Ketamine

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Ketamine
Ketamine.svg
Ketamine3Dan.gif
Systematic (IUPAC) name
(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Clinical data
AHFS/Drugs.com Consumer Drug Information
Licence data US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Controlled (S8) (AU) Schedule I (CA) CD (UK) Schedule III (US)
Dependence liability Moderate
Routes IV, IM, Insufflated, oral, topical
Pharmacokinetic data
Metabolism Hepatic, primarily by CYP3A4[1]
Half-life 2.5–3 hours.
Excretion renal (>90%)
Identifiers
CAS number 6740-88-1 YesY
ATC code N01AX03
PubChem CID 3821
DrugBank DB01221
ChemSpider 3689 YesY
UNII 690G0D6V8H YesY
KEGG D08098 YesY
ChEBI CHEBI:6121 YesY
ChEMBL CHEMBL742 YesY
Chemical data
Formula C13H16ClNO 
Mol. mass 237.725 g/mol
Physical data
Melt. point 262 °C (504 °F)
 YesY (what is this?)  (verify)

Ketamine is a drug used in human and veterinary medicine, primarily for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.[2] Like other drugs of its class, such as tiletamine and phencyclidine (PCP), ketamine induces a state referred to as "dissociative anesthesia"[3] and is used as a recreational drug.

Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist.[4] At high, fully anesthetic level doses, ketamine has also been found to bind to μ-opioid receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity[5] – and to sigma receptors in rats.[6] Ketamine also interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels,[7] and it inhibits hyperpolarization-activated cyclic nucleotide–modulated (HCN1) cation channels.[8]

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, (S)-ketamine, is also available for medical use under the brand name Ketanest S.[9]

Medical use[edit]

One 10 ml vial of 1000 mg ketamine

Indications for use as an anaesthetic:

In medical settings, ketamine is usually injected intravenously or intramuscularly.[10] Since it suppresses breathing much less than most other available anaesthetics,[11] ketamine is still used in human 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 anaesthetic of choice when reliable ventilation equipment is not available.

Ketamine is frequently used in severely injured patients. It is the drug of choice for patients in traumatic shock who are at risk of hypotension.[12] Hypotension is extremely dangerous in patients with severe head injury[13] and ketamine is anaesthetic agent least likely to precipitate hypotension, often even able to prevent it.[14][15] For years medical myth has held that ketamine was dangerous in patients with head injury over concerns that it might transiently increase the pressure inside the skull. This small transient effect is completely outweighed by the devastation caused by hypotension in severely head injured patients. Air medical services and paramedics are using this drug with increasing frequency.[citation needed]

Ketamine tends to increase heart rate and blood pressure. Because it tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient's fluid volume status is unknown (e.g., from traffic accidents). Ketamine can be used in podiatry and other minor surgery, and occasionally for the treatment of migraine. Research is ongoing in France, the Netherlands, Russia, Australia and the US into the drug's usefulness in pain therapy, depression,[16] and for the treatment of alcoholism[17] and heroin addiction.[18]

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. It is an important part of the "rodent cocktail" a mixture of drugs used for anesthetizing rodents.[citation needed] 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.[citation needed] It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.

Ketamine may be used in small doses (0.1–0.5 mg/kg·h) as a local anesthetic, particularly for the treatment of pain associated with movement and neuropathic pain.[19] It may also be used as an intravenous coanalgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). 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.[20] Ketamine is a coanalgesic, so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects.[20] The combination of ketamine with an opioid is, however, particularly useful for pain caused by cancer.[21]

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.[22] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is also a potent analgesic and can be used in subanesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, "going into other worlds" or "seeing God" while anesthetized, and these unwanted psychological side effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant application of a sedative such as a benzodiazepine.[20]

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS).[23] Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some patients have included hallucinations, dizziness, lightheadedness and nausea. Therefore, nurses administering ketamine to patients with CRPS should do so only in a setting where a trained physician is available if needed to assess potential adverse effects on patients.[24]

In some neurological intensive care units, ketamine has been used in cases of prolonged seizures. Some evidence indicates the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.[25]

Ketamine is a "core" medicine in the World Health Organization's "Essential Drugs List", a list of minimum medical needs for a basic healthcare system.[26]

Pain[edit]

The dissociative anesthetic effects of ketamine have also been applied for postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption, as well as reports of nausea following abdominal surgery.[27]

Oral ketamine[edit]

Ketamine can be started using the oral route, or patients may be changed from a subcutaneous infusion once pain is controlled. Bioavailability of oral ketamine hydrochloride is approximately 20%

Converting from a 24-hour subcutaneous ketamine infusion to oral ketamine[edit]

  • Oral ketamine is easily broken down by bile acids and thus has a low bioavailability (~20%). Oftentimes 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.[28]

Nonmedical use[edit]

Ketamine poured onto glass and left to dry.

Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting. It takes effect within approximately 10 minutes,[29] while its hallucinatory effects last 60 minutes when insufflated or injected and up to two hours when ingested orally. The total experience lasts no more than a few hours.[30]

At subanesthetic doses, 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.[31] At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations.[32] John C. Lilly,[33] Marcia Moore[34] and D. M. Turner[35] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. Both Moore and Turner died prematurely in a way that has been indirectly linked to the sedative properties of ketamine.[36]

Side effects[edit]

Short term from continuous subcutaneous infusion[edit]

Up to 40% of patients may experience side effects. (side effects are less common upon oral administration). These include:[37]

Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.[37]

As discussed below, current research suggests that acute ketamine exposure does not cause significant neurotoxicity.

