- Email: [email protected]
Methoxetamine – a novel recreational drug with potent hallucinogenic properties
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TOXLET 8858 1–6 Toxicology Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
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Mini review
Methoxetamine – a novel recreational drug with potent hallucinogenic properties
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Jolanta B. Zawilska *
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Department of Pharmacodynamics, Medical University of Lodz,90-151Lodz, Muszynskiego 1, Poland
H I G H L I G H T S
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Methoxetamine (MXE), a structural analogue of ketamine, is a novel designer drug. MXE is recreationally used due to its potent hallucinogenic and dissociate effects. Consumption of MXE bears a significant health risk. Long-term effects and interaction of MXE with other drugs of abuse remain to be elucidated.
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 June 2014 Received in revised form 7 August 2014 Accepted 11 August 2014 Available online xxx
Methoxetamine is one of the constantly growing group of novel psychoactive substances that has emerged in recent years. The compound belongs to the arylcyclohexylamine class, which is used for its recreational and psychedelic effects. Methoxetamine is a structural analogue of ketamine, with a much longer duration of action and intensity of effects, and has been extensively advertised as its 'legal' and 'bladder friendly' alternative. This review surveys the current state of knowledge regarding the metabolism, pharmacology, prevalence and pattern of methoxetamine use, and analytical methods of its detection. Consumption of methoxetamine bears a significant health risk and may even lead to fatal intoxication. A significant amount of research is still needed in order to fully quantify the short- and longterm effects of methoxetamine and its interaction with other drugs of abuse. ã 2014 Published by Elsevier Ireland Ltd.
Keywords: Methoxetamine Novel psychoactive substances Hallucinogenic/dissociative drugs Toxidrome
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism and pharmacological properties of methoxetamine . . . . . . . . . Prevalence and pattern of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects related to methoxetamine use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methoxetamine-induced toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analytical methods for determination and measurement of methoxetamine Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Tel.: +48 42 6779294. E-mail addresses: [email protected], [email protected] (J.B. Zawilska).
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1. Introduction
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Recently, a new class of psychoactive substances, known as 'legal highs', 'herbal highs', 'designer drugs' or 'research chemicals', has emerged on the drug use market. They include a wide range of
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http://dx.doi.org/10.1016/j.toxlet.2014.08.011 0378-4274/ ã 2014 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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products, from naturalplant-originated substances to semisynthetic and synthetic compounds (EMCDDA, 2013a; Johnson et al., 2013; Papaseit et al., 2014; Zawilska, 2011). Based on the spectrum of exerted psychoactive effects, these compounds can be classified into four basic categories: synthetic cannabimimetics ("Spice"/K2), stimulants, hallucinogens, and opioid-like drugs (Zawilska, 2011). The EU warning system operated by the European Monitoring Centre for Drugs and Drug Addition (EMCDDA) reported the Q3 appearance of 317 new psychoactive substances between 2005 and 2013 (EMCDDA, 2013a, 2014). Importantly, the EU drug market report emphasizes that "...while the appearance of new drugs is not a new phenomenon, over the last few years there has been an unprecedented growth in their number, type, and availability" (EMCDDA, 2013a). Ketamine is awell-known anesthetic with a good safety profile, which is used particularly in pediatric and veterinary anesthesia, and as aco-analgetic in pain management. However, since the mid1990s, its potent hallucinogenic and dissociate effects have afforded ketamine the status of a recreational drug used mainly by teenagers and young adults at dance clubs, raves, and squat parties (Morris and Walach, 2014). Common street names for ketamine include: K, Special K, K2, Vitamin K, Super K, Super C, Lady K,Ket-Kit Kat Ketaset, Ketaject, Jet Super Acid, Green, Purple, Special LA Coke, Cat Tranquilizers, and Cat Valium (www.drugs. com). A growing body of clinical data indicates that repeated misuse of ketamine induces ulcerative cystitis resulting in haematuria, loss of bladder control; it can also lead to neurocognitive impairment (Morgan and Curran, 2011).
In May 2010, the first public report on effects of methoxetamine (2-(3-methoxyphenyl)-2-(ethylamino)cyclohexan-1-one; MXE or3-MeO-2-OxoPCE), a new designer drug, was published on the Internet (Morris and Walach, 2014). An evolution of methoxetamine at the research chemicals and recreational drug market has been described by Morris and Walach (2014) in a comprehensive and elegant review on dissociate drugs. The drug is a member of the arylcyclohexylamine family; more specifically, it is a structural analogue of ketamine, where the2-chloro group on the phenyl ring and the N-methylamino group of ketamine have been replaced by a3-methoxy and N-ethylamino group, respectively (Fig. 1). Soon after, methoxetamine was extensively advertised as a 'legal' and 'bladder friendly' alternative to ketamine (EMCDDA, 2013b; Kjellgren and Jonsson, 2013; Morris and Wallach, 2014). Methoxetamine is typically sold as a free base and hydrochloride salt in powder. The common street names of methoxetamine are: ‘MXE’, ‘Mexxy’, ‘M-ket’, ‘MEX’, ‘Kmax’, ‘Special M’, ‘MA’, ‘legal ketamine’, ‘Minx’, ‘Jipper’, and ‘Roflcoptr’ (EMCDDA, 2013b). According to the EMCDDA report, the following ‘legal highs’ product names have been associated with methoxetamine: ‘Kwasqik’, ‘Hypnotic’, ‘Panoramix’, ‘Magic’, ‘Lotus’, and ‘X’ (EMCDDA, 2013b). By 2013, methoxetamine had been seized in a number of countries throughout Europe, including Belgium, Italy, Sweden, and the United Kingdom (EMCDDA, 2013b). Although in vast majority of samples, methoxetamine was the only detected compound; some of them also contained other psychoactive compounds, such as phenethylamines (e.g.,4-fluoroamphetamine), synthetic cathinones (e.g., methylone,
Fig. 1. Chemical structure of phencyclidine, ketamine, and methoxetamine.
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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mephedrone, and 3,4-methylendioxypyrovalerone), synthetic cannabimimetics (AM-2201,JWH-018), benzodiazepines, methylphenidate, ketamine, amphetamine, methamphetamine, 3,4-methylenedioxy-N-methylamphetamine (MDMA), cannabis, morphine, and heroin (EMCDDA, 2013b). Methoxetamine has been found in 18 out of 173 samples of controlled drugs submitted to the Spanish Drug Checking Service between 2009 and 2012: in 15 ketamine samples, and in single samples of MDMA, amphetamine and cocaine (Giné et al., 2014). In 2013, methoxetamine was brought under permanent control in the United Kingdom as a Class B drug (Home Office, 2013). 2. Metabolism and pharmacological properties of methoxetamine In vitro studies using human liver microsomes and human liver S9 fraction revealed that methoxetamine undergoes a complex phase I metabolism, including N-deethylation, O-demethylation, hydroxylation, reduction, and dehydrogenation (Menzies et al., 2013). Kinetic studies with human hepatic CYP isoenzymes have demonstrated that N-deethylation is catalyzed by CYP2B6 and CYP3A4, O-demethylation by CYP2B6 and CYP2C19, and hydroxylation by CYP2B6 (Meyer et al., 2012). Using liquid chromatography–high resolution mass spectrometry (LC–MS)n, several different metabolites of the drug were identified, namely N-desethylmethoxetamine (normethoxetamine; a major metabolite), O-desmethyl-methoxetamine, O-desmethylnormethoxetamine, dihydronormethoxetamine,
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O-desmethylhydroxynormethoxetamine, and hydroxynormethoxetamine (Fig. 2). Phase II metabolites were mainlymonoglucoronide conjugates (Menzies et al., 2013; Meyer et al., 2012). An analysis of urine samples collected from three individuals presenting acute methoxetamine toxicity demonstrated the presence of in vitro microsomal metabolites, with the exception of O-desmethylhydroxynormetho-xetamine (Menzies et al., 2013). Similar results were obtained by Meyer et al. (2012) for rat and human urine. Confirmation of the important role played by CYP2B6 in methoxetamine metabolism is of clinical importance. As CYP2B6 is involved in metabolism of numerous drugs and xenobiotics, pharmacokinetic interactions between methoxetamine and other compounds are likely to occur. Furthermore, the rate of methoxetamine metabolism and its toxicity may depend on genetic polymorphism of CYP2B6. However, the precise nature of the biological activity of specific methoxetamine metabolites, if any, remains unknown. Little is known about pharmacological activity of methoxetamine. Very recently, Roth et al. (2013) performed an in vitro Q7 examination of the neuropharmacological profile of methoxetamine by screening its activity at 57 molecular targets relevant to the action of the drug with the CNS. They found that methoxetamine has asub-micromolar affinity for the glutamate N-methylD-aspartate (NMDA) receptor (pKi = 6.59), which is comparable to Q8 that of ketamine (pKi = 6.18), and binds to the phencyclidine site on the NMDA receptor. In addition, methoxetamine was found to
Fig. 2. Major metabolic pathways for methoxetamine (modified from Menzies et al., 2013).
