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Official websites use. Share sensitive information only on official, secure websites. Email: Paul. Dargan gstt. Ketamine was originally synthesised for use as a dissociative anaesthetic, and it remains widely used legitimately for this indication. However, there is increasing evidence of non-medical recreational use of ketamine, particularly in individuals who frequent the night-time economy. The population-level and sub-population clubbers prevalence of recreational use of ketamine is not known but is likely to be similar, or slightly lower than, that of other recreational drugs such as cocaine, MDMA, and amphetamine. The predominant features of acute toxicity associated with the recreational use of ketamine are neuro-behavioural abnormalities such as agitation, hallucinations, anxiety, and psychosis. Long-term recreational use of ketamine can be associated with the development of psychological dependence and tolerance. There are reports of gastro-intestinal toxicity, particularly abdominal pain and abnormal liver function tests, and of neuropsychiatric disorders, typically a schizophrenia-like syndrome, in long-term users. Finally, there are increasing reports of urological disorders, particularly haemorrhagic cystitis, associated with long-term use. The management of these problems associated with the long-term use of ketamine is largely supportive and abstinence from ongoing exposure to ketamine. In this review we will collate the available information on the epidemiology of recreational use of ketamine and describe the patterns of acute and chronic toxicity associated with its recreational use and the management of this toxicity. Keywords: ketamine, 2- 2-chlorophenyl methylamino -cyclohexanone, recreational drugs, epidemiology, acute toxicity, chronic toxicity, dependence, haemorrhagic cystitis. Ketamine, 2- 2-chlorophenyl methylamino -cyclohexanone is a dissociative anaesthetic that was first synthesised in the United States in 1. It is listed by the World Health Organisation as an essential medicine 2 and is widely used as a general anaesthetic, both in veterinary and human practice. It is characterised by its ability to cause unconsciousness, amnesia, and analgesia whilst sparing airway reflexes and maintaining haemodynamic stability 3. Ketamine is also gaining favour as an alternative analgesia, particularly in chronic non-cancer pain 4. Its clinical use has always been limited by a hallucinogenic effect, the so-called emergence delirium described during its first human volunteer trial 1. This effect has however led to recreational, non-medical misuse and there has been evidence of this since 5. It should be noted that colloquial names of recreational drugs change with time and differ between countries and communities, so it is not possible to give a contemporaneous and complete list of common street names for ketamine. Ketamine is subject to control under recreational drug legislation in many countries; it was added to Schedule III in the United States in and in the United Kingdom it was controlled as a Class C agent under the Misuse of Drugs Act, in The prevalence and geographic spread of ketamine misuse has increased greatly over the past 20 years, and a pattern of adverse effects that differs from that expected from occasional legitimate general anaesthetic use has become apparent. In addition, there is an accumulating literature on ketamine-related chronic toxicity, in particular neuropsychological and urological effects. This review will collate the available information on the epidemiology of recreational use of ketamine and describe the patterns of acute and chronic toxicity associated with its recreational use. Ketamine produces dissociative anaesthesia by causing electrophysiological dissociation between the limbic and thalamoneocortical systems, resulting in a trance-like cataleptic state characterised by unconsciousness, amnesia, deep analgesia but with intact ocular, laryngeal, and pharyngeal reflexes 1. There are also sympathomimetic, anti-cholinergic and analgesic effects: these start at sub-anaesthetic doses, but persist throughout the period of unconsciousness 1. Ketamine is both water- and lipid-soluble, which allows administration by many routes. Intravenous, intramuscular, subcutaneous, oral, nasal, and rectal administration are described both therapeutically 3 and for recreational, non-medical ketamine misuse 7. Extensive first-pass hepatic metabolism of ketamine to its main metabolite norketamine substantially reduces its bioavailability following either oral or rectal administration see Table 1 3 , 8 — Ketamine has two major