Methoxetamine (MXE) Guide: Effects, Uses, Legality, and Safety

. Similar to ketamine, MXE is an NMDA antagonist but differs in that it is more potent, longer-lasting, and also acts as a serotonin reuptake inhibitor. Preclinical trials suggest that MXE possesses potent antidepressant and analgesic properties, but further research is needed to better understand its pharmacological properties, mechanisms, and safety profile. Methoxetamine is a research chemical with dissociative and psychedelic properties similar to ketamine and phencyclidine (PCP). It was originally developed by an underground chemist in the UK as an allegedly safer alternative to ketamine. Since ketamine is an established, rapid-acting antidepressant, MXE is believed to possess similar antidepressant and analgesic properties. On these fronts, MXE may have therapeutic potential for major depression and a variety of pain syndromes such as phantom limb syndrome. Methoxetamine, also known as 3-MeO-2′-oxo-PCE, is an eticyclidine (PCE) derivative and structural analog of ketamine. Methoxetamine is a contraction of “methoxy-ketamine”.

The name refers to a methoxy group that replaced a chloro group in the chemical structure of ketamine. Like ketamine and PCP, MXE belongs to a family of compounds known as the arylcyclohexylamines.

The name refers to their molecular structure, which is composed of an aryl group bound to a cyclohexylamine unit.

They are a broad group of pharmaceutical and designer drugs known for their dissociative, anesthetic, and psychedelic properties due to their shared mechanism of action as NMDA antagonists. Like ketamine, MXE contains two stereoisomers. Stereoisomers are compounds with the same molecular formula but differ in the spatial arrangement of their atoms. MXE is found on the gray market largely as the racemic mixture, though enantiopure batches (batches of only 1 of the 2 stereoisomers) have been distributed. Methoxetamine is typically found in powder form as a white or off-white hydrochloride salt. It is administered in a multitude of forms, including: Each route produces a different onset of action, duration, and intensity of effects. Circa 2008, MXE was developed by an underground chemist based in the United Kingdom. By May of 2010, MXE began receiving online exposure on several drug forums. A few months later, in September of 2010, it began to be commercially available on a small scale. Methoxetamine maintained growing popularity among the Internet and drug forum members as its distribution in the gray market accelerated. This eventually led to its identification by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in November of 2010, which recognized 58 websites offering MXE by the next year. The chemist who created MXE was interviewed by Hamilton Morris in the February 2011 edition of Vice Magazine. He identified himself as the anonymous pharmaceutical chemist “M.” M. suffered chronic, severe phantom limb pain following the amputation of his left hand when he was a teenager. This experience largely fueled his interest in altered states and his search for better analgesics. Apart from his experiences with ketamine and cannabinoids, all of the analgesics he was prescribed had little to no effect on his phantom limb pain. After academic training in biochemistry and neuropsychopharmacology, he transitioned into independent pharmaceutical research. Here, M. began research investigating arylcyclohexylamines like PCP and ketamine, intrigued by their dual-use as pain relievers and antidepressants. After having the idea of MXE “floating around [his] head for about three years”, he found someone that could finally produce a small batch. As explained in his interview, the concept of MXE was birthed by “tweaking” ketamine at several functional groups in the chemical structure.

The 2-chloro group on the phenyl ring was replaced with a 3-methoxy group.

The 3-methoxy group purportedly gives MXE weaker analgesic and anesthetic properties compared to ketamine.

The N-methyl group on the amine was replaced with an N-ethyl group.

The N-ethyl was chosen to give MXE a longer duration of action and increased potency relative to ketamine. With these structural changes in mind, M. deemed MXE a “stress-free version of ketamine” and eventually began using it successfully to treat his phantom limb pain. As M. states in the Vice interview, “The arylcyclohexylamines have a tremendous therapeutic potential, but they have a great abuse potential as well.” He learned the latter directly after injecting a high dose of MXE and ending up hospitalized, which led to the subsequent confiscation of the arylcyclohexylamine compounds he was researching.

