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Ketamine
C H A P T E R
74 Ketamine Jan Copeland, Paul Dillon National Cannabis Prevention and Information Centre, University of New South Wales, Sydney, NSW, Australia
O U T L I N E Introduction
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History of Ketamine
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Ketamine-Related Morbidity Urological and Upper Gastrointestinal Effects
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Ketamine Dependence
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Pharmacological and Toxicological Effects of Ketamine
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Public Health Issues Associated with Ketamine Use 739
Patterns of Use
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Effects of Ketamine Key Psychoactive Effects of Ketamine Psychosis Depression Teratogenic Effects Safety Profile
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The Legal Status of Ketamine Australia Canada China Mexico Netherlands United Kingdom United States
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Therapeutic Value of Ketamine in Humans
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Summary
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Ketamine-Related Mortality
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INTRODUCTION Ketamine is a short-acting, noncompetitive N-methyl(NMDA) receptor antagonist that acts as a dissociative anesthetic with analgesic and amnestic properties. It has been used for humans and animals since the 1960s and its first reported use as a recreational drug was in the early 1980s. Both popular and research accounts indicate that the recreational use of ketamine has widened in the context of nightclubs, dance parties, and raves. Clinicians and researchers noted that some nonmedical users sought dissociative, hallucinatory experiences. By the end of the 1970s, the United States Food and Drug Administration (FDA) was becoming D-aspartate
Principles of Addiction, Volume 1 http://dx.doi.org/10.1016/B978-0-12-398336-7.00074-7
concerned about the sale of ketamine on the street. By the early 1980s a wide range of unauthorized preparations were available in the United States including capsules, powder, crystals, tablets, and solutions, in addition to the authorized injectable forms. Solutions sold on the street in the United States have gone by many names such as K, Kay, Jet, Super Acid, 1980 Acid, with powders known as Green, Purple, Mauve, Special LA Coke, Super C, and K. Other street names have included Vitamin K and most recently, Special K. Ketamine is available as a liquid, pill, or powder, and can therefore be snorted, swallowed, smoked, or injected. It is typically snorted in measures known as bumps. Bumps are small snorts usually measured by
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a tiny spoon provided within the lid of the container in which it is purchased.
HISTORY OF KETAMINE Ketamine hydrochloride is marketed as a shortacting, general anesthetic for human and veterinary use. Reports have indicated that ketamine, or Special K as it is also known, is being used in social rather than medical and scientific settings in many parts of the world. It was first synthesized by Calvin Stevens in 1962. Early clinical studies on ketamine with human volunteers found it to be more effective and shorter acting than phencyclidine (PCP), with fewer emergence symptoms and less toxicity. The drug was first manufactured in the United States in the 1960s as Ketalar. It was described as a dissociative anesthetic with analgesic and amnesic actions. Use of ketamine as a surgical anesthetic escalated when it gained popularity on the battlefields of Vietnam. It was promoted as a dissociative anesthetic because of its ability to induce a lack of responsive awareness, not only to pain but also to the general environment. It is believed that the drug selectively interrupts association pathways of the brain before producing somesthetic (the consciousness of having a body) sensory blockade.
PHARMACOLOGICAL AND TOXICOLOGICAL EFFECTS OF KETAMINE Ketamine is 2(2-chlorophenyl)-2-(methylamino)-cyclohexanone, an arylcycloalkylamine. It is structurally related to PCP and cyclohexamine. Ketamine is a noncompetitive NMDA receptor antagonist that interferes with the action of excitatory amino acids including glutamate and aspartate. It occurs in racemic form and also as an S enantiomer. Ketamine is manufactured by the chemical industry for use in pharmaceutical products using the precursors cyclopentyl bromide, o-chlorobenzontrile, and methylamine. Due to the complicated multistep synthesis, and the difficulty of obtaining the necessary precursors and numerous solvents and reagents, ketamine sold illicitly for recreational use appears to be mostly obtained by diversion of legitimate supplies of either the bulk drug or its pharmaceutical preparations. Ketamine has a plasma half-life of 2–4 h. It is highly lipid soluble and has a distribution half-life of approximately 7–11 min. Ketamine is metabolized in the liver within the cytochrome P450 system with formation of water-soluble conjugates. Some of the metabolites, namely norketamine, have some potency but do not
penetrate the central nervous system sufficiently to cause hypnosis. Ketamine is typically administered in doses of 1–2 mg kg 1 intravenously over 1–2 min or 4–5 mg kg 1 intramuscularly. Studies of the pharmacokinetics of ketamine report similar plasma concentration profiles for the same dose administered orally, sublingually, and in suppository preparations with nasal preparations having the highest relative concentration of the noninjecting routes of administration. While ketamine has analgesic effects it is not reversed by naloxone. The synthetic alpha2-adrenergic antagonist, atipamezole hydrochloride, is used in veterinary medicine to reverse the effects of medetomidine and ketamine anesthetics in a range of animals. There are no reports of its use in humans. At this stage, therefore, there is no agent available to reverse the effects of ketamine in humans.
PATTERNS OF USE That ketamine-related data are not individually reported in the World Drug Report epidemiology of illicit drug use is testimony to its low level of use in general populations of most participating countries. It was not reported in the triennial Australian National Drug Strategy Household Survey until 2004. That year, 0.3% reported having used ketamine in the previous 12 months, compared with 0.2% in the 2007 survey. In the latter survey, the average age of initiation was 24.0 years (23.8 males; 24.3 females). The typical use pattern was once or twice a year (51.1%) but 6% used ketamine between daily and weekly. The other drugs most commonly reported as being used concurrently with ketamine were alcohol (73.5%), sildenafil citrate (ViagraÒ ) (53.6%), and cannabis (24%). In 1994, however, ketamine was listed in the Australian Illicit Drug Report for the first time. This is an Australian national annual survey of injecting drug users. An additional annual survey of regular ecstasy users has reported a decline between 2003 and 2009 from 26% of participants reporting having used ketamine in the previous six months in 2003 to only 10% in 2009. The British Crime Survey shows that less than half of 1% of all respondents reported the use of ketamine in 2007–08, and that there was no statistically significant change in this figure compared to the previous year. Surveys of nightclub patrons in the United Kingdom, however, have reported an increase in ketamine use from 25 to 40% from 1999 to 2003. A study in 2009 found increased use in 9 out of 20 studied areas (London, Birmingham, Newcastle, Ipswich, Bristol, Blackpool, Portsmouth, Nottingham, and Sheffield) and that ketamine users were experimenting with stronger doses, including injecting the drug.
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EFFECTS OF KETAMINE
One of the few population level data collections to include ketamine is the US Monitoring the Future Study, an ongoing study of the behaviors, attitudes, and values of American secondary school students, college students, and young adults. The 2009 trends for 12th graders reported a reduction in annual ketamine use from a peak of 2.6% in 2002 to 1.7% in 2009. The use of ketamine in Asia appears to be relatively more common. A Taiwanese study reported that ketamine was detected in 47% of the urine samples obtained from a study of those attending rave parties but in only 2% of the urine of police detainees. A recent study of drugged drivers involved in nonfatal driver casualties in Hong Kong reported that ketamine was the most commonly detected substance, being found in 45% of participants. In Shanghai and neighboring cities, ketamine was more frequently detected (0.03%) than 3,4-methylenedioxymethamphetamine (MDMA) (0.1%) in the serum of drivers involved in motor vehicle accidents and traffic violations. The most recent Drug Abuse Warning Network report on trends in drug-related emergency department visits for 1994–2001 reports a 3474% increase in the number of drug mentions for ketamine from 19 in 1994 to 679 in 2001. More recently, from 2005 to 2008, the number has stabilized to between 300 and 344 ketamine mentions per year.
EFFECTS OF KETAMINE Ketamine has systemic effects on a number of organ systems. The predominant effect of ketamine on the cardiovascular system is thought to be due to decreased catecholamine reuptake leading to increase in arterial blood pressure and cardiac output 2–4 min after intravenous injection and 10–20 min after intramuscular injection. A recent study has reported that ketamine reduces left ventricular systolic and diastolic functions among those with ischemic heart disease. Ketamine may cause an increase in cerebral blood flow, oxygen consumption, and intracranial pressure. Animal studies, however, have demonstrated a marked neuroprotective effect, mediated by antagonism of the NMDA channels on central neurons, and may have promise in the future management of cerebrovascular accidents. Upper airway reflexes are usually maintained when ketamine is administered in addition to bronchodilation. Apnea has been seen with ketamine use but is generally associated with rapid and/or large intravenous doses. Additional effects are seen in the gastrointestinal tract (increased salivation), the immune system (a significant reduction in leukocyte activation during sepsis), and the eyes (initial rise in intraocular pressure,
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eye movements throughout surgery, and preservation of the corneal reflex).
