Ketamine Analogue Research Articles

Ketamine analogues: Comparative toxicokinetic in vitro–in vivo extrapolation and quantification of 2-fluorodeschloroketamine in forensic blood and hair samples

Recently, the new psychoactive substance (NPS) ketamine analogue 2-fluoro-deschloroketamine (2FDCK) was observed in driving-under-the-influence-of-drugs whole blood samples and in a forensic hair investigation case in Denmark. The molecular structure variations among the NPS subgroups may alter the metabolic fate and drug potency, thereby posing a threat for drug users. This study reports quantification of 2FDCK in whole blood samples and forensic hair and compares the following toxicokinetic parameters: unbound fraction (fu) and in vitro–in vivo-extrapolation (IVIVE) of hepatic clearance for ketamine, norketamine, 2FDCK, methoxetamine and deschloroketamine. The fu was investigated with ultrafiltration, while clearance studies were conducted at 1 μM with pooled human liver microsomes. Samples were analysed by liquid chromatography and mass spectrometry. For the first time, 2FDCK was determined in a concentration range between 0.005 and 0.48 mg/kg in blood samples. Segmental hair analysis demonstrated 2FDCK at concentrations from 0.007 to 0.034 ng/mg throughout the three investigated segments. Toxicokinetic comparison of the five compounds gave a fu between 0.54 and 0.84, with ketamine being the most bound and deschloroketamine being the least bound, in accordance with the logP of the compounds. Conversely, a negative correlation was observed between the molecular weight of the halogen in the ortho-position and IVIVE hepatic clearance. The IVIVE of hepatic clearance, CLparallel-tube, gave values from 18.1 to 5.44 mL/min/kg for ketamine and methoxetamine, respectively. The deschloroketamine IVIVE was disregarded due to low drug elimination under the experimental conditions used. This study provides a basis for toxicokinetic understanding of ketamine analogues.

P.713 Enantiomers of deschloroketamine, a novel ketamine analogue, inhibit dopamine transporter (DAT) expressed in rat striatum

Implementation of resource-saving technologies can be based on improving the qualitative characteristics of heat and mass transfer equipment, which is widely used in power engineering, chemical, petrochemical, gas and food industries.One of the most effective ways of interaction between the coolant and the working medium is the direct contact of a gravitationally flowing liquid film and a gas. A promising method for passive intensification of heat and mass transfer between the liquid film and gas is the use of contact surfaces with regular roughness, with capillary-porous or mesh coating of channel walls.The launch and emergency stop of the heat and mass transfer device may generate a transition in the cooling mode of liquid from forced to natural convection. This leads to a change in the conditions of heat and mass transfer, and, consequently, to a change in the parameters of the coolant at the output of the device. In this case, using the dependences obtained for forced convection in the channel leads to a significant error in determining the parameters of the heat carrier. Therefore, in order to design and manufacture heat-mass-transfer units of contact type, one would need the information on the patterns of heat and mass transfer under different operating conditions.An important condition for ensuring the efficiency of contact-type devices is to know the features of the interaction between the liquid and gas mediums. The development of boundary layers in the film and gas leads to the need to allocate the initial thermal region and the stabilized heat and mass transfer region. These factors are not taken into account in the engineering calculation methods that exist today.

Determination of 21 synthetic cathinones, phenethylamines, amphetamines and opioids in influent wastewater using liquid chromatography coupled to tandem mass spectrometry