metabolites: norketamine, which has one-third the potency of ketamine 11 and dehydronorketamine. Norketamine is then dehydrogenated to dehydronorketamine and both these metabolites undergo hepatic conjugation. They can be detected in the urine for many days: ketamine, 5—11 days; norketamine, 6—14 days; dehydronorketamine, 10 days 14 , Ketamine has activity at several receptors. This disrupts cortical-cortical and cortical-subcortical signalling 18 , producing dissociative anaesthesia, interference with neuronal plasticity, learning and memory, analgesia at central and spinal cord level, as well as interruption of the central sensitization core to chronic pain syndromes 3. Ketamine also has a profound anticholinergic effect, produced by antagonism of the central nervous system muscarinic acetylcholine receptors 23 and inhibition of acetylcholinesterase 24 , although one of the resultant effects—bronchodilatation—may also be caused by a direct antagonism of endothelininduced bronchial smooth muscle constriction In a rat model, acute ketamine administration resulted in increased dopamine and 5-hydroxyindoleacetic levels in the medial prefrontal cortex 26 ; however, repeated daily ketamine administration for 7 days attenuated dopamine but enhanced 5-hydroxyindoleacetic acid release. Finally, ketamine potentiates gamma-aminobutyric acid GABA synaptic inhibition, through weak GABA A receptor agonism 27 , 28 , but this is not thought to be clinically significant 3. Recreational, non-medical ketamine is available to users in powdered, capsule, and liquid formulations. Most recreational use is by nasal insuffulation, with ketamine powder insuffulated either directly or off the surface of objects such as keys or ketamine spoons or vaporised in solution 8. In tablet form, it is often admixed with other pharmacologically active substances such as amphetamine, caffeine, cocaine, amphetamine, and heroin 8. Importantly, recreational ketamine use often occurs with co-use of other substances, and potentially serious adverse pharmacological and toxicological interactions can occur with concomitant use of either central nervous system depressants e. Recreational use of ketamine was first reported amongst those with access to the drug, particularly medical professionals, in 5. The precise prevalence of recreational, non-medical ketamine use is unknown; small single country studies suggest that the background population use rates of ketamine are low, between 0. Recreational ketamine use is commonly part of poly-substance use and is taken together with another club drug, ethanol, or stimulant 35 , Ketamine use from population surveys, reported by individual country where data has been obtainable. Geographically, recreational use of ketamine use is seen across the world, but it appears to be most common in East and South-East Asia, potentially because of its relatively low price compared to other psychomimetic drugs, particularly MDMA Global reports of ketamine seizure rose from negligible amounts in to over 11 metric tonnes in , with nearly all of this in East and South-East Asia, where ketamine seizures exceeded that of heroin 41 , Hong Kong reported ketamine as the second-most popular drug of abuse after heroin for the period — It is often stated that the bulk of illicitly available ketamine is derived by diversion of legitimate veterinary and medical supplies; however, illicit manufacturing laboratories have now also been reported, particularly in China and South-East Asia Systemic toxicity with cardiovascular effects can occur, but generally clinical features are related to physical harm, either because of ketamine-induced aggression and agitation or because an individual believes that they can do things without suffering significant injury e. Any description of acute ketamine toxicity is complicated by the fact ketamine is commonly part of a poly-substance use scenario. It is therefore important in patients presenting with acute toxicity after ketamine use, particularly if systemic features are present, to consider that this toxicity may, in part, be due to the co-ingested drug s. Users may be become agitated, aggressive, paranoid, and display dissociative-type symptoms. In healthy volunteers, an acute sub-anaesthetic dose of 0. One of the biggest concerns surrounding acute ketamine use is that it reduces awareness of the immediate environment, thus exposing the user to potential physical harm The reduced awareness encompasses a sense of depersonalisation, derealisation, reduced perception of pain, and potentially unconsciousness. This is compounded by users frequently experiencing lack of coordination, temporary