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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exhibit asub-micromolar affinity (pKi = 6.32) for the serotonin transporter, thus resembling the property of phencyclidine (pKi = 5.65). Furthermore, it has been shown that methoxetamine increaseselectrically-stimulated release of dopamine from slices of rat nucleus accumbens and inhibits the re-uptake of the amine (Davidson et al., 2014).
3. Prevalence and pattern of use
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Currently, limited information is available regarding the prevalence and pattern of methoxetamine use, and existing studies should be taken with caution as many of them are based on online surveys and self-reports on user websites. Wood et al. (2012b) surveyed
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Table 1 Case reports of acute and fatalmethoxetamine-induced intoxication. Gender, age
Symptoms
Drugs found in biological samples Treatment
Way of MXE administration
Acute intoxication M/42a Drowsiness, tachycardia (heart rate 135 bpm), hypertension (blood pressure 187/83 mm Hg), pyrexia (38.2 C)
Nasal insufflation
M/29b
Oral
M/28
M/24c
M/28
M/25d M/27
M/19
M/17
M/18
M/21e
M
Diazepam Serum: methoxetamine 0.12 g/mL, 5-APB or6-APB Serum: Diazepam Tremor, visual hallucinations, confusion, tachycardia (heart rate 121 bpm), hypertension (blood pressure 201/104 mm Hg) methoxetamine 0.09 mg/mL, diphenhydramine and venlafaxine Serum: Agitation, aggression, confusion, drowsiness, tachycardia Midazolam methoxetamine 0.20 mg/mL (heart rate 113 bpm), hypertension (blood pressure 198/ 78 mm Hg), dilated pupils Methoxetamine: Drowsiness, dysphasia, hallucinations, impaired motor coordination, blood pressure up to 140/90 mm Hg, heart rate serum 450 ng/mL, up to 120 bpm urine 7200 ng/mL Benzodiazepines Extreme agitation, aggression, confusion, hallucinations, Methoxetamine: tachycardia (heart rate 105 bpm) serum 270 ng/mL, urine 660 ng/mL Lost of consciousness, heart rate 68–140 bpm, blood pressure Benzodiazepines 110–160/70–100 mm Hg, profound agitation Lost of consciousness, incoherent and slurred speech Blood: methoxetamine 0.21 mg/g AM-2201 0.001 mg/g Severe cerebellar ataxia, drowsiness, slurred speech, dilated Serum: pupils, nystagmus, incoordination, reduced conscious level, methoxetamine 0.24 mg/L tachycardia (heart rate 107 bpm), hypertension (blood pressure 194/110 mm Hg), increased serum creatine kinase (701 U/L) Severe cerebellar ataxia, slurred speech, reduced conscious Serum: Intravenous level, imbalance, incoordination, horizontal nystagmus, methoxetamine 0.45 mg/L hydration, hypothermia (34.5 C), hypertension (blood pressure 148/ warming 104 mm Hg) Serum: Truncal ataxia, slurred speech, incoordination, imbalance, methoxetamine 0.16 mg/L reduced conscious level, minor horizontal nystagmus, hypertension (blood pressure 151/112 mm Hg) Clonazepam Methoxetamine: Convulsions, sinus bradycardia (heart rate 48 bpm), serum 30 mg/L, hyponatremia (127 mmol/L), slightly increased serum creatine kinase (270 U/L) urine 408 mg/L, hair (collected 6 weeks after intoxication) 135 and 145 g/mg Slurred and deliberate speech, diminished motor skills, uncontrolled movements
Blood: methoxetamine 10 ng/mL; carboxy-THC, clonazepam,7-aminoclonazepam, diphenhydramine, MDMA
Fatal intoxication M/26 Pulmonary edema
M/31
Femoral blood: methoxetamine 8.6 mg/mg venlafaxine 0.3 mg/g O-desmethylvenlafaxine 0.4 mg/g AM-694 0.00009 mg/g AM-2201 0.0003 mg/g JWH-018 0.00005 mg/g Coma with acute respiratory failure, hyperthermia (>39 C), Serum: generalized seizures, marked leukocytosis, rhabdomyolysis, methoxetamine 0.32 mg/mL hepatic failure, acute renal failure. amphetamine 0.06 mg/mL The patient died 4 weeks after the poisoning in the course ofmulti-organ dysfunction syndrome.
References
Nasal insufflation
Nasal insufflation
Intramuscular injection
Wood et al. (2012a) Hydzik et al. (2012) ŁukasikGłe˛bocka et al. (2013) Sein et al. (2012) Wikström et al. (2013)
Nasal insufflation
Nasal insufflation
Shields et al. (2012)
Nasal insufflation
Inhalation of vapour heated on a sheet of aluminum foil
Imbert et al. (2014)
Elian and Hacket (2014)
Wikström et al. (2013)
Wiegrowski et al. (2014)
5-APB:1-benzofuran-5-ylpropan-2-amine;6-APB:1-benzofuran-6-ylpropan-2-amine. a Patient admitted consumption of approximately 500 mg of ‘methoxetamine, 750 mg of benzofury’ and 1.5 L of beer. b Patient admitted consumption of approximately 200 mg of ‘methoxetamine powder’. c Patient admitted consumption of50–100 mg of ‘methoxyketamine 99.9% – research chemical’. d Patient admitted injection of approximately 100 mg of ‘methoxetamine’ and consumption of codeine tablets 3 h later. e Patient admitted consumption of approximately 50 mg of ‘methoxetamine’.
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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individuals attending gay-friendly nightclubs in south-east London in July 2011 on their use of novel psychoactive substances, cocaine, and MDMA. It was found that 206 out of 313 (65.8%) individuals reported having previously used a ‘legal high’. Of these, 6.4% reported lifetime use of methoxetamine, 1.9% reported its use in the last month, and 1.6% reported use on the night of the survey or planned to use it later that night. The results of the online 2012 Global Drug Survey conducted in November 2011 show that out of 7700 respondents from the United Kingdom, 4.2% and 2.4% reported using methoxetamine in the last year and previous month, respectively (EMCDDA, 2013b). The most common routes of administration for methoxetamine include nasal insufflation (‘sniffing’ or ‘snorting’) and oral consumption, where it is swallowed either as a powder wrapped in a cigarette paper (so-called ‘bombing’) or dissolved in a solution. There are also reports on intramuscular/intravenous injections, sublingual, and rectal administration (Corazza et al., 2012; Kjellgren and Jonsson, 2013; Östberg et al., 2013). Kjellgren and Jonsson (2013) analyzed 33self-reported experiences of methoxetamine use from user websites, where methoxetamine was the only drug reported to have been used at the time, and found the total amount of methoxetamine taken during the experiences ranged from 10 to 200 mg. A common dose of methoxetamine reported by the users was 20–60 mg for insufflation, 40–60 mg for oral administration, and15–30 mg for intramuscular injection. The duration of the drug's action depends on the route of administration: 2.5–4 h for nasal, 3–5 h for oral, and 2–3 h for intramuscular (Kjellgren and Jonsson, 2013). Up to now, the highest reported dose of methoxetamine used was 750 mg injected intramuscularly. Interestingly, a young man used methoxetamine to avoid agitation and excitement after codeine abuse (Sein et al., 2012).
