Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells, however without agonist activity, and to sigma receptors in rats. Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels. Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as "dissociative anesthesia" and is used as a recreational drug.

Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation. Ketamine is primarily used 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. It has been shown to be effective in treating depression in patients with bipolar disorder who have not responded to other anti-depressants. In persons with major depressive disorder it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work. It is also a popular anesthetic in veterinary medicine.

Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in enantiomeric proportions. The more active enantiomer, (''S'')-ketamine, is also available for medical use under the brand name Ketanest S. (''R'')-ketamine, (''S'')-ketamine & racemic (''R,S'')-ketamine all have qualitatively separate distinct effect profiles, although S has the most active potency. Ketamine is a ''core'' medicine in the World Health Organization's "Essential Drugs List", a list of minimum medical needs for a basic health care system.

Medical use

Indications for use as an anaesthetic:

Pediatric anesthesia (as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and endotracheal intubation)

Asthmatics or patients with chronic obstructive airway disease

As part of a cream, gel, or liquid for topical application for nerve pain—the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. Other ingredients found useful by pain specialists and their patients as well as the compounding pharmacists who make the topical mixtures include amitriptyline, cyclobenzaprine, clonidine, tramadol, and mepivicaine and other longer-acting local anaesthetics.

In emergency medicine in entrapped patients suffering severe trauma

Emergency surgery in field conditions in war zones

To supplement spinal / epidural anesthesia / analgesia utilizing low doses

In medical settings, ketamine is usually injected intravenously or intramuscularly. Since it suppresses breathing much less than most other available anaesthetics, ketamine is still used in human medicine as an anesthetic, however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine 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. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug's usefulness in pain therapy, depression suppression, and for the treatment of alcoholism and heroin addiction.

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant rate infusion to help prevent pain wind-up. Ketamine is used to manage pain among large animals, though it has less effect on bovines. It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.

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. It may also be used as an intravenous co-analgesic together 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 counter-acting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines. Ketamine is a co-analgesic, and 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. The combination of ketamine with an opioid is, however, particularly useful for pain caused by cancer.

The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system. It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is also a potent analgesic and can be used in sub-anesthetic 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.

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine. 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 only do so in a setting where a trained physician is available if needed to assess potential adverse effects on patients.

In some neurological ICUs, ketamine has been used in cases of prolonged status epilepticus. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.

Experimental antidepressant use

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was pain management. It was not possible to quantify to what degree depression recovery was secondary to the patient's recovery from CRPS.

One trial administered a short-term ketamine regimen to patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients' normal medications were continued as it was feared that stopping them might result in severe depressive episodes. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-17) were obtained. Two of the patients demonstrated significant, long-term improvement. Another small study found that ketamine significantly improved treatment-resistant major depression within hours of injection. The improvement lasted up to one week after the single dose. These patients were previously treatment resistant, having tried an average of six other treatments that failed. 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."

The researchers apparently attribute the effect to ketamine being an NMDA receptor antagonist. Those findings of Zarate ''et al.'' corroborate earlier findings by Berman ''et al.''. However Zarate et al. do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.

These findings are corroborated by Liebrenz et al., who successfully, according to an attending doctor, treated a patient with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al. who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and one treatment of electroconvulsive therapy with bitemporal electrode placement.

However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research.

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients. 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 it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery. 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.

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 be necessary to produce a rapid onset of antidepressant action in rats.

Treatment of addiction

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. 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.

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 out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out 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. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.

Krupitsky and Kolp summarized their work to date in 2007.

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 subanesthetic ketamine infusion of 0.5 mg/kg·h. 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. There were no differences in effects on outcome after 4 months.

Complex regional pain syndrome

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, it worsens over time, and it 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. There are two treatment modalities, the first consist of a low dose ketamine infusion of between 25–90 mg per day, over five days either in hospital or as an outpatient. This is 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 that "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".

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 3 months or more and 31% remained pain free for 6 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 3 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.

The second treatment modality consists of putting the patient into a medically-induced coma and given an extremely high dosage of ketamine; typically between 600–900 mg. This version, currently not allowed in the United States, is most commonly done in Germany but some treatments are now also taking place in Monterrey, Mexico. According to Dr Schwartzman, 14 cases out 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 that "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."