Key Psychoactive Effects of Ketamine In one of the earliest studies of the recreational use of ketamine, it was reported that the drug was viewed by most of the users in the study as a safe, potent hallucinogen with a short duration of action and an equal balance between positive and negative effects. Selfadministration was titrated to achieve the desired amount of dissociative sensations, hallucinations, and transcendental experiences. Respondents reported ataxia, slurring of speech, dizziness, mental confusion, blurred vision, anxiety, hyperexcitability, and insomnia, amongst other effects. In a later study that examined the subjective effects of ketamine, seven male volunteers were given between 5 and 12 doses of ketamine intermittently over a period of 18 months. They used approximately 10–25% of the anesthetic dose, believing this to reflect the dose level that occurs during the emergence period. The authors describe a series of phenomena experienced by most of the participants: a sensation of light throughout the body; novel experiences concerning body consistency (e.g. feeling as though they are made from wood or plastic); grotesquely distorted shape or size of body parts; sensation of being weightless and floating or hovering; colorful visions (including geometric patterns and figures); absence of sense of time; sudden insights into the nature of the existence or the self; strong feelings of association with others in the environment; and outof-body experiences. Subsequent studies of the psychedelic effects of ketamine in healthy volunteers have reported that these effects are dose related. Anecdotal evidence indicates that many users of other club drugs have hesitated to use it, due to either bad personal experiences or horror stories relayed to them by others. Some users may describe visits to the K hole or K ride as it is known in Asia, as a place referring to where users are when under the influence of ketamine. The K-hole experience appears to vary with the individual, but six main categories of mental effects produced by ketamine have been identified: the perception of contact with aliens; the perception of entry into information networks; access into alternative realities; personal and creative problem solving; out-of-body near-death states; and tantra-like enhancement of sexual activity. Ketamine can sometimes reproduce the features of a near-death experience (NDE), including buzzing/ ringing/whistling sounds at the beginning, travel through a dark tunnel into light at a high speed, the conviction that one is dead, apparent telepathic communion with God, intense visions, and out-of-body
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experiences. A survey of 50 ketamine users who reported experiencing an NDE reported that it typically occurred in their first few occasions of use with the most frequently noted features being altered perception of time (90%), strong sense of detaching from their own body (88%), and a sense of peace and joy (76%). It should be noted that an NDE induced by ketamine does not necessarily mean that the person is physically near death.
of antidepressant treatments. A small study of those with diagnosed major depression reported robust decrease in depressive symptoms, emerging progressively over 3 days, following low-dose ketamine infusion. There are studies currently being conducted in the United States on the use of ketamine as treatment for bipolar disorders.
Teratogenic Effects Psychosis The role of the NMDA neurotransmitter system in relation to psychosis is not completely understood, however, pharmacological, postmortem, and clinical studies have implicated the NMDA system has been implicated in the pathophysiology of schizophrenia. The psychotic states induced by NMDA antagonists such as ketamine have been described as being similar to schizophrenia. The hallucinogenic effect of ketamine arises, at least in part, from its capacity to disrupt thalamocortical gating of external and internal information to the cortex. Deficient gating of sensory and cognitive information is thought to result in an overloading inundation of information and subsequent cognitive fragmentation and psychosis. Animal studies have shown that treatment with ketamine leads to an increase in D2 receptor binding in the hippocampus and a decrease in glutamate receptor binding in the frontal cortex with no change in D1 receptor binding. The density of dopamine receptors was increased in the striatum and 5hydroxytryptamine transporters were increased in the striatum, the hippocampus, and the frontal cortex. Laboratory studies of subanesthetic doses of ketamine in humans report that it produces behaviors similar to the positive (e.g. hallucinations and thought disorder) and negative (e.g. detachment, amotivation, and blunted affect) symptoms of schizophrenia, elicits alterations in perception, impairs performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test, evokes symptoms similar to dissociative states, and preferentially disrupts measures of frontal lobe function such as delayed word recall, sparing immediate recall, and postdistraction recall. Ketamine also exacerbates the core psychotic symptoms in patients with schizophrenia and is not blocked by antipsychotic drugs such as haloperidol. As a result ketamine is a useful model of schizophrenia and is being used to increase our understanding of the illness and to develop new treatments.
Depression A growing body of preclinical research implicates the NMDA class of glutamate receptors in the pathophysiology of major depression and the mechanism of action
Ketamine crosses the placenta easily and concentrations in the fetus are approximately equal to those of the mother. There is accumulating evidence from in vitro and in vivo experiments that suggests that tonic stimulation of NMDA receptors is vital for the survival of developing nerve cells. The NMDA receptor can be pharmacologically blocked by drugs such as alcohol and ketamine, among other drugs. This alters the glutamate and g-aminobutyric acid (GABA) transmission that suppress neuronal activity and cause neuronal death in the developing brain. While there are no human studies, animal studies suggest that the duration of ketamine exposure in 7-day-old rat pups increases neuronal degeneration of the developing rat brain.
Safety Profile Ketamine has a wide margin of safety. The predominant adverse reaction is emergence phenomena post anesthetic for which the risk factors are age, female gender, noisy environment during recovery, prior personality disorders, and excessive dreaming. The experience of emergence phenomena is not associated with dose. Other side effects include a transient rash predominantly on the face and neck, and nausea and vomiting. A reasonably conservative safety ratio of 35 for snorted ketamine and a somewhat higher margin for oral administration has been reported.
THERAPEUTIC VALUE OF KETAMINE IN HUMANS Ketamine has broad areas of application and is a rapidly acting, relatively safe parenteral analgesic and anesthetic agent that has been in clinical use for more than three decades. It is the only injectable anesthetic that induces increase in arterial pressure and heart rate. Although the respiratory and pharyngeal reflexes are sometimes momentarily depressed after injection of substantial quantities, they are usually maintained during the period of unconsciousness. The drug is therefore suitable for short anesthetic and surgical procedures especially in the absence of a trained anesthetist, although the latest Parke-Davis data sheet stresses that
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KETAMINE-RELATED MORBIDITY
a trained professional should be present, together with resuscitation equipment. It is particularly useful in developing countries and remote country areas where a doctor may be working alone. The major concern is the emergence phenomena. Psychic disturbances after ketamine anesthesia have been reported to occur in about 15–40% of adult cases, depending to some extent on how these terms are defined. Other drugs, such as diazepam, lorazepam, and propofol, have been given together with ketamine in an attempt to reduce or abolish these phenomena, with some success. Psychological techniques are also effective in reducing complaints. The emergence phenomena have led to less medical use than was originally anticipated, but ketamine is still to be found in many general hospitals in most countries. It is also currently widely used in veterinary medicine. A number of clinical uses of ketamine have been suggested. Ketamine appears to be best used in the young (less than 10 years old) and the old (over 60 years) as these groups have reported fewer emergence reactions (Radford, 1996). Recent studies have confirmed the effectiveness of ketamine in a variety of pediatric and diagnostic procedures via caudal or intramuscular routes of administration. In addition to anesthesia and sedation, ketamine is used as an analgesic for acute postoperative pain, painful procedures, and more controversially for chronic or neuropathic pain. Analgesic doses of ketamine have been associated with dose-related declines in mood, conscious perception, and intellectual performance. Recent studies also report the successful use of patient controlled analgesia with morphine and ketamine following spinal and hip surgery in adults. An early stage descriptive study of the use of topical ketamine in the management of postherpetic neuralgia suggests it shows promise in the management of this painful condition. Ketamine has also been used as an experimental treatment for complex regional pain syndrome, which is a severe, chronic pain condition characterized by sensory, autonomic, motor, and dystrophic signs and symptoms. The treatment involves one or two cycles of a 10-day, inpatient intravenous infusion for 4 h daily in high doses. While there have been promising findings, the studies to date have been open label and the evidence base is yet to be developed. There is mixed evidence on the effect of ketamine on epilepsy and seizure disorders. Ketamine has been reported as both a pro- and anticonvulsant. Recently, ketamine has been recommended for use with electroconvulsive therapy as it has been shown to prolong seizure duration with more rapid posttreatment reorientation. A larger body of evidence, however, suggests that it displays anticonvulsant and neuroprotective
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properties but should be used with caution over prolonged periods of time. Studies conducted in the 1950s and 1960s suggested that psychedelic drug-assisted psychotherapy might be an effective treatment for alcohol dependence. In the 1990s, these findings were used as a partial basis for ketamine-assisted treatment of alcohol dependence. This is known as ketamine psychedelic therapy (KPT). The same author reports on the use of ketamine psychotherapy for heroin addiction, where dose was found to be related to treatment outcome at 2 years. These are controversial treatments that are yet to be used outside Russia. In the current environment of growing concern about bioterrorism, the neuroprotective and antiepileptic activities of ketamine have led to suggestions that it may be a useful tool in the management of nerve agent poisoning such as sarin.
