Detailed pharmacological evaluation of methoxetamine (MXE), a novel psychoactive ketamine analogue—Behavioural, pharmacokinetic and metabolic studies in the Wistar rat
Rachel R. Horsley, Eva Lhotková, Kateřina Hájková, Bronislav Jurásek, Martin Kuchař, Tomáš Páleníček
Brain Research Bulletin May 4, 2016 DOI: 10.1016/j.brainresbull.2016.05.002 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Wistar rats |
| Intervention | Methoxetamine |
| Dose | 5, 10, and 40 mg/kg subcutaneous |
| Duration | Effects present for at least 60-90 min; brain levels observed over six hours; urine collected over 24 h |
| Measures | open field, prepulse inhibition (PPI), acoustic startle response (ASR) |
| Topics | Ketamine Esketamine |
| Keywords | Thigmotaxis Open field Anxiogenic Stereotypy Habituation Clobazam Stimulant Pharmacokinetics Pharmacology Anesthesia Anxiolytic Amphetamine Epilepsy |
| Citations | 38 |
| Key findings | MXE acts as a typical dissociative anesthetic with stimulant and anxiogenic effects at lower doses, sedative/anaesthetic effects at higher doses, and disrupts sensorimotor gating, with a duration of action exceeding that of ketamine and accumulation in brain tissue. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 21
- Pharmacokinetic, Ambulatory, and Hyperthermic Effects of 3,4-Methylenedioxy-N-Methylcathinone (Methylone) in Rats Frontiers in Psychiatry November 17, 2017
- Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data? Pharmacology & Therapeutics February 1, 2018
- Measuring inhibition of monoamine reuptake transporters by new psychoactive substances (NPS) in real-time using a high-throughput, fluorescence-based assay. Toxicology in Vitro December 1, 2017
- Mephedrone (4-Methylmethcathinone): Acute Behavioral Effects, Hyperthermic, and Pharmacokinetic Profile in Rats Frontiers in Psychiatry January 10, 2018
- Behavioural, Pharmacokinetic, Metabolic, and Hyperthermic Profile of 3,4-Methylenedioxypyrovalerone (MDPV) in the Wistar Rat Frontiers in Psychiatry April 24, 2018
and 16 more in the library
Cites 27
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- The destruction of the lower urinary tract by ketamine abuse: a new syndrome? British Journal of Urology August 1, 2008
- Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. Journal of Medical Toxicology March 1, 2012
- From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Testing and Analysis 2014
- Phenomenon of new drugs on the Internet: the case of ketamine derivative methoxetamine Human Psychopharmacology: Clinical and Experimental March 1, 2012
and 22 more in the library