In Tuebingen, Germany Dr Kiefer treated a patient 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 therapy. 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 5 days. On the second day, edema, and discoloration began to resolve and increased spontaneous movement was noted. On day 6, 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 8 years now. The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within 1 month of treatment.

Postoperative pain

The dissociative anesthetic effects of ketamine have also been applied within the realm of postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption as well as reports of nausea following abdominal surgery.

Recreational use

Illicit sale

Ketamine sold illicitly comes either from diverted legitimate supplies and semi-legitimate suppliers, or from theft of legitimate suppliers.

In 2003, the US Drug Enforcement Agency conducted Operation TKO, a probe into the quality of ketamine being imported from Mexico. As a result of operation TKO, US and Mexican authorities shut down the Mexico City company Laboratorios Ttokkyo, which was the biggest producer of ketamine in Mexico. According to the DEA, over 80% of ketamine seized in the US is of Mexican origin. The World Health Organization Expert Committee on Drug Dependence, in its thirty-third report (2003), recommended research into its recreational use/misuse due to growing concerns about its rising popularity in Europe, Asia and North America.

In the 1993 book ''E for Ecstasy'' (about the uses of the street drug Ecstasy in the UK) the writer, activist and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained ketamine. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine, ephedrine and selegiline", as did a consignment of "Sitting Duck" Ecstasy tablets.

The former chairman of the British Advisory Council on the Misuse of Drugs, David Nutt, suggested that Ketamine should be upgraded from a class C drug due to the harm it can cause to users.

Methods of use

Ketamine is sold in either powdered or liquid form. In its powdered form it can be insufflated (inhaled), injected, or taken orally (though this works as a laxative). The smoke has a distinctive bitter taste but the onset of the high is much faster than when ingested or injected intramuscularly (IM), however the effects dissipate quickly. Ketamine is typically injected into the leg, the onset for IM is about one minute. Heavy ketamine users solely use IM as their primary method of administration due to the bypassing of the liver, its increased efficiency, and smoother high. Oral use usually requires more material, but results in a longer trip. However, when administered orally, ketamine is rapidly metabolised to norketamine, which possesses sedating effects; this route of administration is unlikely to produce a dissociative state characteristic of ketamine unless very high doses (500 mg+) are ingested.

Detection of use

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

Psychological effects

Ketamine produces effects similar to phencyclidine (PCP) and dextromethorphan (DXM). Unlike the other well known dissociatives PCP and DXM, ketamine is very short acting, its hallucinatory effects lasting sixty minutes when insufflated or injected and up to two hours when ingested, the total experience lasting no more than a couple of hours. Like other dissociative anaesthetics, hallucinations caused by ketamine are fundamentally different from those caused by tryptamines and phenethylamines. At low doses, hallucinations are only seen when one is in a dark room with one's eyes closed, while at medium to high doses the effects are far more intense and obvious.

Ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization. At sufficiently high doses (e.g. 150 mg intramuscular), users may experience what is coined the "K-hole", a state of dissociation whose effects are thought to mimic the phenomenology of schizophrenia. Users may experience worlds or dimensions that are ineffable, all the while being completely unaware of their individual identities or the external world. Users have reported intense hallucinations including visual hallucinations, perceptions of falling, fast and gradual movement and flying, "seeing God", feeling connected to other users, objects and the cosmos, experiencing psychotic reactions, and shared hallucinations, and thoughts with adjacent users. John C. Lilly, Marcia Moore and D. M. Turner (among others) have written extensively about their own spiritual/psychonautic use of ketamine. (Both Moore and Turner died prematurely in a way that has been linked to their ketamine use.)

Users may feel as though their perceptions are located so deep inside the mind that the real world seems distant (hence the use of a "hole" to describe the experience). Some users may not remember this part of the experience after regaining consciousness, in the same way that a person may forget a dream. Owing to the role of the NMDA receptor in long-term potentiation, this may be due to disturbances in memory formation. The "re-integration" process is slow, and the user gradually becomes aware of surroundings. At first, users may not remember their own names, or even know that they are human, or what that means. Movement is extremely difficult, and a user may not be aware that he or she has a body at all.

In an article in ''The Guardian'', Simon Reynolds examined the idea of any links between the recreational use of ketamine, a dissociative drug, and the origins of dubstep, writing that a connection "would certainly explain a lot", though also conceding "it could all be just rumour".