KETAMINE-RELATED MORTALITY There are very few deaths by pure ketamine overdose recorded (i.e. not also involving a drug such as alcohol). Of 87 ketamine-linked deaths in New York City, none was purely due to the use of ketamine. Parke-Davis have reported that there are cases of accidental injections with ten times the amount required for surgery, with no obvious lasting effects. The principal physical dangers of most nonmedical uses are currently believed to arise mainly from the setting, or an interaction between the user and the setting of use, as ketamine can leave the user in a confused state. This can, for example, result in burns, falls (sometimes fatal), drowning, death by hypothermia from lying outside in winter, traffic accidents, and becoming a crime victim (e.g. drug rape). A recent paper reported the case of an emergency medical technician who died of a combination of asphyxia and intoxication with administered intravenous ketamine in an autoerotic accident. There are two reports in the literature of deaths by pure ketamine overdose. One described as a homicide for homosexual ends. The other described a middleaged woman who took the drug daily for 7 months.
KETAMINE-RELATED MORBIDITY There is an extensive list of possible physical effects of ketamine that may be seen as adverse by the user, or that may be directly harmful. Some of those of principal concern in a nonmedical use context are difficulty with walking and balance resulting in falls, numbness, slurred speech, dizziness, visual problems, nausea, headaches, spasms, and twitches. A recent study found
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that, consistent with the animal studies, frequent ketamine use produces long-lasting impairments in episodic memory and aspects of retrieval from semantic memory even when other drug use is taken into account. A later study reported that when retested 3–4 years later following significant reductions in levels of ketamine use, semantic memory impairments associated with ketamine use were reversible. The effects upon schizotypal symptoms and perceptual distortions may, however, persist. The use of ketamine has been linked with a range of unpleasant mental effects including anxiety, panic attacks, flashbacks, posttraumatic stress disorder, persistent perceptual changes, mania, depression, suicide, insomnia, nightmares, night terrors, an unpleasant feeling of being unreal or that the world is unreal, paranoid delusions, persistent hallucinations, automatic behavior, and fragmentation of the personality and aggression. A study of 23 recreational users noted a high incidence of flashbacks and attentional dysfunction, but exactly what was meant by flashbacks is not defined. Large anesthetic studies do not confirm the finding and generally conclude that ketamine is usually devoid of significant persistent effects once the drug and its metabolites have cleared the body. For example, in a study of 1400 patients given ketamine as an anesthetic for surgical procedures, three had prolonged hallucinations, none lasting beyond 3 weeks. In no case did hallucinations begin after a period of normality, which is integral to the World Health Organisation (1992) definition of flashbacks. A 2009 study of the consequences of chronic selfadministration on the neurocognitive function and psychological well-being involved 150 individuals. The study over a period of 1 year compared levels of ketamine use frequency (frequent ketamine users, infrequent ketamine users) with abstinent users, polydrug using controls, and drug-free controls. Among frequent ketamine users, increasing use was correlated with decreasing cognitive performance as measured by spatial working memory and pattern recognition memory tasks. Assessments of psychological well-being also showed greater dissociative symptoms among frequent users and a dose–response effect on delusional symptoms. Until recently, there had only been reports that ketamine could cause toxic changes in the rat brain. A Chinese study of 41 ketamine-dependent individuals compared with 44 healthy controls found white matter changes associated with ketamine use in the bilateral frontal and left temperoparietal cortices. These changes were correlated with the severity of ketamine use. These findings suggest a microstructural basis for the changes in cognition and experience observed among those using ketamine for prolonged periods. The similarities
of these changes to those observed in chronic schizophrenia, moreover, have implications for the glutamate model of the illness. The use of ketamine with other neurotoxic drugs like alcohol is an additional cause for concern.
Urological and Upper Gastrointestinal Effects A number of series of case reports have recently identified physical health consequences of ketamine use. A review of 233 ketamine-related presentations to 15 Hong Kong emergency departments reported that the most common presenting symptoms were impaired consciousness (45%), abdominal pain (21%), lower urinary tract symptoms (12%), and dizziness (12%). A retrospective study of 64 heavy ketamine users explored the effects on the upper gastrointestinal tract. When those with other gastrointestinal conditions were excluded, 37 participants were studied. Of these, 28 (75.7%) reported upper gastrointestinal symptoms including epigastric pain and vomiting. It was further reported that despite medications, symptoms tended to persist unless ketamine use ceased. A more concerning consequence of ketamine use that has been newly identified is so-called ketamine bladder syndrome, which was first described in 2007. Clinicians from Canada described nine patients who were daily ketamine users and who presented with severe dysuria, frequency, urgency, and gross hematuria. At cystoscopy, all patients had severe ulcerative cystitis. Clinicians in Hong Kong reported a similar presentation of ten street ketamine users diagnosed with ulcerative cystitis. This unwanted effect of ketamine has also been reported among pediatric patients in less than 2 weeks after commencing use for chronic pain. The largest study to date was conducted in Hong Kong and reports on 59 ketamine users with moderate to severe lower urinary tract symptoms. Patients had frequency rates from 15 to 90 min between voids. Functional voiding capacity was between 20 and 200 ml, which represents a dramatic decrease in bladder capacity. Upon cystoscopy, 71% of these patients showed various degrees of bladder mucosal inflammation similar to that seen in interstitial cystitis. Histological examination showed a largely denuded bladder epithelium and granulation of the lamina propria infiltrated by lymphocytes and eosinophils. Most patients showed detrusor over activity at very low bladder infusion volumes. Even more concerning is the documentation of severe kidney effects among these individuals, where 51% showed unilateral or bilateral hydronephrosis on renal ultrasonography and 7% had features suggestive of papillary necrosis. Similar case series are now being reported in the United Kingdom and other regions of China.
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PUBLIC HEALTH ISSUES ASSOCIATED WITH KETAMINE USE
The urologists treating this disabling condition have also reported on the apparent difficulty their patients experienced in abstaining from ketamine use. A group in Taipei reported that of ten consecutive patients with ketamine bladder syndrome, where clear advice and multidisciplinary support was provided to cease their ketamine use, at 12 months follow-up only 3 had been able to do so successfully.
KETAMINE DEPENDENCE There is a substantial amount of popular literature describing ketamine as having a marked potential for giving rise to nonphysical dependence and case studies in the medical literature are accumulating. Many of these early reports of ketamine dependence were among those with access to the drug such as anesthetists and veterinarians. The Australian National Minimum Dataset of Clients of Specialist Drug and Alcohol Treatment Services records no identified episodes of care for ketamine as the principal drug of concern in its collection over the past decade. The comparable dataset in the United States reported a total of 229 mentions in 2006 where in only 82 was ketamine the primary drug of concern. While this appears to indicate that ketamine is either used by only a small number of individuals or that it is unlikely to cause dependence sufficient to drive treatment seeking, it may be that, as there is no evidencebased intervention for ketamine-related problems, that they are not admitted to treatment services. There is evidence from animal studies to support the view that ketamine can give rise to a dependence syndrome without physical withdrawal phenomena. This resembles cocaine dependence without the crash after use. Ketamine is also self-administered in rats and nonhuman primates. A recent Australian study of 100 recreational ketamine users found that around one in five (22%) of participants reported physical tolerance to ketamine. This is consistent with reports of tolerance to ketamine following multiple anesthetics. There have been at least two reported case histories of inpatient withdrawal from ketamine with observed psychotic symptoms. One case also included reports of a number of previously experienced ketamine withdrawal symptoms such as chills, autonomic arousal, lacrimation, restlessness, nightmares, and psychological craving with ketamine being used to relieve the symptoms. There is no research literature on the management of ketamine abuse or dependence. Case histories of ketamine withdrawal report the use of benzodiazepines for the management of anxiety and insomnia and vitamin supplements. There are some generic
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descriptions of potentially useful interventions that suggest an abstinence-oriented approach similar to that used for psychostimulants.
