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Federal Register / Vol. 86, No. 232 / Tuesday, December 7, 2021 / Proposed Rules
onset compared to PCP or ketamine. At higher doses >40 mg, users describe the experience as reaching the mhole, which is similar to the ketamine k-hole experience and characterized by extreme dissociation from the body, comparable to an out-of-body experience.
HHS reports that commonly reported side effects of methoxetamine include dizziness, confusion, time distortion, aphasia, psychomotor agitation, vertigo, incoordination, nausea, and vomiting.
Similar to PCP and ketamine toxicity, signs and symptoms toxidrome of methoxetamine toxicity can be grouped into three types: Dissociative/delirious, sympathomimetic, and cerebellar symptoms. Dissociative or delirious symptoms include depersonalization, derealization, catatonia, audiovisual hallucinations, delusions, confusion, altered or loss of consciousness, agitation, aggression, amnesia, and mood lability. Sympathomimetic symptoms include rapid heart rate tachycardia, high blood pressure hypertension, elevated body temperature pyrexia, rapid breathing tachypnea, and pupillary dilation mydriasis. Cerebellar symptoms include inability to sit truncal ataxia, incoordination, speech impairment dysarthria, impaired ability to perform rapid alternating movements dysdiadochokinesis, and rapid and repetitive uncontrolled eye movements nystagmus. Summarized withdrawal symptoms reported on online forums include low mood, depressive thoughts, and cognitive impairment for many hours in one user followed by two days of insomnia after a single 100 mg intranasal administration. One user reported a suicide attempt after discontinued use of methoxetamine.
HHS states that treatment of acute toxicity caused by methoxetamine and other drugs of the same class e.g., PCP
and ketamine consists of supportive treatment to control or relieve psychological complications and side effects. This treatment may include administration of benzodiazepines, antiemetics, intravenous fluids, and respiratory support, if needed.
DEA notes that ketamine has been known to cause toxicities to the bladder and renal system. When mice were given daily dose of 30 mg/kg methoxetamine intraperitoneally i.p.
for 90 days, significant bladder and renal toxicity occurred. Thus, like ketamine, chronic administration of methoxetamine is associated with bladder and renal toxicity, including inflammatory changes with subsequent fibrosis that could lead to bladder and kidney damage.

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b. There is Significant Diversion of the Drug or Substance From Legitimate Drug Channels HHS states that methoxetamine is not a Food and Drug Administration FDAapproved drug product for treatment in the United States and is unaware of any country in which its use is legal. There appear to be no legitimate sources for methoxetamine as a marketed drug.
Thus, there is no evidence of significant diversion of methoxetamine from legitimate drug channels.
c. Individuals Are Taking the Substance on Their Own Initiative Rather Than on the Basis of Medical Advice From a Practitioner Licensed by Law To Administer Such Substance Methoxetamine is not approved for medical use and is not formulated or available for clinical use. Therefore, it is assumed that individuals are taking methoxetamine on their own initiative, rather than based on medical advice from a properly-licensed practitioner.
This is consistent with the data from law enforcement seizures and case reports indicating that individuals are taking methoxetamine on their own initiative rather than on the medical advice of a licensed practitioner.
d. The Drug is a New Drug so Related in its Action to a Drug or Other Substance Already Listed as Having a Potential for Abuse To Make it Likely That the Drug Substance Will Have the Same Potential for Abuse as Such Drugs, Thus Making it Reasonable To Assume That There May Be Significant Diversion From Legitimate Channels, Significant Use Contrary to or Without Medical Advice, or That it Has a Substantial Capability of Creating Hazards to the Health of the User or to the Safety of the Community Methoxetamine is a synthetic arylcyclohexylamine and has pharmacological properties similar to other arylcyclohexylamines such as the ethylamine analog of phencyclidine PCE; schedule I, the thiophene analog of phencyclidine TCP; schedule I, phencyclidine PCP, schedule II, and ketamine schedule III. Methoxetamine, similar to PCE, TCP, PCP, and ketamine, has been shown to produce dissociative anesthetic and hallucinogenic effects.
As mentioned in HHS review, the primary mechanism of action of methoxetamine is thought to be on glutamatergic neurotransmission.
Glutamate is the major excitatory neurotransmitter system in the brain. In vitro binding studies show that methoxetamine binds to the glutamatergic N-methyl-D-aspartate
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NMDA receptor and acts as an antagonist with similar potency as PCP
and ketamine. HHS notes that, similar to PCP, methoxetamine also has affinity for the serotonin reuptake transporter and acts as a serotonin reuptake inhibitor.
Further, like many drugs of abuse, methoxetamine acutely increases the firing rate and bursting activity of ventral tegmental area VTA
dopaminergic neurons projecting to the nucleus accumbens NAc, and inhibits the reuptake of dopamine. The VTA is an area of the brain, rich in dopamine and serotonin neurons, which along with the NAc is part of the brain reward pathway. The increase in the firing rate and bursting activity of dopamine neurons produced by PCP, ketamine, and methoxetamine that results in increased dopamine levels in the VTA
may underlie the psychotomimetic and reinforcing properties of these drugs.
Drug discrimination an in vivo test to assess drug abuse liability and compare drugs to known drugs of abuse data demonstrate that methoxetamine, similar to PCP, fully substitutes for the discriminative stimulus effect of ketamine in rats. Additionally, conditioned place preference CPP
studies and self-administration studies used to assess rewarding and reinforcing effects show that methoxetamine produces both rewarding and reinforcing effects. Taken together, methoxetamine produces psychopharmacological effects similar to those produced by ketamine and PCP
in animal models that are predictive of abuse potential in humans.
As stated by HHS, users of methoxetamine experience effects similar to those of ketamine and PCP
including depersonalization, a mild to strong sense of dissociation from the physical body, distortion of the sense of reality, and vivid visual hallucinations.
More negative or challenging effects of methoxetamine, similar to PCP and ketamine, may also occur and include delusions, tachycardia, hypertension, agitation, aggression, and cerebellar toxicity. Case reports of overdose and deaths resulting from methoxetamine abuse have been reported between 2011
and 2019 in scientific literature and by international authorities.
As mentioned by HHS, methoxetamine is being abused for its psychoactive effects. DEA further notes that based on concerns related to trafficking and availability, as well as the risks to the public health associated with its abuse, at least ten states in the United States have controlled methoxetamine. At the international level, as of June 2020, methoxetamine has been controlled in Russia,
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