Adverse effects

Short term

Short term side effects of Ketamine are:

Increase in heart rate

Slurred speech

Confusion, disorientation

Out-of-body experience

Shifts in perception of reality

Nausea

Sedation

Cardiovascular effects, including hypertension and tachycardia

Respiratory depression

Hypersalivation

Pleasant mental and/or body high

Increase in energy

Euphoria

Sense of calm and serenity

Meaningful spiritual experiences

Enhanced sense of connection with the world (beings or objects)

Distortion or loss of sensory perceptions (common)

Open- and closed-eye visuals (common)

Dissociation of mind from body

Analgesia, numbness

Ataxia (loss of motor coordination)

Significant change in perception of time

Double-vision

Long term

Neurological effects

Chronic use of ketamine may lead to cognitive impairments including memory problems. In 1989, psychiatry professor John Olney reported that ketamine caused ireversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.

The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However occasional (1-2 times per month) ketamine users and ex-ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.

Short-term exposure of cultures 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 that 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 morphology and thus might lead to dysfunctions of neural networks.

There is a long list of medicines that could counteract these potential toxic effects , including clonidine, anticholinergics, benzodiazepines, barbiturates and risperidone.

Urinary tract effects

A study in Bristol reported in the British Medical Journal linked urinary tract disease with ketamine use. Symptoms reported by users included an increased need to urinate, passing blood in urine, leakage of urine and pain on urination. These symptoms may be associated with the scarification of the bladder lining, which leads to a shrunken bladder, erythema, and contact bleeding, and can then move to the ureters and damage the kidneys.

Another small study found "marked thickening of the bladder wall, a small capacity, and perivesicular stranding, consistent with severe inflammation. At cystoscopy, all patients had severe ulcerative cystitis. Cessation of ketamine use, with the addition of pentosan polysulfate, appeared to provide some symptomatic relief."

Many long term users report "K cramps". The exact cause of these pains are unknown. The Ketamine induced abdominal pain is primarily limited to users of a gram or more of ketamine a day (route of administration does not seem to affect this symptom). It has been suggested that the amino acid Tyrosine may help alleviate the pain.

Drug interactions

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

Some users mix the drug with stimulants to counteract its sedative effects. Cocaine and ketamine, one of the most common mixes, is known as "CK1".

Pharmacology

Ketamine was long thought to act primarily by inhibiting NMDA receptors. But another NMDA receptor antagonist, MK-801, does not exert the same hypnotic effects. It appears more likely that the hypnotic effects of ketamine are produced by inhibiting hyperpolarization-activated cyclic nucleotide-modulated (HCN1) cation channels, which mediate the "sag" current (''I_h '') in neurons. Inhibition of ''I_h'' by ketamine in cultured neurons causes a hyperpolarizing shift in resting membrane potential and enhances summation of excitatory currents. Such effects, if induced ''in vivo'', would likely induce cortical oscillations reminiscent of sleep. Most importantly, knockout of HCN1 channels in mice eliminates the hypnotic actions of ketamine.

Ketamine is a noncompetitive NMDA receptor antagonist. This receptor opens in response to binding of the neurotransmitter glutamate, and blockade of this receptors is believed to mediate the analgesic (reduction of pain) effects of ketamine at low doses. Evidence for this is reinforced by the fact that naloxone, an opioid antagonist, does not reverse the analgesia. Studies also seem to indicate that ketamine is "use dependent" meaning it only initiates its blocking action once a glutamate binds to the NMDA receptor.

At high, fully anesthetic level concentrations, ketamine has also been found to bind to opioid mu2 receptors in cultured human neuroblastoma cells without being an agonist on them It has also been shown to act as a weak D₂ receptor partial agonist in rat brain cell homogenates, as well as a dopamine reuptake inhibitor.

(''rac'')-ketamine is a noncompetitive inhibitor of human recombinant α7 nAChR expressed in frog eggs at clinically relevant concentrations.

Ketamine is racemic, and its (''R'')- and (''S'')-stereoisomers have different binding affinities: (''S'')-ketamine has about four times greater affinity for the PCP site of the NMDA receptor than does (''R'')-ketamine (in guinea pig brain). (''S'')-ketamine seems to induce drowsiness more strongly than the (''R'')-enantiomer; it is probable that (''R'')-ketamine is the stronger sigma agonist and so this enantiomer is likely to be responsible for the lowering of the seizure threshold that can occur with ketamine. Since (S)-ketamine has greater analgesic effects than (''R'')-ketamine, the pure (''S'')-enantiomer is sometimes preferred to the racemic mix for use in medical procedures, especially when lower doses are used for minor surgical procedures where the patient remains conscious during the operation.

