Article

Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice

Taylor & Francis
Clinical Toxicology
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Abstract

Unlabelled: CONTEXT.: Methoxetamine is a ketamine analogue that has recently emerged as a novel psychoactive substance. Chronic ketamine use is associated with significant bladder and renal toxicity. Methoxetamine has been marketed as "bladder friendly", but there is no data to be able to substantiate this claim. Objective: To characterise the patterns of bladder and renal toxicity associated with 3 months of methoxetamine administration in an animal model. Materials and methods: Two-month-old Institute of Cancer Research mice were administered 30 mg/kg methoxetamine intraperitoneally (n = 5) or saline (n = 3 control) for 3 months. The animals were then sacrificed and histological examination, immuno-cytochemistry using polyclonal anti-CD4 antibodies and sirius-red staining for collagen were performed. Results: The kidneys of methoxetamine-treated animals showed inflammatory cell infiltration, tubular cell necrosis and glomerular damage (1.9 ± 0.3% shrunken glomeruli in control, 9.8 ± 0.8% in methoxetamine-treated mice (p < 0.0001); 2.9 ± 0.3% tubular cell degeneration in control, 20.4 ± 1.1% in methoxetamine-treated mice (p < 0.0001)). There was a greater density of mononuclear cells in the bladder lamina propria and submucosa in methoxetamine-treated mice (43.0 ± 2.1 per 250 × 250 μm) than controls (7.1 ± 1.2 per 250 × 250 μm), p < 0.001. CD4-positive staining was seen in the bladder submucosa and lamina propria of all methoxetamine-treated mice and muscle-layer of two methoxetamine-treated mice; these changes were not seen in the control mice. There was an increase in sirius-red collagen in the bladder sub-mucosa and muscle-layer in the methoxetamine-treated mice compared with control mice. Discussion: This study has shown that 3 months of daily 30 mg/kg intra-peritoneal methoxetamine results in significant bladder and renal toxicity in mice. Changes in the bladder included inflammatory changes with subsequent fibrosis and changes in the kidney were seen at both a tubular and glomerular level. These changes are similar to those seen in comparable animal models of chronic ketamine administration. Further work is required to determine the time course of the onset of these effects and whether the effects are reversible with methoxetamine cessation.

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... The 3-methoxy group is responsible for reduced analgesic and anesthetic properties, whereas the N-ethylamino group is responsible for the increased potency and duration of action ( Adamowicz and Zuba, 2015). The 2-keto group confers the relative safety of MXE compared with ketamine ( Morris and Wallach, 2014), whereas the N-ethyl group is supposed to render MXE safer than ketamine in terms of the occurrence of pathologies of the urinary tract associated with its chronic use ( Wood et al., 2012b), although recent data suggest the opposite ( Dargan et al., 2014). ...
... However, animal studies suggested the opposite. Mice treated with a daily dose of 30 mg/kg of MXE for 3 months showed significant inflammatory changes to the kidney and bladder compared with the saline control group, with irregular lobulation, different size, inflammatory cell infiltration, abnormal glomeruli, and tubular abnormality ( Dargan et al., 2014). Degenerating cell and tubular necrosis was present in the kidney of MXEtreated mice, whereas the bladder presented infiltration of fibroblasts, lymphocytes, macrophages in the lamina propria, and increased collagen deposition. ...
... Degenerating cell and tubular necrosis was present in the kidney of MXEtreated mice, whereas the bladder presented infiltration of fibroblasts, lymphocytes, macrophages in the lamina propria, and increased collagen deposition. In contrast, the control group did not show any renal or bladder changes ( Dargan et al., 2014). Thus, despite initially being considered to be safer than ketamine in terms of renal toxicity, the more recent hypothesis is that chronic administration of MXE in humans would lead to the same urinary tract symptoms described after chronic ketamine use ( Wood et al., 2012b;Craig and Loeffler, 2014). ...
Article
An increasing number of novel psychoactive substances are currently available and sold as 'legal highs' or 'research chemicals' accompanied by the indication that they are 'not for human consumption'. Among those that have emerged in the last few years, methoxetamine (MXE) owes its wide popularity to its easy access on the Internet and its reputation of being a 'safe' drug. MXE is an arylcyclohexylamine with a chemical structure analogous to ketamine and phencyclidine, and similar noncompetitive glutamate N-methyl D-aspartate receptor antagonist properties. Yet, very recent preclinical data highlighted a stimulatory effect of MXE on dopamine neurotransmission within the mesolimbic pathway. The aim of this review is to provide an updated review of the behavioral and toxicological effects of MXE as well as the latest findings on its pharmacology that might explain sought effects and frequent occurrence of adverse effects. In light of the growing number of intoxications induced by MXE, knowledge of its short-term and long-term effects is urgently needed. However, the hypothetical rapid antidepressant activity of MXE suggested by its chemical analogy with ketamine and supported by recent preclinical findings deserves further investigation.
... It is a high-affinity ligand for PCP binding site located within the channel pore of the NMDA receptor [1] and produces dissociativelike behavioral effects and addictive behavior in rodents [8,9]. Similar to ketamine, long-term administration of MXE induces significant bladder and renal toxicity in mice [10]. In humans, recreational use of MXE can cause acute toxicity, such as dissociative state, tachycardia, and hypertension [11]. ...
... MXE can cause sympathomimetic effects, such as tachycardia, hypertension, confusion, stupor, mydriasis, and nystagmus. In mice, long-term administration of MXE induces significant bladder and renal toxicity [10]. ...
... It is a high-affinity ligand for PCP binding site located within the channel pore of the NMDA receptor [1] and produces dissociativelike behavioral effects and addictive behavior in rodents [8,9]. Similar to ketamine, long-term administration of MXE induces significant bladder and renal toxicity in mice [10]. In humans, recreational use of MXE can cause acute toxicity, such as dissociative state, tachycardia, and hypertension [11]. ...
... MXE can cause sympathomimetic effects, such as tachycardia, hypertension, confusion, stupor, mydriasis, and nystagmus. In mice, long-term administration of MXE induces significant bladder and renal toxicity [10]. ...
Article
PurposeThe activity of N-methyl-d-aspartate (NMDA) receptors in the central nervous system is affected by many psychoactive drugs, such as 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (ketamine) and its analog 2-(3-methoxyphenyl)-2-(amino)cyclohexan-1-one (methoxetamine, MXE). Recreational use of MXE can cause acute toxicity, such as dissociative state and tachycardia. After MXE use, confusion, agitation, ataxia, and nystagmus are induced. Moreover, MXE-related deaths have been reported, and this compound is banned in many countries. Recently, MXE’s derivative, 2-(3-methoxyphenyl)-2-(propylamino)cyclohexan-1-one (methoxpropamine, MXPr), was reported as a new psychoactive substance and sold online as a designer drug. The aims were to determine how MXPr affects NMDA receptors in neurons and to compare the potency with MXE.Methods Cartwheel cells in the dorsal cochlear nucleus of mice were used as a model of NMDA receptor-expressing neurons, and patch-clamp method was performed for the recordings. NMDA-induced inward current was initially evoked by microiontophoresis application of NMDA onto the cartwheel cells, and the effects of MXPr, MXE, and (5R,10S)-( +)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801, as a positive control substance) on NMDA-induced response were examined. Moreover, the effects of MXPr on NMDA receptor-mediated excitatory postsynaptic currents were also investigated.ResultsThe IC50 of MXPr, MXE, and MK-801 on NMDA-induced response decreased in the following order: MXPr (1.647 μM) > MXE (0.841 μM) > MK-801 (0.060 μM), indicating that MXPr and MXE act as potent antagonists of NMDA receptors. MXPr suppressed NMDA receptor-mediated excitatory synaptic transmission in a dose-dependent manner.ConclusionsMXPr, which may cause health and social damages to humans by blocking NMDA receptors, is a serious concern like MXE.
... Although results of a survey suggested that MXE use may contribute to LUTS development, all of the MXE abusers in that survey had previously used KET at least once [13], and thus the impact of MXE use by itself on LUTS occurrence could not be analyzed. Although Dargan et al. reported histology results showing that MXE produced toxic effects in the bladders and kidneys of mice, further research on how MXE affects the urinary system is necessary [14]. ...
... Although results of a survey suggested that MXE use may contribute to LUTS development, all of the MXE abusers in that survey had previously used KET at least once [13], and thus the impact of MXE use by itself on LUTS occurrence could not be analyzed. Although Dargan et al. reported histology results showing that MXE produced toxic effects in the bladders and kidneys of mice, further research on how MXE affects the urinary system is necessary [14]. MXE was originally designed and synthesized to function as an antidepressant [5], and was advertised as being less toxic than ketamine to the urinary system [15]. ...
Article
Full-text available
The novel synthetic psychoactive ketamine analog methoxetamine is reportedly being used for recreational purposes. As ketamine use can result in urinary dysfunction, we conducted the present study to investigate how methoxetamine affects the bladder. A cystometry investigation showed that female Sprague-Dawley rats experienced increased micturition frequency bladder dysfunction after receiving a daily intraperitoneal injection of 30 mg/kg methoxetamine or ketamine for periods of 4 or 12 weeks. Histologic examinations of rat bladder tissue revealed damaged urothelium barriers, as well as evidence of inflammatory cell infiltration and matrix deposition. The drug-treated rats showed significantly upregulated levels of pro-inflammatory cytokines such as IL-1β, IL-6, CCL-2, CXCL-1, CXCL-10, NGF, and COX-2. In addition, interstitial fibrosis was confirmed by increased levels of collagen I, collagen III, fibronectin and TGF-β. Besides direct toxic effect on human urothelial cells, methoxetaminealso induced the upregulation related cytokines. Our results indicate that long term methoxetamine treatment can induce bladder dysfunction and inflammation in rats. Methoxetamine was confirmed to produce direct toxic and pro-inflammatory effects on human urothelial cells. Methoxetamine-associated bladder impairment may be similar to ketamine-induced cystitis.