Human consumption of illicit novel psychoactive substances (NPS) is a continuing problem. New derivatives are constantly appearing, circumventing national and international laws. The use of these compounds tend to be sporadic and many are consumed as mixtures, meaning very low amounts of each are detectable at any one time. The analysis of excreted NPS in wastewater provides information on community prevalence. A wastewater-based epidemiology approach has been applied in the current study for the quantification of 21 NPS. These include three phenethylamines (25B–NBOMe, 25C–NBOMe, 25I–NBOMe), ten synthetic cathinones (3-ethylmethcathinone (3-EMC), 3-methylbuphedrone, 3-methylmethcathinone (3-MMC), 4-fluoromethcathinone (4-FMC), 4-methylbuphedrone, 4-methylethcathinone (4-MEC), buphedrone, butylone, N-ethylpentylone and pentylone), five synthetic opioid analgesics (AH-7921, butyryl fentanyl, furanyl fentanyl, U-47700 and valeryl fentanyl) as well as the synthetic amphetamine 4-fluoroamphemtaine (4-FA), ketamine analogue methoxetamine and methiopropamine. Limits of detection were between 0.01 and 0.5 ng/L and limits of quantification were between 0.05 and 1 ng/L. The method was applied to wastewater samples from South Australia collected over the Christmas-New Year period when recreational drug use tends to be high. Seven NPS (butylone, butyryl fentanyl, furanyl fentanyl, methoxetamine, N-ethylpentylone, pentylone and valeryl fentanyl) were found, with N-ethylpentylone showing the highest mass loads at 36 mg/day/1000 inhabitants.

Ketamine-induced regulation of TrkB-GSK3β signaling is accompanied by slow EEG oscillations and sedation but is independent of hydroxynorketamine metabolites

Subanesthetic rather than anesthetic doses are thought to bring the rapid antidepressant effects of the NMDAR (N-methyl-d-aspartate receptor) antagonist ketamine. Among molecular mechanisms, activation of BDNF receptor TrkB along with the inhibition of GSK3β (glycogen synthase kinase 3β) are considered as critical molecular level determinants for ketamine's antidepressant effects. Hydroxynorketamines (2R,6R)-HNK and (2S,6S)–HNK), non-anesthetic metabolites of ketamine, have been proposed to govern the therapeutic effects of ketamine through a mechanism not involving NMDARs. However, we have shown that nitrous oxide, another NMDAR blocking anesthetic and a putative rapid-acting antidepressant, evokes TrkB-GSK3β signaling alterations during rebound slow EEG (electroencephalogram) oscillations. We investigated here the acute effects of ketamine, 6,6-d2-ketamine (a ketamine analogue resistant to metabolism) and cis-HNK that contains (2R,6R) and (2S,6S) enantiomers in 1:1 ratio, on TrkB-GSK3β signaling and concomitant electroencephalographic (EEG) alterations in the adult mouse cortex. Ketamine dose-dependently increased slow oscillations and phosphorylations of TrkBY816 and GSK3βS9 in crude brain homogenates (i.e. sedative/anesthetic doses (>50 mg/kg, i.p.) produced more prominent effects than a subanesthetic dose (10 mg/kg, i.p.)). Similar, albeit less obvious, effects were seen in crude synaptosomes. A sedative dose of 6,6-d2-ketamine (100 mg/kg, i.p.) recapitulated the effects of ketamine on TrkB and GSK3β phosphorylation while cis-HNK at a dose of 20 mg/kg produced negligible acute effects on TrkB-GSK3β signaling or slow oscillations. These findings suggest that the acute effects of ketamine on TrkB-GSK3β signaling are by no means restricted to subanesthetic (i.e. antidepressant) doses and that cis-HNK is not responsible for these effects.

Ketamine esters and amides as short-acting anaesthetics: Structure-activity relationships for the side-chain.

N-Aliphatic ester analogues of the non-opioid ketamine (1) retain effective anaesthetic/analgesic properties while minimising ketamine's psychomimetic side-effects. We show that the anaesthetic/analgesic properties of these ester analogues depend critically on the length (from 2 to 4 carbons), polarity and steric cross-section of the aliphatic linker chain. More stable amide and ethylsulfone analogues generally showed weaker anaesthetic/analgesic activity. There was no correlation between the anaesthetic/analgesic properties of the compounds and their binding affinities for the N-methyl-d-aspartate (NMDA) receptor.

Halogen Substitution Influences Ketamine Metabolism by Cytochrome P450 2B6: In Vitro and Computational Approaches.