paralysis, inability to move, blurred vision, and inability to speak As such, users put themselves at risk of significant injury, through jumping from heights, road traffic accidents, drowning, and hypothermia secondary to incomplete drowning or prolonged environmental exposure 7. Despite media and public concern about the potential for ketamine to be involved in drug-facilitated sexual assault, it is unusual for ketamine to be detected in this scenario. On screening, only 3 of 1, cases in the United Kingdom 47 and 2 of cases from Canada 48 tested positive for ketamine. During , a single trauma centre in Hong Kong reported 4. During ketamine anaesthetic induction, tachycardia and hypertension precede unconsciousness 1 and this effect is also commonly seen with the sub-anaesthetic doses used for recreational ketamine use. The most common reported cardiovascular effect in patients with acute ketamine toxicity is a self-resolving sinus tachycardia with chest pain and palpitations less commonly reported 44 , There have also been isolated reports of acute pulmonary oedema following parental ketamine use, although it is difficult to be certain from these reports whether the pulmonary oedema was due to ketamine or some other factor 52 — Ketamine has a wide therapeutic range and the median lethal dose LD 50 in animals is times the average therapeutic intravenous dose 3 , which makes death from overdose difficult. Indeed, death and non-fatal emergencies attributed to ketamine use are considered to be very rare When ketamine is reported in post-mortem samples, it is often either alongside another intoxicant or in the setting of trauma. From the forensic literature regarding death following recreational ketamine use, blood ketamine concentrations within the range of 0. Of the 23 deaths in which ketamine was identified in post-mortem samples in the United Kingdom between and , only 4 were attributed to lone ketamine poisoning Similarly, in New York City, of 15 out-of-hospital deaths where ketamine was identified in post-mortem samples of persons identified as recreational drug users, 12 were poly-substance overdoses and 2 died as a result of trauma The management of acute ketamine toxicity is largely supportive and involves removing an individual from excessive auditory and visual stimulation until symptoms resolve. Recently, the long-term effects of recreational, non-medical ketamine use have come under scrutiny. We will summarise here the data on associated neuropsychological effects, neurotoxicity, dependence, and urological and gastrointestinal pathology. Ketamine is associated with both neuropsychiatric symptoms and direct neurotoxicity. As described above, ketamine can cause several acute neuropsychiatric effects. Acute and acute-on-chronic use of ketamine has been shown to be associated with impaired information handling within working memory and episodic memory, as well as semantic processing deficits 61 , Men appear to be more affected by these effects than women For up to 3 days following ketamine use, subjects are threefold likelier to report unpleasant dreams Long-term ketamine users appear to have more pronounced and persistent neuropsychiatric symptoms, generally characterised as schizophrenia-like symptoms. In a recent case-control study comparing frequent ketamine users, defined as use at least four-times-a-week, with infrequent users, abstinent users, poly-drug users, and non-drug users, frequent ketamine use was associated with impairment of working memory, episodic memory, executive function and psychological well-being These frequent users were reported as taking an average of 2. The same group were then followed up for a year, and the frequent ketamine users with increasing ketamine doses were more likely to have cognitive deficits, especially with spatial working memory and pattern recognition memory tasks, and both short- and long-term memory was affected From the same studies, delusional thinking was shown to be correlated positively with the amount of ketamine used by frequent users and persisted despite abstinence A dose-dependent relationship was reported on 1-year follow-up, with frequent users being more delusional than infrequent, abstinent, and non-users, respectively Superstitious conditioning, a form of associative learning, is also more common amongst frequent ketamine users and this process may precede outright delusional thinking Frequent ketamine use is also typified by increased dissociative and depressive symptoms 66 , as well as a subtle visual anomaly It is not certain how ketamine causes these effects, but antagonism of the NMDA-R is thought to be important, as is dopaminergic depletion