Long term[edit]

Because ketamine is not administered chronically in a typical clinical setting, long-term effects are primarily reported and investigated in recreational ketamine users and in animal models.[38]

Neurological effects[edit]

In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes in two small areas of the rat brain, which, however, has significant differences in metabolism from the human brain, so may not occur in humans.[39][40][41][42] Indeed, a review published in 2009 found no evidence of ketamine-induced neuron death in humans.[43]

The first large-scale, longitudinal study of ketamine users found that current frequent ketamine users (at least 4 days/week, averaging 20 days/month) had increased depression and impaired memory by several measures, including verbal, short-term memory and visual memory. However, current infrequent (1–4 days/month, 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.[44]

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 non-cell-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.[45][46]

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.[47] 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.[47] A study conducted on rhesus monkeys found that a 24-hour intravenous infusion of ketamine caused signs of brain damage in 5-day-old but not 35-day-old animals.[48]

The acute effects of ketamine cause cognitive impairment including reduced vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.[49]

Urinary tract effects[edit]

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.[50] 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 haematuria (blood in urine). Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases.[38][50] 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.[51]

The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 grams per day reported symptoms of the lower urinary tract.[50] Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time.[38] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.[38]

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.[50] Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, 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.[50]

Case reports of hepatotoxicity in chronic pain management[edit]

In case reports of three patients treated with (S)-(+)-ketamine 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.[52]

Interactions[edit]

Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI anti-depressants, MAOIs. Increase blood pressure, increased heart rate, palpitations and arrhythmias may be potential effects. Ketamine alone additionally increases intracranial pressure (ICP)

Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.[citation needed]

Mechanism of action[edit]

Central nervous system[edit]

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. It appears to inhibit the receptor by binding both in the open channel and at an allosteric site.[53] The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[54] NMDAR 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.[37] Ketamine also inhibits nitric oxide synthase, inhibiting production of nitric oxide, a neurotransmitter involved in pain perception, and hence further contributing to analgesia.[55] It also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.[56]

Ketamine also interacts with a host of other receptors to effect analgesia. It blocks voltage-sensitive calcium channels and depresses sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it acts as a noradrenaline and serotonin uptake inhibitor, which are involved in descending antinociceptive pathways.[37][57]

Peripheral systems[edit]

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[55]

  • Cardiovascular: Ketamine inhibits reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
  • Gastrointestinal: Inhibition of neuronal uptake and increased serotonergic activity are thought to underly nausea and vomiting.
  • Respiratory: Induced catecholamine release and stimulation of β2 adrenergic receptors causes bronchodilation.

Pharmacokinetics[edit]

Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.[58] When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[59] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into 5-hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.[60] As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration.[58][61] Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are as follows: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally.[37][59] Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally.[61] Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.[37]

Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors.[37]

Synthesis[edit]

Ketamine is synthesized from 2-chlorobenzonitrile, which reacts with the Grignard reagent cyclopentylmagnesium bromide to give 1-(2-chlorobenzoyl)cyclopentane.[62][63] The next step is bromination using bromine to the corresponding bromoketone, which upon reaction with an aqueous solution of methylamine forms the methylimino derivative. During this reaction, a simultaneous hydrolysis of the tertiary bromine atom occurs. On heating the reaction product in decalin, a ring-expansion rearrangement occurs, forming ketamine.

Ketamine synthesis.svg

History[edit]

Medical use[edit]

Ketamine vials

Ketamine was originally developed in 1962 as a derivative of phencyclidine (PCP), which was synthesized in 1926, a feat made possible by the discovery of a new organic Grignard reaction by Parke-Davis scientist Harold Maddox.[64] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.[64] These investigations demonstrated that ketamine's shorter duration of action and lesser psychotomimetic profile made it favorable over PCP as a "dissociative" anesthetic.[65] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.[66]

Nonmedical use[edit]

Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.[66] 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.[67] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[68][69][70][71][72] 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;[72] in addition, reports of ketamine being sold as "ecstasy" are common.[73] The use of ketamine as part of a "post-clubbing experience" has also been documented.[74] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[72] Related to its purported ability to cause confusion and amnesiac effects, ketamine can leave users vulnerable to drug-facilitated sexual assault.[75]

Society and culture[edit]

Legal status[edit]

The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.[76]

In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[60][77] On 10 December 2013 the UK ACMD recommended that the government reclassify ketamine to become a Class B drug,[78] and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".[79][80]

The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice said that the issue of its recheduling for medical and veterinary would be addressed "separately to allow for a period of consultation."[79]

In Canada, ketamine is classified as a Schedule I narcotic, as of August 2005.[81] In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.[82] By 2002, ketamine was classified as schedule III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into schedule I or II is being considered.[60]

In December 2013 the government of India added ketamine to Schedule X of the Drug and Cosmetics Act, adding restrictions on who can buy or sell it.[83]

International brand names[edit]

Brand names for ketamine vary internationally:[84]

Research[edit]

Antidepressant use[edit]

Animal studies[edit]

Some research in rodents has attributed the effects of ketamine to being an NMDA receptor antagonist,[53] which increases the activity of the AMPA receptor, and this boost in AMPA activity may be crucial for ketamine’s rapid antidepressant actions.[85] NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system is an emerging target for antidepressant drug discovery and development.[86][87][88]

Acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. The increase of hippocampal BDNF protein levels induced by ketamine might also be necessary to produce a rapid onset of antidepressant action in rats.[89]

Human studies[edit]

Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended ("maintenance") treatment have resulted in only modest success.[90]

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, some patients were observed in the early 2000s to make a significant recovery from depression. This recovery was not formally documented, as the primary concern was pain management and it was not possible to quantify to what degree depression recovery was secondary to the patient's recovery from CRPS.[91] This led the investigators to conduct a study in two patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients demonstrated significant, long-term improvement.[91]

A randomized placebo-controlled study in 18 patients conducted at the US NIH and published in 2006, found ketamine significantly improved treatment-resistant major depression within hours of injection that lasted up to one week after the single dose.[92] NIMH director Dr. Thomas Insel remarked:"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."[93]

A 2013 two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression found that 64% of the patients responded after 24 hours according to the Montgomery–Åsberg Depression Rating Scale compared to 28% responding to midazolam.[94] A 2014 study found that a series of three or six ketamine infusions had a rapid antidepressant effect in treatment-resistant depression (TRD). 29% of a small sample responded, in a period ranging from six hours to the third infusion; beneficial effects lasted from 25 to 168 days. Some test subjects suffered acute adverse reactions during the infusion (7%) or failure to benefit and increasing anxiety (18%). Ketamine was not associated with memory impairment.[95]

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.[96] Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in the active group as compared with the control. The group receiving ketamine also had significantly lower postoperative pain.

Epilepsy[edit]

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.[97] Ketamine was well tolerated and prolonged seizure duration overall, but particularly in those who had a seizure duration shorter than 25 seconds with methohexital at the maximum available stimulus intensity. Ketamine also increased midictal EEG slow-wave amplitude. Thus, a switch to ketamine may be useful when eliciting a robust seizure is difficult. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Treatment of addiction[edit]

The Russian doctor Evgeny Krupitsky (Clinical Director of Research for the Saint Petersburg Regional Center for Research in Addiction and Psychopharmacology) has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.[98][99] This method involved psychotherapy, controlled ketamine use, and group therapy, and resulted in 60 of the 86 alcoholic males selected for the study remaining fully abstinent through one year of treatment. For heroin addiction, the same researcher reached the conclusion that one ketamine-assisted psychotherapy session was significantly more effective than active placebo in promoting abstinence from heroin during one year without any adverse reactions. In a recently published study, 59 detoxified inpatients with heroin dependence received a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and were then randomized into two treatment groups.[citation needed]

Participants in the first group received two addiction counseling sessions followed by two KPT sessions (with a single IM injection of 2 mg/kg ketamine), with sessions scheduled on a monthly interval (multiple KPT group). Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group). At one-year follow-up, survival analysis demonstrated a significantly higher rate of abstinence in the multiple KPT group. Thirteen of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 of 27 subjects (22.2%) in the single KPT group (p < 0.05). No differences between groups were found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. Three sessions of ketamine-assisted psychotherapy were found to be more effective than a single session for the treatment of heroin addiction.[100][101]

Krupitsky and Kolp summarized their work to date in 2007.[102]

Jovaisa et al. from Lithuania demonstrated attenuation of opiate withdrawal symptoms with ketamine. A total of 58 opiate-dependent patients were enrolled in a randomized, placebo-controlled, double-blind study. Patients underwent rapid opiate antagonist induction under general anesthesia. Prior to opiate antagonist induction, patients were given either placebo (normal saline) or a subanesthetic ketamine infusion of 0.5 mg/kg·h. The ketamine group presented better control of withdrawal symptoms, which lasted beyond ketamine infusion itself. Significant differences between ketamine and control groups were noted in anesthetic and early postanesthetic phases. No differences in effects on outcome after four months were observed.[18]

Complex regional pain syndrome[edit]

Ketamine is being used as an experimental and controversial treatment for complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD). CRPS/RSD is a severe chronic pain condition characterized by sensory, autonomic, motor, and dystrophic signs and symptoms. The pain in CRPS is continuous, worsens over time, and is usually disproportionate to the severity and duration of the inciting event. The hypothesis is that ketamine manipulates NMDA receptors which might reboot aberrant brain activity. One treatment modality is a low-dose ketamine infusion of between 25 and 90 mg per day, over five days, either in hospital or as an outpatient, called the awake technique. Open label, prospective, pain journal evaluation of a 10-day infusion of intravenous ketamine (awake technique) in the CRPS patient concluded, "A four-hour ketamine infusion escalated from 40–80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation".[103]

Case notes of 33 patients whose CRPS pain was treated by the inpatient administration of a continuous subanesthetic intravenous infusion of ketamine were reviewed at Mackay Base Hospital, Queensland, Australia. A total of 33 patients with diagnoses of CRPS who had undergone ketamine treatment at least once were identified. Due to relapse, 12 of 33 patients received a second course of therapy, and two of 33 patients received a third. There was complete pain relief in 25 (76%), partial relief in six (18%), and no relief in two (6%) patients.