The effects seem to take place mainly in the hippocampal formation and in the prefrontal cortex. This evidence, along with the NMDA receptor's connection with the memory formation process, explains ketamine's profound effects on memory and thought. These effects inhibit the filtering function of the brain and may mirror the sensory overload associated with schizophrenia and near death experiences.

The local anesthetic effects in frog nerve preparations are likely from the blocking action of ketamine on sodium channels. Its ''in vitro'' blocking potency of rat muscle recombinant sodium channels, expressed in frog eggs, in the resting state is similar to that of lidocaine.

Ketamine has a well-documented neuroprotective effect against ischemic brain-injury and glutamate induced brain injury. One hypothesis of its working mechanism in case of chronic pain management and depression is that it works as an antidote to an overactivity in glutamergic brain circuits.

Chemistry

Ketamine, 2-(''o''-chlorophenyl)-2-(2-methylamino)cyclohexanone, is synthesized from 2-chlorobenzonitrile, which reacts with cyclopentylmagnesium bromide to give 1-(2-chlorobenzoyl)cyclopentane. 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 further heating the reaction product in decalin, a ring expansion rearrangement occurs, causing formation of ketamine. C.L. Stevens, (1966). C.L. Stevens, (1963).

History

Ketamine was developed by Parke-Davis in 1962 as part of an effort to find a safer anesthetic alternative to phencyclidine (PCP), which was likely to cause hallucinations, neurotoxicity and seizures. The drug was first given to American soldiers during the Vietnam War. It is still widely used in humans. It is also used widely in veterinary medicine, or as a battlefield anesthetic in developing nations. The drug was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of John Lilly's ''The Scientist'' and Marcia Moore and Howard Alltounian's ''Journeys into the Bright World'', which documented the unusual phenomenology of ketamine intoxication.

The incidence of recreational ketamine use increased through the end of the century, especially in the context of raves and other parties. The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999. In the United Kingdom, it became outlawed and labeled a Class C drug on 1 January 2006. In Canada ketamine is classified as a Schedule I narcotic, as of August 2005. In Hong Kong, as of the year 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.

Nomenclature

Ketamine was invented as CL369, and it was referred to as CI 581 (clinical investigation 581) during development at Parke-Davis. Commercial brands of ketamine include Ketalar, Ketaset, Ketmex, Ketotal, Ketamine-500 (Astrapin) and Imalgen. The name ketamine derives from "keto-amine", named for the ketone C=O group bonded to carbons either side, as well as an amine group.

Production for recreational use has been traced to 1967, when it was referred to as "mean green" and "rockmesc". Recreational names for ketamine include "K", "Ket", "Special K", "Kitties", "K2" and "Vitamin K".

References

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Category:General anesthetics Category:Dissociative drugs Category:NMDA receptor antagonists Category:Sedatives Category:World Health Organization essential medicines Category:Euphoriants Category:Ketones Category:Amines Category:Organochlorides

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Coordinates	38°53′12″N77°01′47″N
region	Western Philosophy
Era	20th century philosophy
Color	#B0C4DE
image	Mckenna1.jpg
name	Terence Kemp McKenna
Birth date	November 16, 1946
Birth place	Paonia, Colorado, United States
Death date	April 03, 2000
Death place	San Rafael, California, United States
School tradition	Metaphysics, phenomenology|
Main interests	shamanism, ethnobotany, metaphysics, psychedelic drugs, futurism, primitivism, environmentalism, consciousness, phenomenology, historical revisionism, evolution, ontology, Mind at Large, virtual reality, dominator culture, criticizing science, the Logos
Influences	psychedelic drugs, Marshall McLuhan, Alfred North Whitehead, Teilhard de Chardin, Aldous Huxley, I Ching, William Blake, Riane Eisler, James Joyce, Vladimir Nabokov, Heraclitus
Influenced	Rupert Sheldrake, Robert Anton Wilson, Ralph Abraham, RU Sirius, Cliff Pickover, Timothy Leary
Notable ideas	Novelty Theory, The "Stoned Ape" Theory of Human Evolution, Machine elves }}

Terence Kemp McKenna (November 16, 1946 – April 3, 2000) was an Irish-American researcher, philosopher, speaker, spiritual teacher and writer on many subjects; such as human consciousness, psychedelic drugs, the evolution of civilizations, the origin and the end of the universe, cybernetics, alchemy, and extraterrestrial beings.

