Mephedrone

Mephedrone, also known as 4-methylmethcathinone (4-MMC), or 4-methylephedrone, is a synthetic stimulant and entactogen drug of the amphetamine and cathinone classes. Slang names include meph, drone, and MCAT. It is reportedly manufactured in China and is chemically similar to the cathinone compounds found in the khat plant of eastern Africa. It comes in the form of tablets or a powder, which users can swallow, snort or inject, producing similar effects to MDMA, amphetamines, and cocaine.

As well as producing the intended stimulant effects, negative side effects occur when mephedrone is used, with teeth grinding the most common. The metabolism of mephedrone has been studied in rats and humans, and the metabolites can be detected in urine after usage. Nothing is known about the potential neurotoxicity of mephedrone, but scientists have suggested possible dangers associated with its use based on its similarity to other drugs. Several people have died after consuming mephedrone, but some deaths that the media attributed to the drug were later determined to have been caused by other factors.

Mephedrone was first synthesised in 1929 but did not become widely known until it was rediscovered in 2003. By 2007 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 USA it is considered an analog of other illegal drugs and can be controlled by laws similar to the Federal Analog Act. In September 2011 the USA temporarily classified mephedrone as illegal, with effect from October 2011.

History
Mephedrone is one of hundreds of designer drugs or legal highs that have been reported in recent years, including artificial chemicals such as synthetic cannabis and semi-synthetic substances such as methylhexaneamine. These drugs are primarily developed to avoid being controlled by laws against illegal drugs, thus giving them the label of designer drugs. According to the European Monitoring Centre for Drugs and Drug Addiction, the synthesis of mephedrone was first reported in 1929 by Saem de Burnaga Sanchez in the Bulletin de la Société Chimique de France, under the name "toluyl-alpha-monomethylaminoethylcetone", but the compound remained an obscure product of academia until 2003, when it was "re-discovered" and publicised by an underground chemist on The Hive website, working under the pseudonym "Kinetic." Kinetic posted on the site, "I’ve been bored over the last couple of days and had a few fun reagents lying around, so I thought I’d try and make some 1-(4-methylphenyl)-2-methylaminopropanone hydrochloride, or 4-methylmethcathinone." before going on to describe that after taking it they had a "fantastic sense of well-being that I haven’t got from any drug before except my beloved Ecstasy."

A drug similar to mephedrone, containing cathinone, was sold legally in Israel from around 2004, under the name hagigat. When this was made illegal, the cathinone was modified and the new products were sold by the Israeli company, Neorganics. The products had names such as Neodoves pills, but the range was discontinued in January 2008 after the Israeli government made mephedrone illegal. The Psychonaut Research Project, an EU organisation that searches the internet for information regarding new drugs, first identified mephedrone in 2008. Their research suggests that the drug first became available to purchase on the internet in 2007, when it was also discussed on internet forums. Mephedrone was first seized in France in May 2007 after police sent a tablet that they assumed to be ecstasy to be analysed, with the discovery published in a paper titled "Is 4-methylephedrone, an “Ecstasy” of the twenty first century?" Mephedrone was reported as having been sold as ecstasy in the Australian city of Cairns, along with ethylcathinone in 2008. An annual survey of regular ecstasy users in Australia in 2010 found that 21% of those surveyed had used mephedrone, with 17% having done so in the previous six months. The price they paid per gram varied from A$16 to $320.

Europol noted that they became aware of it in 2008, after it was found in Denmark, Finland and the UK. The Drug Enforcement Agency noted it was present in the United States in July 2009. By May 2010, mephedrone had been detected in every one of the 22 EU member states that reported to Europol, as well as in Croatia and Norway. The Daily Telegraph reported in April 2009 that it was manufactured in China, but it has since been made illegal there. In March 2009, Druglink magazine reported that it only cost a "couple hundred pounds" to synthesise a kilogram of mephedrone, the same month, The Daily Telegraph reported that manufacturers were making "huge amounts of money" from selling it. In January 2010 Druglink magazine reported that dealers in Britain spent £2,500 to ship one kilogram from China but could sell it for £10 a gram making a profit of £7,500. A later report, in March 2010, stated that the wholesale price of mephedrone was £4000 per kilogram.