The degree of relief obtained following repeat therapy (N=12) appeared even better, as all 12 patients who received second courses of treatment experienced complete relief of their CRPS pain. The duration of relief was also impressive, as was the difference between the duration of relief obtained after the first and after the second courses of therapy. In this respect, following the first course of therapy, 54% of 33 individuals remained pain-free for three months or more and 31% remained pain free for six months or more. After the second infusion, 58% of 12 patients experienced relief for a year or more, while almost 33% remained pain free for over three years. The most frequent side effect observed in patients receiving this treatment was a feeling of inebriation. Hallucinations occurred in six patients. Less-frequent side effects also included complaints of light-headedness, dizziness, and nausea. In four patients, an alteration in hepatic enzyme profile was noted; the infusion was terminated and the abnormality resolved thereafter. No long-term side effects were noted.[103] This procedure has only recently been allowed in the United States for the treatment of CRPS.

A second treatment modality consists of putting the patient into a medically induced coma and giving an extremely high dosage of ketamine, typically between 600 and 900 mg.[104] This version, previously done in Germany and Mexico, is now currently only preformed in the United States.[105] According to Dr Schwartzman, 14 of 41 patients in the coma-induced ketamine experiments were completely cured. "We haven't cured the original injury", he says, "but we have cured the RSD or kept it in remission. The RSD pain is gone." He added, "No one ever cured it before... In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system."[104]

In Tuebingen, Germany, Dr Kiefer treated a patient who presented with a rapidly progressing contiguous spread of CRPS from a severe ligamentous wrist injury. Standard pharmacological and interventional therapy successively failed to halt the spread of CRPS from the wrist to the entire right arm. Her pain was unmanageable with all standard therapies. As a last treatment option, the patient was transferred to the intensive care unit and treated on a compassionate care basis with anesthetic doses of ketamine in gradually increasing (3–5 mg/kg·h) doses in conjunction with midazolam over a period of five days. On the second day, edema and discoloration began to resolve and increased spontaneous movement was noted. On day six, symptoms completely resolved and infusions were tapered. The patient emerged from anesthesia completely free of pain and associated CRPS signs and symptoms. The patient has maintained this complete remission from CRPS for eight years now. The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within a month of treatment.[106]

Fear of harm[edit]

According to a recent report on NPR,[107] Demitri Papolos uses ketamine to treat children with "fear of harm" profile, a condition characterized by: sleep disturbances including frequent and terrifying nightmares; an extreme reaction when anyone tries to control their behavior; and overheating, especially at night. Although "fear of harm" profile has been lumped in with bipolar disorder over the recent decades that understanding is emerging about these concerns, "fear of harm" may be related to an overly-sensitive "flight-or-fight" reaction, which classical bipolar disorder is not.

See also[edit]

References[edit]