in the prefrontal cortex 3 , 26 , Ketamine is also directly neurotoxic. Animal studies have shown that apoptotic neuro-degeneration is induced by NMDA-R antagonists, including ketamine, in the developing rodent brain This effect for ketamine has since been shown to be more marked in older rats and is synergistic with nitrous oxide 71 — 73 ; it was ameliorated by GABA A agonism with benzodiazepines, and prevented by neuronal nitrous oxide synthase antagonism with 7-nitroindazole 73 , This last finding implicates endogenous nitrous oxide in ketamine-related neurotoxicity. In monkeys, neuronal death was observed after ketamine anaesthesia administered for 9 hours or more but not for 3 hours duration Recently, evidence for harm in humans following frequent ketamine use has been presented, with bilateral frontal and left temporoparietal white matter degeneration shown on brain magnetic resonance imaging being positively correlated to self-reported ketamine dosages There is evidence that ketamine causes a psychological, rather than a physical, dependency. This definition holds true for frequent, long-term ketamine use. In particular, ketamine use can be uncontrolled, over-prioritised, and linked with tolerance but does not cause a physical withdrawal state. Anecdotally, ketamine use in humans is characterised by binging, the drug being repeatedly used until a user's supply has been exhausted 78 , This phenomenon is also seen in pigeons and monkeys, who repeatedly self-administer freely available ketamine, suggesting that it is difficult to control ketamine use during a binge 80 , Tolerance is likely explained by ketamine auto-induction of metabolism. Ketamine pretreatment doubles its hepatic microsomal metabolism in rats, and both the catalytic activity and protein expression of the rat microsomal cytochrome P system is enhanced by repeated daily ketamine administration 83 , Unsurprisingly, frequent ketamine use is associated with increasing doses to achieve the same effect, with a sixfold increase in dosage reported during initiation of chronic use, and frequent users using twice the dose of infrequent users 66 , Recently lower urinary tract symptoms LUTS of dysuria, increased frequency of small volume micturition, suprapubic pain and, if severe, painful haematuria have been reported amongst long-term ketamine users. There have been no large epidemiological studies, but pilot studies suggest that up to a third of long-term ketamine users may be affected: pooling together the results of three small surveys of frequent users, 50 of ketamine users admitted to LUTS 84 — In , investigators from Canada linked these symptoms with ulcerative cystitis 88 ; additionally, those severely affected may also experience obstructive nephropathy There is evidence from beyond the recreational use setting linking ketamine with urological pathology. In an animal study performed following the reports of human pathology, mice administered intraperitoneal ketamine for up to 6 months demonstrated pathological changes, with mononuclear infiltration occurring throughout the urological tract in the glomeruli, ureters, and bladders Four cases have also been reported from the palliative care setting linking analgesic ketamine use with LUTS 91 , In all of these, patients self-reported ketamine use in excess of 3 months with ketamine use preceding LUTS. Except for one case, all had either sterile or contaminant-only urinary cultures. Commonly, reduced bladder volume was associated with bladder wall thickening, detrusor instability, and vesicoureteric reflux, which explains the hydronephrosis as potentially a secondary effect of the bladder pathology 86 , Alternatively, hydronephrosis could also be a result of either peri-ureteric thickening or intraureteric obstruction by ketamine-containing gelatinous debris 86 , 89 , All of those who had cystoscopy had demonstratable cystitis, with abnormal histology being reported in 32 of 34 biopsies. Histologically, bladder biopsies from patients with ketamine-associated cystitis show a consistent picture of urothelial ulceration, with eosinophilic infiltration of the lamina propria with surrounding reactive urothelial atypia 88 , 94 , The appearances are similar to carcinoma in situ , with nuclear enlargement and disorganisation, high p53 immunoreactivity, and moderate-to-high Ki67 immunoreactivity; importantly, what distinguishes the ketamine-related changes from carcinoma in situ is that the ketamine-related biopsies are negative for CK20 The cause of the bladder pathology is unknown. However, in the animal study discussed above, mice were only exposed to intraperitoneal ketamine and still developed