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4. Effects related to methoxetamine use
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Information on effects of methoxetamine are largely limited toself-reported experiences from user websites (Corazza et al., 2012, 2013; Kjellgren and Jonsson, 2013) and case reports/series (Elian and Hacket, 2014; Hofer et al., 2012; Imbert et al., 2014; Shields et al., 2012; Ward et al., 2011; Westwell et al., 2013). The intended effects include euphoria, increased empathy and social interaction, feelings of peacefulness and calmness, vivid visual hallucinations, intensification of sensory experiences (especially to music), introspection, sense of dissociation from the physical body, a sense of going deeper inside the self, brief antidepressant effects, spiritual and transcendental experiences, and at high dosesout-of-body or evennear-death experiences (Corazza et al., 2012, 2013; Kjellgren and Jonsson, 2013). In some cases, the dissociative effects of methoxetamine are described as beingketamine-like, although user reports suggest they may last for a longer period of time, up to 24 h (Corazza et al., 2012). At higher doses, methoxetamine produces awide-range of unwanted effects, among them slurred speech, impairment to understand language, distortion of time perception, reduced ability to concentrate and focus, inability to coordinate movement, anxiety, fear, paranoia, changes in perception of distance, proportion and the body image, and psychomotor agitation (Corazza et al., 2012; Elian and Hacket, 2014; Kjellgren and Jonsson, 2013). Someself-reported experiences on user websites suggest compulsivere-dosing of methoxetamine as well as the unintentional consumption of more than initially planned (e.g., Erowid, 2012). However, no data appears to have been published on the dependence and abuse potential of methoxetamine, both in animals or in humans.
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5. Methoxetamine-induced toxicity
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Although methoxetamine is advertised as a bladder-friendly analogue of ketamine (e.g., Morris and Walach, 2014), results from
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193 recent studies performed on animals indicate that this may not be 194 true. Daily treatment of mice with 30 mg/kg of methoxetamine for 195 3 months resulted in significant bladder inflammation with 196 subsequent fibrosis and renal toxicity (Dargan et al., 2014). 197 A total of 110non-fatal intoxications with methoxetamine have 198 been reported by EMCDDA by the end of 2012, almost half of them 199 being analytically confirmed: 1 in Belgium, 3 in France, 12 in Italy, 200 and 36 in Sweden (EMCDDA, 2013b). There are a few published 201 cases of methoxetamine toxicity (Abe et al., 2013; Hofer et al., 202 2012; Hydzik et al., 2012; Łukasik-Głe˛bocka et al., 2013; Sein et al., 203 2012; Shields et al., 2012; Wikström et al., 2013; Wood et al., 2012a; 204 see also Loeffler and Craig, 2013), summarized in Table 1. In addition, Hill et al. (2013) characterized enquires regarding toxic Q10 205 206 effects of methoxetamine reported to the National Poison 207 Information Service in the United Kingdom. The clinical features 208 ofmethoxetamine-induced toxicity could be divided into the 209 following main groups: (1) psychiatric – anxiety, hallucinations, 210 panic, profound agitation, aggression, violence; (2) cognitive –211 black-outs, confusion, disorientation, amnesia, and lowered 212 consciousness; (3) neurological – catatonic state, cerebral ataxia, 213 mydriasis, slurred speech, drowsiness, tremor, vertigo, insomnia, 214 and motor incoordination; (4) cardiovascular – tachycardia, 215 hypertension, cardiac and respiratory depression, and chest pain. 216 A very recent study of ananalytically-confirmed case of acute 217 intoxication after inhalation of methoxetamine presented epileptic 218 seizures, sinus bradycardia (48 bpm), elevation of theST-segment 219 in the electrocardiogram recording and hyponatrenia (Imbert et al., 220 2014). 221 It has to be emphasized that in addition to methoxetamine, 222 other psychoactive compounds and their metabolites have also 223 been detected in the blood/serum samples of intoxicated subjects, 224 including MDMA (Elian and Hacket, 2014; Hofer et al., 2012), 225 carboxy-D9-tetrahydrocannabinol (carboxy-THC) (Elian and 226 Hacket, 2014), AM-2201 (Wikström et al., 2013), clonazepam 227 and 7-aminoclonazepam (Elian and Hacket, 2014); diphenhydra228 mine, venlafaxine and desmethylvenlafaxine (Wikström et al., 229 2013; Wood et al., 2012a), derivatives of 1-benzofunan: 5-APB/ 230 6-APB (Wood et al., 2012a). Treatment of these intoxication cases 231 was supportive, with the administration of benzodiazepines 232 (for sedation),anti-emetics, intravenous fluids (for dehydration), 233 and physical restraints and respiratory support as required. 234 More than 20 deaths due to methoxetamine overdose have 235 been disseminated. In all these cases, the presence of methoxetamine was analytically confirmed. It should be noted that the Q11 236 237 conducted postmortem analysis also revealed the presence of 238 other psychoactive drugs of abuse, such as alcohol, THC, MDA, 239 amphetamines, MDMA, cocaine, synthetic cannabimimetics, 240 ketamine, APB, and opioids (Chiappini et al., 2014; EMCDDA, 241 2013b; Wiegrowski et al., 2014; Wikström et al., 2013).
6. Analytical methods for determination and measurement of methoxetamine
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The last decade has witnessed an alarming increase in the number of novel psychoactive compounds introduced to the drug market as alternatives of controlled substances of abuse. This phenomenon was accompanied by an urgent need to develop fast and effective analytical methods for qualitative and quantitative measurements of new drugs in products, and more importantly in biological samples. At present, the most common are chromatographic methods with mass spectrometric detection. First measurements of methoxetamine concentration in human blood used gaschromatography–mass spectrometry (Shield et al., 2012; Wood et al., 2012a). Recently, liquid chromatography with electrical ionizationion-trap tandem mass spectrometric detection (LC-EI-IT-MS-MS) has been developed for measurement
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Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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of methoxetamine in human blood, urine, and vitreous body (Abe et al., 2013; Al-Saffar et al., 2013; De Paoli et al., 2013; Soh and Elliott, 2014). Furthermore, a technique established and valided by Abe et al. (2013) allowed to coupleLC-EI-IT-MS-MS with anon-line automatic sample preparation using aTurbo-Flow device. The mass spectrum of methoxetamine contains the parent protonated [M + H]+ ion at m/z 248. The most intense ion product was observed at m/z 203 (Abe et al., 2013; Al-Saffar et al., 2013; De Paoli et al., 2013), a much weaker signal was found at m/z 175 (Al-Saffar et al., 2013; De Paoli et al., 2013). Methoxetamine was found to be stable over 21 days in blood and plasma (Soh and Elliott, 2014) or 3 months in urine (Al-Saffar et al., 2013) stored at room temperature.
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7. Conclusions
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Methoxetamine is a new designer drug with a wide range of effects, some of which resemble and others greatly vary from effects of similar hallucinogenic/dissociative compounds, ketamine, and phencyclidine. The consumption of methoxetamine carries a significant health risk. A great deal of research is still needed to fully quantify the short- andlong-term effects of methoxetamine and its interaction with other drugs of abuse.
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Conflict of interest
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The author declares that there are no conflict of interest.
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Transparency document
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The Transparency document associated with this article can be found in the online version.
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Acknowledgment
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This work was supported by the Medical University of Lodz (503/3-011/503-01).