Biography

Early life

Terence McKenna grew up in Paonia, Colorado. He was introduced to geology through his uncle and developed a hobby of solitary fossil hunting in the arroyos near his home. From this he developed a deep artistic and scientific appreciation of nature.

At age 16, Terence moved to Los Altos, California to live with family friends for a year. He finished high school in Lancaster, CA. In 1963, McKenna was introduced to the literary world of psychedelics through ''The Doors of Perception'' and ''Heaven and Hell'' by Aldous Huxley and certain issues of ''The Village Voice'' that talked about psychedelics.

Terence claimed that one of his early psychedelic experiences with morning glory seeds showed him "that there was something there worth pursuing." In an audio interview Terence Mckenna claims to have started smoking cannabis regularly during the summer following his 17th birthday.

Studying and traveling

In 1965, Terence enrolled in U.C. Berkeley to study Art History. In 1967, while in college, he got involved with shamanism after being lead there by studying Tibetan religions That year, which he called his "opium and kabbala phase," he also traveled to Jerusalem, where he met Kathleen Harrison, who would later become his wife.

In 1969, Terence traveled to Nepal lead by his "interest in Tibetan painting and hallucinogenic shamanism." During his time there, he studied the Tibetan language and worked as a hashish smuggler, until "one of his Bombay-to-Aspen shipments fell into the hands of U. S. Customs." He was forced to move to avoid capture by Interpol. He wandered through Southeast Asia viewing ruins, collected butterflies in Indonesia, and worked as an English teacher in Tokyo. He then went back to Berkeley to continue studying biology, which he called "his first love."

After he completed part of his studies and his mother's death from cancer in 1971, Terence, his brother Dennis, and three friends traveled to the Colombian Amazon in search of oo-koo-hé, a plant preparation containing DMT. Instead of oo-koo-hé they found various forms of ayahuasca, or "yagé," and gigantic psilocybe cubensis which became the new focus of the expedition. In La Chorrera, at the urging of his brother, he was the subject of a psychedelic experiment which he claimed put him in contact with Logos: an informative, divine voice he believed was universal to visionary religious experience. The voice's revelations and his brother's simultaneous peculiar experience prompted him to explore the structure of an early form of the I Ching, which led to his "Novelty Theory." During their stay in the Amazon, Terence also got romantically involved with his translator, Ev.

In 1972, Terence returned to Berkeley to finish his studies. There he decided to switch majors to a Bachelor of Science in Ecology and Conservation, in a then-new experimental section of the same university called the Tussman Experimental College. During his studies, he would also develop techniques for cultivating psilocybin mushrooms with Dennis.

In 1975, he parted with his girlfriend Ev, when she left him for one of Terence's friends from Berkeley. Their parting left him "tormented with migraines and living alone." He graduated in 1975. That same year, he began a relationship with a friend he met in Jerusalem, Kathleen.

Soon after graduating, Terence and Dennis published a book inspired by their Amazon experiences, ''The Invisible Landscape: Mind, Hallucinogens and the I Ching.'' Terence also began lecturing. The brothers' experiences in the Amazon would later play a major role in Terence's book ''True Hallucinations'', published in 1993. In 1976, the brothers published what they had learned about the cultivation of mushrooms in a book entitled ''Psilocybin - Magic Mushroom Grower's Guide'' under the pseudonyms OT Oss and ON Oeric.