Ketamine is analgesic at anesthetic and subanesthetic doses, and it has been used recently to treat depression. Biotransformation mediates ketamine effects, influencing both systemic elimination and bioactivation. CYP2B6 is the major catalyst of hepatic ketamine N-demethylation and metabolism at clinically relevant concentrations. Numerous CYP2B6 substrates contain halogens. CYP2B6 readily forms halogen-protein (particularly Cl-π) bonds, which influence substrate selectivity and active site orientation. Ketamine is chlorinated, but little is known about the metabolism of halogenated analogs. This investigation evaluated halogen substitution effects on CYP2B6-catalyzed ketamine analogs N-demethylation in vitro and modeled interactions with CYP2B6 using various computational approaches. Ortho phenyl ring halogen substituent changes caused substantial (18-fold) differences in Km, on the order of Br (bromoketamine, 10 μM) < Cl < F < H (deschloroketamine, 184 μM). In contrast, Vmax varied minimally (83-103 pmol/min/pmol CYP). Thus, apparent substrate binding affinity was the major consequence of halogen substitution and the major determinant of N-demethylation. Docking poses of ketamine and analogs were similar, sharing a π-stack with F297. Libdock scores were deschloroketamine < bromoketamine < ketamine < fluoroketamine. A Bayesian log Km model generated with Assay Central had a ROC of 0.86. The probability of activity at 15 μM for ketamine and analogs was predicted with this model. Deschloroketamine scores corresponded to the experimental Km, but the model was unable to predict activity with fluoroketamine. The binding pocket of CYP2B6 also suggested a hydrophobic component to substrate docking, on the basis of a strong linear correlation ( R2 = 0.92) between lipophilicity ( Alog P) and metabolism (log Km) of ketamine and analogs. This property may be the simplest design criteria to use when considering similar compounds and CYP2B6 affinity.

Method for the Direct Enantioselective Synthesis of Chiral Primary α-Amino Ketones by Catalytic α-Amination.

A useful catalytic enantioselective approach has been developed for the synthesis of chiral ketamine analogs using Rh(II)-catalyzed amination of triisopropylsilyl enol ethers to form α-amino ketones with O-(4-nitrophenyl)hydroxylamine as nitrogen donor in 81-91% ee.

9-year review of new psychoactive substance use in Hong Kong: A clinical laboratory perspective

Background: New psychoactive substances are constantly evolving structural analogues of traditional drugs of abuse that have become a threat to public health worldwide and within our locality. An understanding of the local pattern of new psychoactive substance use will help guide frontline clinical management. Objectives: This study was conducted to review the new psychoactive substances detected in cases referred to the authors’ laboratory (a tertiary clinical toxicology centre), as well as the associated clinical features and toxicological findings. Methods: All cases referred to the laboratory for toxicology analysis between January 2009 and December 2017, and which were analytically confirmed to involve new psychoactive substance use, were retrospectively reviewed. Demographic data, clinical features and toxicology findings were studied. Results: A total of 111 cases involving 104 patients and 22 types of new psychoactive substances were identified, with an increasing trend in the number of cases and subclass of new psychoactive substances detected. Up to half of the cases (n = 64) were related to the use of 2-phenyl-2-(ethylamino)-cyclohexanone (2-oxo-PCE, a ketamine analogue); other new psychoactive substances detected included para-methoxymethamphetamine, 4-fluoroamphetamine, phenazepam, 3-trifluoromethylphenylpiperazine, 5-methoxy-diisopropyltryptamine, 2-diphenylmethylpyrrolidine, methoxyphenidine, the N-methoxybenzyl drugs, cathinones, synthetic cannabinoids and opioids. Among the acute poisoning cases attributable to new psychoactive substance use, the severity was fatal (n = 3), severe (n = 17), moderate (n = 67) and minor (n = 17). And 11 patients required intensive care unit admission. All three fatal cases were associated with para-methoxymethamphetamine use. Conclusion: A rising trend of new psychoactive substance use is observed locally, which is associated with considerable morbidity and mortality. Continued vigilance from frontline clinicians and medical professionals is imperative in the combat against new psychoactive substance use.