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References
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Abe, E., Ricard, F., Darrouzain, F., Alvarez, J.C., 2013. An automated method for measurement of methoxetamine in human plasma by use of turbulent flowonline extraction coupled with liquid chromatography and mass spectrometric detection. Anal. Bioanal. Chem. 405, 239–245. Al-Saffar, Y., Stephanson, N.N., Beck, O., 2013. Milticomponent LC–MS/MS screening method for detection of new psychoactive drugs, legal highs, in urine – experience from the Swedish population. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 930, 112–120. Chiappini, S., Claridge, H., Cockery, J., Goodair, C., Loi, B., Schifano, F., 2014. Special M related fatalities in the UK. Res. Adv. Psychiatry 1 (Suppl. 1), 38. Corazza, O., Assi, S., Schifano, F., 2013. From special K to special M: the evolution of the recreational use of ketamine and methoxetamine. CNS Neurosci. Ther. 19, 454–460. Corazza, O., Schifano, F., Simonato, P., Fergus, S., Assi, S., Stair, J., Corkery, J., Trincas, G., Deluca, P., Davey, Z., Blaszko, U., Demetrovics, Z., Moskalewicz, J., Enea, A., di Melchiorre, G., Mervo, B., di Furia, L., Farre, M., Flesland, L., Pasinetti, M., Pezzolesi, C., Pisarska, A., Shapiro, H., Siemann, H., Skutle, A., Enea, A., di Melchiorre, G., Sferrazza, E., Torrens, M., van der Kreeft, P., Zummo, D., Scherbaum, N., 2012. Phenomenon of new drugs on the Internet: the case of ketamine derivative methoxetamine. Hum. Psychopharmacol. 27, 145–149. Dargan, P.I., Tang, H.C., Liang, W., Wood, D.M., Yew, D.T., 2014. Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice. Clin. Toxicol. (Phila.) 52, 176–180. Davidson, C., Hashemi, G., Gant, A., Fergus, S., Benha, C., Lione, L., 2014. Effects of methoxetamine in rat bladder and nucleus accumbens brain tissue. Res. Adv. Psychiatry 1 (Suppl. 1), 39. De Paoli, G., Brandt, S.D., Wallach, J., Archer, R.P., Pounder, D.J., 2013. From street to laboratory: analytical profiles of methoxetamine,3-methoxyeticyclidine and 3methoxyphencyclidine and their determinations in three biological matrices. J. Analyt. Toxicol. 37, 277–283. Elian, A.A., Hacket, J., 2014. A polydrug intoxication involving methoxetamine in a drugs and driving case. J. Forensic Sci. 59, 854–858.
301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317
EMCDDA, 2013. EU drug markets reports. A strategic analysis. Available at http://www.emcdda.europa.eu/publications/joint-publications/drug-markets (retrieved 9.06.14.). EMCDDA, 2013. Methoxetamine. EMCDDA – Europol Joint Report on a new psychoactive substance: methoxetamine(2-(3-methoxyphenyl)-2(ethylamino) cyclohexanone). Available at http://www.emcdda.europa.eu/ attachements.cfm/att_222602_EN_TDAS14004ENN-1.pdf. (retrieved 15.05.14.). EMCDDA, 2014. European Drug Report 2014. Available at http://www.emcdda. europa.eu/edr2014. (retrieved 30.05.14.). http://www.drugs.com/ketamine (retrieved 26.05.14.). Erowid, 2012. Available at https://www.erowid.org/experiences/exp.php? ID=97506 (retrieved 9.06.13.). Giné, C.V., Espinosa, I.F., Vilamala, M.V., 2014. New psychoactive substance as adulterants of controlled drugs. A worrying phenomenon? Drug Test Anal. 6, 819–824. Hill, S.L., Harbon, S.C., Coulson, J., Cooper, G.A., Jackson, G., Lupton, D.J., Vale, J.A., Thomas, S.H., 2013. Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order). Emerg. Med. J. 31, 45–47. Hofer, K.E., Grager, B., Müller, D.M., Rauber-Lüthy, C., Kupferschmidt, H., Rentsch, K. M., Ceschi, A., 2012. Ketamine-like effects after recreational use of methoxetamine. Ann. Emerg. Med. 60, 97–99. Home Office, 2013. Available at https://www.gov.uk/government/uploads/system/ uploads/attachment_data/file/170610/offence-recording-codes.pdf. (retrieved 9.07.14.). Hydzik, P., Gomółka, E., Sulka, A., Cudzik-Czop, S., 2012. Acute methoxetamine poisoning – case report. Problems Forensic Sci. 91, 235–242. Imbert, L., Boucher, A., Delhome, G., Cueto, T., Boudinaud, M., Maublanc, J., Dulaurent, S., Descotes, J., Lachâtre, G., Gaulier, J.M., 2014. Analytical findings of an acute intoxication after inhalation of methoxetamine. J. Anal. Toxicol. doi: http://dx.doi.org/10.1093/jat/bku052. Johnson, L.A., Johnson, R.L., Portier, R.B., 2013. Current legal highs. J. Emerg. Med. 44, 1108–1115. Kjellgren, A., Jonsson, K., 2013. Methoxetamine (MXE): a phenomenological study of experiences induced by a legal high from the Internet. J. Psych. Drugs 45, 276–286. Loeffler, G., Craig, C., 2013. Methoxetamine misuse and toxicity. J. Stud. Alcohol Drugs 74, 816–817. ska-Psuja, B., Druzdz, A., 2013. Acute Łukasik-Głe˛bocka, M., Sommerfeld, K., Zielin methoxetamine intoxication – case report with serum and urine concentrations. Przegl. Lek. 70, 671–673. Menzies, E.L., Hudson, S.C., Dargan, P.I., Parkin, M.C., Wood, D.M., Kicman, A.T., 2013. Characterizing metabolites and potential metabolic pathways for the novel psychoactive substance methoxetamine. Drug Test. Anal. 5, 506–515. Meyer, M.R., Bach, M., Welter, J., Bovens, M., Turcant, A., Maurer, H.H., 2012. Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC–MS andLC-(HR-) MSn. Anal. Bioanal. Chem. 405, 6307–6321. Morgan, C.J.A., Curran, H.V., 2011. Ketamine use: a review. Addiction 107, 27–38. Morris, H., Walach, J., 2014. From PCP to MXE: a comprehensive review of thenonmedical use of dissociative drugs. Drug Test. Anal. 6, 214–232. Östberg, L.L., Hultén, P., Al-Saffar, Y., 2013. Methoxetamine: a case series of analytically confirmed cases. Clin. Toxicol. (Phila.) 51, 257–258. Papaseit, E., Farré, M., Schifano, F., Torrens, M., 2014. Emerging drugs in Europe. Curr. Opin. Psychiatry 27, 242–250. Roth, B.L., Gibbons, S., Arunotayanun, W., Huang, X.P., Setola, V., Treble, R., Iversen, L., 2013. The ketamine analogue methoxetamine and 3- and4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One 8, e59334. Sein, A., Wiergowski, M., Barwina, M., Kaletha, K., 2012. Accidental intoxication with high dose of methoxetamine (MXE): a case report. Przegl. Lek. 69, 609–610. Shields, J.E., Dargan, P.I., Wood, D.M., Puchnarewicz, M., Davies, S., Waring, W.S., 2012. Methoxetamine associated reversible cerebellar toxicity: three cases with analytical confirmation. Clin. Toxicol. (Phila.) 50, 438–440. Soh, Y.N.A., Elliott, S., 2014. An investigation of the stability of emerging new psychoactive substances. Drug Test. Anal. 6, 696–704. Ward, J., Rhyee, S., Plansky, J., Boyer, E., 2011. Methoxetamine: a novel ketamine analog and growinghealth-care concern. Clin. Toxicol. (Phila.) 49, 874–875. Westwell, A.D., Hutchings, A., Caldicott, D.G., 2013. The identification and chemical characterization of a new arylcyclohexylamine, methoxetamine, using a novel emergency department toxicosurveillance tool. Drug Test. Anal. 5, 203–207. _ Wiegrowski, M., Anand, J.S., Krzyzanowski, M., Jankowski, Z., 2014. Acute methoxetamine and amphetamine poisoning with fatal outcome – a case report. Int. J. Occup. Med. Environ. Health doi:http://dx.doi.org/10.2478/s 13382-014-0290-8. Wikström, M., Thelander, G., Dahlgren, M., Kronstrand, R., 2013. An accidental fatal intoxication with methoxetamine. J. Anal. Toxicol. 37, 43–46. Wood, D.M., Davies, S., Puchnarewicz, M., Johnston, A., Dargan, P.I., 2012a. Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine. Eur. J. Clin. Pharmacol. 68, 853–856. Wood, D.M., Hunter, L., Measham, F., Dargan, P.I., 2012b. Limited use of novel psychoactive substances in South London nightclubs. QJM 105, 959–964. Zawilska, J.B., 2011. Legal highs – new players in the old drama. Curr. Drug Abuse Rev. 4, 122–130.
