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Federal Register / Vol. 86, No. 232 / Tuesday, December 7, 2021 / Proposed Rules Switzerland, Israel, Sweden, United Kingdom, Japan, Germany, France, Brazil, China, Poland, and the European Union member states.
2. Scientific Evidence of the Drugs Pharmacological Effects, if Known Methoxetamine is an antagonist at the glutamatergic NMDA receptors with moderately high affinity and a reuptake inhibitor at the serotonin transporter.
Acute methoxetamine exposure increases the firing rate and bursting activity of the ventral tegmental area VTA dopaminergic neurons projecting to the nucleus accumbens NAc and inhibits reuptake of dopamine, similarly to PCP and ketamine. The VTA is an area of the brain that is rich in dopamine and serotonin neurons and is a contributing part of the brain reward pathway, as is the NAc. The net result is an increase in dopamine levels in the VTA, which may underlie the psychomimetic and reinforcing effects of these drugs.
Animal testing data in rats show that methoxetamine, like PCP, fully substitutes for ketamine discriminative stimulus. Additionally, rats selfadminister methoxetamine. Data from self-administration and CPP studies show that methoxetamine has rewarding and reinforcing effects. Thus, methoxetamine produces psychopharmacologic effects similar to those produced by other NMDA
antagonists PCP and ketamine in animal models, which are predictive of its abuse in humans.
In humans, users of methoxetamine report dissociative anesthetic and hallucinogenic effects similar to PCP
and ketamine including euphoria, increased empathy, dissociation from the body, vivid visual hallucinations, and pleasant intensification of sensory experiences. Delusion, tachycardia, hypertension, agitation, aggression, and cerebellar toxicity have also been reported. Methoxetamine-associated overdose and deaths have been reported in scientific literature and by international authorities between 2011
and 2019.
3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance lotter on DSK11XQN23PROD with PROPOSALS1

Chemistry Methoxetamine, also known as also known as MXE, 2-ethylamino-2-3methoxyphenylcyclohexan-1-one, or 23-methoxyphenyl-2-Nethylaminocyclohexanone, has a molecular weight of 247.338 g/mol.
Methoxetamine is primarily present as a white crystalline powder and has also
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been reported as being off-white, beige, or yellow in color. The Chemical Abstract Service Registry Numbers for methoxetamine are 1239943760 for methoxetamine base and 1239908485
for methoxetamine as the hydrochloride salt. Its molecular formula as base is C15H21NO2. Methoxetamine hydrochloride salt is soluble in organic solvents like ethanol 10 mg/mL at 25 C, dimethyl sulfoxide DMSO 14
mg/mL, and dimethyl formamide 5
mg/mL. It is also soluble in aqueous solvents like a pH 7.2 phosphate buffer 5 mg/mL. Synthesis and characterization of methoxetamine and analytical data nuclear magnetic resonance spectroscopy, mass spectroscopy, and infrared spectroscopy are reported in the scientific literature.
Pharmacokinetics and Toxicology Controlled pharmacokinetic clinical research studies have not been conducted to characterize the onset of action, the plasma concentrations after ingestion of a fixed dose of methoxetamine, or to determine the half-life of methoxetamine. However, since methoxetamine has been used recreationally, a summary and description of the onset and duration of the effects of methoxetamine that come from user reports, generally via online forums, can be found in the scientific literature.
A summary of online user reports suggests that methoxetamine is generally administered through intranasal insufflation or snorting, oral, sublingual, rectal, and intramuscular routes with additional reports of intravenous use. Dose range administered, onset of drug effects, and duration of drug effects vary by the route of administration. Dose associated with intranasal use is 20 to 60 mg, oral administration is 20 to 100 mg, and intramuscular administration is 10 to 50 mg, with reported onset of drug effects of 30 to 90 minutes following intranasal use, up to 90 minutes following oral administration, and five minutes following intramuscular administration. Drug effects can last 2.5
to 7 hours following nasal use, 3 to 5
hours following oral ingestion, and 1 to 4 hours after intramuscular injection.
Typical doses and drug-related time effects were not reported for other routes of administration.
As HHS reports, the metabolism of methoxetamine was investigated using human liver microsomes in vitro and compared to toxicological analysis of urine from individuals presenting with analytically confirmed acute methoxetamine toxicity. Liquid
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chromatography high-resolution mass spectrometry was used to identify and characterize the metabolites of methoxetamine in vitro and in vivo.
These studies reported complex metabolism of methoxetamine including N-deethylation, O-demethylation, hydroxylation, reduction, and dehydrogenation followed by glucuronization conjugation of the metabolites with glucuronic acid. The normethoxytamine desethylmethoxetamine is the main metabolite identified in both in vivo and in vitro studies.
HHS further states that kinetic studies with human hepatic CYP isozymes have showed that N-deethylation is catalyzed by CYP2B6 and CYP3A4, Odemethylation by CYP2B6 and CYP2C19, and hydroxylation by CYP2B6. These studies also showed that normethoxamine is the major metabolite in humans and rats.
The role of CYP2B6 in methoxetamine metabolism is of particular importance.
Because CYP2B6 is involved in metabolism of numerous drugs e.g., bupropion, methadone, propofol, sertraline, pharmacokinetic interactions between methoxetamine and other compounds are likely to occur. In addition, the rate of methoxetamine metabolism and toxicity may depend on genetic polymorphism of CYP2B6.
Currently, it is unknown if any specific methoxetamine metabolites are biologically active.
4. Its History and Current Pattern of Abuse As HHS notes, methoxetamine, similar to ketamine and PCP, is a synthetic arylcyclohexylamine with dissociative anesthetic properties.
Typical routes of administration by drug users include oral, nasal insufflation, intramuscular, rectal, and intravenous.
Based on available abuse data, public health risk, and drug trafficking data, the World Health Organization WHO
recommended to the United Nations that methoxetamine be controlled internationally. In March 2016, the CND
voted to place methoxetamine in Schedule II of the 1971 Convention.
In 2014, WHO reported that methoxetamine has been available in Europe since 2010. Distribution and trafficking of methoxetamine occurred largely via the internet. According to the law enforcement data, the first encounter in the United States occurred in mid-2011.
In 2015, WHO reported non-fatal intoxications and more than 20 deaths associated with methoxetamine. Since 2014 through 2019, there have been reports of several other overdoses and
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