Syntheses of Ketamine and Related Analogues: A Mini Review

Ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexanone] is a dissociative anaesthetic, first developed in 1963 by Parke-Davis. It finds widespread application in the treatment of battlefield injuries, and in emergency departments for use in children. In recent times the clinical interest in ketamine has increased due to the positive impact it has in treating depression and the rapid onset of its antidepressant effect. This review covers the synthetic effort towards ketamine and related analogues over the past 60 years to give readers an overview of past, current, and future research outlook pertaining to ketamine-like molecules.1 Introduction2 Early Work3 Synthesis3.1 Ketamine3.2 Norketamine3.3 Ketamine Analogues4 Future Outlook and Conclusion

Cluster of acute poisonings associated with an emerging ketamine analogue, 2-oxo-PCE

Ketamine and phencyclidine are well-known drugs of abuse of the arylcyclohexylamine class, the backbone of which is used for the synthesis of new psychoactive substances (NPS). In October 2017, a cluster of acute intoxications was encountered where patients presented with ketamine-like toxidrome. Upon initial toxicology screening, however, neither ketamine nor other causative agents were detected in the patients’ urine. Instead, an unidentified substance was consistently detected. Further investigations using gas- and liquid-chromatography mass spectrometry led to the identification of an arylcyclohexylamine analogue, 2-oxo-PCE. The present study reports the analytical and toxicological profile of this emerging NPS. Chart review found, in total, 56 cases of 2-oxo-PCE associated acute poisoning between October and November 2017. Laboratory analysis confirmed the presence of 2-oxo-PCE in the urine of all patients; nasal swab samples from three patients revealed the lone presence of 2-oxo-PCE. Urine bedside immunoassay for ketamine was found not to cross-react with 2-oxo-PCE. In 55% of the cases, other drugs of abuse were detected on toxicology analysis; whilst in the remainder, 2-oxo-PCE was used alone. The main clinical symptoms associated with sole 2-oxo-PCE use include impaired consciousness (84%), confusion (60%), abnormal behaviour (44%), hypertension (80%) and tachycardia (40%). Convulsion (16%) was also observed relatively frequently. Management was mainly supportive, whilst three patients required intensive care. All patients recovered uneventfully. In conclusion, frontline clinical and laboratory personnel should be highly vigilant in the lookout for 2-oxo-PCE, a dangerous emerging arylcyclohexylamine analogue.

Correction: The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

[This corrects the article DOI: 10.1371/journal.pone.0059334.].

Rapid and simple procedure for the determination of cathinones, amphetamine-like stimulants and other new psychoactive substances in blood and urine by GC–MS

In the last few years an increasing number of new psychoactive substances (NPS), with different chemical structures (of which 37% are stimulants), have been released into the illicit drug market. Their detection and identification in biological samples is hence of great concern.The aim of this work was to develop a high-throughput and rapid method for the determination of different classes of stimulants (amphetamine-type stimulants, cathinones, phenethylamines and ketamine analogues) from blood and urine samples using GC–MS.The proposed method allows the almost simultaneous derivatization and extraction of analytes from biological samples in a very short time, by using hexyl chloroformate as derivatization agent. The extraction of analytes was performed by Dispersive Liquid Liquid Microextraction (DLLME), a very rapid, cheap and efficient extraction technique that employs microliter amounts of organic solvents.The chromatographic method allowed for the separation of 26 stimulants including positional isomers (3-MMC and 4-MMC). The method was validated on urine and blood samples with the ability to detect and quantify all analytes with satisfactory limits of detection (LODs) ranging between 1 and 10ng/mL, limits of quantification (LOQs) between 2 and 50ng/mL, selectivity and linearity (5–1000ng/mL).The method was then applied to real samples from forensic cases, demonstrating its suitability for the screening of a wide number of stimulants in biological specimens.

Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms

Depression afflicts around 16% of the world's population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate-based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic- and serotonergic-related genes in the mouse hippocampus using quantitative real-time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic- and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system.