PUBLIC HEALTH ISSUES ASSOCIATED WITH KETAMINE USE In 1980, nonmedical unauthorized experimentation with ketamine was first reported in Australia. The authors believed that use of the drug was largely confined to medical circles. Since that time, anecdotal evidence indicates that the nature of users has become much more varied. In Australia, ketamine is often marketed in small glass vials with small spoons to measure accurate doses. The spoon is contained in the cap of the bottle, much like a snuff spoon. Other bottles have a self-contained measurer in the cap, which when turned over leaves a measured amount, which can then be snorted as bumps; very few ketamine users snort the drug in lines. This may result in lower doses per snort than its use in lines as is seen more commonly internationally. The effects of differing methods of insufflation on health outcomes have not been examined. Ketamine appears to be obtained from the diversion of legitimate supplies (veterinarians and pharmaceutical companies) or is imported from overseas. Ketamine can be bought over the counter in some Asian countries. Ketamine sold illicitly is often converted from a liquid form to a powder utilizing a simple evaporation process. The liquid ketamine is dried in a variety of ways (microwave oven or sun-dried) until a residue remains. This crystal residue is ground into a powder, leaving a fine powdery material similar to cocaine and heroin. In this form, it is far more convenient and more marketable than the injectable drug. Evidence from the United States indicates that, up until 1996, ketamine was usually not adulterated with other substances. Of all the ketamine submissions to the US Drug Enforcement Agency (DEA) regional laboratories in that period, there was only one instance of this type of dilution recorded. However, this situation may well have changed when price and demand rose sufficiently to make such practices profitable. Both popular and research accounts indicate that the recreational use of ketamine has widened in the context of nightclubs, dance parties, and raves. This has caused concern as ketamine is an anesthetic. One study concluded that it was totally inappropriate to use ketamine as a dance drug. The reasons for this were factors such as set and setting, the rapid onset of the drug, and the intensity of the experience as a whole. The respondents believed that using ketamine in a noisy, busy, or crowded environment was potentially dangerous and
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that use should be confined to a familiar and secure place, such as one’s home. All users had been unprepared for the intensity and nature of the effects when they first used the drug. In a study of the toxic effects of club drugs, it was concluded that the “single most risk-producing behavior of club drug users is combining psychoactive substances, usually involving alcohol.” The use of ketamine and other party or club drugs is reportedly associated with an increased incidence of unsafe sex among gay men on the circuit party scene in the United States. This is clearly a public health issue in the spread of blood-borne viruses and other sexually transmitted diseases. A small study of high-risk youth injecting ketamine in New York City also reported that its use was associated with a range of high-risk injection practices such as group injection with shared paraphernalia. Recent surveys among this sentinel group, however, have shown declines in the levels of ketamine (and other drug use) between 2002 and 2007. An Australian study reported a number of ketaminerelated problems among their sample of nonmedical ketamine users. While only one in five stated that they had ever experienced severe side effects as a result of ketamine use, more than one-third (38%) reported having to deal with someone else who had suffered badly following ketamine use. More than half (58%) of those interviewed had experienced the K hole and this was related to increased exposure to the drug – having used more than 20 times. The most commonly reported problems were employment related (20%). These included vagueness affecting work performance and lesser volume of work being produced. Additional problems reported included relationships (5%), financial (5%), and legal (1%). Of the five participants reporting relationship problems, none also reported financial problems but three of the five also reported work-related problems. Twenty-two participants reported at least one problem, five reported two problem areas, and one reported three problems areas. Ketamine has been sold in the rave scene in the United Kingdom as a key component in fake MDMA (ecstasy) tablets. There are also reports of ketamine being sold as ecstasy in Australia, or used as a cutting agent in other drugs such as cocaine, amphetamines, and heroin.
THE LEGAL STATUS OF KETAMINE Ketamine is scheduled in many jurisdictions. Below are some examples of the legal status of ketamine internationally.
status of ketamine in a number of key jurisdictions. Within Australia prior to December 2003 ketamine was a scheduled drug in New South Wales under the Poisons and Therapeutic Goods Act, which meant that there were strict regulations on the sale and distribution of the substance. In response to increasing trends in ketamine use, the government added it to the list of prohibited drugs in New South Wales. This means that it has now been listed under the Drug Misuse and Trafficking Act 1985, ensuring that tougher penalties are in place for dealing with its illicit use. New penalties for those caught manufacturing or supplying the drug include fines between AU$5500 and AU$550 000 and anywhere from 2 years to life imprisonment or both. These penalties particularly apply to veterinary and medical practitioners who have an authority to purchase ketamine for legitimate purposes and then supply it to others for illicit use. Similar laws apply in some other states of Australia, however, in other states it remains legal to possess ketamine.
Canada Ketamine is Schedule 1 in Canada, pursuant to a February 2004 notice that it “is an analog of phencyclidine (PCP), and is, therefore, captured as item 14 in Schedule I of the CDSA and item 14 in the Narcotic Control Regulations (NCR).” Affected researchers were expected to have complied with the Schedule 1 protocol for the handling of ketamine by August 31, 2005.
China Ketamine is a Class II psychiatric drug; trade is limited to licensed wholesalers and retail sales are prohibited. In July 2004, the state of Sichuan placed ketamine in Class I; other provinces are expected to follow suit.
Mexico Ketamine is a Category 3 drug under Mexico’s General Health Law; Category 3 drugs “have a therapeutic value but constitute a problem for the public health.” Medicines Administration Regulations restricts the acquisition of ketamine to licensed veterinarians only and sets strict rules regarding the management and follow-up of the products.
Australia
Netherlands
Ketamine is scheduled differently within and between countries. Below is a brief overview of the legal
Ketamine is treated as a medication and is not in List 1 or 2 in the Netherlands.
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FURTHER READING
United Kingdom
List of Abbreviations
Prior to January 1, 2006, ketamine was not controlled in the United Kingdom under the Misuse of Drugs Act, making it legal to possess. However, sales and distribution were controlled under the Medicines Act making it illegal to sell or distribute without a license. Ketamine became a Class C drug on January 1, 2006, following a 2004 report to government that recommended moving ketamine into Class C.
NDE near-death experience NMDA N-methyl-D-aspartate PCP phencyclidine
United States Ketamine was unscheduled until August 1999. In early July 1999, the DEA added ketamine to Schedule III with an emergency ruling that took effect on August 12, 1999. It is now a federal offense to possess ketamine in the United States without a license or prescription. Since that time, ketamine has been scheduled in many individual states, and laws are pending in many more. Where ketamine is not scheduled in a specific state, all prosecutions for possession or sales occur at the federal level.
SUMMARY In conclusion, as levels of ketamine in the general population appear to be very low, the harms reported by recreational users are not excessive, adulteration is rare, and the mortality rate is low. Ketamine does not appear to pose a risk to public health at this time. At the individual level, many of those who experiment find the effects aversive and do not persist. The harms that require further investigation are the association with unsafe sex and injecting behaviors, the neurotoxic effects, and use in situations where there is a heightened risk of accidental death when the user’s cognition is grossly impaired. It is recommended that the usual harm minimization strategies; especially not to use the drug when alone, not to concurrently use other neurotoxins such as alcohol, to be in a physically safe environment, and to use safer injecting techniques; should be observed when using ketamine.
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Glossary Bumps bumps are a measure of ketamine that is a small snort usually measured by a tiny spoon provided within the lid of the container in which it is purchased. K hole this is a slang term for a state of dissociation from the body that may mimic the phenomenology of schizophrenia. The K-hole experience appears to vary with the individual and includes intense hallucinations and perceptual distortions.
Further Reading Adler, C.M., Malhotra, A.K., Elma, I., Goldberg, T., Egan, M., Pickar, D., et al., 1999. Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. American Journal of Psychiatry 156 (10), 1646–1649. Bowdle, T.A., Radant, A.D., Cowley, D.S., et al., 1998. Psychedelic effects of ketamine in healthy volunteers. Anesthesiology 88 (1), 82–88. Curran, H.V., Monaghan, L., 2001. In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction 96, 749–760. Curran, H.V., Morgan, C., 2000. Cognitive, dissociative and psychogenic effects of ketamine in recreational users on the night of drug use and 3 days later. Addiction 95 (4), 575–590. Dillon, P., Copeland, J., Jansen, K., 2003. Patterns of use and harms associated with non-medical ketamine use. Drug and Alcohol Dependence 69, 23–28. Dotson, J.W., Ackerman, D.L., West, L.J., 1995. Ketamine abuse. Journal of Drug Issues 25 (4), 751–757. Jansen, K.L.R., 2001. Ketamine, Dreams and Realities. Multidisciplinary Association for Psychedelic Studies, Florida. Morgan, C.J.A., Monaghan, L., Curran, H.V., 2004. Beyond the K-hole: a 3-year longitudinal investigation of the cognitive and subjective effects of ketamine in recreational users who have substantially reduced their use of the drug. Addiction 99 (11), 1450–1461. Vollenweider, F.X., Kometer, M., 2010. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience 11, 642–651. Weiner, A.L., Vieira, L., McKay, C.A., Bayer, M.J., 2000. Ketamine abusers presenting to the emergency department: a case series. Journal of Emergency Medicine 18 (4), 447–451. White, J.M., Ryan, C.F., 1996. Pharmacological properties of ketamine. Drug and Alcohol Review 15 (2), 145–155.