The legality of Methoxetamine began to be heavily examined following its introduction to the gray market in 2010. In this section, we will overview where MXE is currently legal and not, as well as key laws that have been passed to control its purchasing, sale, and possession. As of this writing, MXE is federally unscheduled in the United States. However, several states have added it to to the list of schedule I controlled substances, making it illegal to buy, sell, or possess. This includes: Being an analog of a controlled substance, MXE is illegal to purchase, sell, or possess for human consumption according to the Federal Analogue Act. This has been avoided by the placement of “not for human consumption” on the chemical packaging. Internationally, Methoxetamine has been categorized as a controlled substance in several countries, including: In April of 2012, Methoxetamine was placed under temporary class drug control in the United Kingdom, which prohibited the sale and import within the country for one year. After suggestions by the EMCDDA, it was permanently added to the Class B drug list in February of 2013, This category also includes amphetamines, cannabis, and ketamine. In June of 2014, the European Union designated MXE a controlled substance after a risk assessment by the EMCDDA. This effectively outlawed MXE in European Union member states. In November of 2016, MXE has been controlled as a schedule II substance under the UN 1971 Convention on Psychotropic Substances, a United Nations treaty designed to control psychoactive substances. Schedule II includes substances with therapeutic uses such as THC, amphetamine, and methylphenidate The mechanism of action of MXE overlaps with ketamine, but several differences account for its varying effects. Similar to ketamine, MXE antagonizes the glutamatergic N-methyl-D-aspartate (NMDA) receptor. It binds to the NMDA receptor at the phencyclidine site, an action that’s thought to be responsible for its potent dissociative properties. Unlike ketamine, however, MXE also binds to the serotonin transporter, acting as a serotonin reuptake inhibitor. This mechanism of action is shared with prescription monoamine-based antidepressants and may in part underlie its antidepressant action. In addition, MXE shows a weak affinity for the dopamine and norepinephrine transporters. Its ability to enhance dopaminergic neurotransmission, especially in the mesolimbic dopamine reward pathway, is thought to confer its high abuse liability. On the other hand, its ability to enhance norepinephrine signaling may account for its stimulatory and peripheral effects.

There is a lack of human studies investigating the toxicity of Methoxetamine, so most of the data come from animal studies and case study reports. According to a 2015 report by the World Health Organization, MXE has been associated with 120 non-fatal intoxications.

These hospitalizations were due to either high dosages of MXE or drug-drug interactions with other psychoactive substances. MXE has been advertised as a “bladder friendly” analog of ketamine. It has been speculated that its increased potency would limit the urotoxic metabolites that are commonly associated with chronic ketamine use. However, these claims have not been substantiated in preclinical animal studies. In one 2014 study, mice were administered a large daily dose of MXE (30mg/kg) for three months, resulting in significant damage to the urinary tract. This was seen as bladder inflammation and fibrosis as well as renal toxicity. MXE is known to potently synergize and potentiate the effects of other substances. Users should be cautious and conduct independent research to minimize negative drug-drug interactions. Central nervous system depressants such as benzodiazepines, alcohol, opiates, GHB, and GBL should be avoided with MXE consumption.

These can lead to dangerous synergistic effects that can amplify the depressant effects on movement, breathing, and consciousness. Central nervous system stimulants such as amphetamine, methylphenidate, and cocaine can also cause negative interactions with Methoxetamine.

These combinations can induce manic states and create potentially dangerous side effects by further increasing heart rate and blood pressure. Serotonergic substances, including MDMA and SSRIs, may increase the risk of serotonin syndrome. Serotonin syndrome is a potentially life-threatening neurotoxic reaction caused by an excess of serotonin in the body. Taking MXE with cannabinoids (natural or synthetic) and hallucinogens have been reported to induce intense entheogenic experiences, but other reports mention these combinations can increase the chance of negative psychological effects, including fear, panic attacks, paranoia, and intense hallucinations. A common dose range for MXE is 40-60 mg by oral administration, 20-60 mg by nasal insufflation, and 15-30 mg by intramuscular injection. However, these dose ranges are tentative, given the wide dose ranges used and high variability in effects from person to person.

The effects are typically apparent 10-90 minutes later, depending on the route of administration. Owing to the long onset of action and rewarding effects, many individuals report compulsive dosing or a strong urge to redose. Redosing can result in the consumption of more than initially planned, potentially leading to dangerous cumulative effects and overdose. According to the WHO, there are over 20 reported deaths due to methoxetamine overdose. In these fatal cases, other substances were combined with MXE, including amphetamines, MDMA, cocaine, alcohol, synthetic cannabinoids, and benzodiazepines. According to case studies, MXE overdoses have resulted in acute cerebellar toxicity, seen as incoordination, nystagmus, and reduced conscious level, which resolved over a period of 1-4 days. MXE overdose is associated with depressive symptoms such as slow heart rate, respiratory depression, catatonia, and loss of consciousness. Stimulant effects have been reported in an MXE overdose, including agitation, aggression, tachycardia, and hypertension. A number of negative psychological effects have also been reported in an overdose. This includes anxiety, panic attacks, paranoia, confusion, disorientation, and intense hallucinations. Due to MXE’s limited history of use and lack of human research, not much is known about its long-term safety. It is believed to be moderately addictive because it activates the reward circuitry in the brain. Anecdotal evidence suggests that compulsive use and habit formation are both common, as well as unpleasant withdrawal symptoms after prolonged use.

