onset of action
  • Intravenous: seconds [15]
  • Intramuscular: 1–5 min [15] [16]
  • Subcutaneous: 15–30 min [16]
  • Insufflation: 5–10 min [15]
  • By mouth: 15–30 min [15] [16]
Elimination half-life
  • Ketamine: 2.5–3 hours [15] [7]
  • Norketamine: 12 hours [16]
Duration of action
  • Intramuscular: 0.5–2 hours [16]
  • Insufflation: 45–60 min [15]
  • By mouth: 1–6+ hours [15] [16]
Excretion
Identifiers
  • (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.027.095 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H16ClNO
Molar mass 237.73 g·mol−1
3D model (JSmol)
Chirality Racemic mixture: [15]
Melting point 92 [18]  °C (198 °F)
  • Clc1ccccc1C2(NC)CCCCC2=O
  • 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 Yes check.svgY
  • Key:YQEZLKZALYSWHR-UHFFFAOYSA-N Yes check.svgY
   (verify)

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and in pain management. [19] Ketamine is an NMDA receptor antagonist which accounts for most of its psychoactive effects. [20]

Contents

At anesthetic doses, ketamine induces a state of dissociative anesthesia, a trance-like state providing pain relief, sedation, and amnesia. [21] Its distinguishing features as an anesthestic are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation. [21] At lower, sub-anesthetic doses, it is a promising agent for treatment of pain and treatment-resistant depression. [22] As with many antidepressants, the results of a single administration wane with time. [23]

Ketamine is used as a recreational drug for its hallucinogenic and dissociative effects. [24] When used recreationally, it is found both in crystalline powder and liquid form, and is often referred to by users as "Special K" or simply "K". The long-term effects of repeated use are largely unknown and are an area of active investigation. [25] [26] [27] Liver and urinary toxicity have been reported among regular users of high doses of ketamine for recreational purposes. [28]

Ketamine was first synthesized in 1962, derived from phencyclidine in pursuit of a safer anesthetic with fewer hallucinogenic effects. [29] [30] It was approved for use in the United States in 1970. [19] It has been regularly used in veterinary medicine and was extensively used for surgical anesthesia in the Vietnam War. [31] It is on the World Health Organization's List of Essential Medicines. [32] It is available as a generic medication. [33]

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. [34] 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. [35] When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system. [36] Protective airway reflexes are preserved, [37] and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways. [34] Psychotomimetic effects limit the acceptance of ketamine; however, lamotrigine [38] and nimodipine [39] decrease psychotomimetic effects and can also be counteracted by benzodiazepines or propofol administration. [40] Ketofol is a combination of ketamine and propofol.

Ketamine is frequently used in severely injured people and appears to be safe in this group. [41] It has been widely used for emergency surgery in field conditions in war zones, [42] for example, during the Vietnam War. [43] A 2011 clinical practice guideline supports the use of ketamine as a sedative in emergency medicine, including during physically painful procedures. [21] It is the drug of choice for people in traumatic shock who are at risk of hypotension. [44] Ketamine is unlikely to lower blood pressure, which is dangerous for people with severe head injury; [45] in fact, it can raise blood pressure, often making it useful in treating such injuries. [46] [47]

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. [42] In particular, children with cyanotic heart disease and neuromuscular disorders are good candidates for ketamine anesthesia. [40] [48]

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. [42] [40] [49]

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, 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. [50] [51]

Ketamine is especially useful in the pre-hospital setting due to its effectiveness and low risk of respiratory depression. [52] Ketamine has similar efficacy to opioids in a hospital emergency department setting for the management of acute pain and the control of procedural pain. [53] It may also prevent opioid-induced hyperalgesia [54] [55] and postanesthetic shivering. [56]

For chronic pain, ketamine is used as an intravenous analgesic, mainly if the pain is neuropathic. [30] It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. [57] In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after a traumatic spine injury, fibromyalgia, and complex regional pain syndrome (CRPS). [30] 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. [30]

Depression

Ketamine is a rapid-acting antidepressant, [19] but its effect is transient. [58] Intravenous ketamine infusion in treatment-resistant depression may result in improved mood within 4 hours reaching the peak at 24 hours. [22] [25] 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. [59] Although only a few pilot studies have sought to determine the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome. [60] The antidepressant effect of ketamine is diminished at 7 days, and most people relapse within 10 days. However, for a significant minority, the improvement may last 30 days or more. [25] [26] [59] [61]