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74 Ketamine Jan Copeland, Paul Dillon National Cannabis Prevention and Information Centre, University of New South Wales, Sydney, NSW, Australia
O U T L I N E Introduction
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History of Ketamine
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Ketamine-Related Morbidity Urological and Upper Gastrointestinal Effects
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Ketamine Dependence
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Pharmacological and Toxicological Effects of Ketamine
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Patterns of Use
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Effects of Ketamine Key Psychoactive Effects of Ketamine Psychosis Depression Teratogenic Effects Safety Profile
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The Legal Status of Ketamine Australia Canada China Mexico Netherlands United Kingdom United States
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Therapeutic Value of Ketamine in Humans
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Summary
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INTRODUCTION Ketamine is a short-acting, noncompetitive N-methyl(NMDA) receptor antagonist that acts as a dissociative anesthetic with analgesic and amnestic properties. It has been used for humans and animals since the 1960s and its first reported use as a recreational drug was in the early 1980s. Both popular and research accounts indicate that the recreational use of ketamine has widened in the context of nightclubs, dance parties, and raves. Clinicians and researchers noted that some nonmedical users sought dissociative, hallucinatory experiences. By the end of the 1970s, the United States Food and Drug Administration (FDA) was becoming D-aspartate
Principles of Addiction, Volume 1 http://dx.doi.org/10.1016/B978-0-12-398336-7.00074-7
concerned about the sale of ketamine on the street. By the early 1980s a wide range of unauthorized preparations were available in the United States including capsules, powder, crystals, tablets, and solutions, in addition to the authorized injectable forms. Solutions sold on the street in the United States have gone by many names such as K, Kay, Jet, Super Acid, 1980 Acid, with powders known as Green, Purple, Mauve, Special LA Coke, Super C, and K. Other street names have included Vitamin K and most recently, Special K. Ketamine is available as a liquid, pill, or powder, and can therefore be snorted, swallowed, smoked, or injected. It is typically snorted in measures known as bumps. Bumps are small snorts usually measured by
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Copyright Ó 2013 Elsevier Inc. All rights reserved.
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a tiny spoon provided within the lid of the container in which it is purchased.
HISTORY OF KETAMINE Ketamine hydrochloride is marketed as a shortacting, general anesthetic for human and veterinary use. Reports have indicated that ketamine, or Special K as it is also known, is being used in social rather than medical and scientific settings in many parts of the world. It was first synthesized by Calvin Stevens in 1962. Early clinical studies on ketamine with human volunteers found it to be more effective and shorter acting than phencyclidine (PCP), with fewer emergence symptoms and less toxicity. The drug was first manufactured in the United States in the 1960s as Ketalar. It was described as a dissociative anesthetic with analgesic and amnesic actions. Use of ketamine as a surgical anesthetic escalated when it gained popularity on the battlefields of Vietnam. It was promoted as a dissociative anesthetic because of its ability to induce a lack of responsive awareness, not only to pain but also to the general environment. It is believed that the drug selectively interrupts association pathways of the brain before producing somesthetic (the consciousness of having a body) sensory blockade.
PHARMACOLOGICAL AND TOXICOLOGICAL EFFECTS OF KETAMINE Ketamine is 2(2-chlorophenyl)-2-(methylamino)-cyclohexanone, an arylcycloalkylamine. It is structurally related to PCP and cyclohexamine. Ketamine is a noncompetitive NMDA receptor antagonist that interferes with the action of excitatory amino acids including glutamate and aspartate. It occurs in racemic form and also as an S enantiomer. Ketamine is manufactured by the chemical industry for use in pharmaceutical products using the precursors cyclopentyl bromide, o-chlorobenzontrile, and methylamine. Due to the complicated multistep synthesis, and the difficulty of obtaining the necessary precursors and numerous solvents and reagents, ketamine sold illicitly for recreational use appears to be mostly obtained by diversion of legitimate supplies of either the bulk drug or its pharmaceutical preparations. Ketamine has a plasma half-life of 2–4 h. It is highly lipid soluble and has a distribution half-life of approximately 7–11 min. Ketamine is metabolized in the liver within the cytochrome P450 system with formation of water-soluble conjugates. Some of the metabolites, namely norketamine, have some potency but do not
penetrate the central nervous system sufficiently to cause hypnosis. Ketamine is typically administered in doses of 1–2 mg kg 1 intravenously over 1–2 min or 4–5 mg kg 1 intramuscularly. Studies of the pharmacokinetics of ketamine report similar plasma concentration profiles for the same dose administered orally, sublingually, and in suppository preparations with nasal preparations having the highest relative concentration of the noninjecting routes of administration. While ketamine has analgesic effects it is not reversed by naloxone. The synthetic alpha2-adrenergic antagonist, atipamezole hydrochloride, is used in veterinary medicine to reverse the effects of medetomidine and ketamine anesthetics in a range of animals. There are no reports of its use in humans. At this stage, therefore, there is no agent available to reverse the effects of ketamine in humans.
PATTERNS OF USE That ketamine-related data are not individually reported in the World Drug Report epidemiology of illicit drug use is testimony to its low level of use in general populations of most participating countries. It was not reported in the triennial Australian National Drug Strategy Household Survey until 2004. That year, 0.3% reported having used ketamine in the previous 12 months, compared with 0.2% in the 2007 survey. In the latter survey, the average age of initiation was 24.0 years (23.8 males; 24.3 females). The typical use pattern was once or twice a year (51.1%) but 6% used ketamine between daily and weekly. The other drugs most commonly reported as being used concurrently with ketamine were alcohol (73.5%), sildenafil citrate (ViagraÒ ) (53.6%), and cannabis (24%). In 1994, however, ketamine was listed in the Australian Illicit Drug Report for the first time. This is an Australian national annual survey of injecting drug users. An additional annual survey of regular ecstasy users has reported a decline between 2003 and 2009 from 26% of participants reporting having used ketamine in the previous six months in 2003 to only 10% in 2009. The British Crime Survey shows that less than half of 1% of all respondents reported the use of ketamine in 2007–08, and that there was no statistically significant change in this figure compared to the previous year. Surveys of nightclub patrons in the United Kingdom, however, have reported an increase in ketamine use from 25 to 40% from 1999 to 2003. A study in 2009 found increased use in 9 out of 20 studied areas (London, Birmingham, Newcastle, Ipswich, Bristol, Blackpool, Portsmouth, Nottingham, and Sheffield) and that ketamine users were experimenting with stronger doses, including injecting the drug.
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EFFECTS OF KETAMINE
One of the few population level data collections to include ketamine is the US Monitoring the Future Study, an ongoing study of the behaviors, attitudes, and values of American secondary school students, college students, and young adults. The 2009 trends for 12th graders reported a reduction in annual ketamine use from a peak of 2.6% in 2002 to 1.7% in 2009. The use of ketamine in Asia appears to be relatively more common. A Taiwanese study reported that ketamine was detected in 47% of the urine samples obtained from a study of those attending rave parties but in only 2% of the urine of police detainees. A recent study of drugged drivers involved in nonfatal driver casualties in Hong Kong reported that ketamine was the most commonly detected substance, being found in 45% of participants. In Shanghai and neighboring cities, ketamine was more frequently detected (0.03%) than 3,4-methylenedioxymethamphetamine (MDMA) (0.1%) in the serum of drivers involved in motor vehicle accidents and traffic violations. The most recent Drug Abuse Warning Network report on trends in drug-related emergency department visits for 1994–2001 reports a 3474% increase in the number of drug mentions for ketamine from 19 in 1994 to 679 in 2001. More recently, from 2005 to 2008, the number has stabilized to between 300 and 344 ketamine mentions per year.
EFFECTS OF KETAMINE Ketamine has systemic effects on a number of organ systems. The predominant effect of ketamine on the cardiovascular system is thought to be due to decreased catecholamine reuptake leading to increase in arterial blood pressure and cardiac output 2–4 min after intravenous injection and 10–20 min after intramuscular injection. A recent study has reported that ketamine reduces left ventricular systolic and diastolic functions among those with ischemic heart disease. Ketamine may cause an increase in cerebral blood flow, oxygen consumption, and intracranial pressure. Animal studies, however, have demonstrated a marked neuroprotective effect, mediated by antagonism of the NMDA channels on central neurons, and may have promise in the future management of cerebrovascular accidents. Upper airway reflexes are usually maintained when ketamine is administered in addition to bronchodilation. Apnea has been seen with ketamine use but is generally associated with rapid and/or large intravenous doses. Additional effects are seen in the gastrointestinal tract (increased salivation), the immune system (a significant reduction in leukocyte activation during sepsis), and the eyes (initial rise in intraocular pressure,
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eye movements throughout surgery, and preservation of the corneal reflex).