... H 2 S has been reported to protect the kidney against different forms of injury [16]. Therefore, this volatile molecule Numerous reports have demonstrated that ketamine, a recreational drug owing to its anesthetic and hallucinogenic actions, could produce significant nephrotoxicity [4,6,12,33,39]. In this study, this agent was noted to suppress I K amplitude, and its effect could ascribe from its suppression of BK Ca channels as reported previously [11]. Whether ketamine-induced tubular cell necrosis or obstructive uropathy described previously [4,6,12,33,39] is associated with an inhibition of BK Ca channels remain to be further studied. ...
... In this study, this agent was noted to suppress I K amplitude, and its effect could ascribe from its suppression of BK Ca channels as reported previously [11]. Whether ketamine-induced tubular cell necrosis or obstructive uropathy described previously [4,6,12,33,39] is associated with an inhibition of BK Ca channels remain to be further studied. Moreover, the administration of bisphosphonates would potentially exacerbate ketamine-mediated damage, because both agents suppress the activity of BK Ca channels in renal tubular cells or smooth muscle cells of a urinary bladder. ...
Article
Full-text available
The nitrogen-containing bisphosphonates used for management of the patients with osteoporosis were reported to influence the function of renal tubular cells. However, how nitrogen-containing bisphosphates exert any effects on ion currents remains controversial. The effects of ibandronate (Iban), a nitrogen-containing bisphosphonate, on ionic channels, including two types of Ca2+-activated K+ (KCa) channels, namely, large-conductance KCa (BKCa) and intermediate-conductance KCa (IKCa) channels, were investigated in Madin-Darby canine kidney (MDCK) cells. In whole-cell current recordings, Iban suppressed the amplitude of voltage-gated K+ current elicited by long ramp pulse. Addition of Iban caused a reduction of BKCa channels accompanied by a right shift in the activation curve of BKCa channels, despite no change in single-channel conductance. Ca2+ sensitivity of these channels was modified in the presence of this compound however, the magnitude of Iban-mediated decrease in BKCa-channel activity under membrane stretch with different negative pressure remained unchanged. Iban suppressed the probability of BKCa-channel openings linked primarily to a shortening in the slow component of mean open time in these channels. The dissociation constant needed for Iban-mediated suppression of mean open time in MDCK cells was 12.2μM. Additionally, cell exposure to Iban suppressed the activity of IKCa channels, and DC-EBIO or 9-phenanthrol effectively reversed its suppression. Under current-clamp configuration, Iban depolarized the cells and DC-EBIO or PF573228 reversed its depolarizing effect. Taken together, the inhibitory action of Iban on KCa-channel activity may contribute to the underlying mechanism of pharmacological or toxicological actions of Iban and its structurally similar bisphosphonates on renal tubular cells occurring in vivo.
... This study indicates that 4-F-MDMB-BUTINACA has high toxicity, its toxic effects on liver tissue were close to the effect of cocaine, which is classified as highly toxic and causes liver damage and inflammation. 25 The inflammation, necrosis, and congestion seen in kidneys of 4-F-MDMB-BUTINACA -treated mice were similar to the changes found by Dargan et al. (2014), who studied the effects of methoxetamine (analogue of ketamine) in renal toxicity in mice. 26 Conclusion 4-F-MDMB-BUTINACA is of high acute toxicity but had rapid effects after administration. ...
Article
The purpose of this research was to evaluate the single-dose toxicity of 4-F-MDMB-BUTINACA in Swiss albinomice using histopathological analysis of liver and kidney specimens.The experimental protocol included oral treatment of mice with different doses (5, 50, 300, 2000 mg/kg bodyweight of 4-F-MDMB-BUTINACA) for 24 hours. At the end of the treatment, blood samples had been drawn, andrenal and hepatic tissues have been excised from the experimental mice groups for histological examinations.The results revealed that dose-dependent treatment with 4-F-MDMB-BUTINACA causes mild tremor clinicalsigns with low doses and photophobia (sensitivity to light) and even cessation of breathing as a potential cause ofdeath with high doses in treated mice.The LD50 value of 4-F-MDMB-BUTINACA was 32.60 mg/kg, which is considered as a chemical compound of lowtoxicity. Histological studies confirmed that liver and kidney toxicities have been manifested in the findings ofcongestion, necrosis, inflammation, and bleeding within the liver and to lesser extent in the kidneys.
... PCP and MXE have been reported to cause rhabdomyolysis and lead to AKI [33]. For example, Dargan et al. [34] observed that 3 months of daily intraperitoneal MXE administration to mice increased bladder inflammation that led to fibrosis and kidney damage at tubular and glomerular levels. Also, lower urinary tract dysfunction, including bilateral hydronephrosis and decreased bladder capacity, have been observed in ketamine users [35]. ...
Article
The increasing consumption of drugs of abuse represents a global public health concern. Kidneys are especially vulnerable to the toxic effects of these substances, as these organs are involved in their filtration, concentration and metabolism to potentially toxic metabolites. Distinct clinical manifestations known to precede acute and chronic kidney injury (e.g., rhabdomyolysis, vasoconstriction, decreased estimated glomerular filtration rate) have indeed been reported following consumption of different drugs of abuse (e.g., cannabinoids, cocaine, opioids, substituted phenethylamines), However, the mechanisms underlying their nephrotoxicity remain poorly understood. As such, we herein review the most recent updates on the nephrotoxicity associated with drugs of abuse, as understanding their nephrotoxic profile assumes major relevance to improve risk assessment and therapeutic responses to drug-related complications.
... Methoxetamine is one of ketamine derivatives that has a high binding affinity to the active site of the N-methyl-D-aspartate (NMDA) receptor. This compound causes a number of side effects on human body, including the loss of consciousness and hallucinogenic effects [27,28]. It is one of the subdivisions of new psychoactive substances (NPSs), which is being widely used in the pharmacology industry. ...
Article
Density functional theory (DFT) calculations were made to investigate the interaction between enantiomers of methoxetamine (R & S) and achiral organic reagents, such as oxalate, succinate, fumarate, maleate, glutarate, adipate, pimelate, and suberate anions. The obtained results indicate that the oxalate and maleate anions have a greater ability to form conglomerate crystal of methoxetamine in the gas phase and in solution with chloroform, ethanol, and water. Results of the energy analysis reveal that, in comparison to gas phase and chloroform, the Gibbs energy, enthalpy, and internal thermal energy become more positive in the presence of water and ethanol solvents, confirming the negative effect of solvent polarity on enantiomer separation. It should also be noted that the presence of carbon-chain lengths greater than 3 atoms in organic reagents is not suitable for enantiomer separation and conglomerate crystal formation. .
... Proposed in the drug market as a legal and "bladder-friendly" alternative to ketamine, MXE rapidly appeared associated with worse side effects than ketamine (Corazza et al., 2013). Prolonged (3 months) exposure to MXE, for example, resulted in significant bladder and renal toxicity in mice (Dargan et al., 2014), but shorter periods of exposure can also result in bladder dysfunction and inflammation in rats (Wang et al., 2017). MXE-induced cardiotoxicity has also been reported recently by in vitro studies (Yoon et al., 2019). ...
Article
Methoxetamine (MXE) is a dissociative substance of the arylcyclohexylamine class that has been present on the designer drug market as a ketamine-substitute since 2010. We have previously shown that MXE (i) possesses ketamine-like discriminative and positive rewarding effects in rats, (ii) affects brain processing involved in cognition and emotional responses, (iii) causes long-lasting behavioral abnormalities and neurotoxicity in rats and (iv) induces neurological, sensorimotor and cardiorespiratory alterations in mice. To shed light on the mechanisms through which MXE exerts its effects, we conducted a multidisciplinary study to evaluate the various neurotransmitter systems presumably involved in its actions on the brain. In vivo microdialysis study first showed that a single administration of MXE (0.25 and 0.5 mg/kg i.v.) is able to significantly alter serotonin levels in the rat medial prefrontal cortex (mPFC) and nucleus accumbens. Then, we observed that blockade of the serotonin 5-HT2 receptors through two selective antagonists, ketanserin (0.1 mg/kg, i.p.) and MDL 100907 (0.03 mg/kg, i.p.), at doses not affecting animals behavior per se, attenuated the facilitatory motor effect and the inhibition on visual sensory responses induced by MXE (3 mg/kg i.p.) and ketamine (3 mg/kg i.p.), and prevented MXE-induced reduction of the prepulse inhibition in rats, pointing to the 5-HT2 receptors as a key target for the recently described MXE-induced sensorimotor effects. Finally, in-vitro electrophysiological studies revealed that the GABAergic and glutamatergic systems are also likely involved in the mechanisms through which MXE exerts its central effects since MXE inhibits, in a concentration-dependent manner, NMDA-mediated field postsynaptic potentials and GABA-mediated spontaneous currents. Conversely, MXE failed to alter both the AMPA component of field potentials and presynaptic glutamate release, and seems not to interfere with the endocannabinoid-mediated effects on mPFC GABAergic synapses. Altogether, our results support the notion of MXE as a NMDA receptor antagonist and shed further lights into the central mechanisms of action of this ketamine-substitute by pointing to serotonin 5-HT2 receptors as crucial players in the expression of its sensorimotor altering effects and to the NMDA and GABA receptors as potential further important targets of action.
... This overall pattern for deaths registered in a calendar year is broadly similar to the pattern evidenced by NPSAD cases occurring in a calendar, even allowing for other differences such as cases definition, geographical coverage and completeness of reporting. The decline in deaths between 2010 and 2013 may be due, in part, to the appearance of methoxetamine in 2010 and other ketamine derivatives, for example N-ethylnorketamine, 3-MeO-PCE, 3-MeO-PCP in 2012 and/or fears about bladder/urinary problems (Dargan et al., 2014;Wang et al., 2017). However, these analogues quickly lost favour following several deaths in 2012 (Chiappini et al., 2015). ...