One of the main challenges with ketamine treatment can be the length of time that the antidepressant effects last after finishing a course of treatment. A possible option may be maintenance therapy with ketamine, which usually runs twice a week to once in two weeks. [25] [26] [27] Ketamine may decrease suicidal thoughts for up to three days after the injection. [62]

An enantiomer of ketamine – esketamine commercially sold as Spravato– was approved as an antidepressant by the European Medicines Agency in 2019. [63] Esketamine was approved as a nasal spray for treatment-resistant depression in the United States [64] 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. [26]

A Cochrane review of randomized controlled trials in adults with unipolar major depressive disorder, [19] found that when compared with placebo, people treated with either ketamine or esketamine experienced reduction or remission of symptoms lasting 1 to 7 days. [65] 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%) encountered some relief at 24 hours, and 10.3% (4.5 to 18.2%) had few or no symptoms. These effects did not persist beyond one week, although a higher dropout rate in some studies means that the benefit duration remains unclear. [65]

Ketamine may partially improve depressive symptoms [19] among people with bipolar depression at 24 hours after treatment, but not three or more days. [66] Potentially, ten more people with bipolar depression per 1000 may experience brief improvement, but not the cessation of symptoms, one day following treatment. These estimates are based on limited available research. [66]

In February 2022, the US Food and Drug Administration issued an alert to healthcare professionals concerning compounded nasal spray products containing ketamine intended to treat depression. [67]

Seizures

Ketamine is used to treat status epilepticus [68] that has not responded to standard treatments, but only case studies and no randomized controlled trials support its use. [69] [70]

Asthma

Ketamine has been suggested as a possible therapy for children with severe acute asthma who do not respond to standard treatment. [71] This is due to its bronchodilator effects. [71] A 2012 Cochrane review found there were minimal adverse effects reported, but the limited studies showed no significant benefit. [71]

Contraindications

Some major contraindications for ketamine are: [30] [50]

Adverse effects

Table from the 2010 ISCD study ranking various drugs (legal and illegal) based on statements by drug-harm experts. Ketamine was found to be the 11th overall most dangerous drug. HarmCausedByDrugsTable.svg
Table from the 2010 ISCD study ranking various drugs (legal and illegal) based on statements by drug-harm experts. Ketamine was found to be the 11th overall most dangerous drug.

At anesthetic doses, 10–20% of adults and 1–2% of children [10] experience adverse psychiatric reactions that occur during emergence from anesthesia, ranging from dreams and dysphoria to hallucinations and emergence delirium. [73] Psychotomimetic effects decrease adding lamotrigine [38] and nimodipine [39] and can be counteracted by pretreatment with a benzodiazepine or propofol. [73] [40] Ketamine anesthesia commonly causes tonic-clonic movements (greater than 10% of people) and rarely hypertonia. [16] [73] Vomiting can be expected in 5–15% of the patients; pretreatment with propofol mitigates it as well. [10] [73] 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. [73]

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.[ citation needed ] 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. [74]

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. [30] [75] It includes a range of disorders from cystitis to hydronephrosis to kidney failure. [76] The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and blood in urine. [77] 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. [76] 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. [78]

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. [76]

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%.[ citation needed ] There are case reports of increased liver enzymes involving ketamine treatment of chronic pain. [76] Chronic ketamine abuse has also been associated with biliary colic, [79] cachexia, gastrointestinal diseases, hepatobiliary disorder, and acute kidney injury. [80]

Near-death experience

Most people who were able to remember their dreams during ketamine anesthesia report near-death experiences (NDEs) when the broadest possible definition of an NDE is used. [81] Ketamine can reproduce features that commonly have been associated with NDEs. [82] 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. [83]

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. [24] 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. [24] Cognitive deficits as well as increased dissociation and delusion symptoms were observed in frequent recreational users of ketamine. [84]

Interactions

Ketamine potentiates the sedative effects of propofol [85] and midazolam. [86] Naltrexone potentiates psychotomimetic effects of a low dose of ketamine, [87] while lamotrigine [38] and nimodipine [39] decrease them. Clonidine reduces the increase of salivation, heart rate, and blood pressure during ketamine anesthesia and decreases the incidence of nightmares. [88]

Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine. [89] It appears most conventional antidepressants can be safely combined with ketamine. [89]

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. [11] Pure blocking of the NMDA receptor is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine. [20] [90] 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. [16]

The mechanism of action of ketamine in alleviating depression is not well understood and is an area of active investigation. Due to the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant. [11] However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, have thus far failed to demonstrate significant effectiveness for depression. [11] [91] 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. [11] [92] This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine. [11] [93] [91] 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. [94] [95] [96]