Key Psychoactive Effects of Ketamine In one of the earliest studies of the recreational use of ketamine, it was reported that the drug was viewed by most of the users in the study as a safe, potent hallucinogen with a short duration of action and an equal balance between positive and negative effects. Selfadministration was titrated to achieve the desired amount of dissociative sensations, hallucinations, and transcendental experiences. Respondents reported ataxia, slurring of speech, dizziness, mental confusion, blurred vision, anxiety, hyperexcitability, and insomnia, amongst other effects. In a later study that examined the subjective effects of ketamine, seven male volunteers were given between 5 and 12 doses of ketamine intermittently over a period of 18 months. They used approximately 10–25% of the anesthetic dose, believing this to reflect the dose level that occurs during the emergence period. The authors describe a series of phenomena experienced by most of the participants: a sensation of light throughout the body; novel experiences concerning body consistency (e.g. feeling as though they are made from wood or plastic); grotesquely distorted shape or size of body parts; sensation of being weightless and floating or hovering; colorful visions (including geometric patterns and figures); absence of sense of time; sudden insights into the nature of the existence or the self; strong feelings of association with others in the environment; and outof-body experiences. Subsequent studies of the psychedelic effects of ketamine in healthy volunteers have reported that these effects are dose related. Anecdotal evidence indicates that many users of other club drugs have hesitated to use it, due to either bad personal experiences or horror stories relayed to them by others. Some users may describe visits to the K hole or K ride as it is known in Asia, as a place referring to where users are when under the influence of ketamine. The K-hole experience appears to vary with the individual, but six main categories of mental effects produced by ketamine have been identified: the perception of contact with aliens; the perception of entry into information networks; access into alternative realities; personal and creative problem solving; out-of-body near-death states; and tantra-like enhancement of sexual activity. Ketamine can sometimes reproduce the features of a near-death experience (NDE), including buzzing/ ringing/whistling sounds at the beginning, travel through a dark tunnel into light at a high speed, the conviction that one is dead, apparent telepathic communion with God, intense visions, and out-of-body
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experiences. A survey of 50 ketamine users who reported experiencing an NDE reported that it typically occurred in their first few occasions of use with the most frequently noted features being altered perception of time (90%), strong sense of detaching from their own body (88%), and a sense of peace and joy (76%). It should be noted that an NDE induced by ketamine does not necessarily mean that the person is physically near death.
of antidepressant treatments. A small study of those with diagnosed major depression reported robust decrease in depressive symptoms, emerging progressively over 3 days, following low-dose ketamine infusion. There are studies currently being conducted in the United States on the use of ketamine as treatment for bipolar disorders.
Teratogenic Effects Psychosis The role of the NMDA neurotransmitter system in relation to psychosis is not completely understood, however, pharmacological, postmortem, and clinical studies have implicated the NMDA system has been implicated in the pathophysiology of schizophrenia. The psychotic states induced by NMDA antagonists such as ketamine have been described as being similar to schizophrenia. The hallucinogenic effect of ketamine arises, at least in part, from its capacity to disrupt thalamocortical gating of external and internal information to the cortex. Deficient gating of sensory and cognitive information is thought to result in an overloading inundation of information and subsequent cognitive fragmentation and psychosis. Animal studies have shown that treatment with ketamine leads to an increase in D2 receptor binding in the hippocampus and a decrease in glutamate receptor binding in the frontal cortex with no change in D1 receptor binding. The density of dopamine receptors was increased in the striatum and 5hydroxytryptamine transporters were increased in the striatum, the hippocampus, and the frontal cortex. Laboratory studies of subanesthetic doses of ketamine in humans report that it produces behaviors similar to the positive (e.g. hallucinations and thought disorder) and negative (e.g. detachment, amotivation, and blunted affect) symptoms of schizophrenia, elicits alterations in perception, impairs performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test, evokes symptoms similar to dissociative states, and preferentially disrupts measures of frontal lobe function such as delayed word recall, sparing immediate recall, and postdistraction recall. Ketamine also exacerbates the core psychotic symptoms in patients with schizophrenia and is not blocked by antipsychotic drugs such as haloperidol. As a result ketamine is a useful model of schizophrenia and is being used to increase our understanding of the illness and to develop new treatments.
Depression A growing body of preclinical research implicates the NMDA class of glutamate receptors in the pathophysiology of major depression and the mechanism of action
Ketamine crosses the placenta easily and concentrations in the fetus are approximately equal to those of the mother. There is accumulating evidence from in vitro and in vivo experiments that suggests that tonic stimulation of NMDA receptors is vital for the survival of developing nerve cells. The NMDA receptor can be pharmacologically blocked by drugs such as alcohol and ketamine, among other drugs. This alters the glutamate and g-aminobutyric acid (GABA) transmission that suppress neuronal activity and cause neuronal death in the developing brain. While there are no human studies, animal studies suggest that the duration of ketamine exposure in 7-day-old rat pups increases neuronal degeneration of the developing rat brain.
Safety Profile Ketamine has a wide margin of safety. The predominant adverse reaction is emergence phenomena post anesthetic for which the risk factors are age, female gender, noisy environment during recovery, prior personality disorders, and excessive dreaming. The experience of emergence phenomena is not associated with dose. Other side effects include a transient rash predominantly on the face and neck, and nausea and vomiting. A reasonably conservative safety ratio of 35 for snorted ketamine and a somewhat higher margin for oral administration has been reported.
THERAPEUTIC VALUE OF KETAMINE IN HUMANS Ketamine has broad areas of application and is a rapidly acting, relatively safe parenteral analgesic and anesthetic agent that has been in clinical use for more than three decades. It is the only injectable anesthetic that induces increase in arterial pressure and heart rate. Although the respiratory and pharyngeal reflexes are sometimes momentarily depressed after injection of substantial quantities, they are usually maintained during the period of unconsciousness. The drug is therefore suitable for short anesthetic and surgical procedures especially in the absence of a trained anesthetist, although the latest Parke-Davis data sheet stresses that
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KETAMINE-RELATED MORBIDITY
a trained professional should be present, together with resuscitation equipment. It is particularly useful in developing countries and remote country areas where a doctor may be working alone. The major concern is the emergence phenomena. Psychic disturbances after ketamine anesthesia have been reported to occur in about 15–40% of adult cases, depending to some extent on how these terms are defined. Other drugs, such as diazepam, lorazepam, and propofol, have been given together with ketamine in an attempt to reduce or abolish these phenomena, with some success. Psychological techniques are also effective in reducing complaints. The emergence phenomena have led to less medical use than was originally anticipated, but ketamine is still to be found in many general hospitals in most countries. It is also currently widely used in veterinary medicine. A number of clinical uses of ketamine have been suggested. Ketamine appears to be best used in the young (less than 10 years old) and the old (over 60 years) as these groups have reported fewer emergence reactions (Radford, 1996). Recent studies have confirmed the effectiveness of ketamine in a variety of pediatric and diagnostic procedures via caudal or intramuscular routes of administration. In addition to anesthesia and sedation, ketamine is used as an analgesic for acute postoperative pain, painful procedures, and more controversially for chronic or neuropathic pain. Analgesic doses of ketamine have been associated with dose-related declines in mood, conscious perception, and intellectual performance. Recent studies also report the successful use of patient controlled analgesia with morphine and ketamine following spinal and hip surgery in adults. An early stage descriptive study of the use of topical ketamine in the management of postherpetic neuralgia suggests it shows promise in the management of this painful condition. Ketamine has also been used as an experimental treatment for complex regional pain syndrome, which is a severe, chronic pain condition characterized by sensory, autonomic, motor, and dystrophic signs and symptoms. The treatment involves one or two cycles of a 10-day, inpatient intravenous infusion for 4 h daily in high doses. While there have been promising findings, the studies to date have been open label and the evidence base is yet to be developed. There is mixed evidence on the effect of ketamine on epilepsy and seizure disorders. Ketamine has been reported as both a pro- and anticonvulsant. Recently, ketamine has been recommended for use with electroconvulsive therapy as it has been shown to prolong seizure duration with more rapid posttreatment reorientation. A larger body of evidence, however, suggests that it displays anticonvulsant and neuroprotective
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properties but should be used with caution over prolonged periods of time. Studies conducted in the 1950s and 1960s suggested that psychedelic drug-assisted psychotherapy might be an effective treatment for alcohol dependence. In the 1990s, these findings were used as a partial basis for ketamine-assisted treatment of alcohol dependence. This is known as ketamine psychedelic therapy (KPT). The same author reports on the use of ketamine psychotherapy for heroin addiction, where dose was found to be related to treatment outcome at 2 years. These are controversial treatments that are yet to be used outside Russia. In the current environment of growing concern about bioterrorism, the neuroprotective and antiepileptic activities of ketamine have led to suggestions that it may be a useful tool in the management of nerve agent poisoning such as sarin.
