Methoxetamine

Methoxetamine, abbreviated as MXE, is a dissociative hallucinogen that has been sold as a designer drug. It differs from many dissociatives such as ketamine and phencyclidine (PCP) that were developed as pharmaceutical drugs for use as general anesthetics in that it was designed for grey market distribution. MXE is an arylcyclohexylamine. It acts mainly as an NMDA receptor antagonist, similarly to other arylcyclohexylamines like ketamine and PCP. MXE is reported to have a similar effect to ketamine. It was often believed to possess opioid properties due to its structural similarity to 3-HO-PCP, but this assumption is not supported by data, which shows insignificant affinity for the µ-opioid receptor by the compound. Recreational use of MXE has been associated with hospitalizations from high and/or combined consumption in the US and UK. Acute reversible cerebellar toxicity has been documented in three cases of hospital admission due to MXE overdose, lasting for between one and four days after exposure. MXE was designed in part in an attempt to avoid the urotoxicity associated with ketamine abuse; it was thought the compound's increased potency and reduced dose would limit the accumulation of urotoxic metabolites in the bladder. Like ketamine, MXE has been found to produce bladder inflammation and fibrosis after high dose, chronic administration in mice (although the dosages used were quite large). Reports of urotoxicity in humans have yet to appear in the medical literature. MXE acts mainly as a selective and high-affinity NMDA receptor antagonist, specifically of the dizocilpine (MK-801) site (Ki = 257 nM). It produces ketamine-like effects. In addition to antagonism of the NMDA receptor, MXE has been found to act as a serotonin reuptake inhibitor (Ki = 479 nM; IC50 = 2,400 nM). Conversely, it shows little or no effect on the reuptake of dopamine and norepinephrine (Ki and IC50 > 10,000 nM). Nonetheless, MXE has been found to activate dopaminergic neurotransmission, including in the mesolimbic reward pathway. This is a characteristic that it shares with other NMDA receptor antagonists, including ketamine, PCP, and dizocilpine (MK-801). Animal studies suggest MXE may have rapidly-acting antidepressant effects similar to those of ketamine. A study that assessed binding of MXE at 56 sites including neurotransmitter receptors and transporters found that MXE had Ki values of >10,000 nM for all sites except the dizocilpine site of the NMDA receptor and the serotonin transporter (SERT). MXE has a longer duration of action than that of ketamine. MXE is an arylcyclohexylamine and a derivative of eticyclidine (PCE). It can also be thought of as the β-Keto-derivative of 3-methoxyeticyclidine (3-MeO-PCE), or the N-ethyl homologue of methoxmetamine (MXM). It is closely related structurally to ketamine, and more distantly to PCP. MXE hydrochloride is soluble in ethanol up to 10 mg/ml at 25 °C.