In the United Kingdom


Between the summer of 2009 and March 2010 the use of mephedrone grew rapidly in the UK, with it becoming readily available at music festivals, head shops and on the internet. A survey of Mixmag readers in 2009, found that it was the fourth most popular street drug in the United Kingdom, behind cannabis, cocaine, and ecstasy. The drug is used by a diverse range of social groups. Whilst the evidence is anecdotal, researchers, charity workers, teachers and users have reported widespread and increasing use of the drug. The drug's rapid growth in popularity was believed to be related to both its availability and legality. Fiona Measham, a criminologist at The University of Lancaster, believes that the emergence of mephedrone was also related to the decreasing purity of ecstasy and cocaine on sale in the UK, a view reinforced in a report by the National Treatment Agency for Substance Misuse. The average cocaine purity fell from 60% in 1999 to 22% in 2009 and about half of ecstasy pills seized in 2009 contained no MDMA, and by June 2010, almost all pills seized in the UK, contained no MDMA.

A similar pattern was observed in the Netherlands, with the number of ecstasy tablets containing no MDMA rising from 10% in mid 2008 to 60% by mid 2009 and mephedrone being detected in 20% of ecstasy tablets by mid 2009. The decrease of MDMA was thought in part, to be due to the seizure of 33 tonnes of sassafras oil, the precursor to MDMA, in Cambodia in June 2008, which could have been used to make 245 million doses of MDMA. According to John Ramsey, a toxicologist at St George's, University of London, the emergence of mephedrone was also related to the UK government banning the benzylpiperazine class of drugs in December 2009. gamma-Butyrolactone (GBL), another previously "legal high" was also banned in August 2009, despite concerns that it would be replaced by other drugs. By December 2009, mephedrone was available on at least 31 websites based in the UK and by March 2010 there were at least 78 online shops; half of which sold amounts of less than 200 grams and half that also sold bulk quantities. The price per gram varied from £9.50 to £14. Between July 2009 and February 2010, UK health professionals accessed the National Poisons Information Service's (NPIS) entry on mephedrone 1664 times and made 157 telephone inquiries; the requests increased month on month over this period. In comparison over a similar time period, the entries for cocaine and MDMA were accessed approximately 2400 times. After mephedrone was made illegal, the number of inquiries to the NPIS fell substantially, to only 19 in June 2010.

Media organisations including the BBC and The Guardian, as well as a news section in the Annals of Botany (later corrected ), incorrectly reported that mephedrone was commonly used as a plant fertiliser. In fact sellers of the drug described it as "plant food" because it was illegal to sell the compound for human consumption. In late 2009, UK newspapers began referring to the drug as meow or miaow (sometimes doubled as meow meow or miaow miaow), a name that was almost unknown on the street at the time. In November 2009, the tabloid newspaper, The Sun published a story stating that a man had ripped off his own scrotum whilst using mephedrone, but this story was later shown to be an online hoax. Other myths that the media often repeated during 2010 were that mephedrone had led to the deaths of over 20 people, that teachers were unable to confiscate the drug off pupils and that the government was too slow to ban the drug. Parallels were drawn between the media coverage of mephedrone and a piece of satire by Chris Morris in 1997 on Brass Eye, when he tricked public figures into talking of the dangers of taking the fictional legal drug "cake". The Advisory Council on the Misuse of Drugs (ACMD) have suggested that the media coverage of the drug led to increased usage of it. Jon Silverman, a former BBC Home Affairs Correspondent, has written two articles discussing how the media had a strong influence over the governments drugs policy, particularly in that the government wished to demonstrate that they were being “tough” on drugs.

A survey of 1000 secondary school pupils and university students in Tayside, conducted in February 2010, found that 20% of them had previously taken mephedrone. Although at the time it was available legally over the internet, only 10% of users reported purchasing it online, with most purchasing it from street dealers. Of those who had used mephedrone, 97% said that it was easy or very easy to obtain. Around 50% of users reported at least one negative effect associated with the use of mephedrone, of which teeth grinding is the most common. Detailed interviews with users in Northern Ireland similarly, found that few purchased mephedrone online, with most interviewees citing concerns that their address would be traced or that family members could intercept the package.