KETAMINE-RELATED MORTALITY There are very few deaths by pure ketamine overdose recorded (i.e. not also involving a drug such as alcohol). Of 87 ketamine-linked deaths in New York City, none was purely due to the use of ketamine. Parke-Davis have reported that there are cases of accidental injections with ten times the amount required for surgery, with no obvious lasting effects. The principal physical dangers of most nonmedical uses are currently believed to arise mainly from the setting, or an interaction between the user and the setting of use, as ketamine can leave the user in a confused state. This can, for example, result in burns, falls (sometimes fatal), drowning, death by hypothermia from lying outside in winter, traffic accidents, and becoming a crime victim (e.g. drug rape). A recent paper reported the case of an emergency medical technician who died of a combination of asphyxia and intoxication with administered intravenous ketamine in an autoerotic accident. There are two reports in the literature of deaths by pure ketamine overdose. One described as a homicide for homosexual ends. The other described a middleaged woman who took the drug daily for 7 months.
KETAMINE-RELATED MORBIDITY There is an extensive list of possible physical effects of ketamine that may be seen as adverse by the user, or that may be directly harmful. Some of those of principal concern in a nonmedical use context are difficulty with walking and balance resulting in falls, numbness, slurred speech, dizziness, visual problems, nausea, headaches, spasms, and twitches. A recent study found
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that, consistent with the animal studies, frequent ketamine use produces long-lasting impairments in episodic memory and aspects of retrieval from semantic memory even when other drug use is taken into account. A later study reported that when retested 3–4 years later following significant reductions in levels of ketamine use, semantic memory impairments associated with ketamine use were reversible. The effects upon schizotypal symptoms and perceptual distortions may, however, persist. The use of ketamine has been linked with a range of unpleasant mental effects including anxiety, panic attacks, flashbacks, posttraumatic stress disorder, persistent perceptual changes, mania, depression, suicide, insomnia, nightmares, night terrors, an unpleasant feeling of being unreal or that the world is unreal, paranoid delusions, persistent hallucinations, automatic behavior, and fragmentation of the personality and aggression. A study of 23 recreational users noted a high incidence of flashbacks and attentional dysfunction, but exactly what was meant by flashbacks is not defined. Large anesthetic studies do not confirm the finding and generally conclude that ketamine is usually devoid of significant persistent effects once the drug and its metabolites have cleared the body. For example, in a study of 1400 patients given ketamine as an anesthetic for surgical procedures, three had prolonged hallucinations, none lasting beyond 3 weeks. In no case did hallucinations begin after a period of normality, which is integral to the World Health Organisation (1992) definition of flashbacks. A 2009 study of the consequences of chronic selfadministration on the neurocognitive function and psychological well-being involved 150 individuals. The study over a period of 1 year compared levels of ketamine use frequency (frequent ketamine users, infrequent ketamine users) with abstinent users, polydrug using controls, and drug-free controls. Among frequent ketamine users, increasing use was correlated with decreasing cognitive performance as measured by spatial working memory and pattern recognition memory tasks. Assessments of psychological well-being also showed greater dissociative symptoms among frequent users and a dose–response effect on delusional symptoms. Until recently, there had only been reports that ketamine could cause toxic changes in the rat brain. A Chinese study of 41 ketamine-dependent individuals compared with 44 healthy controls found white matter changes associated with ketamine use in the bilateral frontal and left temperoparietal cortices. These changes were correlated with the severity of ketamine use. These findings suggest a microstructural basis for the changes in cognition and experience observed among those using ketamine for prolonged periods. The similarities
of these changes to those observed in chronic schizophrenia, moreover, have implications for the glutamate model of the illness. The use of ketamine with other neurotoxic drugs like alcohol is an additional cause for concern.
Urological and Upper Gastrointestinal Effects A number of series of case reports have recently identified physical health consequences of ketamine use. A review of 233 ketamine-related presentations to 15 Hong Kong emergency departments reported that the most common presenting symptoms were impaired consciousness (45%), abdominal pain (21%), lower urinary tract symptoms (12%), and dizziness (12%). A retrospective study of 64 heavy ketamine users explored the effects on the upper gastrointestinal tract. When those with other gastrointestinal conditions were excluded, 37 participants were studied. Of these, 28 (75.7%) reported upper gastrointestinal symptoms including epigastric pain and vomiting. It was further reported that despite medications, symptoms tended to persist unless ketamine use ceased. A more concerning consequence of ketamine use that has been newly identified is so-called ketamine bladder syndrome, which was first described in 2007. Clinicians from Canada described nine patients who were daily ketamine users and who presented with severe dysuria, frequency, urgency, and gross hematuria. At cystoscopy, all patients had severe ulcerative cystitis. Clinicians in Hong Kong reported a similar presentation of ten street ketamine users diagnosed with ulcerative cystitis. This unwanted effect of ketamine has also been reported among pediatric patients in less than 2 weeks after commencing use for chronic pain. The largest study to date was conducted in Hong Kong and reports on 59 ketamine users with moderate to severe lower urinary tract symptoms. Patients had frequency rates from 15 to 90 min between voids. Functional voiding capacity was between 20 and 200 ml, which represents a dramatic decrease in bladder capacity. Upon cystoscopy, 71% of these patients showed various degrees of bladder mucosal inflammation similar to that seen in interstitial cystitis. Histological examination showed a largely denuded bladder epithelium and granulation of the lamina propria infiltrated by lymphocytes and eosinophils. Most patients showed detrusor over activity at very low bladder infusion volumes. Even more concerning is the documentation of severe kidney effects among these individuals, where 51% showed unilateral or bilateral hydronephrosis on renal ultrasonography and 7% had features suggestive of papillary necrosis. Similar case series are now being reported in the United Kingdom and other regions of China.
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The urologists treating this disabling condition have also reported on the apparent difficulty their patients experienced in abstaining from ketamine use. A group in Taipei reported that of ten consecutive patients with ketamine bladder syndrome, where clear advice and multidisciplinary support was provided to cease their ketamine use, at 12 months follow-up only 3 had been able to do so successfully.
KETAMINE DEPENDENCE There is a substantial amount of popular literature describing ketamine as having a marked potential for giving rise to nonphysical dependence and case studies in the medical literature are accumulating. Many of these early reports of ketamine dependence were among those with access to the drug such as anesthetists and veterinarians. The Australian National Minimum Dataset of Clients of Specialist Drug and Alcohol Treatment Services records no identified episodes of care for ketamine as the principal drug of concern in its collection over the past decade. The comparable dataset in the United States reported a total of 229 mentions in 2006 where in only 82 was ketamine the primary drug of concern. While this appears to indicate that ketamine is either used by only a small number of individuals or that it is unlikely to cause dependence sufficient to drive treatment seeking, it may be that, as there is no evidencebased intervention for ketamine-related problems, that they are not admitted to treatment services. There is evidence from animal studies to support the view that ketamine can give rise to a dependence syndrome without physical withdrawal phenomena. This resembles cocaine dependence without the crash after use. Ketamine is also self-administered in rats and nonhuman primates. A recent Australian study of 100 recreational ketamine users found that around one in five (22%) of participants reported physical tolerance to ketamine. This is consistent with reports of tolerance to ketamine following multiple anesthetics. There have been at least two reported case histories of inpatient withdrawal from ketamine with observed psychotic symptoms. One case also included reports of a number of previously experienced ketamine withdrawal symptoms such as chills, autonomic arousal, lacrimation, restlessness, nightmares, and psychological craving with ketamine being used to relieve the symptoms. There is no research literature on the management of ketamine abuse or dependence. Case histories of ketamine withdrawal report the use of benzodiazepines for the management of anxiety and insomnia and vitamin supplements. There are some generic
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descriptions of potentially useful interventions that suggest an abstinence-oriented approach similar to that used for psychostimulants.