Article
Full-text available
Background: Ketamine is a phencyclidine derivative with dissociative anaesthetic properties. Increasing numbers of individuals in England take ketamine recreationally. Information on deaths arising from such use In England is presented. Methods: Cases were extracted on 31 January 2020 from the National Programme on Substance Abuse Deaths database, based on text searches of the cause of death, coroner’s verdict and positive toxicology results for the terms ‘ketamine’ or ‘norketamine’. Findings: During 1997-2005 there were < 5 deaths p.a. in which ketamine was implicated. Numbers increased until 2009 (21), plateauing until 2016; thereafter deaths have risen to about 30 p.a. Decedents’ characteristics (N=283): male 84.1%; mean age 31.2 (SD 10.0) years; employed 56.5%; drug use history 79.6%; living with others 60.3%. Ketamine was detected with other substances in most cases. Main (74.6%) underlying cause of death was accidental poisoning. Ketamine may have impaired judgement in other cases. Conclusions: Although controlled, recreational ketamine use and related fatalities continue to increase. Consumers need to be more aware of the potentially fatal risks they face.
... This overall pattern for deaths registered in a calendar year is broadly similar to the pattern evidenced by NPSAD cases occurring in a calendar, even allowing for other differences such as cases definition, geographical coverage and completeness of reporting. The decline in deaths between 2010 and 2013 may be due, in part, to the appearance of methoxetamine in 2010 and other ketamine derivatives, for example N-ethylnorketamine, 3-MeO-PCE, 3-MeO-PCP in 2012 and/or fears about bladder/urinary problems (Dargan et al., 2014;Wang et al., 2017). However, these analogues quickly lost favour following several deaths in 2012 (Chiappini et al., 2015). ...
Article
Full-text available
Background Ketamine is a phencyclidine derivative with dissociative anaesthetic properties. Increasing numbers of individuals in England take ketamine recreationally. Information on deaths arising from such use in England is presented. Methods Cases were extracted on 31 January 2020 from the National Programme on Substance Abuse Deaths database, based on text searches of the cause of death, coroner’s verdict and positive toxicology results for the terms ‘ketamine’ or ‘norketamine’. Findings During 1997–2005, there were <5 deaths p.a. in which ketamine was implicated. Numbers increased until 2009 (21), plateauing until 2016; thereafter, deaths have risen to about 30 p.a. Decedents’ characteristics ( N = 283): male 84.1%, mean age 31.2 (SD 10.0) years, employed 56.5%, drug use history 79.6% and living with others 60.3%. Ketamine was detected with other substances in most cases. Main (74.6%) underlying cause of death was accidental poisoning. Ketamine may have impaired judgement in other cases. Conclusions Although controlled, recreational ketamine use and related fatalities continue to increase. Consumers need to be more aware of the potentially fatal risks they face.
... 167 MXE use by humans has been associated with acute neurological impairment including psychomotor agitation and altered motor coordination, 168 and chronic bladder and urinary tract toxicity reported in mice. 169 Case reports have reported serious adverse effects including seizures, hyponatremia, and sinus bradycardia, 170 neurological impairment with significant cerebellar toxicity and a number of fatalities associated with intoxication. [171][172][173][174][175][176] Synthetic depressants Synthetic depressants are broadly classified into two sub-categories: synthetic benzodiazepines and synthetic opiates. ...
Article
Full-text available
New psychoactive substances (NPS) are a heterogeneous group of substances. They are associated with a number of health and social harms on an individual and societal level. NPS toxicity and dependence syndromes are recognised in primary care, emergency departments, psychiatric inpatient and community care settings. One pragmatic classification system is to divide NPS into one of four groups: synthetic stimulants, synthetic cannabinoids, synthetic hallucinogens and synthetic depressants (which include synthetic opioids and benzodiazepines). We review these four classes of NPS, including their chemical structures, mechanism of action, modes of use, intended intoxicant effects, and their associated physical and mental health harms. The current challenges faced by laboratory testing for NPS are also explored, in the context of the diverse range of NPS currently available, rate of production and emergence of new substances, the different formulations, and methods of acquisition and distribution.
... For instance, ketamine has been associated with bladder toxicity.132 Similar to ketamine, animal models showed significant bladder and renal toxicity in rodents following the administration of 30 mg/kg methoxetamine intraperitoneally.126 Symptoms included inflammatory cell infiltration, tubular cell necrosis, glomerular damage and increased micturition frequency bladder dysfunction.NET and DAT but not SERT McLaughlin, G. et al., M.D. et al., 2014 97 H9c2 rat cardiac cell line Cytotoxic assay TFMPP seems to be the most potent cytotoxic compound Brandt, S.D. et al., assays " release of DA, NA, 5-HT. ...
Article
Full-text available
Novel psychoactive substances (NPS) are new drugs of abuse. Over the last 10 years 50–100 new NPS have been detected for the first time each year. This has led to numerous deaths and challenges to healthcare providers and law‐makers worldwide. We review preclinical studies of NPS and discuss how these studies have influenced legislative decisions. We focus on the UK legal system but include experiences from Europe. We reviewed manuscripts from 2008–2019 and have summarised the in vitro and in vivo data on NPS, highlighting how these studies define pharmacological mechanisms and how they might predict harm in humans. We found that only a small percentage of NPS have been examined in preclinical studies. Most preclinical studies of NPS focus on basic pharmacological mechanisms (46% of studies reviewed) and/or addictive liability (32%) rather than toxicity and harm (24%). Very few preclinical studies into NPS include data from chronic dosing schedules (9%) or female rodents (4%). We conclude that preclinical studies can predict harm to humans, but most of the predictions are based on basic pharmacology rather than demonstrated toxicity. Some of these studies have been used to make changes to the law in the UK and Europe and perhaps, because of the paucity of toxicology data, most NPS have been placed in the highly dangerous schedule 1 or Class A category in the UK. We suggest that in silico studies and high throughput toxicology screens might be the most economical way forward to rapidly screen the health harms of NPS.
... Following chronic use, anxiety and suicidal ideation have been a reason of concern [21][22]57]. Although MXE was marketed as 'bladder friendly', related preclinical studies [88] suggested both urological toxicity and unique cerebellar features [89]. Several analytically confirmed MXE-related fatalities have been reported [90,91]. ...
Article
Full-text available
Purpose of the Review A significant increase in the number, type and availability of new psychoactive substances (NPS) with dissociative and psychedelic potential has occurred worldwide over the last few decades. Psychedelic substances have historically been used in order to achieve altered states of consciousness such as dissociative states.We aimed here at describing both a large number of novel ketamine-like dissociatives and tryptamine/lysergamide/phenethylamine psychedelics available, whilst describing the acute/long-term clinical scenarios most commonly associated with their intake. Recent Findings An updated overview of the clinical and clinical pharmacological issues related to some of the most popular NPS categories has been provided, describing both psychosis and remaining psychopathological issues related to them. Conclusions Although the complex link between NPS and psychiatric illnesses is yet to be fully understood, NPS misuse is now a significant clinical issue and an increasing challenge for clinicians working in both mental health and emergency departments.
... Following chronic use, anxiety and suicidal ideation have been a reason of concern [21][22]57]. Although MXE was marketed as 'bladder friendly', related preclinical studies [88] suggested both urological toxicity and unique cerebellar features [89]. Several analytically confirmed MXE-related fatalities have been reported [90,91]. ...
Article
Full-text available
Purpose of the Review A significant increase in the number, type and availability of new psychoactive substances (NPS) with dissociative and psychedelic potential has occurred worldwide over the last few decades. Psychedelic substances have historically been used in order to achieve altered states of consciousness such as dissociative states. We aimed here at describing both a large number of novel ketamine-like dissociatives and tryptamine/lysergamide/phenethylamine psychedelics available, whilst describing the acute/long-term clinical scenarios most commonly associated with their intake. Recent Findings An updated overview of the clinical and clinical pharmacological issues related to some of the most popular NPS categories has been provided, describing both psychosis and remaining psychopathological issues related to them. Conclusions Although the complex link between NPS and psychiatric illnesses is yet to be fully understood, NPS misuse is now a significant clinical issue and an increasing challenge for clinicians working in both mental health and emergency departments.
... Although THJ-2201 has low toxicity, its toxic effects on liver tissue were close to the effect of cocaine, which is classified as highly toxic and causes liver damage and inflammation (Vilela et al. 2015). The inflammation, necrosis, and congestion seen in kidneys of THJ-2201-treated mice were similar to the changes found by Dargan et al. (2014), who studied the effects of methoxetamine (analogue of ketamine) in renal toxicity in mice. ...
Article
Full-text available
Abstract Background This study aimed to assess the single-dose toxicity of THJ-2201 by hematological and histopathological evaluation of liver and kidney specimens in Swiss albino mice. The experimental protocol included oral treatment of mice with different doses (5, 50, 300, 2000 mg/kg body weight of THJ-2201) for 24 h. At the end of the treatment, blood samples had been drawn, and renal and hepatic tissues have been excised from the experimental mice groups for hematological and histological examinations. Results Results showed that dose-dependent treatment with THJ-2201 leads to mild tremor clinical signs with low doses and photophobia (sensitivity to light) and even cessation of breathing as a potential cause of death with high doses in treated mice. Conclusion The LD50 value of THJ-2201 was 822.20 mg/kg, which is considered as a chemical compound of low toxicity. Histological studies confirmed that liver and kidney toxicities have been manifested in the findings of congestion, necrosis, inflammation, and bleeding within the liver and to lesser extent in the kidneys.
... This is what we are waiting to see as the neonates grow up. Furthermore, many other organs, e.g., the brain, the heart and the kidneys of the progeny have to be investigated in adulthood, specifically in terms of the pathomorphological, pathophysiological, pharmacological and biochemical changes of these areas before any conclusive statements could be made [12][13][14][15][16][17][18][19][20][21][22]. ...
Article
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It is well known that ketamine abuse can induce liver damage in adult addicts, but the effects of ketamine abuse in pregnant mothers on their offspring have received less attention. In this study, we investigated the effects of 5-day ketamine injections (30 mg/kg) to pregnant Institute for Cancer Research (ICR) mice during early gestation or mid-gestation on the aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities of the mothers and the offspring. We also looked into whether administering ketamine treatment to the mothers had any effects on the extent of fibrosis, cell proliferation and cell death in the livers of the newborns. No significant biochemical differences were found between treatment and control groups in the mothers. In the offspring, ketamine treatment mildly suppressed the gradual increase of hepatic AST activity in neonates during liver maturation. Measurements of hepatic ALP activity and lactic acid dehydrogenase (LDH) immunoreactivity revealed that ketamine treatment may lead to increased cell death. Proliferation of liver cells of the newborns was also retarded as shown by reduced proliferative cell nuclear antigen (PCNA) immunoreactivity in the ketamine groups. No obvious fibrosis was evident. Thus, we demonstrated that ketamine administration to pregnant mice suppressed hepatic development and also induced liver cell death of the offspring.
