mephedrone mephedrone 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. not to be confused with methedrine, methedrone, mephedrene, methadone, methylone, methcathinone, or ephedrone. mephedroneclinical dataother names4-methyl-n-methylcathinone; 2-methylamino-1-p-tolylpropan-1-oneroutes ofadministrationoral, insufflation, iv, rectalatc codenonelegal statuslegal status au: s8 (controlled drug) de: anlage i (authorized scientific use only) uk: class b us: schedule i identifiers iupac name (rs)-2-methylamino-1-(4-methylphenyl)propan-1-one: 5 cas number1189805-46-6 n 1189726-22-4 (hcl): 5 pubchem cid29982893chemspider21485694 yunii8ba8t27317chebichebi:59331 ycomptox dashboard (epa)dtxsid20891437 echa infocard100.189.720 chemical and physical dataformulac11h15nomolar mass177.247 g·mol−13d model (jsmol)interactive image smiles cc1=cc=c(c(c(nc)c)=o)c=c1 inchi inchi=1s/c11h15no/c1-8-4-6-10(7-5-8)11(13)9(2)12-3/h4-7,9,12h,1-3h3 ykey:yelgftgwjgbaqu-uhfffaoysa-n y ny (what is this?) (verify) in addition to its stimulant effects, mephedrone produces side effects, of which bruxism is the most common. the metabolism of mephedrone has been studied in rats and humans and the metabolites can be detected in urine after usage. mephedrone was first synthesised in 1929, but did not become widely known until it was rediscovered in 1999–2000 at which point it was legal to produce and possess in many countries. by 2000, mephedrone was reported to be available for sale on the internet, by 2008 law enforcement agencies had become aware of the compound, and by 2010, it had been reported in most of europe, becoming particularly prevalent in the united kingdom. mephedrone was first made illegal in israel in 2008, followed by sweden later that year. in 2010, it was made illegal in many european countries and in december 2010, the eu ruled it illegal. in australia, new zealand and the united states, it is considered an analog of other illegal drugs and can be controlled by laws similar to the us federal analog act. in september 2011, the us temporarily classified mephedrone as a schedule i drug, effective october 2011. this classification was made permanent in july 2012 with the passage of the synthetic drug abuse prevention act (sdapa). uses recreational users have reported that mephedrone causes euphoria, stimulation, an enhanced appreciation for music, an elevated mood, decreased hostility, improved mental function and mild sexual stimulation; these effects are similar to the effects of cocaine, amphetamines and mdma, and last different amounts of time depending on the way the drug is taken. of 70 dutch users of mephedrone, 58 described it as an overall pleasant experience and 12 described it as an unpleasant experience. in a survey of uk users who had previously taken cocaine, most users found it produced a better-quality and longer-lasting high and was less addictive. the users were also asked to compare the "risk", and they answered that it was equal. a study of users in northern ireland found they did not equate the fact that mephedrone was legal with it being safe to use. this was contrary to another study in new zealand, where users of benzylpiperazine thought that because it was legal, it was safe. available forms mephedrone can come in the form of capsules, tablets or white powder that users may swallow, snort, inject, smoke or use rectally.: 12 when taken orally, users reported they could feel the effects within 15–45 minutes; when snorted, the effects were felt within minutes and peaked within half an hour. the effects last for between two and three hours when taken orally or nasally, but only half an hour if taken intravenously.: 12 it is sometimes sold mixed with methylone in a product called bubbles in the uk and also mixed with other cathinones, including ethcathinone, butylone, fluoromethcathinone and methedrone.: 9 purity one published study that analysed samples of mephedrone bought using the internet in the uk in 2010 found it was racemic (a mixture of both stereoisomers) and of high purity. an unpublished study of six samples also ordered off the internet in the uk in 2010 found they contained very few organic impurities. four products sold in irish head shops were tested in 2010 and were found to contain between 82% and 14% mephedrone, with some products containing benzocaine and caffeine. adverse effects short-term effects the emcdda reported mephedrone can cause various unintended side effects including: dilated pupils, poor concentration, teeth grinding, problems focusing visually, poor short-term memory, hallucinations, delusions, and erratic behaviour.: 13 they noted the most severe effects appear anecdotally to be linked with high doses or prolonged use, and the effects may be due to users taking other intoxicants at the same time. other effects users in internet forums have noted include changes in body temperature, increased heart rate, breathing difficulties, loss of appetite, increased sweating, discolouration of extremities, anxiety, paranoia and depression.: 13 when snorted, it can also cause nose bleeds and nose burns.: 13 a survey conducted by the uk national addiction centre found 67% of mephedrone users experienced sweating, 51% suffered from headaches, 43% from heart palpitations, 27% from nausea and 15% from cold or blue fingers, indicative of vasoconstriction occurring. doctors at guy's hospital in london reported that of 15 patients they treated after taking mephedrone in 2009, 53% were agitated, 40% had increased heart rates, 20% had systolic hypertension and 20% had seizures; three required treatment with benzodiazepines, predominantly to control their agitation. they reported none of their patients suffered from cold or blue peripheries, contrary to other reports. nine of the 15 of patients had a glasgow coma scale (gcs) of 15, indicating they were in a normal mental state, four had a gcs below 8, but these patients all reported using a central nervous system depressant, most commonly ghb, with mephedrone. the patients also reported polydrug use of a variety of compounds. neurotoxicity neurotoxic effect of mephedrone on serotonin (5-ht) and dopamine (da) systems remains controversial. although some studies in animal models reported no damage to da nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-ht and da transporter function. persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. reinforcement