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. [94] 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. [20] [94] [97] 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. [59] [94] [98] 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. [59] [94] [99] [100]

Molecular targets

Ketamine and biological targets (with Ki below 100 μM)
SiteValue (μM)TypeActionSpeciesRef
NMDA Tooltip N-Methyl-D-aspartate receptor0.25–0.66KiAntagonistHuman [101] [102]
MOR Tooltip μ-Opioid receptor42KiAntagonistHuman [103]
MOR2 Tooltip μ-Opioid receptor12.1KiAntagonistHuman [104]
KOR Tooltip κ-Opioid receptor28
25		Ki
Ki		Antagonist
Agonist		Human [103]
[105]
σ2 26KiNDRat [106]
D2 0.5
>10		Ki
Ki		Agonist
ND		Human [107]
[102] [108] [109]
M1 45KiNDHuman [110]
α2β2 Tooltip Nicotinic acetylcholine receptor92IC50AntagonistHuman [111]
α2β4 Tooltip Nicotinic acetylcholine receptor29IC50AntagonistHuman [111]
α3β2 50IC50AntagonistHuman [111]
α3β4 9.5IC50AntagonistHuman [111]
α4β2 72IC50AntagonistHuman [111]
α4β4 18IC50AntagonistHuman [111]
α7 3.1 (HNK)IC50 NAM Rat [92]
ERα Tooltip Estrogen receptor alpha0.34KiNDHuman [112]
NET Tooltip Norepinephrine transporter82–291IC50InhibitorHuman [113] [114]
DAT Tooltip Dopamine transporter63KiInhibitorRat [113]
HCN1 Tooltip Hyperpolarization-activated cyclic nucleotide-gated channel 18–16EC50InhibitorMouse [115]
TRPV1 1-100KiAgonistRat [116]
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. [117] 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. [118]

Ketamine may interact with and inhibit the NMDAR via another allosteric site on the receptor. [119]

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). [7] [120]

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. [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. [108] [117] 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. [121] [122] Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans. [121] [117] [108] [122] 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. [117] [108]

Whether ketamine is an agonist of D2 receptors is controversial. Early research by the Philip Seeman group found ketamine to be a D2 partial agonist with a potency similar to that of its NMDA receptor antagonism. [107] [123] [124] However, later studies by different researchers found the affinity of ketamine of >10 μM for the regular human and rat D2 receptors, [102] [108] [109] Moreover, whereas D2 receptor agonists such as bromocriptine can rapidly and powerfully suppress prolactin secretion, [125] 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. [126] [127] 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. [128] 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. [128]

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). [20] 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). [58] At similar plasma concentrations (70 to 160 ng/mL; 0.29–0.67 μM) it also shows analgesic effects. [58] In 1–5 minutes after inducing anesthesia by rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60–110 μM. [129] [130] When the anesthesia was maintained using nitrous oxide together with continuous injection of ketamine, the ketamine concentration stabilized at approximately 9.3 μM. [129] 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). [131] 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. [132]

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%, [7] and epidural bioavailability is 77%. [9] Subcutaneous bioavailability has never been measured but is presumed to be high. [133] Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%) [7] [10] and oral – the lowest (16–20%). [7] [10] Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%. [7] [11] [10]

After absorption ketamine is rapidly distributed into the brain and other tissues. [90] The plasma protein binding of ketamine is variable at 23–47%. [12]

Major routes of ketamine metabolism Ketamine metabolites2.png
Major routes of ketamine metabolism

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. [20] Low oral bioavailability of ketamine is due to the first-pass effect and, possibly, ketamine intestinal metabolism by CYP3A4. [14] 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. [7] [14] This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels. [14] [134]

After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces. [17] 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. [31]

Chemistry

Structure

S-ketamine-2D-skeletal.png
(S)-ketamine
R-ketamine-2D-skeletal.png
(R)-ketamine

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, [135] 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. [19]

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. [136]

Detection

Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized people, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma ketamine concentrations are usually in a range of 0.5–5.0 mg/L in persons receiving the drug therapeutically (during general anesthesia), 1–2 mg/L in those arrested for impaired driving, and 3–20 mg/L in victims of acute fatal overdosage. Urine is often the preferred specimen for routine drug use monitoring purposes. The presence of norketamine, a pharmacologically active metabolite, is useful for confirmation of ketamine ingestion. [137] [138] [139]