The vast majority of intoxications and deaths have resulted from high doses and combinations with other substances (reference previous section “Interactions”). When taken alone and moderately within a common dose range, the greater risk of harm or death arises from improper set and setting. Having a safe trip area and a sitter can prevent accidents such as falls and reduce undesirable psychological effects. Being a young research chemical, MXE’s effects have not been parsed out in clinical trials. Much of what is known is based on anecdotal reports over the last decade. With this in mind, the MXE trip may be very different from person to person depending on the dose, set and setting, and route of administration. MXE’s duration of effects depends on the route of administration. Intravenous or intravenous injections lead to the quickest onset and shortest duration. If it is orally or sublingually administered, the MXE high is more gradual and lasts longer. The probability of adverse physiological effects increases with increasing dose. This may include: Common psychological effects include: At high doses, MXE produces effects that resemble a Near Death Experience (NDE), including: MXE is associated with a multitude of undesirable side effects, especially at high doses. Physiologically, this includes: Psychological adverse effects may include: While little data exists on MXE’s potential for physical dependence, users have reported compulsive use and psychological dependence. Psychological dependence is compounded by the development of tolerance, where users have to administer increasingly larger doses to maintain the same effect. This may happen with MXE if it used in an extended and repetitive manner. In this case, it takes approximately 1-2 weeks for the tolerance to return to normal without continued use. In addition, being an NMDA receptor antagonist, MXE demonstrates cross-tolerance with other dissociatives. That is to say, after consuming MXE, other dissociatives will produce a reduced effect. MXE and ketamine are both NMDA antagonists and dissociative anesthetics of the arylcyclohexylamine class. Both compounds produce similar effects on cognition, producing rapid antidepressant effects, analgesia, euphoria, dissociation, and hallucinations. At high doses, MXE produces an “M-hole” that parallels a K-hole experience, characterized by a profound dissociation of mind from body. Due to some modifications of ketamine’s chemical structure, MXE has a slower onset of action, longer duration, and a higher intensity of effects. Due to this increased potency, MXE has been advertised as a “bladder friendly” analog of ketamine, but clinical data hasn’t supported this claim. According to trip reports, the MXE experience is similar to the ketamine experience, but some believe it is easier to recall and integrate after the trip. Starting in 2010, MXE began to be used recreationally for its dissociative and hallucinogenic effects. Recreationally, it is typically consumed orally or intranasally in home environments and nighttime party environments such as dances and raves. Around its inception, MXE’s recreational popularity expanded as a result of its higher accessibility and lower cost compared to ketamine. It was initially marketed as safer for the liver and kidneys than ketamine, but this was speculative and not clinically supported.

The recreational use of MXE grew largely among young adults as a legal high purchasable from head shops and research chemical vendors on the Internet. Once government bans began to take effect in the mid-2010s, MXE began to be seized and its appearance on the gray market largely disappeared. Ketamine has been widely used as an analgesic in high doses for a variety of pain-related disorders. This suggests MXE possesses similar medical utility for pain management. A 2016 case study documented a 29-year old man’s use of MXE to alleviate chronic foot pain associated with a foot surgery he had the year prior.

The man used 5-10mg every four hours for 5 days to treat his foot pain prior to his admittance to the emergency department for MXE-related intoxication. Recent rodent studies have supported MXE’s pain-inhibiting effects. Researchers have found MXE produces analgesic effects in rats at 5 mg/kg and raises the pain threshold in mice better than ketamine. MXE may exert its analgesic effects by binding to NMDA receptors and μ-opioid receptors (the same receptors targeted by opioids like morphine). Additional research is needed to reveal how exactly it inhibits pain. MXE possesses potent antidepressant properties due to its pharmacological and structural similarities to ketamine. According to many self-reports, MXE produces rapid depression relief and an antidepressant afterglow, similar to ketamine, which can last up to a week. Rodent studies have found that MXE creates rapid and sustained antidepressant and anxiolytic (anxiety-reducing) effects at sub-anesthetic doses.

The antidepressant effects were found to be mediated through serotonergic and glutamatergic mechanisms. Specifically, MXE was found to alter gene expression of serotonin and glutamate in the hippocampus, a region of the brain critically involved in learning and memory. MXE has also been reportedly used to treat post-traumatic stress disorder (PTSD). According to a 2017 case report, a US veteran suffering from PTSD used daily high doses of MXE (intranasal and intravenous) to produce calming effects and facilitate spiritual experiences.