... Despite these obvious risks, the neuropharmacology of MXE is largely unknown. In vivo data show that MXE use is associated with bladder and renal toxicity, although MXE is advertised as a 'bladder-friendly' alternative to ketamine (Dargan et al., 2014). In rats, MXE acts as a typical dissociative anesthetic: it produces anxiogenic and stimulant effects at low doses and sedative effects at high doses. ...
Article
Full-text available
The use of new psychoactive substances (NPS) is steadily increasing. One commonly used NPS is methoxetamine (MXE), a ketamine analogue. Several adverse effects have been reported following MXE, while only limited data are available on the neuropharmacological modes of action.
... MXE was designed to have greater potency at lower doses than ketamine in order to limit the accumulation of urotoxic metabolites (Morris, 2011;Morris and Wallach, 2014) that are associated with chronic ketamine use ( Chu et al., 2008;Muetzelfeldt et al., 2008). According to recently published findings its bladder 'safety' is debatable, since (in mice) bladder and renal toxicity have been observed after chronic use ( Dargan et al., 2014). In humans, MXE produces similar subjective effects to ketamine, i.e., mood enhancement with hallucinogenic and dissociative aspects, and at higher doses a profoundly altered state of consciousness ( Corazza et al., 2012;Kjellgren and Jonsson, 2013;Rosenbaum et al., 2012). ...
Article
Methoxetamine (MXE) is a novel psychoactive compound (NPS) that emerged in 2010 as a substitute for the dissociative anaesthetic ketamine. MXE has a reputation of carrying a lower risk of harm than ketamine, however a number of deaths have been reported. Currently very little is known about the psychopharmacological effects of this compound or its toxicity, therefore we tested in Wistar rats, the effects of MXE in a series of behavioural tasks, measured its pharmacokinetics, and urinary metabolites.
... Er is (nog) geen onderzoek gedaan naar het mogelijk optreden van tolerantie en/of verslaving. Er is slechts één dierstudie waarin de chronische toxiciteit van methoxetamine is onderzocht en waaruit blijkt dat methoxetamine waarschijnlijk (net als ketamine) bij chronisch gebruik kan leiden tot ernstige aan-doeningen van blaas en urinewegen (Dargan et al. 2014). Dit is opmerkelijk, omdat methoxetamine aanvankelijk op websites gepromoot werd als een veilig alternatief voor ketamine met betrekking tot urologische klachten (Morris 2011). ...
... Since the first report on effects of methoxetamine, which appeared in May 2010, the drug has been extensively advertised as a 'legal' and 'bladder friendly' alternative to ketamine (EMCDDA, 2013; Kjellgren and Jonsson, 2013). In light of experimental data demonstrating that prolonged administration of methoxetamine to mice produced significant bladder and kidney toxicity (Dargan et al., 2014), an issue as to whether, in humans, this drug is far less toxic than ketamine remains to be elucidated. In 2013, methoxetamine was one out of four most frequently detected NPS by the Drugs Information and Monitoring System in the Netherlands (Hondebrink et al., 2015). ...
... Ostatnio opublikowane wyniki badań wykazały jednak, że 3-miesięczne podawanie myszom metoksetaminy w dawce 30 mg/kg m.c. powodowało zapalenie pęcherza moczowego z następczym zwłóknieniem oraz uszkodzeniem nerek [40]. Wywołane przez ketaminę uszkodzenie dolnych dróg moczowych objawia się bolesnym, utrudnionym oddawaniem moczu, krwiomoczem, częstym oddawaniem małych objętości moczu, nietrzymaniem moczu, nokturią, jałowym ropomoczem [37][38][39]. ...
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During the last decade, numerous new psychoactive substances have appeared on the illegal recreational drug market. One of them is methoxetamine, a structural analogue of ketamine. The increasing popularity of methoxetamine as a recreational drug may be attributed to its potent hallucinogenic and dissociative effects. Methoxetamine exerts a wide range of effects on the central and peripheral nervous system, and some of which resemble the effects of ketamine while others vary greatly. The consumption of methoxetamine carries a significant health risk, and may even lead to fatal intoxication.
... A survey by Winstock and colleagues [Winstock et al. 2012] found that urinary symptoms were significantly related to frequency and dose of ketamine use, and were present in over a quarter of regular users. Suggesting that this is similar to at least methoxetamine, rodent data shows that the estimated equivalence to human dosing delivered over three months results in damage to the kidneys and bladders of mice [Dargan et al. 2014]. ...
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There has been growing clinical, public, and media awareness and concern about the availability and potential harmfulness of so-called ‘legal highs’, which are more appropriately called new or novel psychoactive substances (NPS). A cat-and-mouse process has emerged wherein unknown chemists and laboratories are producing new, and as yet nonproscribed, compounds for human consumption; and as soon as they are banned, which they inevitably are, slightly modified analogues are produced to circumvent new laws. This rapidly changing environment, 81 new substances were identified in 2013 alone, has led to confusion for clinicians, psychopharmacologists, and the public at large. Our difficulties in keeping up with the process has had a two-fold negative effect: the danger of ignoring what is confusing; and the problem that some of the newer synthesized compounds appear ever more potent. This review aims to circumscribe a quick moving and growing field, and to categorize NPS into five major groups based upon their ‘parent’ compounds: stimulants similar to cocaine, amphetamines and ecstasy; cannabinoids; benzodiazepine based drugs; dissociatives similar to ketamine and phencyclidine (PCP); and those modelled after classic hallucinogens such as LSD and psilocybin. Pharmacodynamic actions, subjective and physical effects, harmfulness, risk of dependency and, where appropriate, putative clinical potentials are described for each class. Clinicians might encounter NPS in various ways: anecdotal reportage; acute intoxication; as part of a substance misuse profile; and as a precipitant or perpetuating factor for longer-term physical and psychological ill health. Current data are overall limited, and much of our knowledge and treatment strategies are based upon those of the ‘parent’ compound. There is a critical need for more research in this field, and for professionals to make themselves more aware of this growing issue and how it might affect those we see clinically and try to help: a brave new world of so-called ‘psychonauts’ consuming NPS will also need informed ‘psychotherapeutonauts’. The paper should serve as a primer for clinicians and interested readers, as well as provide a framework into which to place the new substances that will inevitably be synthesized in the future.
... The lack of sufficient experience of this substance means that the hypothesis cannot be confirmed, all the more so because in a recent study this type of toxicity was observed in mice after administration of MXE for three months. [71] Finally, concerning addictive potential, the structural analogy with ketamine suggests the risk of mental dependency, and the development of tolerance. Certain remarks by users on the Internet do indeed report compulsive behaviours in the use of MXE. ...
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New substances, also known as "designer drugs" or "legal highs" are increasingly available to drug users. Two hundred and fifteen hitherto unlisted substances have been notified by European Union member states since 2005. These synthetic drugs, which have been developed to side-step the legislation on drugs, are analogues or derivatives of existing drugs and medications. The availability of these "legal highs", sold on Internet under various denominations such as bath salt, plant fertilizer, chemical not intended for human use, or spice, is unlimited. The effects felt by users vary, and the substances may be stimulant, entactogenic, hallucinogenic, psychedelic or dissociative. The pharmacological targets also vary, and may be either the increase of extracellular levels of neurotransmitters via different mechanisms (reuptake inhibition, stimulation of intracellular release) or else fixation on specific receptors. Several chemical classes, themselves divided into sub-classes, are involved: phenethylamines, tryptamines, piperazines, cathinones, cannabinoids etc. The toxicity of the main members of these categories is increasingly well known, the most deleterious being behavioural effects, physical manifestations, and cardiovascular consequences. However, small variations in their chemical structure can generate effects that are quantitatively different, thus enhancing their toxicity or addictive potential, and much remains to be achieved in terms of knowledge about these new drugs. These substances are indeed present on the French territory, as shown by data provided by the Observatoire Français des Drogues et Toxicomanies, and notifications by the French Addictovigilance network. Screening in clinical toxicology laboratories is not widespread, since these molecules are not detected by the standard screening tests, so that there is probably an under-estimation of the use of these new drugs. The legislation on these substances changes regularly, with more and more countries classifying them as "narcotics" or illegal psychotropic drugs so as to restrict their use, applying a generic classification when possible. see end of article. © 2015 Société Française de Pharmacologie et de Thérapeutique.
Article
There are global concerns about the proliferation and misuse of club drugs and novel psychoactive substances, yet we know little about their harms and research on clinical management and treatment remains limited. This book fills the knowledge gap by providing a detailed overview of the research evidence available to date. The book provides a framework that allows readers to understand this large number of new drugs, using classifications based on primary psychoactive effect. Within this framework, the book provides detailed reviews of the more commonly used drugs. Each chapter explores pharmacology, patterns and mode of use, acute and chronic harms, and clinical interventions supported by research evidence. An invaluable resource for clinical staff, this book will support clinicians working in the emergency department, substance misuse and addiction services, mental health services, primary care, sexual health services and more. It will also be of interest to academics and those developing drug policy.
Article
Arylcyclohexylamines are a category of substances to which the anesthetic ketamine belongs. The arylcyclohexylamines have been reported to act as antagonists of the N-methyl-d-aspartate (NMDA) receptor. An analog of ketamine, 2-(ethylamino)-2-(3-methoxyphenyl)-cyclohexanone (methoxetamine; MXE), has been controlled as a narcotic in Japan and overdoses of MXE have been reported to cause health problems. In recent years, MXE derivatives have beendetected in illegal products in Japan. In this study, we describe the identification of three MXE derivatives, 2-(3-methoxyphenyl)-2-(propylamino)cyclohexan-1-one (methoxpropamine; MXPr), 2-(isopropylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxisopropamine; MXiPr) and 2-(3-methoxyphenyl)-2-(propylamino)cyclohexan-1-one (deoxymethoxetamine; DMXE), from illegal products.