History

Ketamine was first synthesized in 1962 by Calvin L. Stevens, [19] a professor of chemistry at Wayne State University and a Parke-Davis consultant. It was known by the developmental code name CI-581. [19] After promising preclinical research in animals, ketamine was tested in human prisoners in 1964. [31] These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as an anesthetic. [140] The researchers wanted to call the state of ketamine anesthesia "dreaming", but Parke-Davis did not approve of the name. Hearing about this problem and the "disconnected" appearance of treated people, Mrs. Edward F. Domino, [141] the wife of one of the pharmacologists working on ketamine, suggested "dissociative anesthesia". [31] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War. [142]

The discovery of antidepressive action of ketamine in 2000 [143] has been described as the single most important advance in the treatment of depression in more than 50 years. [61] [11] It has sparked interest in NMDA receptor antagonists for depression, [144] and has shifted the direction of antidepressant research and development. [145]

Society and culture

While ketamine is marketed legally in many countries worldwide, [146] it is also a controlled substance in many countries. [7]

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. [154] At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucination. [155] 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. [156] Turner died prematurely due to drowning during presumed unsupervised ketamine use. [157] In 2006, the Russian edition of Adam Parfrey's Apocalypse Culture was banned and destroyed by authorities owing to its inclusion of an essay by Woodard about the entheogenic use of, and psychonautic experiences with, ketamine. [158] : 288–295 

Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005–2013. [159] They include accidental poisonings, drownings, traffic accidents, and suicides. [159] The majority of deaths were among young people. [160] 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. [161] Due to its ability to cause confusion and amnesia, ketamine has been used for date rape. [162] [142]

Research

Ketamine is under investigation for its potential in treating treatment-resistant depression. [163] [164] [165] Ketamine is a known psychoplastogen, which refers to a compound capable of promoting rapid and sustained neuroplasticity. [166]

Ketamine has shown anthelmintic activity in rats, with an effect comparable to ivermectin and albendazole at extremely high concentrations. [167]

Veterinary uses

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, [168] dogs, [169] rabbits, rats, and other small animals. [170] [171] 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. [172] 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. [173]

Ketamine appears not to produce sedation or anesthesia in snails. Instead, it appears to have an excitatory effect. [174]

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<span class="mw-page-title-main">Phencyclidine</span> Dissociative hallucinogenic drug, mostly used recreationally

Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptions of sounds, and violent behavior. As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected. It may also be mixed with cannabis or tobacco.

Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of such action, dissociatives are unique in that they do so in such a way that they produce hallucinogenic effects, which may include dissociation, a general decrease in sensory experience, hallucinations, dream-like states or anesthesia. Despite most dissociatives' main mechanism of action being tied to NMDA receptor antagonism, some of these substances, which are nonselective in action and affect the dopamine and/or opioid systems, may be capable of inducing more direct and repeatable euphoria or symptoms which are more akin to the effects of typical "hard drugs" or common drugs of abuse. This is likely why dissociatives are considered to be addictive with a fair to moderate potential for abuse, unlike psychedelics. Despite some dissociatives, such as phencyclidine (PCP) possessing stimulating properties, most dissociatives seem to have a general depressant effect and can produce sedation, respiratory depression, nausea, disorientation, analgesia, anesthesia, ataxia, cognitive and memory impairment as well as amnesia.

<span class="mw-page-title-main">Propofol</span> Intravenous medication used in anesthesia

Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was approved under the brand name Diprivan. Numerous generic versions have since been released. Intravenous administration is used to induce unconsciousness after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectable emulsion formulation using soybean oil and lecithin, giving it a white milky coloration.

<span class="mw-page-title-main">Dextromethorphan</span> Cough suppressant, antidepressant, and dissociative drug

Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropion to serve as a rapid-acting antidepressant in people with major depressive disorder.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Allopregnanolone</span> Endogenous inhibitory neurosteroid

Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.

<span class="mw-page-title-main">Esketamine</span> Medication

Esketamine, sold under the brand names Spravato and Ketanest among others, is the S(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.

<span class="mw-page-title-main">Etoxadrol</span> Chemical compound

Etoxadrol (CL-1848C) is a dissociative anaesthetic drug that has been found to be an NMDA antagonist and produce similar effects to PCP in animals. Etoxadrol, along with another related drug dexoxadrol, were developed as analgesics for use in humans, but development was discontinued in the late 1970s after patients reported side effects such as nightmares and hallucinations.