  1. ^ Hijazi, Y.; Boulieu, R. (July 2002). "Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes". Drug Metabolism and Disposition 30 (7): 853–8. doi:10.1124/dmd.30.7.853. PMID 12065445. 
  2. ^ Peck, T. E.; Hill, S. A.; Williams, M. (2008). Pharmacology for anaesthesia and intensive care (3rd edition). Cambridge: Cambridge University Press. p. 111. ISBN 978-0-521-70463-2. 
  3. ^ Bergman, S. A. (1999). "Ketamine: review of its pharmacology and its use in pediatric anesthesia". Anesthesia Progress 46 (1): 10–20. PMC 2148883. PMID 10551055. 
  4. ^ Harrison, N. L.; Simmonds, M. A. (February 1985). "Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex". British Journal of Pharmacology 84 (2): 381–91. doi:10.1111/j.1476-5381.1985.tb12922.x. PMC 1987274. PMID 2858237. 
  5. ^ Hirota K, Sikand KS, Lambert DG (1999). "Interaction of ketamine with mu2 opioid receptors in SH-SY5Y human neuroblastoma cells". Journal of Anesthesia 13 (2): 107–9. doi:10.1007/s005400050035. PMID 14530949. 
  6. ^ Narita M, Yoshizawa K, Aoki K, Takagi M, Miyatake M, Suzuki T (September 2001). "A putative sigma1 receptor antagonist NE-100 attenuates the discriminative stimulus effects of ketamine in rats". Addiction Biology 6 (4): 373–376. doi:10.1080/13556210020077091. PMID 11900615. 
  7. ^ Pharmaceutical Society of Australia. "2.1.1 IV general anaesthetics". Australian Medicines Handbook. 2011. Australian Medicines Handbook Pty Ltd. p. 13. 
  8. ^ Chen et al. (2009)J Neurosci. 29(3):600-609.
  9. ^ Krüger, A. D. (1998). "Current aspects of using ketamine in childhood". Anaesthesiologie Und Reanimation (in German) 23 (3): 64–71. PMID 9707751. 
  10. ^ Lankenau SE, Sanders B, Bloom JJ, et al. (March 2007). "First injection of ketamine among young injection drug users (IDUs) in three U.S. cities". Drug and Alcohol Dependence 87 (2–3): 183–93. doi:10.1016/j.drugalcdep.2006.08.015. PMC 1852477. PMID 16979848. 
  11. ^ Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A (December 2003). "Use of ketamine in severe status asthmaticus in intensive care unit". Iranian Journal of Allergy, Asthma, and Immunology 2 (4): 175–80. PMID 17301376. 
  12. ^ "Intubation, Hypotension and Shock". Critical Care Compendium. Life in the Fastlane. 2013-08-07. Retrieved 2014-04-10. "ketamine is the induction agent of choice in the shock patient" 
  13. ^ Manley, G; Knudson, M. M.; Morabito, D; Damron, S; Erickson, V; Pitts, L (2001). "Hypotension, hypoxia, and head injury: Frequency, duration, and consequences". Archives of surgery (Chicago, Ill. : 1960) 136 (10): 1118–23. PMID 11585502.  edit
  14. ^ Hemmingsen, C; Nielsen, J. E. (1991). "Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia". Acta anaesthesiologica Scandinavica 35 (8): 755–7. PMID 1763596.  edit
  15. ^ Wong, D. H. W.; Jenkins, L. C. (1975). "The cardiovascular effects of ketamine in hypotensive states". Canadian Anaesthetists' Society Journal 22 (3): 339. doi:10.1007/BF03004843.  edit
  16. ^ Zarate CA Jr, et al (January 2012). "Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial". Biological Psychiatry 71 (11): 939–46. doi:10.1016/j.biopsych.2011.12.010. PMC 3343177. PMID 22297150. 
  17. ^ Krystal JH, Madonick S, Perry E, et al. (August 2006). "Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism". Neuropsychopharmacology 31 (8): 1793–800. doi:10.1038/sj.npp.1300994. PMID 16395307. 
  18. ^ a b Jovaisa T, Laurinenas G, Vosylius S, Sipylaite J, Badaras R, Ivaskevicius J (2006). "Effects of ketamine on precipitated opiate withdrawal". Medicina 42 (8): 625–34. PMID 16963828. 
  19. ^ Lynch ME, Clark AJ, Sawynok J, Sullivan MJ (October 2005). "Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study". The Journal of Pain 6 (10): 644–9. doi:10.1016/j.jpain.2005.04.008. PMID 16202956. 
  20. ^ a b c Elia N, Tramèr MR (January 2005). "Ketamine and postoperative pain--a quantitative systematic review of randomised trials". Pain 113 (1–2): 61–70. doi:10.1016/j.pain.2004.09.036. PMID 15621365. 
  21. ^ Saito O, Aoe T, Kozikowski A, Sarva J, Neale JH, Yamamoto T (September 2006). "Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain". Canadian Journal of Anesthesia 53 (9): 891–8. doi:10.1007/BF03022832. PMID 16960267. 
  22. ^ Adams HA (December 1997). "[S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation]". Der Anaesthesist (in German) 46 (12): 1081–7. doi:10.1007/s001010050510. PMID 9451493. 
  23. ^ Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE (September 2004). "Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome". Pain Medicine 5 (3): 263–75. doi:10.1111/j.1526-4637.2004.04043.x. PMID 15367304. 
  24. ^ "Severe Pain Relief may be Possible with a Common Anesthetic Drug" (Press release). Blackwell Publishing. 1 October 2004. Retrieved 13 December 2009. 
  25. ^ Fujikawa DG (1995). "Neuroprotective Effect of Ketamine Administered After Status Epilepticus Onset". Epilepsia 36 (2): 186–195. doi:10.1111/j.1528-1157.1995.tb00979.x. PMID 7821277. 
  26. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2011. Retrieved 2013-05-02. 