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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TOXLET 8858 1–6 Toxicology Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
1
Mini review
Methoxetamine – a novel recreational drug with potent hallucinogenic properties
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4 Q1
Jolanta B. Zawilska *
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Department of Pharmacodynamics, Medical University of Lodz,90-151Lodz, Muszynskiego 1, Poland
H I G H L I G H T S
Q2
Methoxetamine (MXE), a structural analogue of ketamine, is a novel designer drug. MXE is recreationally used due to its potent hallucinogenic and dissociate effects. Consumption of MXE bears a significant health risk. Long-term effects and interaction of MXE with other drugs of abuse remain to be elucidated.
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 June 2014 Received in revised form 7 August 2014 Accepted 11 August 2014 Available online xxx
Methoxetamine is one of the constantly growing group of novel psychoactive substances that has emerged in recent years. The compound belongs to the arylcyclohexylamine class, which is used for its recreational and psychedelic effects. Methoxetamine is a structural analogue of ketamine, with a much longer duration of action and intensity of effects, and has been extensively advertised as its 'legal' and 'bladder friendly' alternative. This review surveys the current state of knowledge regarding the metabolism, pharmacology, prevalence and pattern of methoxetamine use, and analytical methods of its detection. Consumption of methoxetamine bears a significant health risk and may even lead to fatal intoxication. A significant amount of research is still needed in order to fully quantify the short- and longterm effects of methoxetamine and its interaction with other drugs of abuse. ã 2014 Published by Elsevier Ireland Ltd.
Keywords: Methoxetamine Novel psychoactive substances Hallucinogenic/dissociative drugs Toxidrome
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism and pharmacological properties of methoxetamine . . . . . . . . . Prevalence and pattern of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects related to methoxetamine use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methoxetamine-induced toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analytical methods for determination and measurement of methoxetamine Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Tel.: +48 42 6779294. E-mail addresses: [email protected], [email protected] (J.B. Zawilska).
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1. Introduction
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Recently, a new class of psychoactive substances, known as 'legal highs', 'herbal highs', 'designer drugs' or 'research chemicals', has emerged on the drug use market. They include a wide range of
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http://dx.doi.org/10.1016/j.toxlet.2014.08.011 0378-4274/ ã 2014 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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products, from naturalplant-originated substances to semisynthetic and synthetic compounds (EMCDDA, 2013a; Johnson et al., 2013; Papaseit et al., 2014; Zawilska, 2011). Based on the spectrum of exerted psychoactive effects, these compounds can be classified into four basic categories: synthetic cannabimimetics ("Spice"/K2), stimulants, hallucinogens, and opioid-like drugs (Zawilska, 2011). The EU warning system operated by the European Monitoring Centre for Drugs and Drug Addition (EMCDDA) reported the Q3 appearance of 317 new psychoactive substances between 2005 and 2013 (EMCDDA, 2013a, 2014). Importantly, the EU drug market report emphasizes that "...while the appearance of new drugs is not a new phenomenon, over the last few years there has been an unprecedented growth in their number, type, and availability" (EMCDDA, 2013a). Ketamine is awell-known anesthetic with a good safety profile, which is used particularly in pediatric and veterinary anesthesia, and as aco-analgetic in pain management. However, since the mid1990s, its potent hallucinogenic and dissociate effects have afforded ketamine the status of a recreational drug used mainly by teenagers and young adults at dance clubs, raves, and squat parties (Morris and Walach, 2014). Common street names for ketamine include: K, Special K, K2, Vitamin K, Super K, Super C, Lady K,Ket-Kit Kat Ketaset, Ketaject, Jet Super Acid, Green, Purple, Special LA Coke, Cat Tranquilizers, and Cat Valium (www.drugs. com). A growing body of clinical data indicates that repeated misuse of ketamine induces ulcerative cystitis resulting in haematuria, loss of bladder control; it can also lead to neurocognitive impairment (Morgan and Curran, 2011).
In May 2010, the first public report on effects of methoxetamine (2-(3-methoxyphenyl)-2-(ethylamino)cyclohexan-1-one; MXE or3-MeO-2-OxoPCE), a new designer drug, was published on the Internet (Morris and Walach, 2014). An evolution of methoxetamine at the research chemicals and recreational drug market has been described by Morris and Walach (2014) in a comprehensive and elegant review on dissociate drugs. The drug is a member of the arylcyclohexylamine family; more specifically, it is a structural analogue of ketamine, where the2-chloro group on the phenyl ring and the N-methylamino group of ketamine have been replaced by a3-methoxy and N-ethylamino group, respectively (Fig. 1). Soon after, methoxetamine was extensively advertised as a 'legal' and 'bladder friendly' alternative to ketamine (EMCDDA, 2013b; Kjellgren and Jonsson, 2013; Morris and Wallach, 2014). Methoxetamine is typically sold as a free base and hydrochloride salt in powder. The common street names of methoxetamine are: ‘MXE’, ‘Mexxy’, ‘M-ket’, ‘MEX’, ‘Kmax’, ‘Special M’, ‘MA’, ‘legal ketamine’, ‘Minx’, ‘Jipper’, and ‘Roflcoptr’ (EMCDDA, 2013b). According to the EMCDDA report, the following ‘legal highs’ product names have been associated with methoxetamine: ‘Kwasqik’, ‘Hypnotic’, ‘Panoramix’, ‘Magic’, ‘Lotus’, and ‘X’ (EMCDDA, 2013b). By 2013, methoxetamine had been seized in a number of countries throughout Europe, including Belgium, Italy, Sweden, and the United Kingdom (EMCDDA, 2013b). Although in vast majority of samples, methoxetamine was the only detected compound; some of them also contained other psychoactive compounds, such as phenethylamines (e.g.,4-fluoroamphetamine), synthetic cathinones (e.g., methylone,
Fig. 1. Chemical structure of phencyclidine, ketamine, and methoxetamine.
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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mephedrone, and 3,4-methylendioxypyrovalerone), synthetic cannabimimetics (AM-2201,JWH-018), benzodiazepines, methylphenidate, ketamine, amphetamine, methamphetamine, 3,4-methylenedioxy-N-methylamphetamine (MDMA), cannabis, morphine, and heroin (EMCDDA, 2013b). Methoxetamine has been found in 18 out of 173 samples of controlled drugs submitted to the Spanish Drug Checking Service between 2009 and 2012: in 15 ketamine samples, and in single samples of MDMA, amphetamine and cocaine (Giné et al., 2014). In 2013, methoxetamine was brought under permanent control in the United Kingdom as a Class B drug (Home Office, 2013). 2. Metabolism and pharmacological properties of methoxetamine In vitro studies using human liver microsomes and human liver S9 fraction revealed that methoxetamine undergoes a complex phase I metabolism, including N-deethylation, O-demethylation, hydroxylation, reduction, and dehydrogenation (Menzies et al., 2013). Kinetic studies with human hepatic CYP isoenzymes have demonstrated that N-deethylation is catalyzed by CYP2B6 and CYP3A4, O-demethylation by CYP2B6 and CYP2C19, and hydroxylation by CYP2B6 (Meyer et al., 2012). Using liquid chromatography–high resolution mass spectrometry (LC–MS)n, several different metabolites of the drug were identified, namely N-desethylmethoxetamine (normethoxetamine; a major metabolite), O-desmethyl-methoxetamine, O-desmethylnormethoxetamine, dihydronormethoxetamine,
3
O-desmethylhydroxynormethoxetamine, and hydroxynormethoxetamine (Fig. 2). Phase II metabolites were mainlymonoglucoronide conjugates (Menzies et al., 2013; Meyer et al., 2012). An analysis of urine samples collected from three individuals presenting acute methoxetamine toxicity demonstrated the presence of in vitro microsomal metabolites, with the exception of O-desmethylhydroxynormetho-xetamine (Menzies et al., 2013). Similar results were obtained by Meyer et al. (2012) for rat and human urine. Confirmation of the important role played by CYP2B6 in methoxetamine metabolism is of clinical importance. As CYP2B6 is involved in metabolism of numerous drugs and xenobiotics, pharmacokinetic interactions between methoxetamine and other compounds are likely to occur. Furthermore, the rate of methoxetamine metabolism and its toxicity may depend on genetic polymorphism of CYP2B6. However, the precise nature of the biological activity of specific methoxetamine metabolites, if any, remains unknown. Little is known about pharmacological activity of methoxetamine. Very recently, Roth et al. (2013) performed an in vitro Q7 examination of the neuropharmacological profile of methoxetamine by screening its activity at 57 molecular targets relevant to the action of the drug with the CNS. They found that methoxetamine has asub-micromolar affinity for the glutamate N-methylD-aspartate (NMDA) receptor (pKi = 6.59), which is comparable to Q8 that of ketamine (pKi = 6.18), and binds to the phencyclidine site on the NMDA receptor. In addition, methoxetamine was found to
Fig. 2. Major metabolic pathways for methoxetamine (modified from Menzies et al., 2013).