Later life

In the early 1980s, McKenna began to speak publicly on the topic of psychedelic drugs, lecturing extensively and conducting weekend workshops. Though associated with the New Age and human potential movements, McKenna himself had little patience for New Age sensibilities. He repeatedly stressed the importance and primacy of felt experience, as opposed to dogma. Timothy Leary once introduced him as "one of the five or six most important people on the planet." }}He soon became a fixture of popular counterculture. His growing popularity culminated in the early to mid-1990s with the publication of several books: ''True Hallucinations'', relating the tale of his 1971 La Chorrera experience; ''Food of the Gods''; and ''The Archaic Revival''. He became a popular personality in the psychedelic rave/dance scene of the early 1990s, with frequent spoken word performances at raves and contributions to psychedelic and goa trance albums by The Shamen, Spacetime Continuum, Alien Project, Capsula, Entheogenic, Zuvuya, Shpongle, and Shakti Twins. His speeches were, and are, sampled by many. In 1994 he appeared as a speaker at the Starwood Festival, documented in the book ''Tripping'' by Charles Hayes. His lectures were produced on both cassette tape and CD.

McKenna was a colleague of chaos mathematician Ralph Abraham, and biologist Rupert Sheldrake, creator of the theory of "morphogenetic fields", not to be confused with the mainstream usage of the same term. He conducted several public debates known as ''trialogues'' with them from the late 1980s until his death. Books containing transcriptions of some of these events were published. He was also a friend and associate of Ralph Metzner, Nicole Maxwell, and Riane Eisler, participating in joint workshops and symposia with them. He was a personal friend of Tom Robbins, and influenced the thought of many scientists, writers, artists, and entertainers. His influences include comedian Bill Hicks, whose routines about psychedelic drugs drew heavily from McKenna's works. He is also the inspiration for the Twin Peaks character Dr. Jacoby.

In addition to psychedelic drugs, McKenna spoke on the subjects of virtual reality, which he saw as a way to artistically communicate the experience of psychedelics; techno-paganism; artificial intelligence; evolution; extraterrestrials; and aesthetic theory, specifically about art/visual experience as ''information'' representing the significance of hallucinatory visions experienced under the influence of psychedelics.

In 1985, McKenna co-founded Botanical Dimensions with his then-wife Kathleen, a nonprofit ethnobotanical preserve in Hawaii, where he lived for many years before he died. In 1997 he and Kathleen divorced. Before moving to Hawaii permanently, McKenna split his time between Hawaii and Occidental, located in the redwood-studded hills of Sonoma County, California.

Death

A longtime sufferer of migraines, in mid-1999 McKenna returned to his home on the big island of Hawaii after a long lecturing tour. He began to suffer from increasingly painful headaches. This culminated in three brain seizures in one night, which he claimed were the most powerful psychedelic experiences he had ever known. Upon his emergency trip to the hospital on Oahu, Terence was diagnosed with glioblastoma multiforme, a highly aggressive form of brain cancer. For the next several months he underwent various treatments, including experimental gamma knife radiation treatment. According to Wired magazine, McKenna was worried that his tumour was caused by his 35-years of smoking cannabis; though his doctors assured him there was no causal relation.

In late 1999, Erik Davis conducted what would be the last interview of McKenna. During the interview McKenna also talked about the announcement of his death:

Terence died on April 3, 2000, at the age of 53, with his loved ones at his bedside. He is survived by his brother Dennis, his son Finn, and his daughter Klea.

The library fire

On February 7, 2007, McKenna's library of rare books and personal notes was destroyed in a fire which burned offices belonging to Big Sur's Esalen Institute storing the collection. An index maintained by his brother Dennis survives, though little else.

Ideas

Terence McKenna advocated the exploration of altered states of mind via the ingestion of naturally occurring psychedelic substances. For example, and in particular, as facilitated by the ingestion of high doses of psychedelic mushrooms, and DMT, which he believed was the apotheosis of the psychedelic experience. He spoke of the "jeweled, self-dribbling basketballs" or "self-transforming machine elves" that one encounters in that state.

Although he avoided giving his allegiance to any one interpretation (part of his rejection of monotheism), he was open to the idea of psychedelics as being "trans-dimensional travel"; literally, enabling an individual to encounter what could be ancestors, or spirits of earth. He remained opposed to most forms of organized religion or guru-based forms of spiritual awakening.

Either philosophically or religiously, he expressed admiration for Marshall McLuhan, Pierre Teilhard de Chardin, Gnostic Christianity, Alfred North Whitehead and Alchemy. McKenna always regarded the Greek philosopher Heraclitus as his favorite philosopher.

He also expressed admiration for the works of James Joyce (calling ''Finnegans Wake'' "the quintessential work of art, or at least work of literature of the 20th century") and Vladimir Nabokov: McKenna once said that he would have become a Nabokov lecturer if he had never encountered psychedelics.