<span class="mw-page-title-main">Rapastinel</span> Chemical compound

Rapastinel is a novel antidepressant that was under development by Allergan as an adjunctive therapy for the treatment of treatment-resistant depression. It is a centrally active, intravenously administered amidated tetrapeptide that acts as a novel and selective modulator of the NMDA receptor. The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to enhance NMDA receptor-mediated signal transduction and synaptic plasticity.

<span class="mw-page-title-main">Lanicemine</span> Chemical compound

Lanicemine (AZD6765) is a low-trapping NMDA receptor antagonist that was under development by AstraZeneca for the management of severe and treatment-resistant depression. Lanicemine differs from ketamine in that it is a low-trapping NMDA receptor antagonist, showing similar rapid-acting antidepressant effects to ketamine in clinical trials but with little or no psychotomimetic side effects. However, lanicemine did not meet study endpoints, and its development was terminated by AstraZeneca in 2013.

<span class="mw-page-title-main">7-Chlorokynurenic acid</span> Chemical compound

7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor. It produces ketamine-like rapid antidepressant effects in animal models of depression. However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use. As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder, and anti-nociception. In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles, an action that it mediates via competitive blockade of vesicular glutamate transporters.

<span class="mw-page-title-main">Arketamine</span> Chemical compound

Arketamine (developmental code names PCN-101, HR-071603), also known as (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the S(+) enantiomer of ketamine, arketamine is biologically active; however, it is less potent as an NMDA receptor antagonist and anesthetic and thus has never been approved or marketed for clinical use as an enantiopure drug. Arketamine is currently in clinical development as a novel antidepressant.

<span class="mw-page-title-main">Norketamine</span> Major active metabolite of ketamine

Norketamine, or N-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist, but is about 3–5 times less potent as an anesthetic in comparison.

<span class="mw-page-title-main">Dehydronorketamine</span> Chemical compound

Dehydronorketamine (DHNK), or 5,6-dehydronorketamine, is a minor metabolite of ketamine which is formed by dehydrogenation of its metabolite norketamine. Though originally considered to be inactive, DHNK has been found to act as a potent and selective negative allosteric modulator of the α7-nicotinic acetylcholine receptor (IC50 = 55 nM). For this reason, similarly to hydroxynorketamine (HNK), it has been hypothesized that DHNK may have the capacity to produce rapid antidepressant effects. However, unlike ketamine, norketamine, and HNK, DHNK has been found to be inactive in the forced swim test (FST) in mice at doses up to 50 mg/kg. DHNK is inactive at the α3β4-nicotinic acetylcholine receptor (IC50 > 100 μM) and is only very weakly active at the NMDA receptor (Ki = 38.95 μM for (S)-(+)-DHNK). It can be detected 7–10 days after a modest dose of ketamine, and because of this, is useful in drug detection assays.

<span class="mw-page-title-main">Hydroxynorketamine</span> Chemical compound

Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. As of late 2019, (2R,6R)-HNK is in clinical trials for the treatment of depression.

<span class="mw-page-title-main">4-Chlorokynurenine</span> Investigational antidepressant compound

L-4-Chlorokynurenine is an orally active small molecule prodrug of 7-chlorokynurenic acid, a NMDA receptor antagonist. It was investigated as a potential rapid-acting antidepressant.

Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.

Psychoplastogens are a group of small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including ketamine, MDMA, scopolamine, and the serotonergic psychedelics, including LSD, psilocin, DMT, and 5-MeO-DMT. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.

Ketamine-assisted psychotherapy(KAP) is the use of prescribed doses of ketamine as an adjunct to psychotherapy sessions. KAP shows significant potential in treating mental disorders such as treatment-resistant depression (TRD), anxiety, obsessive–compulsive disorders (OCD), post-traumatic stress disorders (PTSD), and other conditions. It can also be used for those experiencing substance abuse and physical pain. While it is primarily used as a veterinary anaesthetic, ketamine has also been found to have rapid analgesic and hallucinogenic effects, which has sparked interest in its use as an antidepressant. Despite initial trials of its use in the treatment of mental disorders focussing primarily on its antidepressant effects, newer studies are attempting to harness its psychedelic effects to bring about altered states of consciousness, which will augment the adjunct psychotherapy. Ketamine's neuroplasticity-promoting effects strengthen the cognitive restructuring that takes place through traditional psychotherapy, thereby leading to long-lasting behavioural change. KAP offers promising directions for research on new antidepressant alternatives, but is still not sufficiently defined or evaluated as a treatment combination.

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