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Elimination half-life | 26.2±0.7 (h) |
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ECHA InfoCard | 100.209.920 |
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Formula | C11H15NO2 |
Molar mass | 193.246 g·mol−1 |
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Chirality | Racemic mixture |
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Methedrone (para-methoxymethcathinone, 4-methoxymethcathinone, bk-PMMA, PMMC, methoxyphedrine, 4-MeOMC) is a recreational drug of the cathinone chemical class. [2] Chemically, methedrone is closely related to para-methoxymethamphetamine (PMMA), methylone and mephedrone. Methedrone received media attention in 2009 after the death of two young Swedish men. In both cases toxicology analysis showed methedrone was the only drug present in both men during the time of their overdose and subsequent deaths. [3] [4]
There is little information available about how Methedrone is dosed. According to users, a single dose of Methedrone varies from 50 to 500 mg with effects lasting 45 minutes to two hours. There are at least two cases known of fatal intoxications with Methedrone. In the first case, the postmortem femoral blood sample of the patient contained a concentration of 8.4 µg/g Methedrone, the patient died 16 hours after consumption (with polysubstance use detected). In the second body the concentration in the femoral blood sample was 9.6 µg/g, with Methedrone being the only toxic compound detected. The scientific investigation [3] of these cases suggests that the Methedrone alone was responsible for these deaths and that the concentrations in the femoral blood represent the fatal levels of methedrone. These studies show that the therapeutic index (or safety ratio) is low compared to other illegal drugs like Amphetamine. A fatal dose is likely to be around 8 µg/g whereas the dose among users varies from 0.1 to 4.8 µg/g blood according to studies. [3]
Methedrone is a synthetic cathinone. It is related to the parent compound cathinone. Methedrone belongs to the phenethylamine family due to the presence of the cyclic group of atoms C 6 H 5 in which six carbons bind to form a hexagonal ring with five hydrogens each bonding to a carbon and the remaining carbon bonded to an atom or group of atoms other than hydrogen. [5] [6] [7]
The synthesis of methedrone is described in figure 1. and can be written as the following steps.
The synthesis of mephedrone, a structurally similar compound with only one less ether group than methedrone, is well documented. [8]
There are no articles found about the reactivity of methedrone.
Methedrone has been found to be a potent serotonin transporter (SERT) and norepinephrine transporter (NET) inhibitor, but a weak dopamine transporter (DAT) inhibitor. Clinically, the DAT/SERT ratio of methedrone is less than one. Other analog compounds commonly have a DAT/SERT ratio less than half, meaning unlike other MDMA-like compounds methedrone does not prefer inhibition of the NET and DAT over the SERT. The resulting lack of inhibition despite its proclivity to release DAT can lead to a life-threatening adrenergic storm. Methedrone's high selectivity for SERT places it among the highest selectivity when compared to structurally similar compounds. [9]
Methedrone induces the transportation mediated release of NE, DA and 5-HT from cells preloaded with monoamines making it a serotonin–norepinephrine–dopamine (SNDRA) releasing agent, also known as triple releasing agent (TRA), which is a common characteristic among drugs of abuse. [9]
It has been found that methedrone is similar to MDMA in terms of the monoamine transporter interactions but an in vivo study of the drug resulted in a stronger hyperthermic reaction than what is normally reported in studies of MDMAs. Methedrone's affects on the serotonin transporter, SERT, can interfere and cause complications in individuals co-administering with serotonin altering medications such as selective serotonin reuptake inhibitors (SSRIs). [9]
To consider how methedrone (4-MeOMC) acts in a biological system, it is necessary to study the stability in an aqueous solution. Because, when tested directly in blood or urine, it is not known whether the compound will be degraded by enzymes available in the biological solutions or cause the chemical mechanisms, such as pH or dissolved oxygen. The length of the half-life of the compound has been examined and the percent remaining after 12 hours in buffers with various pHs. The tested pHs were 4, 7, 10 and 12. [10]
The conclusions are that methedrone, just as most analogs, is stable in acid solutions. However, in neutral and basic solutions it is decomposed, where a stronger decomposing takes place as the solution turns more basic.
When comparing methedrone with its analogs, it has been found that there are several factors which affect their stability:
Methedrone and four other analogs have their groups substituted in the meta- or para-positions. For these compounds the rate constant, k, has been determined and a Hammett plot was constructed by plotting the decomposition rate constant (0.693/half-life) in the pH of 12 against their Hammett constants, taken from literature. This again shows that methedrone is a relatively stable compound even in basic solution.