The "Stoned Ape" Theory of Human Evolution

In his book ''Food of the Gods'', McKenna proposed that the transformation from humans' early ancestors ''Homo erectus'' to the species ''Homo sapiens'' mainly had to do with the addition of the mushroom ''Psilocybe cubensis'' in its diet - an event which according to his theory took place in about 100,000 BC (this is when he believed that the species diverged from the Homo genus). He based his theory on the main effects, or alleged effects, produced by the mushroom. One of the effects that comes about from the ingestion of low doses, which agrees with one of scientist Roland Fischer's findings from the late 60s-early 70s, is it significantly improves the visual acuity of humans - so theoretically, of other human-like mammals too. According to McKenna, this effect would have definitely prove to be of evolutionary advantage to humans' omnivorous hunter-gatherer ancestors that would have stumbled upon it "accidentally"; as it would make it easier for them to hunt.

In higher doses, McKenna claims, the mushroom acts as a sexual stimulator, which would make it even more beneficial evolutionarily, as it would result in more offspring. At even higher doses, the mushroom would have acted to "dissolve boundaries", which would have promoted community-bonding and group sexual activities-that would result in a mixing of genes and therefore greater genetic diversity. Generally McKenna believed that the periodic ingestion of the mushroom would have acted to dissolve the ego in humans before it ever got the chance to grow in destructive proportions. In this context he likened the ego to a cancerous tumor that can grow uncontrollable and become destructive to its host. In his own words:

The mushroom, according to McKenna, had also given humans their first truly religious experiences (which, as he believed, were the basis for the foundation of all subsequent religions to date). Another factor that McKenna talked about was the mushroom's potency to promote linguistic thinking. This would have promoted vocalisation, which in turn would have acted in cleansing the brain (based on a scientific theory that vibrations from speaking cause the precipitation of impurities from the brain to the cerebrospinal fluid), which would further mutate the brain. All these factors according to McKenna were the most important factors that promoted evolution towards the ''Homo sapiens'' species. After this transformation took place, the species would have begun moving out of Africa to populate the rest of the planet Later on, this theory by McKenna was given the name "The 'Stoned Ape' Theory of Human Evolution".

Bibliography

1975 - ''The Invisible Landscape: Mind, Hallucinogens, and the I Ching'' (with Dennis McKenna) (Seabury; 1st Ed) ISBN 0-8164-9249-2.

1976 - ''The Invisible Landscape'' (with Dennis McKenna, and Quinn Taylor) (Scribner) ISBN 0-8264-0122-8

1976 - ''Psilocybin - Magic Mushroom Grower's Guide'' (with Dennis McKenna: credited under the pseudonyms OT Oss and ON Oeric) (2nd edition 1986) (And/Or Press) ISBN 0-915904-13-6

1992 - ''Psilocybin - Magic Mushroom Grower's Guide'' (with Dennis McKenna: (credited under the pseudonyms OT Oss and ON Oeric) (Quick American Publishing Company; Revised edition) ISBN 0-932551-06-8

1992 - ''The Archaic Revival'' (HarperSanFrancisco; 1st edition) ISBN 0-06-250613-7

1992 - ''Food of the Gods: The Search for the Original Tree of Knowledge - A Radical History of Plants, Drugs, and Human Evolution'' (Bantam) ISBN 0-553-37130-4

1992 - ''Synesthesia'' (with Timothy C. Ely) (Granary Books 1st Ed) ISBN 1-887123-04-0

1992 - ''Trialogues at the Edge of the West: Chaos, Creativity, and the Resacralization of the World'' (with Ralph H. Abraham, Rupert Sheldrake and Jean Houston) (Bear & Company Publishing 1st Ed) ISBN 0-939680-97-1

1993 - ''True Hallucinations: Being an Account of the Author’s Extraordinary Adventures in the Devil’s Paradise'' (HarperSanFrancisco 1st Ed) ISBN 0-06-250545-9

1994 - ''The Invisible Landscape'' (HarperSanFrancisco; Reprint edition) ISBN 0-06-250635-8

1998 - ''True Hallucinations & the Archaic Revival: Tales and Speculations About the Mysteries of the Psychedelic Experience'' (Fine Communications/MJF Books) (Hardbound) ISBN 1-56731-289-6