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The black market for new psychoactive substances has been constantly evolving and the substances that appear on this market cause a considerable number of issues, in extreme cases leading to human deaths. While monitoring the drug black market, we detected a sample of a dissociative anesthetic methoxphenidine, the salt of which contained an unusual anion in the form of bromo- and chloro-zincate complex. Concerning the unknown and potentially hazardous properties of this sample, we performed an in vitro cytotoxicity screening in cell lines of various origins (e.g., kidney, liver, bladder) which was compared with the toxicity results of the methoxphenidine standard prepared for this purpose. The street methoxphenidine sample exhibited markedly higher toxicity than the standard, which was probably caused by the anion impurity. Since it is not usual to analyze anions in salts of novel psychoactive substances, but such samples may be commonly available at the drug black market, we have developed a method for their identification with X-ray powder diffraction (XRPD), which also enabled us to distinguish between different polymorphs/solvates of methoxphenidine that were crystallized in the laboratory. XRPD offers additional data about samples, which may not be discovered by routine techniques, and in some cases, they may help to find out essential information.
Chapter
The arylcyclohexamines are a group of psychoactive agents broadly derived from a cyclohexamine unit with an aryl moiety. The major agents in this group include phencyclidine, ketamine and methoxetamine, which expand into analogues and derivative agents. Their common shared property involves antagonism of the NMDA glutamate receptor. The chapter reviews the effects of each of the major agents by examining the latest animal and human evidence on acute and chronic toxicity from case reports, clinical studies and reported deaths. To complete the chapter, other new arylcyclohexamine agents are identified and briefly reviewed for their clinical effect and prevalence to alert the reader to their growing influence within the novel psychoactive drug scene. These structurally and pharmacodynamically similar derivates include methoxphenidine and several methoxy- analogues of phencyclidine.
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Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at μ-opioid receptors and γ-aminobutyric acid-A (GABAA) or GABAB receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-d-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.
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the article reviews Russian and international literature on synthetic (designer) drugs. A special place is given to the most common designer drugs-synthetic cathinones («salts») and synthetic cannabinoids («spice»). On the basis of this literature the authors analyse the chemical structure of synthetic cathinones and synthetic cannabinoids, the psychoactive effects of these substances on the body, the ability to produce mental, somatic and neurological disorders.
Article
Methoxetamine (MXE) is an N-methyl-D-aspartate (NMDA) receptor antagonist that is chemically and pharmacologically similar to other dissociative substances, such as ketamine and phencyclidine. There are reports on the misuse of MXE, which sometimes resulted in adverse consequences and death. Studies have also shown that MXE has abuse liability and stimulates dopamine neurotransmission in the mesolimbic reward pathway in the brain. These findings have contributed to the negative impression on MXE. However, recent preclinical studies have identified the antidepressant properties of MXE, which are attributed to its ability to affect the glutamatergic and serotonergic systems. MXE is also reported to have analgesic effects. These findings show some of the “redeeming qualities” of MXE and indicate its possible therapeutic uses. In this paper, we have reviewed the findings that provide insights into the adverse and potential therapeutic effects of MXE. We compiled studies on the toxicity, psychotomimetic effects, and abuse liability of MXE, as well as its promising antidepressant and analgesic properties. We also have discussed the mechanism of action that might mediate the somewhat paradoxical effects observed. Importantly, this review provides valuable information on MXE for future research and will enable a better understanding of its psychopharmacological properties and the mechanisms responsible for its unique effects.
Chapter
While phencyclidine (PCP) and ketamine remain the most well-studied and widely known dissociative drugs, a number of other agents have appeared since the late 1950s and early 1960s, when the pharmacological potential of this class was first realized. For example, hundreds of compounds have been pursued as part of legitimate research efforts to explore these agents. Some of these found their way out of the research labs and onto illicit markets of the 1960s and following decades as PCP analogs. Other “illicit analogs” apparently never appeared in the scientific literature prior to their existence on clandestine markets, thus originating as novel innovations in the minds of clandestine chemists and their colleagues. Like so much else in this world, new technologies changed this dynamic. In the 1990s individuals separated by vast geographical distances could now communicate nearly instantaneously with ease through the Internet. Some individuals used this newly found opportunity to discuss the chemistry and psychoactive effects of dissociative drugs as well as to collaborate on the design and development of novel dissociative compounds. Similar to modern pharmaceutical companies and academic researchers, these seekers tinkered with the structure of their leads pursuing goals such as improved duration of action, analgesic effects, and reduced toxicity. Whether all these goals were achieved for any individual compound remains to be seen, but their creations have been let out of the bag and are now materialized as defined compositions of matter. Moreover, these creations now exist not only in and of themselves but live on further as permutations into various novel analogs and derivatives. In some cases these compounds have made their way to academic labs where potential clinical applications have been identified. These compounds reached wider distribution when other individuals picked up on these discussions and began to market them as “research chemicals” or “legal highs”. The result is a continuously evolving game that is being played between legislatures, law enforcement, and research chemical market players. Two structurally distinct classes that have appeared as dissociative-based new psychoactive substances (NPS) are the 1,2-diarylethylamines and β-keto-arylcyclohexylamines. Examples of the former include diphenidine and various analogs such as fluorolintane and N-ethyl-lanicemine, and examples of the latter are analogs of ketamine such as methoxetamine, deschloroketamine, and 2-fluoro-2-deschloroketamine. The subject of this chapter is the introduction to some of the dissociative NPS from these classes and their known pharmacology that have emerged on the market in recent years.
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Methoxetamine, a designer drug marketed as a replacement for the dissociative anaesthetic ketamine, has been associated with significant numbers of hospital related intoxications and deaths in Europe. The fast and user-friendly identification and quantification of methoxetamine and its metabolites is a key factor for successful treatment of intoxication. Therefore, we suggested a convenient preparation method which was used for the synthesis of methoxetamine, seven methoxetamine metabolites and a deuterium labelled derivative as analytical standards. Methoxetamine and normethoxetamine were used as starting materials for the preparation of O-demethylated and N-dealkylated metabolites. The multistep synthesis starts from commercially available compounds and offers good yields. Our prepared analytical standards were used for the confirmation of the suggested structure of methoxetamine metabolites in rat urine by LCMS. Capillary electrophoresis was used for the chiral separation of MXE and its metabolites using β-cyclodextrin, carboxymethylated β-cyclodextrin, and sulphated β-cyclodextrin as chiral selectors at various concentrations. Chiral separation was successful for four analytes. A mixture of MXE and its metabolites was subsequently analyzed under optimal conditions, i.e. when using 15 mmol L⁻¹ β-cyclodextrin in 50 mmol L⁻¹ phosphate buffer, pH 2.5. In this case, chiral separation was achieved for three analytes and all analytes were separated from each other.
Chapter
The kidney carries out a number of crucial roles in the regulation of homeostasis. In addition to maintaining normal body volume, electrolyte concentration, and excretion of waste substances, kidneys regulate blood pressure and red cell carrying capacity and carry out a host of other functions. It is therefore not surprising that even small acute deteriorations in renal function lead to significant morbidity and mortality [1–3]. Acute kidney injury (AKI) is a common finding in hospitalized patients, with an incidence of 3–20% depending on the population studied; the incidence of AKI increases to 16–67% in intensive care units and appears to be growing [2, 3].
Chapter
Arylcyclohexamines (also known as arylcyclohexylamines) are a group of compounds that contain a cyclohexamine unit with an aryl moiety, typically a phenyl ring, attached to the same atom to which the amine group is linked (see Fig. 1). They all exhibit dissociative effects due to their antagonism of N-methyl-d-aspartate (NMDA) receptors, and many have been studied as alternatives to traditional anesthetic agents but subsequently abused recreationally in pursuit of these same effects. The most well-characterized arylcyclohexamines are phencyclidine ((1-(1-phencyclohexyl) piperidine; PCP)), ketamine, and, of the novel analogues, methoxetamine.
Article
Since the public demonstration of ether as a novel, viable anesthetic for surgery in 1846, the field of anesthesia has continually sought the ideal anesthetic-rapid onset, potent sedation-hypnosis with a high therapeutic ratio of toxic dose to minimally effective dose, predictable clearance to inactive metabolites, and minimal side effects. This article aims to review current progress of novel induction agent development and provide an update on the most promising drugs poised to enter clinical practice. In addition, the authors describe trends in novel agent development, implications for health care costs, and implications for perioperative care.
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according to the authors, appeared not long ago new psychoactive substances (designer drugs), including synthetic cannabinoids, derivatives of cathinone, phenethylamines, new stimulants, synthetic opioids, tryptamine derivatives, phencyclidine, piperazine, agonists of GABA (A/B) receptors have become a serious problem for both consumers and doctors. Consumers of these substances are attracted primarily by the intensity of psychoactive effects, as well as «legal purity», which is declared by shadow producers. This indicates that there are some significant difficulties of laboratory typing of new surfactants. Designer drugs when ingested, can affect a range of neurotransmitter pathways/receptors: dopamine, cannabinoid (CB1), GABA(A/B), 5-HT2A, glutamate, and k-opioid receptors (KOR), the imbalance of which leads to the development of polymorphic psychotic disorders.
Chapter
The kidney carries out a number of crucial roles in the regulation of homeostasis. In addition to maintaining normal body volume, electrolyte concentration, and excretion of waste substances, kidneys regulate blood pressure and red cell carrying capacity and carry out a host of other functions. It is therefore not surprising that even small acute deteriorations in renal function lead to significant morbidity and mortality [1–3]. Acute kidney injury (AKI) is a common finding in hospitalized patients, with an incidence of 3–20 % depending on the population studied; the incidence of AKI increases to 16–67 % in intensive care units and appears to be growing [2, 3].
Chapter
Arylcyclohexamines (also known as arylcyclohexylamines) are a group of compounds that contain a cyclohexamine unit with an aryl moiety, typically a phenyl ring, attached to the same atom to which the amine group is linked (see Fig. 1). They all exhibit dissociative effects due to their antagonism of N-methyl-d-aspartate (NMDA) receptors, and many have been studied as alternatives to traditional anesthetic agents but subsequently abused recreationally in pursuit of these same effects. The most well-characterized arylcyclohexamines are phencyclidine ((1-(1-phencyclohexyl) piperidine; PCP)), ketamine, and, of the novel analogues, methoxetamine.