PUBLIC HEALTH ISSUES ASSOCIATED WITH KETAMINE USE In 1980, nonmedical unauthorized experimentation with ketamine was first reported in Australia. The authors believed that use of the drug was largely confined to medical circles. Since that time, anecdotal evidence indicates that the nature of users has become much more varied. In Australia, ketamine is often marketed in small glass vials with small spoons to measure accurate doses. The spoon is contained in the cap of the bottle, much like a snuff spoon. Other bottles have a self-contained measurer in the cap, which when turned over leaves a measured amount, which can then be snorted as bumps; very few ketamine users snort the drug in lines. This may result in lower doses per snort than its use in lines as is seen more commonly internationally. The effects of differing methods of insufflation on health outcomes have not been examined. Ketamine appears to be obtained from the diversion of legitimate supplies (veterinarians and pharmaceutical companies) or is imported from overseas. Ketamine can be bought over the counter in some Asian countries. Ketamine sold illicitly is often converted from a liquid form to a powder utilizing a simple evaporation process. The liquid ketamine is dried in a variety of ways (microwave oven or sun-dried) until a residue remains. This crystal residue is ground into a powder, leaving a fine powdery material similar to cocaine and heroin. In this form, it is far more convenient and more marketable than the injectable drug. Evidence from the United States indicates that, up until 1996, ketamine was usually not adulterated with other substances. Of all the ketamine submissions to the US Drug Enforcement Agency (DEA) regional laboratories in that period, there was only one instance of this type of dilution recorded. However, this situation may well have changed when price and demand rose sufficiently to make such practices profitable. Both popular and research accounts indicate that the recreational use of ketamine has widened in the context of nightclubs, dance parties, and raves. This has caused concern as ketamine is an anesthetic. One study concluded that it was totally inappropriate to use ketamine as a dance drug. The reasons for this were factors such as set and setting, the rapid onset of the drug, and the intensity of the experience as a whole. The respondents believed that using ketamine in a noisy, busy, or crowded environment was potentially dangerous and
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that use should be confined to a familiar and secure place, such as one’s home. All users had been unprepared for the intensity and nature of the effects when they first used the drug. In a study of the toxic effects of club drugs, it was concluded that the “single most risk-producing behavior of club drug users is combining psychoactive substances, usually involving alcohol.” The use of ketamine and other party or club drugs is reportedly associated with an increased incidence of unsafe sex among gay men on the circuit party scene in the United States. This is clearly a public health issue in the spread of blood-borne viruses and other sexually transmitted diseases. A small study of high-risk youth injecting ketamine in New York City also reported that its use was associated with a range of high-risk injection practices such as group injection with shared paraphernalia. Recent surveys among this sentinel group, however, have shown declines in the levels of ketamine (and other drug use) between 2002 and 2007. An Australian study reported a number of ketaminerelated problems among their sample of nonmedical ketamine users. While only one in five stated that they had ever experienced severe side effects as a result of ketamine use, more than one-third (38%) reported having to deal with someone else who had suffered badly following ketamine use. More than half (58%) of those interviewed had experienced the K hole and this was related to increased exposure to the drug – having used more than 20 times. The most commonly reported problems were employment related (20%). These included vagueness affecting work performance and lesser volume of work being produced. Additional problems reported included relationships (5%), financial (5%), and legal (1%). Of the five participants reporting relationship problems, none also reported financial problems but three of the five also reported work-related problems. Twenty-two participants reported at least one problem, five reported two problem areas, and one reported three problems areas. Ketamine has been sold in the rave scene in the United Kingdom as a key component in fake MDMA (ecstasy) tablets. There are also reports of ketamine being sold as ecstasy in Australia, or used as a cutting agent in other drugs such as cocaine, amphetamines, and heroin.
THE LEGAL STATUS OF KETAMINE Ketamine is scheduled in many jurisdictions. Below are some examples of the legal status of ketamine internationally.
status of ketamine in a number of key jurisdictions. Within Australia prior to December 2003 ketamine was a scheduled drug in New South Wales under the Poisons and Therapeutic Goods Act, which meant that there were strict regulations on the sale and distribution of the substance. In response to increasing trends in ketamine use, the government added it to the list of prohibited drugs in New South Wales. This means that it has now been listed under the Drug Misuse and Trafficking Act 1985, ensuring that tougher penalties are in place for dealing with its illicit use. New penalties for those caught manufacturing or supplying the drug include fines between AU$5500 and AU$550 000 and anywhere from 2 years to life imprisonment or both. These penalties particularly apply to veterinary and medical practitioners who have an authority to purchase ketamine for legitimate purposes and then supply it to others for illicit use. Similar laws apply in some other states of Australia, however, in other states it remains legal to possess ketamine.
Canada Ketamine is Schedule 1 in Canada, pursuant to a February 2004 notice that it “is an analog of phencyclidine (PCP), and is, therefore, captured as item 14 in Schedule I of the CDSA and item 14 in the Narcotic Control Regulations (NCR).” Affected researchers were expected to have complied with the Schedule 1 protocol for the handling of ketamine by August 31, 2005.
China Ketamine is a Class II psychiatric drug; trade is limited to licensed wholesalers and retail sales are prohibited. In July 2004, the state of Sichuan placed ketamine in Class I; other provinces are expected to follow suit.
Mexico Ketamine is a Category 3 drug under Mexico’s General Health Law; Category 3 drugs “have a therapeutic value but constitute a problem for the public health.” Medicines Administration Regulations restricts the acquisition of ketamine to licensed veterinarians only and sets strict rules regarding the management and follow-up of the products.
Australia
Netherlands
Ketamine is scheduled differently within and between countries. Below is a brief overview of the legal
Ketamine is treated as a medication and is not in List 1 or 2 in the Netherlands.
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FURTHER READING
United Kingdom
List of Abbreviations
Prior to January 1, 2006, ketamine was not controlled in the United Kingdom under the Misuse of Drugs Act, making it legal to possess. However, sales and distribution were controlled under the Medicines Act making it illegal to sell or distribute without a license. Ketamine became a Class C drug on January 1, 2006, following a 2004 report to government that recommended moving ketamine into Class C.
NDE near-death experience NMDA N-methyl-D-aspartate PCP phencyclidine
United States Ketamine was unscheduled until August 1999. In early July 1999, the DEA added ketamine to Schedule III with an emergency ruling that took effect on August 12, 1999. It is now a federal offense to possess ketamine in the United States without a license or prescription. Since that time, ketamine has been scheduled in many individual states, and laws are pending in many more. Where ketamine is not scheduled in a specific state, all prosecutions for possession or sales occur at the federal level.
SUMMARY In conclusion, as levels of ketamine in the general population appear to be very low, the harms reported by recreational users are not excessive, adulteration is rare, and the mortality rate is low. Ketamine does not appear to pose a risk to public health at this time. At the individual level, many of those who experiment find the effects aversive and do not persist. The harms that require further investigation are the association with unsafe sex and injecting behaviors, the neurotoxic effects, and use in situations where there is a heightened risk of accidental death when the user’s cognition is grossly impaired. It is recommended that the usual harm minimization strategies; especially not to use the drug when alone, not to concurrently use other neurotoxins such as alcohol, to be in a physically safe environment, and to use safer injecting techniques; should be observed when using ketamine.
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Glossary Bumps bumps are a measure of ketamine that is a small snort usually measured by a tiny spoon provided within the lid of the container in which it is purchased. K hole this is a slang term for a state of dissociation from the body that may mimic the phenomenology of schizophrenia. The K-hole experience appears to vary with the individual and includes intense hallucinations and perceptual distortions.
Further Reading Adler, C.M., Malhotra, A.K., Elma, I., Goldberg, T., Egan, M., Pickar, D., et al., 1999. Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. American Journal of Psychiatry 156 (10), 1646–1649. Bowdle, T.A., Radant, A.D., Cowley, D.S., et al., 1998. Psychedelic effects of ketamine in healthy volunteers. Anesthesiology 88 (1), 82–88. Curran, H.V., Monaghan, L., 2001. In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction 96, 749–760. Curran, H.V., Morgan, C., 2000. Cognitive, dissociative and psychogenic effects of ketamine in recreational users on the night of drug use and 3 days later. Addiction 95 (4), 575–590. Dillon, P., Copeland, J., Jansen, K., 2003. Patterns of use and harms associated with non-medical ketamine use. Drug and Alcohol Dependence 69, 23–28. Dotson, J.W., Ackerman, D.L., West, L.J., 1995. Ketamine abuse. Journal of Drug Issues 25 (4), 751–757. Jansen, K.L.R., 2001. Ketamine, Dreams and Realities. Multidisciplinary Association for Psychedelic Studies, Florida. Morgan, C.J.A., Monaghan, L., Curran, H.V., 2004. Beyond the K-hole: a 3-year longitudinal investigation of the cognitive and subjective effects of ketamine in recreational users who have substantially reduced their use of the drug. Addiction 99 (11), 1450–1461. Vollenweider, F.X., Kometer, M., 2010. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience 11, 642–651. Weiner, A.L., Vieira, L., McKay, C.A., Bayer, M.J., 2000. Ketamine abusers presenting to the emergency department: a case series. Journal of Emergency Medicine 18 (4), 447–451. White, J.M., Ryan, C.F., 1996. Pharmacological properties of ketamine. Drug and Alcohol Review 15 (2), 145–155.
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