1998 - ''The Evolutionary Mind : Trialogues at the Edge of the Unthinkable'' (with Rupert Sheldrake and Ralph H. Abraham) (Trialogue Press; 1st Ed) ISBN 0-942344-13-8

1999 - ''Food of the Gods: A Radical History of Plants, Drugs, and Human Evolution'' (Rider & Co; New edition) ISBN 0-7126-7038-6

1999 - ''Robert Venosa: Illuminatus'' (with Robert Venosa, Ernst Fuchs, H. R. Giger, and Mati Klarwein) (Craftsman House) ISBN 90-5703-272-4

2001 - ''Chaos, Creativity, and Cosmic Consciousness'' (with Rupert Sheldrake and Ralph H. Abraham) (Park Street Press; revised ed) ISBN 0-89281-977-4 (Revised edition of Trialogues at the Edge of the West)

2005 - ''The Evolutionary Mind: Trialogues on Science, Spirit & Psychedelics'' (Monkfish Book Publishing; Revised Ed) ISBN 0-9749359-7-2

Spoken word

''History Ends In Green: Gaia, Psychedelics and the Archaic Revival'', 6 audiocassette set, Mystic Fire audio, 1993, ISBN 1-56176-907-x (recorded at the Esalen Institute, 1989)

''TechnoPagans at the End of History'' (transcription of rap with Mark Pesce from 1998)

''Psychedelics in the Age of Intelligent Machines'' (1999) 90 minutes video

''Alien Dreamtime'' with Spacetime Continuum & Stephen Kent (Magic Carpet Media) (CD) video

''Conversations on the Edge of Magic'' (1994) (CD & Cassette) ACE

''Rap-Dancing Into the Third Millennium'' (1994) (Cassette) (Re-issued on CD as ''The Quintessential Hallucinogen'') ACE

''Packing For the Long Strange Trip'' (1994) (Cassette) ACE

Coast to Coast AM with Art Bell, broadcast on May 22, 1997, Five hour interview covering various topics

''Global Perspectives and Psychedelic Poetics'' (1994) (Cassette) Sound Horizons Audio-Video, Inc.

''The Search for the Original Tree of Knowledge'' (1992) (Cassette) Sounds True

Discography

''Re : Evolution'' with The Shamen (1992)

''Alien Dreamtime'' with Spacetime Continuum & Stephen Kent (Magic Carpet Media) (DVD)

2009 - ''Cognition Factor'' (2009)

See also

Ethnomycology

Exopheromone

List of notable brain tumor patients

Machine Elf

References

External links

Terence McKenna Land at Deoxy.org

Terence McKenna at Levity.com

Erowid's Terence McKenna Vault

Botanical Dimensions

Rotten.com bio

FloatingWorldWeb's McKenna Pages

Terence McKenna's Last Trip 2000 Wired Magazine article by Erik Davis

"Mind contagions" (2001) at disinfo.com

Psychedelics, Evolution & Fun 2008 essay by Patrick Lundborg

Machine Elves 101, or Why Terence McKenna Matters - Reallity Sandwish by Daniel Moler

Transcription from 1991 interview regarding cannabis

Audio and video resources

Terence McKenna's interview Conducted by John Hazard in October 1998

Audio and video archive at Deoxy.org

Terence McKenna media archive at EROCx1.com

FutureHi.net MP3 Downloads - Terence McKenna, Albert Hoffman, Robert Anton Wilson, and more

McKenna at the 1999 Entheobotany Seminar - Audio Podcast

Psychedelics in the Age of Intelligent Machines - Video samples from the 1999 DVD

McKenna Video on FloatingWorldWeb - McKenna Video Portal

Over 100 podcasts of Terence McKenna talks - Audio Podcast

Transcripts

MindofMcKenna - McKenna Audio Excerpts, Transcriptions and Quotes

Category:2012 theorists Category:Deaths from brain cancer Category:Cancer deaths in Hawaii Category:Psychedelic drug advocates Category:Psychedelic researchers Category:American cannabis activists Category:American book and manuscript collectors Category:Contemporary philosophers Category:Counterculture festivals activists Category:1946 births Category:2000 deaths Category:American anarchists Category:Philosophers of science Category:Western mystics Category:Ethnobotanists Category:Religious skeptics

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