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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exhibit asub-micromolar affinity (pKi = 6.32) for the serotonin transporter, thus resembling the property of phencyclidine (pKi = 5.65). Furthermore, it has been shown that methoxetamine increaseselectrically-stimulated release of dopamine from slices of rat nucleus accumbens and inhibits the re-uptake of the amine (Davidson et al., 2014).
3. Prevalence and pattern of use
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Currently, limited information is available regarding the prevalence and pattern of methoxetamine use, and existing studies should be taken with caution as many of them are based on online surveys and self-reports on user websites. Wood et al. (2012b) surveyed
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Table 1 Case reports of acute and fatalmethoxetamine-induced intoxication. Gender, age
Symptoms
Drugs found in biological samples Treatment
Way of MXE administration
Acute intoxication M/42a Drowsiness, tachycardia (heart rate 135 bpm), hypertension (blood pressure 187/83 mm Hg), pyrexia (38.2 C)
Nasal insufflation
M/29b
Oral
M/28
M/24c
M/28
M/25d M/27
M/19
M/17
M/18
M/21e
M
Diazepam Serum: methoxetamine 0.12 g/mL, 5-APB or6-APB Serum: Diazepam Tremor, visual hallucinations, confusion, tachycardia (heart rate 121 bpm), hypertension (blood pressure 201/104 mm Hg) methoxetamine 0.09 mg/mL, diphenhydramine and venlafaxine Serum: Agitation, aggression, confusion, drowsiness, tachycardia Midazolam methoxetamine 0.20 mg/mL (heart rate 113 bpm), hypertension (blood pressure 198/ 78 mm Hg), dilated pupils Methoxetamine: Drowsiness, dysphasia, hallucinations, impaired motor coordination, blood pressure up to 140/90 mm Hg, heart rate serum 450 ng/mL, up to 120 bpm urine 7200 ng/mL Benzodiazepines Extreme agitation, aggression, confusion, hallucinations, Methoxetamine: tachycardia (heart rate 105 bpm) serum 270 ng/mL, urine 660 ng/mL Lost of consciousness, heart rate 68–140 bpm, blood pressure Benzodiazepines 110–160/70–100 mm Hg, profound agitation Lost of consciousness, incoherent and slurred speech Blood: methoxetamine 0.21 mg/g AM-2201 0.001 mg/g Severe cerebellar ataxia, drowsiness, slurred speech, dilated Serum: pupils, nystagmus, incoordination, reduced conscious level, methoxetamine 0.24 mg/L tachycardia (heart rate 107 bpm), hypertension (blood pressure 194/110 mm Hg), increased serum creatine kinase (701 U/L) Severe cerebellar ataxia, slurred speech, reduced conscious Serum: Intravenous level, imbalance, incoordination, horizontal nystagmus, methoxetamine 0.45 mg/L hydration, hypothermia (34.5 C), hypertension (blood pressure 148/ warming 104 mm Hg) Serum: Truncal ataxia, slurred speech, incoordination, imbalance, methoxetamine 0.16 mg/L reduced conscious level, minor horizontal nystagmus, hypertension (blood pressure 151/112 mm Hg) Clonazepam Methoxetamine: Convulsions, sinus bradycardia (heart rate 48 bpm), serum 30 mg/L, hyponatremia (127 mmol/L), slightly increased serum creatine kinase (270 U/L) urine 408 mg/L, hair (collected 6 weeks after intoxication) 135 and 145 g/mg Slurred and deliberate speech, diminished motor skills, uncontrolled movements
Blood: methoxetamine 10 ng/mL; carboxy-THC, clonazepam,7-aminoclonazepam, diphenhydramine, MDMA
Fatal intoxication M/26 Pulmonary edema
M/31
Femoral blood: methoxetamine 8.6 mg/mg venlafaxine 0.3 mg/g O-desmethylvenlafaxine 0.4 mg/g AM-694 0.00009 mg/g AM-2201 0.0003 mg/g JWH-018 0.00005 mg/g Coma with acute respiratory failure, hyperthermia (>39 C), Serum: generalized seizures, marked leukocytosis, rhabdomyolysis, methoxetamine 0.32 mg/mL hepatic failure, acute renal failure. amphetamine 0.06 mg/mL The patient died 4 weeks after the poisoning in the course ofmulti-organ dysfunction syndrome.
References
Nasal insufflation
Nasal insufflation
Intramuscular injection
Wood et al. (2012a) Hydzik et al. (2012) ŁukasikGłe˛bocka et al. (2013) Sein et al. (2012) Wikström et al. (2013)
Nasal insufflation
Nasal insufflation
Shields et al. (2012)
Nasal insufflation
Inhalation of vapour heated on a sheet of aluminum foil
Imbert et al. (2014)
Elian and Hacket (2014)
Wikström et al. (2013)
Wiegrowski et al. (2014)
5-APB:1-benzofuran-5-ylpropan-2-amine;6-APB:1-benzofuran-6-ylpropan-2-amine. a Patient admitted consumption of approximately 500 mg of ‘methoxetamine, 750 mg of benzofury’ and 1.5 L of beer. b Patient admitted consumption of approximately 200 mg of ‘methoxetamine powder’. c Patient admitted consumption of50–100 mg of ‘methoxyketamine 99.9% – research chemical’. d Patient admitted injection of approximately 100 mg of ‘methoxetamine’ and consumption of codeine tablets 3 h later. e Patient admitted consumption of approximately 50 mg of ‘methoxetamine’.
Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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individuals attending gay-friendly nightclubs in south-east London in July 2011 on their use of novel psychoactive substances, cocaine, and MDMA. It was found that 206 out of 313 (65.8%) individuals reported having previously used a ‘legal high’. Of these, 6.4% reported lifetime use of methoxetamine, 1.9% reported its use in the last month, and 1.6% reported use on the night of the survey or planned to use it later that night. The results of the online 2012 Global Drug Survey conducted in November 2011 show that out of 7700 respondents from the United Kingdom, 4.2% and 2.4% reported using methoxetamine in the last year and previous month, respectively (EMCDDA, 2013b). The most common routes of administration for methoxetamine include nasal insufflation (‘sniffing’ or ‘snorting’) and oral consumption, where it is swallowed either as a powder wrapped in a cigarette paper (so-called ‘bombing’) or dissolved in a solution. There are also reports on intramuscular/intravenous injections, sublingual, and rectal administration (Corazza et al., 2012; Kjellgren and Jonsson, 2013; Östberg et al., 2013). Kjellgren and Jonsson (2013) analyzed 33self-reported experiences of methoxetamine use from user websites, where methoxetamine was the only drug reported to have been used at the time, and found the total amount of methoxetamine taken during the experiences ranged from 10 to 200 mg. A common dose of methoxetamine reported by the users was 20–60 mg for insufflation, 40–60 mg for oral administration, and15–30 mg for intramuscular injection. The duration of the drug's action depends on the route of administration: 2.5–4 h for nasal, 3–5 h for oral, and 2–3 h for intramuscular (Kjellgren and Jonsson, 2013). Up to now, the highest reported dose of methoxetamine used was 750 mg injected intramuscularly. Interestingly, a young man used methoxetamine to avoid agitation and excitement after codeine abuse (Sein et al., 2012).