mononuclear infiltration occurring throughout the urological tract, in the glomeruli, ureters, and bladders In addition, there are four reported cases from the palliative care setting in patients using pharmaceutical-grade analgesic ketamine who developed LUTS 91 , Additionally, the bladder is exposed to ketamine and its active metabolites for over a week following a single dose of ketamine 14 , 15 , which suggests frequent ketamine users would have a prolonged exposure. The evidence for a dose-dependent relationship is strengthened by evidence from a case report of a palliative care patient whose urinary symptoms paralleled the use, discontinuation, reintroduction, and repeat discontinuation of analgesic ketamine Abstinence of continuing ketamine use is central to managing patients with urological pathology 86 , 94 , A number of therapies have been explored for the management of ketamine associated urological problems. Some authors have described symptom relief with the use of elmiron pentosan polysulphate sodium , which is a low molecular weight heparin-like compound that is thought to help increase the glycosaminoglycan layer of the damaged bladder wall urothelium Intravesical hyaluronic acid has also been used 94 , 97 — Hyaluronic acid is a mucopolysaccharide and it is thought that it acts as a urothelial protective barrier. Its use has been described in both general and ketamine-related interstitial and haemorrhagic cystitis 94 , 97 — In one series of six patients with ketamine-related bladder pathology and LUTS, weekly intravesical hyaluronic acid for 1 month resulted in improvement in painful bladder, frequency, and haematuria Surgical intervention, such as augmentation enterocystoplasty or cystectomy with conduit diversion, is generally considered a last resort in patients who have continued symptoms and haematuria despite the above therapies and abstinence from ketamine 93 , 94 , Recently, certain authors have described gastric and hepatic pathology in long-term ketamine users investigated for abdominal pains. In a small retrospective analysis of 37 recreational ketamine users from Hong Kong, typical symptoms of epigastric pain, with or without vomiting, was associated with biopsy-proven Helicobacter Pylori -negative gastritis These symptoms were improved by self-reported abstinence, but neither the abstinence nor gastritis resolution was objectively confirmed. In that same analysis, abnormal liver function tests were reported, but no statistical relationship to symptoms was detected Abnormal liver function tests, irrespective of associated pain, have also been reported elsewhere after clinical ketamine use and non-medical ketamine use 89 , — However, this effect has not been shown to cause abdominal pains. Choledochal cysts, benign cystic dilatations of the common bile duct, in association with abnormal liver function tests have been described in ketamine users from the United Kingdom and Hong Kong 89 , , One chronic ketamine user from the United Kingdom had a dilated common bile duct that regressed with abstinence but recurred following a return to ketamine use All five patients reported from Hong Kong were diagnosed with choledochal cysts following investigations for recurrent epigastric pain and abnormal liver function tests and improvement in both symptoms and common bile duct dilatation occurred with self-reported abstinence. It is unclear what the mechanism for these effects is. Recreational, non-medical ketamine use is an important public health issue, with evidence of its increasing use in certain population sub-groups, the youth clubbing scene in particular. In the acute setting, the neuro-behavioural and neuropsychiatric effects of ketamine increase the risk of injury and harm to the individual. In the long-term there is evidence of psychological dependency and strong evidence for deleterious neuropsychiatric and urological effects. Long-term users may develop schizophrenia-type symptoms, have poor psychological well-being, memory difficulties, and are at risk of haemorrhagic cystitis with significant associated lower urinary tract symptoms. More work is still needed to better elucidate the epidemiology of ketamine use and the pathophysiological basis of the chronic neuropsychiatric and urological harms. As a library, NLM provides access to scientific literature. Emerg Health Threats J. Find articles by Sarbjeet S Kalsi. Find articles by David M Wood. Find articles by Paul I Dargan. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Induction of general anaesthesia 3. Onset of effect 3. Duration of effect 3. Taiwan United Kingdom

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