Chapter
There has been a change in the recreational drugs available to users, with the increasing accessibility of a wide range of novel psychoactive substances (NPS). The two most common categories of NPS are the synthetic cannabinoid receptor agonists (SCRA) and synthetic cathinones. Collection of data on the acute toxicity of NPS is difficult as there is no systematic collection of such data, therefore a process known as data triangulation is used to combine data from a variety of sources to describe the acute toxicity of NPS. Mephedrone is the most commonly used cathinone and it causes stimulant toxicity that is similar to the pattern of toxicity associated with amphetamines and cocaine. The SCRAs cause cannabis-like neuropsychiatric effects, but in addition to these they are associated with stimulant toxicity and there are reports of acute kidney injury associated with their use. There is limited data available on the chronic toxicity of NPS with no human data and only one published animal study; this showed that chronic methoxetamine (a ketamine analogue) administration is associated with a similar pattern of renal and lower urinary tract damage as ketamine. There are emerging reports of deaths associated with the use of NPS, including mephedrone and the SCRAs, similar to all drug-related deaths, detection of NPS in postmortem samples from fatalities thus needs to be interpreted with caution.
Article
Ketamine, a dissociative anesthetic, is misused and abused worldwide as an illegal recreational drug. In addition to its neuropathic toxicity, ketamine abuse has numerous effects, including renal failure; however, the underlying mechanism is poorly understood. The process called epithelial phenotypic changes (EPCs) causes the loss of cell-cell adhesion and cell polarity in renal diseases, as well as the acquisition of migratory and invasive properties. Madin-Darby canine kidney cells, an in vitro cell model, were subjected to experimental manipulation to investigate whether ketamine could promote EPCs. Our data showed that ketamine dramatically decreased transepithelial electrical resistance and increased paracellular permeability and junction disruption, which were coupled to decreased levels of apical junctional proteins (ZO-1, Occludin and E-cadherin). Consistent with the downregulation of epithelial markers, the mesenchymal markers N-cadherin, Fibronectin and Vimentin were markedly upregulated following ketamine stimulation. Of the E-cadherin repressor complexes tested, the mRNA levels of Snail, Slug, Twist, and ZEB1 were elevated. Moreover, ketamine significantly enhanced migration and invasion. Ketamine-mediated changes were at least partly caused by the inhibition of GSK-3β activity through Ser-9 phosphorylation by the PI3K/Akt pathway. Inhibiting PI3K/Akt with LY294002 reactivated GSK-3β and suppressed ketamine-enhanced permeability, EPCs and motility. These findings were recapitulated by the inactivation of GSK-3β using the inhibitor 3F8. Taken together, these results provide evidence that ketamine induces renal distal tubular EPCs through the downregulation of several junction proteins, the upregulation of mesenchymal markers, the activation of Akt, and the inactivation of GSK-3β. This article is protected by copyright. All rights reserved.
Article
Ketamine is a dissociative anesthetic. The misuse of ketamine as a recreational drug has increased over the last decade, especially in rave parties or clubs. Short-term ketamine pilot protocols have been undertaken for treatment-resistant depressive clients. In this study, we review and comment on the evidence relating to the potential of ketamine as a causative/contributory factor in traffic accidents. To determine the causal role of ketamine in traffic accidents, a literature search on the psychomotor, cognitive, visual and perceptual functions related to safe driving was conducted. Furthermore, to interpret related data better, an overview of ketamine and its congeners' clinical pharmacology issues, recreational psychoactive effects, and identification in biological specimens is also provided. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Article
To assess the prevalence of use and subjective effect profile of methoxetamine among a group of polydrug users. Cross-sectional, anonymous, online survey of UK-based polydrug users was conducted. Prevalence of lifetime, last year and last month use, sourcing of the drugs, motivations for use, and subjective effect and risk profile compared with that of ketamine were measured. There were 7700 UK-based polydrug users, of whom 326 reported recent use of methoxetamine. Of the whole sample, 4.2% reported last 12 month use of methoxetamine compared with 24.5% for ketamine. The most common route of use was intranasal and the predominate effect described as psychedelic. Of the 15.5% of last year users of ketamine reporting last year use of methoxetamine, only 18.7% reported that they thought methoxetamine was less damaging to their kidneys or bladder than ketamine. Its broad effect profile, based on participants' first experience of use, was very similar to that of ketamine. Almost one-third of users reported that they did not intend to try the drug again. Methoxetamine appears to have a broadly similar effect profile to that of ketamine. Only a minority of participants were motivated to use it because they believed it was less damaging to their kidneys or bladder than ketamine. The impact of the recent temporary banning order on availability and use of both methoxetamine and ketamine should be monitored carefully. [Winstock AR, Lawn W, Deluca P, Borschmann R. Methoxetamine: An early report on the motivations for use, effect profile and prevalence of use in a UK clubbing sample. Drug Alcohol Rev 2015]. © 2015 Australasian Professional Society on Alcohol and other Drugs.
Article
Résumé Depuis 2005, 215 nouvelles drogues ont été signalées dans l'Union européenne. Ces produits de synthèse, créés pour esquiver la législation sur les stupéfiants, sont des dérivés de médicaments ou drogues existants. Leur disponibilité est sans limite. Les effets recherchés incluent des effets stimulants, entactogènes, hallucinogènes, psychédéliques ou dissociatifs. Plusieurs classes chimiques sont représentées : phénéthylamines, tryptamines, pipérazines, cathinones, cannabinoïdes, … La toxicité inclut des effets comportementaux et physiques, les conséquences cardiovasculaires étant les plus redoutables. Cependant, de faibles variations de structure chimique peuvent entraîner des effets quantitativement différents, majorant ainsi la toxicité ou la dépendance. Ces substances ont une existence réelle sur le territoire national comme le montrent les données de l'Observatoire Français des Drogues et des Toxicomanies ainsi que celles du réseau des Centres d'Addictovigilance. La législation concernant ces produits change régulièrement avec de plus en plus de pays les classant comme « stupéfiants » pour en limiter l'usage.
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Novel psychoactive substances include synthetic cannabinoids, cathinone derivatives, psychedelic phenethylamines, novel stimulants, synthetic opioids, tryptamine derivatives, phencyclidine-like dissociatives, piperazines,GABA-A/B receptor agonists, a range of prescribedmedications, psychoactive plants/herbs, and a large series of performance and image enhancing drugs. Users are typically attracted by these substances due to their intense psychoactive effects and likely lack of detection in routine drug screenings. This paper aims at providing psychiatrists with updated knowledge of the clinical pharmacology and psychopathological consequences of the use of these substances. Indeed, these drugs act on a range of neurotransmitter pathways/receptors whose imbalance has been associated with psychopathological conditions, including dopamine, cannabinoid CB1, GABA-A/B, 5-HT2A, glutamate, and k opioid receptors. An overall approach in terms of clinical management is briefly discussed. Key words: Novel psychoactive substances, legal highs, smart drugs, research chemicals, substance abuse, dual diagnosis, psychedelic phenethylamines, synthetic cannabimimetics, phencyclidine-like drugs, cathinones, tryptamines
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Context: Envenomation by the Eastern coral snake is rare but may be associated with significant morbidity. While effective, acquisition of North American Coral Snake Antivenin (NACSAV) is difficult because production was discontinued for many years. Objective: The purpose of this study is to characterize coral snake exposures in Florida and determine the effects of varying treatment paradigms on patient outcomes. Methods: This study is an observational case series of cases received at Florida poison centers. Included cases were Eastern coral snake exposures occurring between January 1, 1998 and October 31, 2010. Excluded cases included those found to be unrelated or those not followed for at least 24 h post envenomation. Case comments were reviewed to obtain data. Comparisons were made between asymptomatic patients receiving empiric antivenom therapy (empiric group) and those asymptomatic patients who received antivenom upon developing signs of systemic envenomation (withhold group). Results: Of the 553 cases identified, 387 were included in the final analysis. According to case comments, 56.3% of patients had no reported systemic symptoms. Most commonly, patients were reported to have pain (40.6%), paresthesias (28.4%), nausea (12.7%), and emesis (11.4%). NACSAV was administered to 252 patients (65%). Of those patients receiving NACSAV, 18.25% were reported to have had an adverse reaction. Patients in the withhold group (n = 106) had significantly fewer minor, moderate, and major outcomes than patients in the empiric group (n = 134, p < 0.01). Discussion: While patients in the withhold group had favorable outcomes compared with those in the empiric group, this strategy cannot be applied to all patients presenting asymptomatic to healthcare facilities due to study limitations. Conclusion: Further studies are needed to determine what treatment strategy is most appropriate for asymptomatic patients presenting to healthcare facilities.
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Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been found to induce schizophrenia-type symptoms in humans and is a potent and fast-acting anti-depressant. It is also a relatively widespread drug of abuse, particular in China and the UK. Acute administration has been well characterised, but the effect of extended periods of ketamine use-on brain structure in humans-remains poorly understood. We measured indices of white matter microstructural integrity and connectivity in the brain of 16 ketamine users and 16 poly-drug using controls, and used probabilistic tractography to quantify changes in cortico-subcortical connectivity associated with ketamine use. We found a reduction in the axial diffusivity profile of white matter in a right hemisphere network of white matter regions in ketamine users compared to controls. Within the ketamine user group, we found a significant positive association between the connectivity profile between caudate nucleus and lateral prefrontal cortex and dissociative experiences. These findings suggest that chronic ketamine use may be associated with widespread disruption of white matter integrity, and white matter pathways between subcortical and prefrontal cortical areas may in part predict individual differences in dissociative experiences due to ketamine use.Neuropsychopharmacology accepted article preview online, 9 August 2013. doi:10.1038/npp.2013.195.
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In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.