Neuropharmacological characterization of the new psychoactive substance methoxetamine

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 exposure, while only limited data are available on its neuropharmacological modes of action.We investigated the effects of MXE and ketamine on several endpoints using multiple in vitro models. These included rat primary cortical cells, human SH-SY5Y cells, human induced pluripotent stem cell (hiPSC)-derived iCell® Neurons, DopaNeurons and astrocyte co-cultures, and human embryonic kidney (HEK293) cells. We investigated effects on several neurotransmitter receptors using single cell intracellular calcium [Ca2+]i imaging, effects on neuronal activity using micro-electrode array (MEA) recordings and effects on human monoamine transporters using a fluorescence-based plate reader assay.In rat primary cortical cells, 10 μM MXE increased the glutamate-evoked increase in [Ca2+]i, whereas 10 μM ketamine was without effect. MXE and ketamine did not affect voltage-gated calcium channels (VGCCs), but inhibited spontaneous neuronal activity (IC50 0.5 μM and 1.2 μM respectively). In human SH-SY5Y cells, 10 μM MXE slightly inhibited the K+- and acetylcholine-evoked increase in [Ca2+]i. In hiPSC-derived iCell®(Dopa)Neurons, only the ATP-evoked increase in [Ca2+]i was slightly reduced. Additionally, MXE inhibited spontaneous neuronal activity (IC50 between 10 and 100 μM). Finally, MXE potently inhibits uptake via monoamine transporters (DAT, NET and SERT), with IC50 values in the low micromolar range (33, 20, 2 μM respectively).Our combined in vitro data provide an urgently needed first insight into the multiple modes of action of MXE. The use of different models and different (neuronal) endpoints can be complementary in pharmacological profiling. Rapid in vitro screening methods as those presented here, could be of utmost importance for gaining a first mechanistic insight to aid the risk assessment of emerging NPS.

Ketamine Analog Methoxetamine Induced Inflammation and Dysfunction of Bladder in Rats.

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.

Chemistry, Pharmacology and Toxicology of New Designer Drugs - A Comprehensive Review

Drugs have been used for recreational purposes since time immemorial. Addicting potential and the propensity to harm has led to a ban on many of these drugs. New compounds are being developed to circumvent the ban. They are similar in effect to the banned drugs but are slightly different in their chemical structure so that they can escape detection in the standard drug tests. These drugs are commonly known as designer drugs or new psychoactive substances (NPS).This work aimed to do a comprehensive review on chemistry, pharmacology and toxicology of new designer drugs for establishing the basic knowledge about them, focusing on their assessment and management and recent methods for their detection.According to the United Nations Office on Drugs and Crime (UNODC) classification, NPS include the following groups: Synthetic cannabinoids, synthetic cathinones, piperazine, phenethylamines, ketamine analogues, plant-based substances(Kratom, Salvia Divinorum) and miscellaneous substances (aminoindanes and tryptamines). NPS have become a global phenomenon with over 100 countries and territories from all regions of the world having reported one or more NPS. Up to December 2015, more than 600 substances have been reported to the UNODC Early Warning Advisory (EWA) on NPS by Governments, laboratories and partner organizations.NPS represent a challenge both in forensic analytical toxicology as well as in clinical toxicology as they may cause serious toxicity and can escape detection in the standard drug tests.Clinicians should keep designer drugs in mind when evaluating substance use in young adults or in anyone presenting with acute neuropsychiatric complaintsCoordination among emergency medical personnel, forensic toxicologists, scientific researchers, law enforcement and policymakers is essential to foster more effective responses in dealing with this evolving drug-abuse phenomenon

Development of Rapidly Metabolized and Ultra-Short–Acting Ketamine Analogs

Development of Rapidly Metabolized and Ultra-Short–Acting Ketamine Analogs

Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic vasodilations in porcine basilar arteries

The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O2 demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp, and calcium imaging. In U46619-contracted basilar arterial rings, nicotine (100μM) and electrical depolarization of nitrergic nerves by transmural nerve stimulation (TNS, 8Hz) elicited neurogenic nitrergic vasodilations. Ketamine and amphetamine analogs concentration-dependently inhibited nicotine-induced parasympathetic-nitrergic vasodilation without affecting that induced by TNS, nitroprusside or isoproterenol. Ketamine and amphetamine analogs also concentration-dependently blocked nicotine-induced inward currents in Xenopus oocytes expressing α3β2-nicotinic acetylcholine receptors (nAChRs), and nicotine-induced inward currents as well as calcium influxes in rat superior cervical ganglion neurons. The potency in inhibiting both inward-currents and calcium influxes is ketamine>methamphetamine>hydroxyamphetamine. These results indicate that ketamine and amphetamine analogs, by blocking nAChRs located on cerebral perivascular sympathetic nerves, reduce nicotine-induced, axo-axonal interaction mechanism-mediated neurogenic dilation of the basilar arteries. Chronic abuse of these drugs, therefore, may interfere with normal sympathetic-parasympathetic interaction mechanism resulting in diminished neurogenic vasodilation and, possibly, normal blood flow in the brainstem.