The authors note that the alleviation of PTSD symptoms likely arises from MXE’s blockade of the NMDA receptor, similar to ketamine’s antidepressant action, as well as its ability to increase Brain-Derived Neurotrophic Factor (BDNF). BDNF is a growth factor involved in learning, memory, and the extinction of fear memory. Studies have found that BDNF levels are significantly lower in individuals with PTSD. At low doses in social settings, MXE may reduce negative moods and enhance empathy and sociability, leading to more authentic and meaningful conversation. In addition, MXE may heighten creativity and aesthetic appreciation, leading to a deeper interest or involvement with meditation, spirituality, film, and music. In solitary settings, MXE may enhance introspection, allowing users to go deeper inside and examine interpersonal issues and relationships from a novel vantage point. MXE’s ability to foster new perspectives on problems can promote the development of new coping strategies (such as deep acceptance) for fear, anxiety, and depression. Many individuals report MXE facilitates the vivid recall of emotionally-charged memories, which can bring about catharsis and healing. At high doses, MXE can bring on profound spiritual and transcendent experiences, leading to the dissolution of normal space-time constraints. Similar to the classic psychedelics, these mystical experiences may bring on ego dissolution, where the boundaries between inner and outer dissolve.

These profound experiences can lead to existential self-realization, inner personal growth, and newfound philosophical views on consciousness. According to several online surveys, MXE use peaked around 2011 and has since declined as global bans on MXE increasingly took effect. An online survey conducted in 2011 by the Global Drug Survey (GDS) investigated the prevalence of MXE use within poly-drug users in the UK clubbing scene. Out of the 7,770 UK-based respondents, 326 (4.2%) reported past-year use of MXE, while 197 (2.6%) reported past-month use.

The majority of the survey respondents were employed white men younger than 30 years of age. A similar study by Lawn and colleagues sought to determine the prevalence of MXE use in the United States and the United Kingdom between 2011 and 2012.

The researchers found MXE use significantly increased in the United States from 1.6% in 2011 (n=3830) to 5% in 2012 (n=3756) for past year use, while past-month use rose slightly from 1.6% in 2011 to 2.0% in 2012. During this same time period, MXE use significantly declined in the UK in parallel with legislative bans. Indeed, past-year use decreased from 4.2% in 2011 (n=8184) to 3.0% in 2012 (n=7360), while past-month use decreased from 2.4% in 2011 to 0.7% in 2012. As of this writing, only 108 studies relating to MXE are found on Pubmed. Most of the MXE literature is comprised of toxicology studies and individual case studies of MXE intoxication. Several preliminary animal studies have investigated MXE’s addictive, analgesic, dissociative, and antidepressant properties. No past or ongoing controlled clinical studies involving MXE exist in humans. MXE cannot be detected with standard urine drug tests. Only specialized toxicology screenings can detect MXE. While MXE was widely available at the start of the previous decade, it has now largely vanished from the online research chemical market after global bans outlawed its manufacturing, sale, use, and possession. Prior to its global bans, MXE was primarily synthesized in China. However, it is now listed as a Schedule I substance there and in numerous other countries (reference ‘Legality’ section) MXE primarily acts as an NMDA receptor antagonist and serotonin reuptake inhibitor.

These mechanisms of action result in MXE’s dissociative, anesthetic, hallucinogenic, and antidepressant effects. Yes.

The addition of the N-ethyl group to ketamine’s chemical structure is responsible for MXE’s increased potency and duration of action. Users should start with the lowest possible dose to gauge reactions, as the effects can differ widely from user to user.

The effects of MXE last from 2.5-4 hours when used intranasally, 3-5 hours when used orally, and 2-3 hours when used intramuscularly. Some users report effects lasting up to 24 hours, which is more likely to occur when redosed or used in high doses. All routes of administration have after-effects that may last between 2 to 48 hours. MXE has an elimination half-life of 3-6 hours.

Therefore, in 15-30 hours, 97% of an MXE dose is eliminated from the body. MXE can be dangerous when used excessively in high doses, in combination with other drugs, and under improper set and setting. Given that MXE is a recent research chemical, no controlled human trials have been conducted to evaluate its safety, especially in the long term. Animal studies suggest chronic, high doses of MXE may be neurotoxic and damage the urinary tract similar to ketamine. There is no literature concerning the abuse liability of MXE in humans, however, self-reports indicate that MXE can lead to compulsive misuse and addictive behavior. Animal studies have demonstrated that MXE activates dopaminergic brain regions associated with addiction, and rats will self-administer MXE similar to common drugs of abuse. MXE deaths are unheard of when used by itself in common dose ranges and under proper set and setting.

The more than 20 fatal overdoses associated with MXE were caused by hyperthermia (accidents from improper set and setting) or combinations with other drugs. Disclaimer: Methoxetamine is a potentially categorised as an illegal drug. Reality Sandwich is not encouraging the use of this drug where it is prohibited. However, we believe that providing information is imperative for the safety of those who choose to explore this substance. This guide is intended to give educational content and should in no way be viewed as medical recommendations.

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