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Aim: Analysis of urine samples collected across a city centre, for the detection of novel psychoactive substances (NPS). Design: Cross-sectional study of anonymized urine samples used for the analysis of classical recreational drugs, NPS and metabolites. Methods: Pooled urine samples collected from portable stand-alone four-person urinals across a city centre were analysed using full-scan accurate-mass high-resolution liquid chromatography coupled to tandem mass spectrometry. Data were processed against compound databases containing >1700 drug compounds and metabolites. Results: Seven established recreational drugs (3,4-methylenedioxyamphetamine, cocaine, cannabis, ketamine, 3,4-methylenedioxy-N-methylamphetamine, methamphetamine and amphetamine) and six potential NPS [hordenine (all 12 urinals), cathine (11), methylhexaneamine (9), 4-methylmethcathinone (6), methiopropamine and metabolites (2) and methoxetamine and metabolites (1)] were detected. Methylhexaneamine, methiopropamine and hordenine are currently uncontrolled in the UK, whereas methoxetamine is currently subject to a Temporary Class Drug Order. Metabolites of the anabolic steroid nandrolone were found in two urinals and trenbolone metabolites and clenbuterol in one urinal. Conclusion: Analysis of pooled urine samples collected anonymously from stand-alone urinals in a large inner city can detect the use of recreational drugs, NPS and anabolic steroids. Metabolite detection indicates actual drug use, metabolism and elimination rather than simply discarded drugs in the urinals. This technique by confirming the actual drug(s) used has the potential to be additive to currently used datasets/key indicators providing more robust information for healthcare authorities, legislative and law enforcement on the drugs actually being used.
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Ketamine is one of the common recreational drugs used in rave parties and it is frequently taken with alcohol. In spite of this, the potential toxicity of ketamine in liver and kidney has not been fully documented. In this study, ICR mice were treated for periods of 6, 16 and 28 weeks with 30 mg/kg ketamine injected daily intraperitoneally, and together with alcohol (0.5 ml of 10% alcohol for each mouse) during the last 4 weeks of the treatment periods. Our experimental results showed significant damage in liver, including fatty degeneration of liver cells, fibrosis and increase in liver glutamic oxaloacetic transaminase, proliferative cell nuclear antigen and lactate dehydrogenase after 16 weeks of treatment with ketamine. Hydropic degenerations of the kidney tubules were observed as early as 6 weeks of treatment. Long-term ketamine administration (28 weeks) led to atresia of glomeruli in the kidney. Proteinuria was confirmed in the 67% of the ketamine-treated animals after 28 weeks of treatment. It was apparent that ketamine when taken chronically (16 weeks of treatment and thereafter) affected both liver and kidney definitively. The damages in both liver and kidney of these mice were more severe when the animals were treated with both ketamine and alcohol.
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Ketamine abuse has been shown to have a deleterious impact on brain function. However, the precise mechanisms of ketamine dependence-induced pathological change remain poorly understood. Although there is evidence for white matter changes in drug abuse, the presence of white matter abnormalities in chronic ketamine users has not been studied. White matter volumes were measured using in vivo diffusion tensor magnetic resonance imaging data in 41 ketamine-dependent subjects and 44 drug-free healthy volunteers. White matter changes associated with chronic ketamine use were found in bilateral frontal and left temporoparietal cortices. There was also evidence that frontal white matter fractional anisotropy correlated with the severity of drug use (as measured by estimated total ketamine consumption). We provide direct evidence for dose-dependent abnormalities of white matter in bilateral frontal and left temporoparietal regions following chronic ketamine use. The findings suggest a microstructural basis for the changes in cognition and experience observed with prolonged ketamine use. Moreover, the similarities of these changes to those observed in chronic schizophrenia have implications for the glutamate model of this illness.
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To assess the impact of ketamine abuse on genitourinary tract dysfunction. Eleven patients with urinary tract symptoms and a history of ketamine abuse in recent years were studied. Urinalysis, urine culture, renal function tests, abdominal sonography and urodynamic studies were done. Bladder biopsies were carried out in selected cases. The most common complaints were lower urinary tract symptoms, including dysuria, frequency, urgency and gross hematuria. Urinalyses showed nonbacterial pyuria and were negative for tuberculosis. All biopsy specimens showed infiltrations of granulocytes (mostly eosinophils) and mast cells within the bladder tissue. Medications produced only slight clinical improvements. Intravesical instillation of hyaluronan solution was performed for some patients and a significant improvement of lower urinary tract symptoms was observed. Although the dosage and duration of ketamine abuse causing severe side-effects are still unclear, some patients develop irreversible histological changes in the urinary tract. Therefore, clinicians should be aware of the negative effects of ketamine abuse on genitourinary tract function.
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Substance abuse is a major health and social problem among Hong Kong youth and ketamine is the drug most commonly abused. Ketamine abuse is associated with a series of side-effects that include hallucination, nausea, vomiting, elevation of blood pressure, and urinary bladder dysfunction. Here we report three cases of ketamine abuse in which the abusers presented with recurrent epigastric pain and dilated common bile ducts that mimicked choledochal cysts on imaging. The dilated biliary tree may occur more frequently than was once assumed.
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To report the clinical spectrum seen in young abusers of street-ketamine (regular recreational abusers of street-ketamine, for its hallucinogenic effects) in Hong Kong, presenting with significant lower urinary tract symptoms (LUTS) but with no evidence of bacterial infection. We retrospectively analysed the clinical presentations, pelvic pain and urgency/frequency scores, video-urodynamic studies, cystoscopy findings, histological features of bladder biopsies and radiological findings of 59 ketamine abusers who were referred to the urology units of Princess Margaret and Tuen Mun Hospital, Hong Kong, from March 2000 to December 2007. Of the 59 patients, all had moderate to severe LUTS, i.e. frequency, urgency, dysuria, urge incontinence and occasionally painful haematuria. Forty-two (71%) patients had a cystoscopy that showed various degrees of epithelial inflammation similar to that seen in chronic interstitial cystitis. All of 12 available bladder biopsies had histological features resembling those of interstitial cystitis. Urodynamically, either detrusor overactivity or decreased bladder compliance with or without vesico-ureteric reflux was detected to some degree in all of 47 patients. Thirty patients (51%) had unilateral or bilateral hydronephrosis on renal ultrasonography, and four (7%) showed features suggestive of papillary necrosis on radiological imaging. Eight patients had a raised serum creatinine level. A syndrome of cystitis and contracted bladder can be associated with street-ketamine abuse. Secondary renal damage can occur in severe cases which might be irreversible, rendering patients dependent on dialysis. The present data do not establish the precise cause nor the incidence. Street-ketamine abuse is not only a drug problem, but might be associated with a serious urological condition causing a significant burden to healthcare resources.
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Introduction Ketamine is attracting increasing research interest not only because of its powerful amnestic effects but also as a putative model of schizophrenia and as a substance with an expanding following of recreational users. Objective This article reviews the existing literature on the effects of acute ketamine on the memory of healthy volunteers and of repeated doses of ketamine in recreational users. Current trends Although there have been relatively few, often methodologically diverse, studies to date of the mnemonic effects of ketamine, there is an emerging consensus that an acute dose of the drug impairs the manipulation of information in working memory and produces decrements in the encoding of information into episodic memory. Preliminary evidence suggests that ketamine may differ from other classic amnestic drugs in impairing aspects of semantic memory. Acute-on-chronic effects in ketamine users generally mimic the pattern seen in controlled studies with healthy volunteers. However, chronic ketamine use may be associated with a more specific pattern of memory decrements and with episodic memory impairment, which might not abate following cessation of use. Future trends An important aim of future research should be to detail the specificity of ketamine’s amnestic effects on both a neuropharmacological and a cognitive level.
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Ten young ketamine abusers presented with lower urinary tract symptoms to two regional hospitals in Hong Kong. Investigations demonstrated contracted bladders and other urinary tract abnormalities. These types of findings have never been reported before in ketamine abusers. The possible aetiology is also discussed.
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There has been significant media interest in the use of novel psychoactive substances (also known as 'legal highs') and reports in the medical literature of toxicity associated with their use. However, most surveys of recreational drug use focus on classical drugs such as cocaine and ecstasy, and there is limited information on how commonly emerging novel psychoactive substances are used. To collect data on use prevalence patterns of a wider range of novel psychoactive substances in South London gay nightclubs. Questionnaire survey. Individuals attending gay-friendly nightclubs in South East London (July 2011) were asked about life-time use, last month use and/or use on the night of the survey/planned use later that night of novel psychoactive substances, cocaine and MDMA/ecstasy. A total of 313 individuals were surveyed over 4 nights; 206 (65.8%) had previously used a 'legal high'. Mephedrone had the highest prevalence of last month use (53.2%) and use on the night of the survey (41.0%). This was greater than both cocaine (44.6% and 16.7%, respectively) and MDMA/ecstasy (26.9% and 5.8%). There was limited on the night use of the non-mephedrone 'legal highs': methoxetamine (1.6%) and 1-benzylpiperazine (0.6%), Spice/K2 (0.6%) and pipradrols (0.6%). Although a significant proportion of individuals report previous use of novel psychoactive substances, it seems that only mephedrone has become an established part of the recreational drug scene. It is important that there is a considered approach to determining the utilization of drug prevention/education and enforcement budgets to ensure that this is appropriately targeted to drugs that are used recreationally.
Article
There have been recent concerns about increasing use and accessibility of methoxetamine, a ketamine derivative. Few data are available to describe the clinical features associated with methoxetamine exposure. We report three cases that presented to hospital with acute neurological toxicity associated with analytically confirmed methoxetamine exposure. A 19-year-old male presented with severe truncal ataxia, nystagmus, incoordination and reduced conscious level several hours after nasal insufflation of what was initially thought to be ketamine. Features of cerebellar toxicity persisted for 3-4 days before gradual recovery. Two more patients aged 17 and 18 years presented with severe cerebellar ataxia, imbalance and reduced conscious level 40 minutes after nasal insufflation of methoxetamine (MXE). Both had slurred speech, incoordination and cerebellar ataxia that resolved within 24 hours. Serum methoxetamine concentrations were 0.24 mg/L, 0.45 mg/L and 0.16 mg/L, respectively, and no other drugs were identified on an extended toxicological screen. Methoxetamine may cause rapid onset of neurological impairment, characterised by acute cerebellar toxicity. Spontaneous recovery was observed, but the duration of recovery may extend to several days. Presentation with an acute cerebellar toxidrome should alert clinicians to the possibility of methoxetamine exposure.