disorders there have been reports of users craving mephedrone, suggesting it may be addictive.: 13 overdose toxicity in 2009, one case of sympathomimetic toxicity was reported in the uk after a person took 0.2 g of mephedrone orally, and after this did not achieve the desired effect, subcutaneously injected 3.8 g mixed with water into his thighs. shortly afterwards, the user "developed palpitations, blurred tunnel vision, chest pressure and sweating". the patient was treated with 1 mg of lorazepam and the sympathomimetic features decreased and the user was discharged within six hours of arrival. one case of serotonin syndrome has been reported, where the patient was already prescribed fluoxetine and olanzapine, and then took 40 tablets containing mephedrone in one night. he was treated with lorazepam and discharged 15 hours after admission. both enantiomers of methcathinone, which differs only in the lack of the methyl group on the aryl ring when compared to mephedrone, have been shown to be toxic to rat dopamine neurons, and the s-enantiomer was also toxic against serotonin neurons. simon gibbons and mire zloh of the school of pharmacy, university of london stated, based on the chemical similarities between methcathinone and mephedrone, "it is highly likely that mephedrone will display neurotoxicity". however, brunt and colleagues stated, "extreme caution" should be used when inferring the toxicity of mephedrone from methcathinone, noting some of the toxicity associated with methcathinone is due to manganese impurities related to its synthesis, rather than the compound itself. they concluded more experimental research is needed to investigate the toxicity of mephedrone. doctors who treated a 15-year-old female suffering from mephedrone intoxication suggested in the lancet that, like mdma, mephedrone may promote serotonin-mediated release of antidiuretic hormone, resulting in hyponatraemia and an altered mental state. in another case, a 19-year-old male was admitted to hospital suffering from inflammation of the heart, 20 hours after taking one gram of mephedrone. the doctors treating the patient stated it was caused by either a direct toxic effect of mephedrone on the heart muscle, or by an immune response. one case of acquired methaemoglobinaemia, where a patient had "bluish lips and fingers", has also been reported, after the user snorted one gram of mephedrone. the patient started to recover after arriving at the hospital and it was not necessary to administer any medication. sweden in 2008, an 18-year-old swedish woman died in stockholm after taking mephedrone. the newspaper svenska dagbladet reported the woman went into convulsions and turned blue in the face. doctors reported she was comatose and suffering from hyponatremia and severe hypokalemia; the woman died one and a half days after the onset of symptoms. an autopsy showed severe brain swelling. mephedrone was scheduled to be classified as a "dangerous substance" in sweden even before the woman's death at karolinska university hospital on 14 december, but the death brought more media attention to the drug. the possession of mephedrone became classified as a criminal offence in sweden on 15 december 2008. united kingdom in 2010, unconfirmed reports speculated about the role mephedrone has played in the deaths of several young people in the uk. by july 2010, mephedrone had been alleged to be involved in 52 fatalities in the uk, but detected in only 38 of these cases. of the nine that coroners had finished investigating, two were caused directly by mephedrone. the first death reported to be caused by mephedrone use was that of 46-year-old, john sterling smith, who had underlying health problems and repeatedly injected the drug. a report in forensic science international in august 2010 stated mephedrone intoxication has been recorded as the cause of death in two cases in scotland. post mortem samples showed the concentration of mephedrone in their blood was 22 mg/l in one case and 3.3 mg/l in the other. the death of a teenager in the uk in november 2009 was widely reported as being caused by mephedrone, but a report by the coroner concluded she had died from natural causes. in march 2010, the deaths of two teenagers in scunthorpe were widely reported by the media to be caused by mephedrone. toxicology reports showed the teenagers had not taken any mephedrone and had died as a result of consuming alcohol and the synthetic opioid agonist methadone. according to fiona measham, a criminologist who is a member of the acmd, the reporting of the unconfirmed deaths by newspapers followed "the usual cycle of 'exaggeration, distortion, inaccuracy and sensationalism'" associated with the reporting of recreational drug use. united states mephedrone has been implicated in the death of a 22-year-old man, who had also injected black tar heroin. mephedrone was found in his blood at a concentration of 0.50 mg/l and in his urine at a concentration of 198 mg/l. the blood concentration of morphine, a metabolite of heroin, was 0.06 mg/l. for comparison, the average blood morphine concentration resulting from deadly overdoses involving only heroin is around 0.34 mg/l. pharmacology pharmacodynamics mephedrone is a monoamine releasing agent. it is a chiral compound and both of its enantiomers display similar potency as substrates at dopamine transporters. r-mephedrone is much less potent than s-mephedrone as a substrate at serotonin transporters. the keto oxygen renders mephedrone more hydrophilic than the corresponding amphetamine 4-methylmethamphetamine, which may account for the higher doses required to achieve a similar effect, because mephedrone is less able to cross the blood–brain barrier.: 12 mephedrone is often consumed with alcohol. a study in mice investigated the interrelation between these two substances, focusing on the psychostimulant and rewarding properties of mephedrone. it found that at low (non-stimulant) doses alcohol significantly enhanced the psychostimulant effects of mephedrone. this effect was mediated by an increase in synaptic dopamine, as haloperidol, but not ketanserin, was able to block the potentiation by alcohol. similarly, the rewarding properties of mephedrone were enhanced by a low non-rewarding dose of alcohol. pharmacokinetics several articles published near the end of 2011 examined the effects