On 30 March 2010, Alan Johnson, the then Home Secretary, announced that mephedrone would be made illegal "within weeks" after the ACMD sent him a report on the use of cathinones. The legislation would make all cathinones illegal which Johnson said would "stop unscrupulous manufacturers and others peddling different but similarly harmful drugs". The ACMD had run into problems with the UK Government in 2009 regarding drugs policy, after the government did not follow the advice of the ACMD to reclassify ecstasy and cannabis, culminating in the dismissal of the ACMD chairman, David Nutt after he reiterated the ACMD's findings in an academic lecture. Several members resigned after he was sacked and prior to the announcement that mephedrone was to be banned the trend continued when Dr Polly Taylor resigned, saying she "did not have trust" in the way the government would use the advice given by the ACMD. Eric Carlin, a member of the ACMD and former chairman of the English Drug Education Forum, also resigned after the announcement. He said that the decision by the Home Secretary was "unduly based on media and political pressure" and there was "little or no discussion about how our recommendation to classify this drug would be likely to impact on young people's behaviour." Some ex-members of the ACMD, and various charity groups expressed concern over the banning of the drug, arguing it would inevitably criminalise users, particularly young people. Others expressed concern that the drug would be left in the hands of black market dealers, who will only compound the problem. Carlin's resignation was specifically linked to the criminalisation of mephedrone, he stated: "We need to review our entire approach to drugs, dumping the idea that legally-sanctioned punishments for drug users should constitute a main part of the armoury in helping to solve our country’s drug problems. We need to stop harming people who need help and support".

The parliamentary debate was held on 8 April, one day after the 2010 general election had been announced, meaning it was during the so-called "wash-up period" when legislation is passed with little scrutiny. Only one hour was spent debating the ban and all three parties agreed, meaning that no vote was required. In an interview conducted in July 2010, when he was no longer a minister, Johnson admitted that the decision to ban mephedrone was sped up after widespread reporting of deaths caused by the drug and that because the government wished to pass the law, before parliament was dissolved prior to the upcoming general election. In January 2011 however, Johnson told the Scunthorpe Telegraph that the decision was based only on information from the ACMD. An editorial in the April 2010 edition of The Lancet questioned the decision to ban mephedrone, saying that the ACMD did not have enough evidence to judge the potential harms caused by mephedrone and arguing that policy makers should have sought to understand why young people took it and how they could be influenced to not take it. Evan Harris, then the Liberal Democrat science spokesman, stated that the ACMD "was not 'legally constituted'" as required by the Misuse of Drugs Act, when the report on cathinones was published, since after Taylor resigned it lacked a veterinary surgeon. In the rush to make mephedrone illegal, the act that was passed specified the inactive enantiomer of mephedrone, leaving the active form legal until the loophole was closed in February 2011 by another act of parliament. In Chemistry World, John Mann professor of chemistry at Queen's University Belfast, suggested that the UK create a law similar to the Federal Analog Act of the United States, which would have made mephedrone illegal as an analog of cathinone. In August 2010, James Brokenshire, the Home Office drugs minister, announced plans to create a new category in the Misuse of Drugs Act, through the Police Reform and Social Responsibility Bill, that would allow new legal highs to be made temporarily illegal, without the need for a vote in parliament or advice from the ACMD, as was required to categorise mephedrone.

According to the Independent Scientific Committee on Drugs, since mephedrone was made illegal a street trade in the drug has emerged, with prices around double those prior to the ban, at £20-£25 per gram. In September 2010, Druglink reported that the ban had had a mixed effect on mephedrone use, with it decreasing in some areas, remaining similar in others and becoming more prevalent in some areas. An online survey of 150 users after the ban, 63% said that they were continuing to use mephedrone, half of those used the same amount and half said they used less. Compared to previous surveys, more users purchased it off dealers, rather than the internet. The average price per gram was £16, compared to around £10 before the ban. The 2010 Mixmag survey of 2500 nightclubbers found that one quarter had used mephedrone in the previous month, that the price had roughly doubled since it was made illegal and that it was more likely to be cut with other substances. Of those who had already used mephedrone prior to the ban, 75% had continued to use it after the ban. Of the various drugs used by the survey participants, it was the most likely for users to have concerns about.