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On the basis of the material available both in the scientific literature and on the web, this paper aims to provide a pharmacological, chemical and behavioural overview of the novel compound methoxetamine. This is a dissociative drug related to ketamine, with a much longer duration of action and intensity of effects. A critical discussion of the availability of information on the web of methoxetamine as a new recreational trend is here provided. Those methodological limitations, which are intrinsically associated with the analysis of online, non-peer reviewed, material, are here discussed as well. It is concluded that the online availability of information on novel psychoactive drugs, such as methoxethanine, may constitute a pressing public health challenge. Better international collaboration levels and novel forms of intervention are necessary to tackle this fast-growing phenomenon.
Article
'Legal highs' are psychoactive chemicals which are sold from 'head shops', the internet and from street suppliers and may be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes an evaluation of their harm difficult. This review covers the basic chemistry of these novel psychoactive compounds and relates them to endogenous neurotransmitters and existing drugs of abuse. A survey of the internet was used to identify websites that are marketing 'legal highs' in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline, 4-fluorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds. This search elicited no citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N,N-diallyl-tryptamine. 'Legal highs' from the phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is cited in the literature on their true chemical identity, pharmacology or toxicology. 'Legal highs' are gaining in popularity and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new legislation can be used to reduce the supply of these materials, investment in better education for young people on the harms associated with 'legal highs' is needed.
Article
Methoxetamine, the N-ethyl derivative of ketamine, is a novel recreational drug that is not at present subject to restrictive regulations in most countries. To our knowledge, no case of methoxetamine abuse has been published to date in the scientific literature, and the only sources of information are illegal drug users' Web discussion forums. We report the first case of analytically confirmed intravenous methoxetamine abuse in a 19-year-old man. Observed signs and symptoms such as tachycardia, hypertension, confusion, agitation, stupor, ataxia, mydriasis, and nystagmus were consistent with ketamine-induced adverse effects and resolved with symptomatic treatment. According to this case report, user Web reports, and the chemical structure, methoxetamine produces ketamine-like effects. Complete recovery can be expected with supportive care.
Article
Long-term regular use of ketamine has been reported to be associated with severe symptomatic urinary tract problems. Methoxetamine, an arylcyclohexylamine derivative of ketamine, is marketed as a "bladder safe" derivative of ketamine, and no cases of acute toxicity following analytically confirmed methoxetamine use have been reported to date. We report here a case series of three individuals with acute toxicity related to the analytically confirmed use of methoxetamine. Three patients aged between 28 and 42 years presented to the Emergency Department (ED) on unrelated occasions having used methoxetamine. Clinical features were suggestive of a "dissociative/catatonic" state similar to that seen with ketamine; in addition, they had clinical features of acute sympathomimetic toxicity with significant tachycardia and hypertension. All were managed with low-dose benzodiazepines and discharged home once their symptoms/signs had settled. TOXICOLOGICAL SCREENING: Serum collected at the time of presentation to the ED was analysed qualitatively and quantitatively by gas chromatography-mass spectrometry. Serum concentrations ranged from 0.09 to 0.2 mg/L; in addition, detectable levels of 6-APB/5-APB were found in one of the patients. These three analytically confirmed cases demonstrate that acute methoxetamine-related toxicity is associated with both "dissociative" and "sympathomimetic" clinical features. The information from these three cases is useful to clinical pharmacologists, not only in managing individuals with acute methoxetamine toxicity but also in advising the appropriate legislative authorities on the risk of acute harm related to methoxetamine use. Further work is needed to determine whether methoxetamine is more "bladder friendly" than ketamine, as has been suggested by those marketing methoxetamine.
Article
Different doses of ketamine (10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, and 60 mg/kg) were injected i.p. (I.P.), respectively, to male ICR mice to determine the optimal dosage for chronic administration. At and above 40 mg/kg I.P. injection, mice had almost no hindlimb movement during swimming test. Subsequently, 30 mg/kg was used as the dose for the study in the toxicity of long-term ketamine administration on urinary bladder and sperm motility. The treatment group were subdivided into two (n = 10 each group); one received daily ketamine treatment i.p. for 3 months and another group for 6 months. Corresponding number of mice in control groups (n = 5 each group) received saline injection instead of ketamine. Terminal dUTP nick and labeling (TUNEL) study and Sirius red staining were carried out on the sectioned slides of the urinary bladders to study the degree of apoptosis in both epithelium and muscular layers of the urinary bladder and the relative thickness of the muscular layers in this organ was also computed. Apoptosis in the bladder epithelium was observed initially in the 3-month ketamine treated mice and the number of apoptotic cells was significantly different (P < 0.05) between the 3-month and 6-month ketamine treated mice and the control. The relative thickness of muscular layers in the bladder wall also decreased significantly (P < 0.05) when the 6-month treated mice and the control were compared. Sirius red staining revealed increase of collagen in the urinary bladder of the treated mice, most evidently 6 months after ketamine treatment. In addition, the sperm motility was studied and there was a statistically significant difference between the control and ketamine treated groups in the percentages of sperms which were motile (P < 0.05). This suggested that the chronic administration of ketamine affected the genital system as well.
Article
To study the association between upper gastrointestinal (GI) problems and inhalational ketamine abuse. This is a retrospective study of 64 ketamine abusers treated from 2001 to 2008. Variables studied included clinical presentations, findings of upper GI endoscopy, abstinence from ketamine and relief of epigastric pain. The following patients with (i) a previous history of upper GI problem; (ii) a history of non-steroidal anti-inflammatory drug (NSAID), aspirin or other substance abuse; and (iii) a known history of Helicobacter pylori (H. pylori) infection were excluded. The study group thus consisted of 37 ketamine abusers, of whom 28 had upper GI symptoms. Overall 14 of these patients had an upper endoscopy performed. The endoscopic diagnoses were: 12 (85.7%) with gastritis, one (7.1%) with gastroduodenitis, and one (7.1%) normal finding. Test for H. pylori, infection was negative. Abstinence from ketamine was found to be associated significantly with relief of symptoms (P= 0.027). Logistic regression showed the odds ratio of symptomatic relief for abstinence versus continued use of ketamine is 12.5 (95% CI[1.20, 130.6], P= 0.035). In patients whom an upper GI endoscopy was performed, H. pylori negative gastritis was the commonest histopathological finding (78.6%). Despite the use of medications, symptoms are commonly not relieved and that is associated with the continued abuse of ketamine. Ketamine abusers frequently presented with upper GI symptoms, the commonest of which is epigastric pain (73% of abusers). Abstinence from ketamine abuse can lead to the relief of symptoms, which is an important message for ketamine abusers.
Article
ICR mice were injected with ketamine for 1, 3 and 6 months and the kidneys and urinary bladders were excised and processed for histology. Starting from 1 month, all addicted mice showed invasion of mononuclear white cells, either surrounding the glomerulus or the other tubules in the kidney. The aggregation of these cells extended all the way to the pelvis and ureter. As well, in the urinary bladder, the epithelium became thin and there was submucosal infiltration of mononuclear inflammatory cells. Silver staining revealed a loss of nerve fibers amongst the muscles of the urinary bladder of the treated. Immunohistochemistry on choline acetyltransferase which is a marker for cholinergic neurons also demonstrated a decrease of those cells. We hypothesized that prolonged ketamine addiction resulted in the animals prone to urinary infection.
Article
The detrusor smooth muscle is the main muscle component of the urinary bladder wall. Its ability to contract over a large length interval and to relax determines the bladder function during filling and micturition. These processes are regulated by several external nervous and hormonal control systems, and the detrusor contains multiple receptors and signaling pathways. Functional changes of the detrusor can be found in several clinically important conditions, e.g., lower urinary tract symptoms (LUTS) and bladder outlet obstruction. The aim of this review is to summarize and synthesize basic information and recent advances in the understanding of the properties of the detrusor smooth muscle, its contractile system, cellular signaling, membrane properties, and cellular receptors. Alterations in these systems in pathological conditions of the bladder wall are described, and some areas for future research are suggested.
Interview with a ketamine chemist: or 18. to be more precise, an arylcyclohexylamine chemist . Vice Magazine Available at: http://www.vice.com/read/interview-with-ketamine-chemist-704-v18n2. Accessed on 16 Phenomenon of new drugs on the Internet: the case of ketamine derivative methoxetamine
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Interview with a ketamine chemist: or to be more precise, an arylcyclohexylamine chemist. Vice Magazine
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Morris H (11-February-2011). Interview with a ketamine chemist: or 18. to be more precise, an arylcyclohexylamine chemist. Vice Magazine. Available at: http://www.vice.com/read/interview-with-ketaminechemist-704-v18n2. Accessed on 16 December 2013.
The destruction of the lower urinary tract by ketamine abuse: a new syndrome?
  • Ps Chu
  • Wk Ma
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Chu PS, Ma WK, Wong SCW, Chu RWH, Cheng CH, Wong S, et al. 20. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int 2008 ; 102 : 1616-1622.
‘Street ketamine’-associated bladder dysfunction: a report of ten cases
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Dilated common bile ducts mimicking choledochal cysts in ketamine abusers
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Ketamine effects on the urogenital system-changes in the urinary bladder and sperm motility
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  • Ms Wai
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Tan S, Chan WM, Wai MS, Hui LK, Hui VW, James AE, 14. et al. Ketamine effects on the urogenital system-changes in the urinary bladder and sperm motility. Microsc Res Tech 2011 ; 74 : 1192-1198.
Methoxetamine associated cerebellar toxicity: Three cases with analytical confi rmation
Waring S. Methoxetamine associated cerebellar toxicity: Three cases with analytical confi rmation. Clin Toxicol (Phila) 2012 ; 50 : 438 -440.
Ketamine-associated bladder dysfunction
Ketamine-associated bladder dysfunction. Int J Urol 2009 ; 16 : 826 -829.
The destruction of the lower urinary tract by ketamine abuse: a new syndrome?
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Chu PS, Ma WK, Wong SCW, Chu RWH, Cheng CH, Wong S, et al. 20. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int 2008 ; 102 : 1616 -1622.
Annual Report on the implementation of Council Decision
  • Emcdda - Europol