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4. Effects related to methoxetamine use
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Information on effects of methoxetamine are largely limited toself-reported experiences from user websites (Corazza et al., 2012, 2013; Kjellgren and Jonsson, 2013) and case reports/series (Elian and Hacket, 2014; Hofer et al., 2012; Imbert et al., 2014; Shields et al., 2012; Ward et al., 2011; Westwell et al., 2013). The intended effects include euphoria, increased empathy and social interaction, feelings of peacefulness and calmness, vivid visual hallucinations, intensification of sensory experiences (especially to music), introspection, sense of dissociation from the physical body, a sense of going deeper inside the self, brief antidepressant effects, spiritual and transcendental experiences, and at high dosesout-of-body or evennear-death experiences (Corazza et al., 2012, 2013; Kjellgren and Jonsson, 2013). In some cases, the dissociative effects of methoxetamine are described as beingketamine-like, although user reports suggest they may last for a longer period of time, up to 24 h (Corazza et al., 2012). At higher doses, methoxetamine produces awide-range of unwanted effects, among them slurred speech, impairment to understand language, distortion of time perception, reduced ability to concentrate and focus, inability to coordinate movement, anxiety, fear, paranoia, changes in perception of distance, proportion and the body image, and psychomotor agitation (Corazza et al., 2012; Elian and Hacket, 2014; Kjellgren and Jonsson, 2013). Someself-reported experiences on user websites suggest compulsivere-dosing of methoxetamine as well as the unintentional consumption of more than initially planned (e.g., Erowid, 2012). However, no data appears to have been published on the dependence and abuse potential of methoxetamine, both in animals or in humans.
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5. Methoxetamine-induced toxicity
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Although methoxetamine is advertised as a bladder-friendly analogue of ketamine (e.g., Morris and Walach, 2014), results from
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193 recent studies performed on animals indicate that this may not be 194 true. Daily treatment of mice with 30 mg/kg of methoxetamine for 195 3 months resulted in significant bladder inflammation with 196 subsequent fibrosis and renal toxicity (Dargan et al., 2014). 197 A total of 110non-fatal intoxications with methoxetamine have 198 been reported by EMCDDA by the end of 2012, almost half of them 199 being analytically confirmed: 1 in Belgium, 3 in France, 12 in Italy, 200 and 36 in Sweden (EMCDDA, 2013b). There are a few published 201 cases of methoxetamine toxicity (Abe et al., 2013; Hofer et al., 202 2012; Hydzik et al., 2012; Łukasik-Głe˛bocka et al., 2013; Sein et al., 203 2012; Shields et al., 2012; Wikström et al., 2013; Wood et al., 2012a; 204 see also Loeffler and Craig, 2013), summarized in Table 1. In addition, Hill et al. (2013) characterized enquires regarding toxic Q10 205 206 effects of methoxetamine reported to the National Poison 207 Information Service in the United Kingdom. The clinical features 208 ofmethoxetamine-induced toxicity could be divided into the 209 following main groups: (1) psychiatric – anxiety, hallucinations, 210 panic, profound agitation, aggression, violence; (2) cognitive –211 black-outs, confusion, disorientation, amnesia, and lowered 212 consciousness; (3) neurological – catatonic state, cerebral ataxia, 213 mydriasis, slurred speech, drowsiness, tremor, vertigo, insomnia, 214 and motor incoordination; (4) cardiovascular – tachycardia, 215 hypertension, cardiac and respiratory depression, and chest pain. 216 A very recent study of ananalytically-confirmed case of acute 217 intoxication after inhalation of methoxetamine presented epileptic 218 seizures, sinus bradycardia (48 bpm), elevation of theST-segment 219 in the electrocardiogram recording and hyponatrenia (Imbert et al., 220 2014). 221 It has to be emphasized that in addition to methoxetamine, 222 other psychoactive compounds and their metabolites have also 223 been detected in the blood/serum samples of intoxicated subjects, 224 including MDMA (Elian and Hacket, 2014; Hofer et al., 2012), 225 carboxy-D9-tetrahydrocannabinol (carboxy-THC) (Elian and 226 Hacket, 2014), AM-2201 (Wikström et al., 2013), clonazepam 227 and 7-aminoclonazepam (Elian and Hacket, 2014); diphenhydra228 mine, venlafaxine and desmethylvenlafaxine (Wikström et al., 229 2013; Wood et al., 2012a), derivatives of 1-benzofunan: 5-APB/ 230 6-APB (Wood et al., 2012a). Treatment of these intoxication cases 231 was supportive, with the administration of benzodiazepines 232 (for sedation),anti-emetics, intravenous fluids (for dehydration), 233 and physical restraints and respiratory support as required. 234 More than 20 deaths due to methoxetamine overdose have 235 been disseminated. In all these cases, the presence of methoxetamine was analytically confirmed. It should be noted that the Q11 236 237 conducted postmortem analysis also revealed the presence of 238 other psychoactive drugs of abuse, such as alcohol, THC, MDA, 239 amphetamines, MDMA, cocaine, synthetic cannabimimetics, 240 ketamine, APB, and opioids (Chiappini et al., 2014; EMCDDA, 241 2013b; Wiegrowski et al., 2014; Wikström et al., 2013).
6. Analytical methods for determination and measurement of methoxetamine
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The last decade has witnessed an alarming increase in the number of novel psychoactive compounds introduced to the drug market as alternatives of controlled substances of abuse. This phenomenon was accompanied by an urgent need to develop fast and effective analytical methods for qualitative and quantitative measurements of new drugs in products, and more importantly in biological samples. At present, the most common are chromatographic methods with mass spectrometric detection. First measurements of methoxetamine concentration in human blood used gaschromatography–mass spectrometry (Shield et al., 2012; Wood et al., 2012a). Recently, liquid chromatography with electrical ionizationion-trap tandem mass spectrometric detection (LC-EI-IT-MS-MS) has been developed for measurement
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Please cite this article in press as: Zawilska, J.B., Methoxetamine – a novel recreational drug with potent hallucinogenic properties. Toxicol. Lett. (2014), http://dx.doi.org/10.1016/j.toxlet.2014.08.011
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of methoxetamine in human blood, urine, and vitreous body (Abe et al., 2013; Al-Saffar et al., 2013; De Paoli et al., 2013; Soh and Elliott, 2014). Furthermore, a technique established and valided by Abe et al. (2013) allowed to coupleLC-EI-IT-MS-MS with anon-line automatic sample preparation using aTurbo-Flow device. The mass spectrum of methoxetamine contains the parent protonated [M + H]+ ion at m/z 248. The most intense ion product was observed at m/z 203 (Abe et al., 2013; Al-Saffar et al., 2013; De Paoli et al., 2013), a much weaker signal was found at m/z 175 (Al-Saffar et al., 2013; De Paoli et al., 2013). Methoxetamine was found to be stable over 21 days in blood and plasma (Soh and Elliott, 2014) or 3 months in urine (Al-Saffar et al., 2013) stored at room temperature.
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7. Conclusions
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Methoxetamine is a new designer drug with a wide range of effects, some of which resemble and others greatly vary from effects of similar hallucinogenic/dissociative compounds, ketamine, and phencyclidine. The consumption of methoxetamine carries a significant health risk. A great deal of research is still needed to fully quantify the short- andlong-term effects of methoxetamine and its interaction with other drugs of abuse.
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Conflict of interest
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The author declares that there are no conflict of interest.
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Transparency document
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The Transparency document associated with this article can be found in the online version.
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Acknowledgment
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This work was supported by the Medical University of Lodz (503/3-011/503-01).