Interviews with users in Northern Ireland also found that the price had roughly doubled since it was made illegal, to around £30 a gram. Rather than the price rising due to increased scarcity of the drug, it is thought to have risen for two other reasons. Firstly dealers know that there is still demand for mephedrone, but are aware that supplies of mephedrone may be exhausted in the future. Secondly, the dealers perceive that customers are likely to be willing to pay more, for an illegal substance. Professor Shiela Bird, a statistician at the Medical Research Council, has suggested that the ban of mephedrone may lead to more cocaine related deaths. In the first six months of 2009, the number of cocaine related deaths fell for the first time in four years, and fewer soldiers tested positive for cocaine in 2009 than in 2008. She suggested that this may have been due to users switching to mephedrone from cocaine, but cautioned that before full figures are available for 2009 and 2010, it will be difficult to determine whether mephedrone saved lives, rather than cost them. Other supposedly legal drugs have filled the gap in the market since mephedrone was made illegal, including naphyrone (NRG-1) (since made illegal) and Ivory Wave, which has been found to contain MDPV, a compound made illegal at the same time as mephedrone. However it is possible that some products branded as Ivory Wave do not contain MDPV. When tested, some products sold six weeks after mephedrone was banned, advertised as NRG-1, NRG-2 and MDAI were found to be mephedrone.

Effects
There have been no formal published studies into the effects of mephedrone psychological and behavioural effects of mephedrone on humans nor on animals from which the potential effects could be extrapolated. As a result, the only information available comes from users themselves and clinical reports of acute mephedrone toxicity. Psychologists at Liverpool John Moores University were to conduct research into the effects of mephedrone on up to 50 students already using the drug, when it was still legal in the UK. At the time the study was proposed, Les Iversen, the chair of the Advisory Council on the Misuse of Drugs called the experiments "pretty unethical". The study was discontinued in August 2010, following the change in the legal status of the drug.

Intended effects
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. These effects last different amounts of time, depending on the way the drug is taken. When taken orally, users report they can feel the effects within 15–45 minutes, when snorted the effects are felt within minutes and peak 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. Out of 70 Dutch users of mephedrone, 58 described it as an overall pleasant experience and 12 described it as an unpleasant experience. A survey of UK users, who had previously taken cocaine, found that most users found it produced a better quality and longer lasting high, was less addictive and carried the same risk as using cocaine.

Side effects
The ECMDDA reported that mephedrone can cause various unintended side effects including: poor concentration, teeth grinding, problems focusing visually, poor short-term memory, hallucinations, delusions, erratic behaviour and dilated pupils. They noted that the most severe effects appear anecdotally to be linked with high doses or prolonged usage and that the effects may be due to users taking other intoxicants at the same time. Other effects that users in internet forums have noted include changes in body temperature, increased heart rate, breathing difficulties, loss of appetite, increased sweating, discolouration of extremeties, anxiety, paranoia and depression. When snorted it can also cause nose bleeds, and nose burns. A survey conducted by the National Addiction Centre, UK found that 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, 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 that none of their patients suffered from cold or blue peripheries, contrary to other reports. Nine out of the 15 of patients had a Glasgow Coma Scale (GCS) of 15 indicating that they were in a normal mental state, 4 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.

Long-term effects
Almost nothing is known about the long-term effects of the drug due to the short history of its use. BBC News reported that one person who used the drug for 18 months became dependent on the drug, in the end using it twice a week, had to be admitted to a psychiatric unit after he started experiencing hallucinations, agitation, excitability and mania. Because of its similarity to cathinone, John Mann has posited that mephedrone may cause impotence with long-term use.

Typical use and consumption
Mephedrone can come in the form of capsules, tablets or white powder that users may swallow, snort, inject, smoke or use rectally. 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. The Guardian reported that some users compulsively redose, consuming their whole supply when they are only meant to use a small dose and there have been other similar reports of users craving mephedrone, suggesting that it may be addictive. A survey conducted in late 2009 by the National Addiction Centre (UK) found 41.3% of readers of Mixmag had used mephedrone in the last month, making it the fourth most popular drug amongst clubbers. Of those, two thirds snorted the drug and the average dosage per session was 0.9 g; the length of sessions increased as the dosage increased. Users who snorted the drug reported using more per session than those who took it orally (0.97 g compared to 0.74  g) and also reported using it more often (5 days per month compared to 3 days per month). An Irish study of people on a methadone treatment program for heroin addicts found that 29 out of 209 patients tested positive for mephedrone usage. A study of users in Northern Ireland, found that 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.