  27. ^ Lundberg GD (2008). "Postoperative Ketamine Can Reduce Morphine Consumption and Nausea". The Medscape Journal of Medicine 10 (10): 234. PMC 2605142. 
  28. ^ http://www.palliativecareguidelines.scot.nhs.uk/documents/Ketaminefinal.pdf[full citation needed]
  29. ^ "Do you know... Ketamine". Knowledgex.camh.net. Retrieved 2014-04-10. 
  30. ^ Giannini AJ, Loiselle RH, Giannini MC, Price WA (1985). "Phencyclidine and the dissociatives". Psychiatric Medicine 3 (3): 197–217. PMID 2893430. 
  31. ^ Giannini AJ, Underwood NA, Condon M (November 2000). "Acute ketamine intoxication treated by haloperidol: a preliminary study". American Journal of Therapeutics 7 (6): 389–91. doi:10.1097/00045391-200007060-00008. PMID 11304647. 
  32. ^ Giannini AJ (1999). Drug Abuse. Los Angeles: Health Information Press. p. 104. ISBN 1-885987-11-0. [page needed]
  33. ^ Lilly, John Cunningham (1997). The scientist: a metaphysical autobiography. Berkeley, CA: Ronin Pub. ISBN 0-914171-72-0. [page needed]
  34. ^ Alltounian, Howard Sunny; Marcia Moore (1978). Journeys into the bright world. Rockport, Mass: Para Research. ISBN 978-0-914918-12-7. [page needed]
  35. ^ Turner, D. M. (1994). The essential psychedelic guide. San Francisco, CA: Panther Press. ISBN 0-9642636-1-0. [page needed]
  36. ^ Jansen, Karl (2001). Ketamine: Dreams and Realities. Multidisciplinary Association for Psychedelic Studies. pp. 50, 89. ISBN 0-9660019-3-1. 
  37. ^ a b c d e f g Quibell, Rachel; Prommer, Eric E., Mihalyo, Mary, Twycross, Robert, Wilcock, Andrew (1 March 2011). "Ketamine*". Journal of Pain and Symptom Management 41 (3): 640–649. doi:10.1016/j.jpainsymman.2011.01.001. PMID 21419322. 
  38. ^ a b c d Morgan, Celia J. A.; Curran, H. Valerie (1 January 2012). "Ketamine use: a review". Addiction 107 (1): 27–38. doi:10.1111/j.1360-0443.2011.03576.x. PMID 21777321. 
  39. ^ Olney JW, Labruyere J, Price MT (June 1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263. 
  40. ^ Erowid DXM Vaults: Health: The Bad News Isn't In: A Look at Dissociative-Induced Brain Damage, by Anderson C
  41. ^ Tryba M, Gehling M (October 2002). "Clonidine--a potent analgesic adjuvant". Current Opinion in Anaesthesiology 15 (5): 511–7. doi:10.1097/00001503-200210000-00007. PMID 17019247. 
  42. ^ Dong C, Anand KJ (June 2013). "Developmental neurotoxicity of ketamine in pediatric clinical use". Toxicol. Lett. 220 (1): 53–60. doi:10.1016/j.toxlet.2013.03.030. PMID 23566897. 
  43. ^ Green SM, Coté CJ (August 2009). "Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine". Ann Emerg Med 54 (2): 181–90. doi:10.1016/j.annemergmed.2008.10.003. PMID 18990467. 
  44. ^ Morgan, Celia J. A.; Muetzelfeldt, Leslie; Curran, H. Valerie (2009). "Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study". Addiction 105 (1): 121–33. doi:10.1111/j.1360-0443.2009.02761.x. PMID 19919593. 
  45. ^ Vutskits L, Gascon E, Potter G, Tassonyi E, Kiss JZ (May 2007). "Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture". Toxicology 234 (3): 216–26. doi:10.1016/j.tox.2007.03.004. PMID 17418473. 
  46. ^ Hargreaves RJ, Hill RG, Iversen LL (1994). "Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology". Acta Neurochirurgica. Supplementum 60: 15–9. PMID 7976530. 
  47. ^ a b Sun, Lin; Qi Li, Qing Li, Yuzhe Zhang, Dexiang Liu, Hong Jiang, Fang Pan, David T. Yew (November 2012). "Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys". Addiction Biology: n/a. doi:10.1111/adb.12004. PMID 23145560. 
  48. ^ Slikker, W.; Zou, X.; Hotchkiss, C. E.; Divine, R. L.; Sadovova, N.; Twaddle, N. C.; Doerge, D. R.; Scallet, A. C.; Patterson, T. A.; Hanig, J. P.; Paule, M. G.; Wang, C. (2007). "Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey". Toxicological Sciences 98 (1): 145–158. doi:10.1093/toxsci/kfm084. PMID 17426105.  edit
  49. ^ Krystal JH, Karper LP, Seibyl JP, et al. (March 1994). "Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses". Arch. Gen. Psychiatry 51 (3): 199–214. PMID 8122957. 
  50. ^ a b c d e Middela, S.; Pearce, I. (1 January 2011). "Ketamine-induced vesicopathy: a literature review". International Journal of Clinical Practice 65 (1): 27–30. doi:10.1111/j.1742-1241.2010.02502.x. PMID 21155941. 
  51. ^ Yeung, LY; Rudd, JA, Lam, WP, Mak, YT, Yew, DT (2009-12-15). "Mice are prone to kidney pathology after prolonged ketamine addiction". Toxicology letters 191 (2–3): 275–8. doi:10.1016/j.toxlet.2009.09.006. PMID 19766175. 
  52. ^ Sear, JW (2011). "Ketamine hepato-toxicity in chronic pain management: Another example of unexpected toxicity or a predicted result from previous clinical and pre-clinical data?". Pain 152 (9): 1946–7. doi:10.1016/j.pain.2011.04.031. PMID 21555186. 
  53. ^ a b Orser BA, Pennefather PS, MacDonald JF. (1997) "Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors".Anesthesiology. 86 (4) PMID 9105235
  54. ^ Hirota, K; Lambert, DG (October 1996). "Ketamine: its mechanism(s) of action and unusual clinical uses". British journal of anaesthesia 77 (4): 441–4. doi:10.1093/bja/77.4.441. PMID 8942324. 
  55. ^ a b Aroni, F; Iacovidou, N, Dontas, I, Pourzitaki, C, Xanthos, T (August 2009). "Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug". Journal of clinical pharmacology 49 (8): 957–64. doi:10.1177/0091270009337941. PMID 19546251. 