Another conclusion based on the results from the literature is that there is negative charge built up in the transition state during the rate determining step. This reasoning is based on the good linear correlation (r=0.9805) and the positive slope (determined as 1.76). [10]
There are two possible metabolites known for methedrone: [11]
Anecdotal and case reports of human use of "bath salts", such as methedrone, suggest that these substances produce powerful psychological effects. These psychological effects include psychotic behavior, paranoia, delusions, hallucinations and also self-injury. [12] There is very little known of the physical effects of methedrone in humans, but there have been some studies to the effects of methedrone in animals, so we[ who? ] focused on the effects in mice. Studies to the effects of Methedrone in mice show that Methedrone produces a significant increase in circling, beam breaks and hyperactivity. Furthermore, the mice also showed a significant increase in salivation, head weaving and stimulation. Methedrone is currently a legal drug in many jurisdictions, however studies show that it shares major pharmacological properties with drugs that have been banned, such as mephedrone and methylone. Also, the effects of Methedrone are very similar to the effects of banned drugs in mice. [12] This suggests that Methedrone may be just as harmful as most commonly found Illicit drugs.
The health risks associated with methedrone are mostly unknown, but are expected to be similar to other cathinones. [13] Methedrone was almost immediately withdrawn from sale by initial vendors after reports of adverse health effects.[ citation needed ] Some amphetamine analogs containing a para-methoxy group are known to cause severe hyperthermia and even death due to concurrent MAOI and monoamine releasing action. [14]
The deaths of two young men in southeast Sweden in 2009 were attributed to methedrone overdose. [3] [15]
Both were comatose when found. One suffered cardiorespiratory arrest on the way to the hospital, while the second survived for 16 hours in the emergency department.
There is little research regarding the toxicity of methedrone. Research has been done by animal-testing on mice once. [12] Also, the lethal doses found in the two Swedish methedrone-victims have been compared to the methedrone concentrations in the blood of two other males dying in similar conditions. [3]
The mean of the methedrone concentrations in the blood of the two deceased was 1.3 μg/g blood. One of these victims had a very high concentration of Methedrone in the blood, approximately 4.8 μg/g blood. The mean of the concentrations found in the blood of the deceased victims was 8.0 μg/g blood. None of the non-lethal doses or lethal doses is known, suggesting that the safety gap between a lethal and non-lethal dose of methedrone is probably very small, thus making use of this drug dangerous because poisonings, and simultaneously death, are accidental. [3]
In a study of the effects of synthetic cathiones in ‘bath salts’ the effects of methedrone on mice were tested, these effects were compared to the effects of cocaine and methamphetamine. Different tests were performed to get insight into motor coordination, balance and overall behavioral effects. The mice did not show any difference in motor coordination or balance (doses administered were 10.0 mg/kg and 30.0 mg/kg). However significant changes were shown in overall behavioral effects. Administration of methedrone led to: [12]
These effects are related with addiction potential. [16] [17] Excessive salivation is not an effect that is typically reported in humans. It is suggested that methedrone increases salivation via brain systems that primarily regulate autonomic responses. [3]
Compared with mephedrone, methylenedioxypyrovalerone (MDPV) and 4-fluoromethcathinone (4-FMC), methedrone has a relatively slow onset. Thereby increasing the risk; because effects are not immediately shown, this could lead to an accidental overdose. It could also make the drug less popular, because humans tend to favor drugs that cause large, rapid initial increases in locomotor activity. [12]
Even in comparison with acute toxicity, chronic toxicity is poorly researched. Only the post-mortem study did little investigation on this subject. The findings of this study only showed that hair of the deceased victims contained methedrone, however, no conclusions were made regarding these findings. [3]
No studies have examined the effect of methedrone-use during or before pregnancy by a pregnant female on the embryo, nor is the carcinogenicity researched.
The synthesis of methedrone was first reported in 1933. [18]
Its sale has been banned in Sweden since December 9, 2009. [3]
It is a controlled substance in China since October 1, 2015. [19]
Methedrone can be purchased legally in Europe (excluding Sweden) and in most states in the US on the Internet, but also it can also be found at head shops and other retailers. [20] It is, along with other new or unregulated synthetic drugs and research chemicals, commonly labeled as a "bath salt". [21]
Methedrone is a research chemical and its euphoric and stimulant properties can be abused. Similarly to MDMA it can be administered through insufflation, ingestion, smoking, rectal, and intravenous routes; however, it differs greatly in both duration and toxicity and great care should be taken when used due to the lack of medical literature available common among designer drugs. [21]
Methedrone has been found to have an effect on the overall behavior of mice which includes: [12]
3,4-Methyl
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.
3,4-Methylenedioxyamphetamine is an empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.
Benzylpiperazine (BZP) is a recreational drug with euphoriant and stimulant properties. Several studies conducted between 2000 and 2011 found that the effects of BZP are similar to amphetamine, although BZP's dosage is roughly 10 times higher by weight.
Butylone, also known as β-keto-N-methylbenzodioxolylbutanamine (βk-MBDB), is an entactogen, psychedelic, and stimulant psychoactive drug of the phenethylamine chemical class. It is the β-keto analogue of MBDB and the substituted methylenedioxyphenethylamine analogue of buphedrone.