Harm reduction
The drugs advice charity Lifeline recommends that to reduce the potential harm caused by using mephedrone, users should only use mephedrone occasionally (less than weekly), use less than 0.5 g per session, dose orally rather than snorting the drug, and avoid mixing it with alcohol and other drugs. Users should also drink plenty of water whilst taking the drug as it causes dehydration.

Pharmacology
Very little is known about the pharmacology of mephedrone. Writing in the British Medical Journal, psychiatrists stated that given its chemical structure, "mephedrone is likely to stimulate the release of, and then inhibit the reuptake of monoamine neurotransmitters". The cathinone derivatives methcathinone and methylone, act in a similar way to amphetamines mainly acting on catecholamine transporters so it is expected that mephedrone also acts in this way. The actions of amphetamines and cathinones are determined by the differences in how they bind to noradrenalin, dopamine and serotonin transporters. Molecular modelling of mephedrone suggests it is more hydrophilic than methyl-amphetamines which may account for the higher doses required to achieve a similar effect, because mephedrone is less able to cross the blood-brain barrier. Mephedrone has a chiral centre and therefore exists in two forms, called enantiomers, it is thought that the S form is more potent than the R form, based on the fact that this applies to cathinone. Professor David Nutt, former chair of the Advisory Council on the Misuse of Drugs (ACMD) in the UK has said "people are better off taking ecstasy or amphetamines than those [drugs] we know nothing about" and "Who knows what's in [mephedrone] when you buy it? We don't have a testing system. It could be very dangerous, we just don't know. These chemicals have never been put into animals, let alone humans." Les King, a former member of the ACMD, has stated that mephedrone appears to be less potent than amphetamine and ecstasy but that any benefit associated with this could be negated by users taking larger amounts. He also told the BBC "all we can say is [mephedrone] is probably as harmful as ecstasy and amphetamines and wait until we have some better scientific evidence to support that."

An article published in a 2011 edition of British Journal of Pharmacology examined the effects of mephedrone, MDMA, and amphetamine in the nucleus accumbens of rats. Dopamine and serotonin were collected using microdialysis, and increases in dopamine and serotonin were measured using HPLC. Reward and drug seeking are linked to increases in dopamine concentrations in the nucleus accumbens, and drug half-life plays a role in drug seeking as well. Based on histological examination, most of the author's probes were in the nucleus accumbens shell. Mephedrone administration caused a ~500% increase in dopamine, and a ~950% increase in serotonin. They reached their peak concentrations at 40 minutes and 20 minutes, respectively, and returned to baseline by 120 minutes post injection. In comparison, MDMA caused a ~900% increase in serotonin at 40 minutes, with a non-significant increase in dopamine. Amphetamine administration resulted in a ~400% increase in dopamine peaking at 40 minutes, with a non-significant increase in serotonin. Analysis of the ratio of the AUC for dopamine (DA) and serotonin (5-HT) indicated that mephedrone was preferentially a serotonin releaser, with a ratio of 1.22:1 (serotonin vs. dopamine). Additionally, half-lives for the decrease in DA and 5-HT were calculated for each drug. Mephedrone had decay rates of 24.5 minutes and 25.5 minutes, respectively. MDMA had decay values of 302.5 minutes and 47.9 minutes, respectively, while amphetamine values were 51 minutes and 84.1 minutes, respectively. Taken together, these findings show that mephedrone induces a massive increase in both DA and 5-HT, combined with rapid clearance. The rapid rise and subsequent fall of DA levels could explain some of the addictive properties that mephedrone displays in some users.

Metabolism
Based on the analysis of rat and human urine by gas chromatography and mass spectrometry, mephedrone is thought to be metabolised by three phase I pathways. It can be demethylated to the primary amine (producing compounds 2, 3 and 5) the ketone group can be reduced (producing 3) or the tolyl group can be oxidised (producing 6). It is thought that 5 and 6 are further metabolised by conjugation to the glucuronide and sulfate derivatives. Knowledge of the primary routes of metabolism should allow the intake of mephedrone to be confirmed by drug tests, as well as more accurate determination of the cause of side effects and potential for toxicity.