  56. ^ Rowland, LM (July 2005). "Subanesthetic ketamine: how it alters physiology and behavior in humans". Aviation, space, and environmental medicine 76 (7 Suppl): C52–8. PMID 16018330. 
  57. ^ Meller, ST (December 1996). "Ketamine: relief from chronic pain through actions at the NMDA receptor?". Pain 68 (2–3): 435–6. doi:10.1016/S0304-3959(96)03167-3. PMID 9121834. 
  58. ^ a b Aroni, F.; Iacovidou, N., Dontas, I., Pourzitaki, C., Xanthos, T. (22 June 2009). "Pharmacological Aspects and Potential New Clinical Applications of Ketamine: Reevaluation of an Old Drug". The Journal of Clinical Pharmacology 49 (8): 957–964. doi:10.1177/0091270009337941. PMID 19546251. 
  59. ^ a b Sinner, B; Graf, BM (2008). "Ketamine". Handbook of experimental pharmacology. Handbook of Experimental Pharmacology 182 (182): 313–33. doi:10.1007/978-3-540-74806-9_15. ISBN 978-3-540-72813-9. PMID 18175098. 
  60. ^ a b c Li, Jih-Heng; Kasinather, Vickna, Cheung, Zhou, Nurhidayat, Jarlais, Des, Schottenfeld, Richard (1 March 2011). "To use or not to use: an update on licit and illicit ketamine use". Substance Abuse and Rehabilitation: 11. doi:10.2147/SAR.S15458. 
  61. ^ a b Haas, DA; Harper, DG (1992). "Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia". Anesthesia progress 39 (3): 61–8. PMC 2148758. PMID 1308374. 
  62. ^ C.L. Stevens, U.S. Patent 3,254,124 (1966)
  63. ^ C.L. Stevens, BE 634208  (1963
  64. ^ a b Domino, EF (September 2010). "Taming the ketamine tiger. 1965". Anesthesiology 113 (3): 678–84. doi:10.1097/ALN.0b013e3181ed09a2. PMID 20693870. 
  65. ^ Corssen, G; Domino, EF (Jan–Feb 1966). "Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581". Anesthesia and Analgesia 45 (1): 29–40. PMID 5325977. 
  66. ^ a b "Ketamine". University of Maryland Center for Substance Abuse Research. Retrieved 23 February 2014. 
  67. ^ Alltounian, Howard Sunny; Marcia Moore (1978). Journeys into the bright world. Rockport, Mass: Para Research. ISBN 0-914918-12-5. [page needed]
  68. ^ Awuonda, Moussa (1 July 1996). "Swedes alarmed at ketamine misuse". The Lancet 348 (9020): 122. doi:10.1016/S0140-6736(05)64628-4. 
  69. ^ Curran, HV; Morgan, C (April 2000). "Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later". Addiction (Abingdon, England) 95 (4): 575–90. doi:10.1046/j.1360-0443.2000.9545759.x. PMID 10829333. 
  70. ^ Gahlinger, PM (2004-06-01). "Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine". American family physician 69 (11): 2619–26. PMID 15202696. 
  71. ^ Jansen, KL (1993-03-06). "Non-medical use of ketamine". BMJ (Clinical research ed.) 306 (6878): 601–2. doi:10.1136/bmj.306.6878.601. PMC 1676978. PMID 8461808. 
  72. ^ a b c Joe-Laidler, Karen; Hunt, Geoffery (1 January 2008). "Sit Down to Float: The Cultural Meaning of Ketamine Use in Hong Kong". Addiction Research & Theory 16 (3): 259–271. doi:10.1080/16066350801983673. 
  73. ^ Parker, Fiona Measham, Judith Aldridge, Howard (2001). Dancing on drugs : risk, health and hedonism in the British club scene. London: Free Association. ISBN 1-85343-512-0. [page needed]
  74. ^ Moore, Karenza; Measham, Fiona (1 January 2006). "Ketamine use: minimising problems and maximising pleasure". Drugs and Alcohol Today 6 (3): 29–32. doi:10.1108/17459265200600047. 
  75. ^ "Ketamine". Center for Substance Abuse Research. 2003-02-21. Retrieved 2014-02-24. "The combined effects can leave the user vulnerable to particular forms of crime, especially "date rape"." 
  76. ^ "Ketamine - Schedule III of The Controlled Substances Act (CSA)". Anestesiología Mexicana en Internet. Retrieved 2006-12-22. 
  77. ^ "Club 'horse' drug to be outlawed". BBC News. 28 December 2005. Retrieved 7 May 2010. 
  78. ^ Advisory Council on the Misuse of Drugs (2013-12-10). "Ketamine: a review of use and harm". Retrieved 2014-01-22. "This report details the harms associated with the misuse of ketamine, an anaesthetic and analgesic. The ACMD recommends that ketamine be controlled under the Misuse of Drugs Act 1971 as a Class B substance and that it is placed in Schedule II of the Misuse of Drugs Regulations 2001." 
  79. ^ a b Advisory Council on the Misuse of Drugs (2014-02-12). "Response to ACMD recommendation on ketamine". Retrieved 2014-02-21. "Minister writes to Les Iversen, chair of the ACMD, accepting the council’s recommendation to reclassify ketamine as a Class B drug and announcing the intention to consult on its scheduling." 
  80. ^ "Home Office announces that ketamine will be re-classified from class C drug to class B drug". twitter.com. SkyNewsBreak. 12 February 2014. Retrieved 12 February 2014. 
  81. ^ Controlled Drugs and Substances Act
  82. ^ Government to tighten control on Ketamine
  83. ^ Sumitra Deb Roy for the Times of India. Dec 30, 2013. Govt makes notorious 'date rape' drug ketamine harder to buy or sell
  84. ^ Lexi-Comp. "Ketamine Drug Information". The Merck Manuals. Retrieved 6 January 2012. 