Detailed pharmacological evaluation of methoxetamine (MXE), a novel psychoactive ketamine analogue-Behavioural, pharmacokinetic and metabolic studies in the Wistar rat.

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. Locomotor activity and its spatial characteristics (in the open field) and sensorimotor gating (prepulse inhibition; PPI) were evaluated after 5, 10 and 40mg/kg subcutaneous (sc.) MXE. Pharmacokinetics and brain: serum ratios were evaluated after 10mg/kg sc. MXE so that peak drug concentration data could be used to complement interpretation of maximal behavioural effects. Finally, quantification of metabolites in rat urine collected over 24h was performed after single bolus of MXE 40mg/kg sc. 5 and 10mg/kg MXE induced significant locomotor stimulation, in addition it increased thigmotaxis and decreased time spent in the centre of the open field (indicative of anxiogenesis). By contrast, 40mg/kg reduced locomotion and increased time spent in the centre of the arena, suggesting sedation/anaesthesia or stereotypy. The duration of effects was present for at least 60-90min, although for 5mg/kg, locomotion diminished after 60min. MXE decreased baseline acoustic startle response (ASR) and disrupted PPI, irrespective of testing-onset. MXE (all doses) reduced habituation but only at 60min. Maximal brain levels of MXE were observed 30min after administration, remained high at 60min and progressively declined to around zero after six hours. MXE accumulated in the brain; the brain: serum ratio was between 2.06 and 2.93 throughout the whole observation. The most abundant urinary metabolite was O-desmethylmethoxetamine followed by normethoxetamine. To conclude, MXE acts behaviourally as a typical dissociative anaesthetic with stimulant and anxiogenic effects at lower doses, sedative/anaesthetic effects at higher doses, and as a disruptor of sensorimotor gating. Its duration of action exceeds that of ketamine which is consistent with reports from MXE users. The accumulation of the drug in brain tissue might reflect MXE's stronger potency compared to ketamine and indicate increased toxicity.

The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents.

Methoxetamine (MXE) is a ketamine analog sold online that has been subject to widespread abuse for its dissociative and hallucinogenic effects. Previous studies have shown that MXE has high affinity for the phencyclidine (PCP) binding site located within the channel pore of the NMDA receptor (NMDAR), but little is known about its behavioral effects. Dissociative anesthetics such as ketamine and PCP produce a characteristic behavioral profile in rats that includes locomotor hyperactivity and disruption of prepulse inhibition (PPI) of acoustic startle. The goal of the present investigation was to determine whether MXE produces PCP-like effects in Sprague-Dawley rats using the PPI paradigm and the behavioral pattern monitor (BPM), which enables analyses of patterns of locomotor activity and investigatory behavior. PPI studies were conducted with several other uncompetitive NMDAR antagonists that produce dissociative effects in humans, including PCP, the S-(+) and R-(-) isomers of ketamine, and N-allylnormetazocine (NANM; SKF-10,047). MXE disrupted PPI when administered at 3 and 10mg/kg SC. The rank order of potency of MXE and the other test compounds in the PPI paradigm (PCP > MXE > S-(+)-ketamine > NANM > R-(-)-ketamine) parallels their affinities for the PCP binding site reported in the literature. When tested in the BPM, 10mg/kg MXE induced locomotor hyperactivity, reduced the number of rearings, increased the roughness of locomotor paths, and produced perseverative patterns of locomotion. Administration of PCP (2.25 and 6.75mg/kg, SC) produced a similar profile of effects in the BPM. These results indicate that MXE produces a behavioral profile similar to that of other psychotomimetic uncompetitive NMDAR antagonists. Our findings support the classification of MXE as a dissociative drug and suggest that it likely has effects and abuse potential similar to that of PCP and ketamine.