Toxicity
As of March 2010, there have been no reported studies on the potential neurotoxicity of mephedrone nor is the median lethal dose known. In 2009, one case of sympathomimetic toxicity was reported in the UK after a person took 0.2 g of mephedrone orally and then after this did not achieve the desired effect subcutaneously injected 3.8 g mixed with water into his thighs. Shortly afterwards they "developed palpitations, 'blurred tunnel vision,' chest pressure and sweating". The patient was treated with 1 mg of lorazepam and the sympathomimetic features decreased and they were discharged within 6 hours of arrival. The Swedish medical journal Läkartidningen reported that mephedrone could theoretically cause the cardiovascular problems associated with the use of cocaine and amphetamines and serotonin syndrome associated with the use of ecstasy and LSD. 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 that based on the chemical similarities between methcathinone and mephedrone, "it is highly likely that mephedrone will display neurotoxicity". However, Brunt and colleagues stated that "extreme caution" should be used when inferring the toxicity of mephedrone from methcathinone, noting that some of the toxicity associated with methcathinone is due to manganese impurities related to its synthesis, rather than the compound itself. They concluded that 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 they 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 tabloid newspaper Svenska Dagbladet reported that the woman went into convulsions and turned blue in the face. Doctors reported that 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 girl's death at Karolinska University Hospital on Sunday, 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.

UK
In 2010, there were unconfirmed reports speculating 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, Stirling Smith, who had underlying health problems and repeatedly injected the drug. A report in Forensic Science International in August 2010 stated that 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 that she 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 that the teenagers had in fact not taken any mephedrone and that they in fact died as a result of consuming alcohol and the heroin substitute 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.

USA
Mephedrone has been implicated in the death of a 22 year old male, 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.

Appearance
Mephedrone is a white substance. It is sold most commonly as crystals or a powder, but also in the form of capsules or pills. It can have a distinctive odour, reported to range from a synthetic fishy smell to the smell of vanilla and bleach, stale urine, electric circuit boards.

Synthesis
Mephedrone can be synthesised in several ways. The simplest method, due to the availability of the compounds, is to add 4-methylpropiophenone dissolved in glacial acetic acid to bromine, creating an oil fraction of 4'-methyl-2-bromopropiophenone. The oil fraction can then be dissolved in dichloromethane (CH2Cl2) and drops of the solution added to another solution of CH2Cl2 containing methylamine hydrochloride and triethylamine. Hydrochloric acid (HCl) is then added and the aqueous layer is removed and turned alkaline using sodium hydroxide before the amine is extracted using CH2Cl2. The CH2Cl2 is then evaporated using a vacuum, creating an oil which is then dissolved in a non-aqueous ether. HCl gas is then bubbled through the mixture to produce 4-methylmethcathinone hydrochloride. This method produces a mixture of both enantiomers and requires similar knowledge to that required to synthesise amphetamines and MDMA.



It can also be produced by oxidising the ephedrine analogue (4-methylephedrine) using potassium permanganate dissolved in sulfuric acid. Because 4-methylephedrine can be obtained in a specific enantiomeric form it is possible to produce mephedrone consisting of only one enantiomer. There is a danger associated with this method as it may cause manganese poisoning if the product is not correctly purified.

A stereospecific form of (S)-mephedrone could be prepared via Friedel–Crafts acylation. The first step in the synthesis would react toluene and (S)-N-trifluoroacetylalanoyl chloride in the presence of aluminium chloride, then deprotect the intermediate with hydrochloric acid-propyl alcohol. This would produce (S)-4-methylcathinone, which could then be methylated to produce mephedrone.

Purity
One published study that analysed samples of mephedrone bought off the internet in the UK in 2010 found that 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 that they contained very few organic impurities. Four products sold in Irish head shops that were tested in 2010 were found to contain between 82% and 14% mephedrone, with some products containing benzocaine and caffeine.