  85. ^ Koike, Hiroyuki; Iijima, Michihiko; Chaki, Shigeyuki (2011). "Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression". Behavioural Brain Research 224 (1): 107–11. doi:10.1016/j.bbr.2011.05.035. PMID 21669235. 
  86. ^ Pilc, Andrzej; Wierońska, Joanna M.; Skolnick, Phil (2013). "Glutamate-Based Antidepressants: Preclinical Psychopharmacology". Biological Psychiatry 73 (12): 1125–32. doi:10.1016/j.biopsych.2013.01.021. PMID 23453290. 
  87. ^ Murrough, James; Soleimani, Kyle; Murrough, Laili (2013). "Novel glutamatergic drugs for the treatment of mood disorders". Neuropsychiatric Disease and Treatment 9: 1101–12. doi:10.2147/NDT.S36689. PMC 3747027. PMID 23976856. 
  88. ^ Hayley, Shawn; Litteljohn, Darcy (2013). "Neuroplasticity and the next wave of antidepressant strategies". Frontiers in Cellular Neuroscience 7: 218. doi:10.3389/fncel.2013.00218. PMC 3834236. PMID 24312008. 
  89. ^ Garcia, Lêda S.B.; Comim, Clarissa M.; Valvassori, Samira S.; Réus, Gislaine Z.; Barbosa, Luciana M.; Andreazza, Ana Cristina; Stertz, Laura; Fries, Gabriel R.; Gavioli, Elaine Cristina; Kapczinski, Flavio; Quevedo, João (2008). "Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus". Progress in Neuro-Psychopharmacology and Biological Psychiatry 32 (1): 140–4. doi:10.1016/j.pnpbp.2007.07.027. PMID 17884272. 
  90. ^ Katalinic N, Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK. (Aug 2013). "Ketamine as a new treatment for depression: a review of its efficacy and adverse effects". Aust N Z J Psychiatry 47 (8): 710–27. doi:10.1177/0004867413486842. PMID 23661785. 
  91. ^ a b Correll GE, Futter GE (2006). "Two case studies of patients with major depressive disorder given low-dose (subanesthetic) ketamine infusions". Pain Medicine 7 (1): 92–5. doi:10.1111/j.1526-4637.2006.00101.x. PMID 16533209. 
  92. ^ Zarate, Carlos A.; Singh, Jaskaran B.; Carlson, Paul J.; Brutsche, Nancy E.; Ameli, Rezvan; Luckenbaugh, David A.; Charney, Dennis S.; Manji, Husseini K. (2006). "A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression". Archives of General Psychiatry 63 (8): 856–64. doi:10.1001/archpsyc.63.8.856. PMID 16894061. 
  93. ^ NIH. "Experimental Medication Kicks Depression in Hours Instead of Weeks" NIH News, 7 August 2006
  94. ^ Murrough, James W.; Iosifescu, Dan V.; Chang, Lee C.; Al Jurdi, Rayan K.; Green, Charles E.; Perez, Andrew M.; Iqbal, Syed; Pillemer, Sarah; Foulkes, Alexandra; Shah, Asim; Charney, Dennis S.; Mathew, Sanjay J. (2013). "Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial". American Journal of Psychiatry 170 (10): 1134–42. doi:10.1176/appi.ajp.2013.13030392. ISSN 0002-953X. PMID 23982301. 
  95. ^ Diamond, P. R.; Farmery, A. D.; Atkinson, S.; Haldar, J.; Williams, N.; Cowen, P. J.; Geddes, J. R.; McShane, R. (2014). "Ketamine infusions for treatment resistant depression: A series of 28 patients treated weekly or twice weekly in an ECT clinic". Journal of Psychopharmacology. doi:10.1177/0269881114527361.  edit
  96. ^ Kudoh A, Takahira Y, Katagai H, Takazawa T (July 2002). "Small-dose ketamine improves the postoperative state of depressed patients". Anesthesia and Analgesia 95 (1): 114–8, table of contents. doi:10.1097/00000539-200207000-00020. PMID 12088953. 
  97. ^ Krystal AD, Weiner RD, Dean MD, et al. (2003). "Comparison of seizure duration, ictal EEG, and cognitive effects of ketamine and methohexital anesthesia with ECT". The Journal of Neuropsychiatry and Clinical Neurosciences 15 (1): 27–34. doi:10.1176/appi.neuropsych.15.1.27. PMID 12556568. 
  98. ^ The Combination of Psychedelic and Aversive Approaches in Alcoholism Treatment - Eleusis
  99. ^ Krupitsky EM, Grinenko AY (1997). "Ketamine psychedelic therapy (KPT): a review of the results of ten years of research". Journal of Psychoactive Drugs 29 (2): 165–83. doi:10.1080/02791072.1997.10400185. PMID 9250944. 
  100. ^ http://www.eleusis.us/resource-center/references/ketamine-psychotherapy-heroin.pdf
  101. ^ Krupitsky EM, Burakov AM, Dunaevsky IV, Romanova TN, Slavina TY, Grinenko AY (March 2007). "Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence". Journal of Psychoactive Drugs 39 (1): 13–9. doi:10.1080/02791072.2007.10399860. PMID 17523581. 
  102. ^ Krupitsky; Kolp. "Ketamine Psychedelic Psychotherapy". In Michael J. Winkelman and Thomas B., Roberts. Psychedelic Medicine: New Evidence for Hallucinogens as Treatments. Westport, CT: Praeger/Greenwood. [page needed]
  103. ^ a b Goldberg ME, Domsky R, Scaringe D, et al. (April 2005). "Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome". Pain Physician 8 (2): 175–9. PMID 16850072. 
  104. ^ a b CNN report on ketamine therapy for CRPS/RSD 1 September 2006
  105. ^ http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/P02.011[full citation needed]
  106. ^ Kiefer RT, Rohr P, Ploppa A, Altemeyer KH, Schwartzman RJ (June 2007). "Complete recovery from intractable complex regional pain syndrome, CRPS-type I, following anesthetic ketamine and midazolam". Pain Practice 7 (2): 147–50. doi:10.1111/j.1533-2500.2007.00123.x. PMID 17559485. 
  107. ^ http://www.npr.org/blogs/health/2013/03/25/174928768/how-an-unlikely-drug-helps-some-children-consumed-by-fear[full citation needed]

External links[edit]