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References
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Abe, E., Ricard, F., Darrouzain, F., Alvarez, J.C., 2013. An automated method for measurement of methoxetamine in human plasma by use of turbulent flowonline extraction coupled with liquid chromatography and mass spectrometric detection. Anal. Bioanal. Chem. 405, 239–245. Al-Saffar, Y., Stephanson, N.N., Beck, O., 2013. Milticomponent LC–MS/MS screening method for detection of new psychoactive drugs, legal highs, in urine – experience from the Swedish population. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 930, 112–120. Chiappini, S., Claridge, H., Cockery, J., Goodair, C., Loi, B., Schifano, F., 2014. Special M related fatalities in the UK. Res. Adv. Psychiatry 1 (Suppl. 1), 38. Corazza, O., Assi, S., Schifano, F., 2013. From special K to special M: the evolution of the recreational use of ketamine and methoxetamine. CNS Neurosci. Ther. 19, 454–460. Corazza, O., Schifano, F., Simonato, P., Fergus, S., Assi, S., Stair, J., Corkery, J., Trincas, G., Deluca, P., Davey, Z., Blaszko, U., Demetrovics, Z., Moskalewicz, J., Enea, A., di Melchiorre, G., Mervo, B., di Furia, L., Farre, M., Flesland, L., Pasinetti, M., Pezzolesi, C., Pisarska, A., Shapiro, H., Siemann, H., Skutle, A., Enea, A., di Melchiorre, G., Sferrazza, E., Torrens, M., van der Kreeft, P., Zummo, D., Scherbaum, N., 2012. Phenomenon of new drugs on the Internet: the case of ketamine derivative methoxetamine. Hum. Psychopharmacol. 27, 145–149. Dargan, P.I., Tang, H.C., Liang, W., Wood, D.M., Yew, D.T., 2014. Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice. Clin. Toxicol. (Phila.) 52, 176–180. Davidson, C., Hashemi, G., Gant, A., Fergus, S., Benha, C., Lione, L., 2014. Effects of methoxetamine in rat bladder and nucleus accumbens brain tissue. Res. Adv. Psychiatry 1 (Suppl. 1), 39. De Paoli, G., Brandt, S.D., Wallach, J., Archer, R.P., Pounder, D.J., 2013. From street to laboratory: analytical profiles of methoxetamine,3-methoxyeticyclidine and 3methoxyphencyclidine and their determinations in three biological matrices. J. Analyt. Toxicol. 37, 277–283. Elian, A.A., Hacket, J., 2014. A polydrug intoxication involving methoxetamine in a drugs and driving case. J. Forensic Sci. 59, 854–858.
301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317
EMCDDA, 2013. EU drug markets reports. A strategic analysis. Available at http://www.emcdda.europa.eu/publications/joint-publications/drug-markets (retrieved 9.06.14.). EMCDDA, 2013. Methoxetamine. EMCDDA – Europol Joint Report on a new psychoactive substance: methoxetamine(2-(3-methoxyphenyl)-2(ethylamino) cyclohexanone). Available at http://www.emcdda.europa.eu/ attachements.cfm/att_222602_EN_TDAS14004ENN-1.pdf. (retrieved 15.05.14.). EMCDDA, 2014. European Drug Report 2014. Available at http://www.emcdda. europa.eu/edr2014. (retrieved 30.05.14.). http://www.drugs.com/ketamine (retrieved 26.05.14.). Erowid, 2012. Available at https://www.erowid.org/experiences/exp.php? ID=97506 (retrieved 9.06.13.). Giné, C.V., Espinosa, I.F., Vilamala, M.V., 2014. New psychoactive substance as adulterants of controlled drugs. A worrying phenomenon? Drug Test Anal. 6, 819–824. Hill, S.L., Harbon, S.C., Coulson, J., Cooper, G.A., Jackson, G., Lupton, D.J., Vale, J.A., Thomas, S.H., 2013. Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order). Emerg. Med. J. 31, 45–47. Hofer, K.E., Grager, B., Müller, D.M., Rauber-Lüthy, C., Kupferschmidt, H., Rentsch, K. M., Ceschi, A., 2012. Ketamine-like effects after recreational use of methoxetamine. Ann. Emerg. Med. 60, 97–99. Home Office, 2013. Available at https://www.gov.uk/government/uploads/system/ uploads/attachment_data/file/170610/offence-recording-codes.pdf. (retrieved 9.07.14.). Hydzik, P., Gomółka, E., Sulka, A., Cudzik-Czop, S., 2012. Acute methoxetamine poisoning – case report. Problems Forensic Sci. 91, 235–242. Imbert, L., Boucher, A., Delhome, G., Cueto, T., Boudinaud, M., Maublanc, J., Dulaurent, S., Descotes, J., Lachâtre, G., Gaulier, J.M., 2014. Analytical findings of an acute intoxication after inhalation of methoxetamine. J. Anal. Toxicol. doi: http://dx.doi.org/10.1093/jat/bku052. Johnson, L.A., Johnson, R.L., Portier, R.B., 2013. Current legal highs. J. Emerg. Med. 44, 1108–1115. Kjellgren, A., Jonsson, K., 2013. Methoxetamine (MXE): a phenomenological study of experiences induced by a legal high from the Internet. J. Psych. Drugs 45, 276–286. Loeffler, G., Craig, C., 2013. Methoxetamine misuse and toxicity. J. Stud. Alcohol Drugs 74, 816–817. ska-Psuja, B., Druzdz, A., 2013. Acute Łukasik-Głe˛bocka, M., Sommerfeld, K., Zielin methoxetamine intoxication – case report with serum and urine concentrations. Przegl. Lek. 70, 671–673. Menzies, E.L., Hudson, S.C., Dargan, P.I., Parkin, M.C., Wood, D.M., Kicman, A.T., 2013. Characterizing metabolites and potential metabolic pathways for the novel psychoactive substance methoxetamine. Drug Test. Anal. 5, 506–515. Meyer, M.R., Bach, M., Welter, J., Bovens, M., Turcant, A., Maurer, H.H., 2012. Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC–MS andLC-(HR-) MSn. Anal. Bioanal. Chem. 405, 6307–6321. Morgan, C.J.A., Curran, H.V., 2011. Ketamine use: a review. Addiction 107, 27–38. Morris, H., Walach, J., 2014. From PCP to MXE: a comprehensive review of thenonmedical use of dissociative drugs. Drug Test. Anal. 6, 214–232. Östberg, L.L., Hultén, P., Al-Saffar, Y., 2013. Methoxetamine: a case series of analytically confirmed cases. Clin. Toxicol. (Phila.) 51, 257–258. Papaseit, E., Farré, M., Schifano, F., Torrens, M., 2014. Emerging drugs in Europe. Curr. Opin. Psychiatry 27, 242–250. Roth, B.L., Gibbons, S., Arunotayanun, W., Huang, X.P., Setola, V., Treble, R., Iversen, L., 2013. The ketamine analogue methoxetamine and 3- and4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One 8, e59334. Sein, A., Wiergowski, M., Barwina, M., Kaletha, K., 2012. Accidental intoxication with high dose of methoxetamine (MXE): a case report. Przegl. Lek. 69, 609–610. Shields, J.E., Dargan, P.I., Wood, D.M., Puchnarewicz, M., Davies, S., Waring, W.S., 2012. Methoxetamine associated reversible cerebellar toxicity: three cases with analytical confirmation. Clin. Toxicol. (Phila.) 50, 438–440. Soh, Y.N.A., Elliott, S., 2014. An investigation of the stability of emerging new psychoactive substances. Drug Test. Anal. 6, 696–704. Ward, J., Rhyee, S., Plansky, J., Boyer, E., 2011. Methoxetamine: a novel ketamine analog and growinghealth-care concern. Clin. Toxicol. (Phila.) 49, 874–875. Westwell, A.D., Hutchings, A., Caldicott, D.G., 2013. The identification and chemical characterization of a new arylcyclohexylamine, methoxetamine, using a novel emergency department toxicosurveillance tool. Drug Test. Anal. 5, 203–207. _ Wiegrowski, M., Anand, J.S., Krzyzanowski, M., Jankowski, Z., 2014. Acute methoxetamine and amphetamine poisoning with fatal outcome – a case report. Int. J. Occup. Med. Environ. Health doi:http://dx.doi.org/10.2478/s 13382-014-0290-8. Wikström, M., Thelander, G., Dahlgren, M., Kronstrand, R., 2013. An accidental fatal intoxication with methoxetamine. J. Anal. Toxicol. 37, 43–46. Wood, D.M., Davies, S., Puchnarewicz, M., Johnston, A., Dargan, P.I., 2012a. Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine. Eur. J. Clin. Pharmacol. 68, 853–856. Wood, D.M., Hunter, L., Measham, F., Dargan, P.I., 2012b. Limited use of novel psychoactive substances in South London nightclubs. QJM 105, 959–964. Zawilska, J.B., 2011. Legal highs – new players in the old drama. Curr. Drug Abuse Rev. 4, 122–130.
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