Methylone, also known as 3,4-methylenedioxy-N-methylcathinone (MDMC), is an empathogen and stimulant psychoactive drug. It is a member of the amphetamine, cathinone and methylenedioxyphenethylamine classes.
Methylenedioxypyrovalerone (MDPV) is a stimulant of the cathinone class that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It was first developed in the 1960s by a team at Boehringer Ingelheim. Its activity at the dopamine transporter is six times stronger than at the norepinephrine transporter and it is virtually inactive at the serotonin transporter. MDPV remained an obscure stimulant until around 2004 when it was reportedly sold as a designer drug. In the US, products containing MDPV and labeled as bath salts were sold as recreational drugs in gas stations, similar to the marketing for Spice and K2 as incense, until it was banned in 2011.
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.
Mephedrone, also known as 4-methylmethcathinone, 4-MMC, and 4-methylephedrone, is a synthetic stimulant drug of the amphetamine and cathinone classes. Slang names include drone, M-CAT, White Magic, meow meow and bubble. It is chemically similar to the cathinone compounds found in the khat plant of eastern Africa. It comes in the form of tablets or crystals, which users can swallow, snort or inject, producing effects similar to those of MDMA, amphetamines and cocaine.
MDAI (5,6-methylenedioxy-2-aminoindane) is a drug developed in the 1990s by a team led by David E. Nichols at Purdue University. It acts as a non-neurotoxic and highly selective serotonin releasing agent (SSRA) in vitro and produces entactogen effects in humans.
A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.
Naphyrone, also known as O-2482 and naphthylpyrovalerone, is a substituted cathinone drug derived from pyrovalerone that acts as a triple reuptake inhibitor, producing stimulant effects and has been reported as a novel designer drug. No safety or toxicity data is available on the drug.
Salicylmethylecgonine, (2′-Hydroxycocaine) is a tropane derivative drug which is both a synthetic analogue and a possible active metabolite of cocaine. Its potency in vitro is around 10x that of cocaine, although it is only around three times more potent than cocaine when administered to mice Note however that the compound 2′-Acetoxycocaine would act as a prodrug to Salicylmethylecgonine in humans, and has a more efficient partition coefficient which would act as a delivery system and would circumvent this reason for a drop in potency. Salicylmethylecgonine also shows increased behavioral stimulation compared to cocaine similar to the phenyltropanes. The hydroxy branch renders the molecule a QSAR of a 10-fold increase over cocaine in its binding potency for the dopamine transporter & a 52-fold enhanced affinity for the norepinephrine transporter. It also has a reduced selectivity for the serotonin transporter though only due to its greater increase at NET binding; its SERT affinity being 4-fold increased compared to cocaine. However, in overall binding affinity it displaces ligands better across the board than cocaine in all monoamine categories.
A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.
Bath salts are a group of recreational designer drugs. The name derives from instances in which the drugs were disguised as bath salts. The white powder, granules, or crystals often resemble Epsom salts, but differ chemically. The drugs' packaging often states "not for human consumption" in an attempt to circumvent drug prohibition laws. Additionally, they may be mislabeled as plant food, powdered cleaner, and other such products.
3-Methylmethcathinone, also known as 3-MMC and metaphedrone, is a designer drug from the substituted cathinone family. 3-MMC is closely related in structure to the more commonly known illicit drug mephedrone (4-MMC), and is also illegal in most countries that have banned mephedrone due to 3-MMC being a structural isomer of 4-MMC. However, 3-MMC has still appeared on the recreational drug market as an alternative to mephedrone, and was first identified being sold in Sweden in 2012. Unlike some synthetic cathinones, 3-MMC has been evaluated in at least one large mammal study. 3-MMC is a monoamine transporter substrate that potently inhibits norepinephrine uptake and displays more pronounced dopaminergic vs. serotonergic activity.
Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have contributed to the major advances as antidepressants where they have revolutionised the treatment of depression and other psychiatric disorders. The SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), and anorexia. There is also clinical evidence of SSRIs efficiency in the treatment of the negative symptoms of schizophrenia and their ability to prevent cardiovascular diseases.
4-Methylcathinone, is a stimulant drug of the cathinone chemical class that has been sold online as a designer drug. It is a metabolite of the better known drug mephedrone (4-methylmethcathinone).
Mexedrone is a stimulant and an entactogen drug of the cathinone class that has been sold online as a designer drug. It is the alpha-methoxy derivative of Mephedrone.
N-Ethylhexedrone (also known as α-ethylaminocaprophenone, N-ethylnorhexedrone, hexen, and NEH) is a stimulant of the cathinone class that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) with IC50 values of 0.0978 and 0.0467 μM, respectively. N-Ethylhexedrone was first mentioned in a series of patents by Boehringer Ingelheim in the 1960s which led to the development of the better-known drug methylenedioxypyrovalerone (MDPV). Since the mid-2010s, N-ethylhexedrone has been sold online as a designer drug. In 2018, N-ethylhexedrone was the second most common drug of the cathinone class to be identified in Drug Enforcement Administration seizures.