Legal status
When mephedrone was rediscovered in 2003, it was not specifically illegal to possess in any country. As its use has increased many countries have passed legislation making the possession, sale and manufacturing of mephedrone illegal. It was first made illegal in Israel, where it had been found in products such as Neodoves pills, in January 2008. After the death of a young woman in Sweden in December 2008 was linked to the use of mephedrone, it was classified as a hazardous substance a few days later, making it illegal to sell in Sweden. In June 2009, it was classified as a narcotic with the possession of 15 grams or more resulting in a minimum of two years in prison - a longer sentence, gram for gram than given for the possession of cocaine or heroin. In December 2008, Denmark also made it illegal and through the Medicines Act of Finland it was made illegal to possess without a prescription. In November 2009, it was classified as a "narcotic or psychotropic" substance and added to the list of controlled substances in Estonia and made illegal to import into Guernsey along with other legal highs, before being classified as a Class B drug in April 2010. It was classified as a Class C drug in Jersey in December 2009.

In 2010, as its use became more prevalent, many countries passed legislation prohibiting mephedrone. It became illegal in Croatia and Germany in January, followed by Romania and the Isle of Man in February. In March 2010, it was classified as an unregulated medicine in the Netherlands, making the sale and distribution of it illegal. The importation of mephedrone into the UK was banned on 29 March 2010. The next day, the ACMD in the UK published a report on the cathinones, including mephedrone, and recommended that they be classifed as Class B drugs. On 7 April 2010 the Misuse of Drugs Act 1971 (Amendment) Order 2010 was passed by parliament, making mephedrone and other substituted cathinones, Class B drugs from 16 April 2010. Prior to the ban taking effect, mephedrone was not covered by the Misuse of Drugs Act 1971. It was however an offence under the Medicines Act to sell it for human consumption, so it was often sold as "plant food" or "bath salts" although, as it has no use as these products, this too was possibly illegal under the Trade Descriptions Act 1968. In the USA similar descriptions have been used to describe mephedrone as well as methylenedioxypyrovalerone (MDPV). In May 2010 the Republic of Ireland made mephedrone illegal,  followed by Belgium, Italy, Lithuania, France  and Norway in June and Russia in July. In August 2010, Austria and Poland made it illegal and China announced that it would be illegal as of 1 September 2010. Mephedrone had been reported to be used in Singapore in February 2010, but it was made illegal in November 2010. In December 2010, following the advice of the EMCDDA, mephedrone was made illegal throughout the EU, a move that Switzerland also made shortly afterwards. In countries, which have not already banned it, such as the Netherlands, Greece and Portugal, they will need to change legislation to comply with the EU ruling. In Hungary, a government advisory body recommended that mephedrone should be made illegal in August 2010, which was followed, making it illegal in January 2011.

In some countries, mephedrone is not specifically listed as illegal but is controlled under legislation that makes compounds illegal if they are analogs of drugs already listed. In Australia during 2010 it was not specifically listed as prohibited, but the Australian Federal Police state that it is an analogue to methcathinone and therefore illegal. In February 2010, 22 men were arrested in conjunction with importing mephedrone. By January 2011, every state in Australia, other than Victoria had listed it as a controlled drug. In New Zealand it is not included in the Misuse of Drugs Act 1975, but is illegal as it is similar to controlled substances. In Canada, mephedrone is not explicitly listed in any Schedule of the Controlled Drugs and Substances Act, "amphetamines, their salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues" are included in Section I of Schedule III of the act. Cathinone and methcathinone are listed in separate sections of Schedule III while diethylpropion and pyrovalerone (also cathinones), are listed in separate sections of Schedule IV, each without language to capture analogues, isomers, etc. According to The Globe and Mail, mephedrone is considered a controlled substance by Health Canada. According to the Canadian Medical Association, mephedrone is grouped with other amphetamines as Schedule III controlled substances. There have been several media reports of the Canadian police seizing mephedrone. Mephedrone is also currently unscheduled in the United States. The Drug Enforcement Administration state that as an analogue of methcathinone, possession of mephedrone can be controlled by the Federal Analog Act, but according to the Los Angeles Times this only applies if it is sold for human consumption. Several cities and states, such as New York, have passed legislation to specifically list mephedrone as illegal, but in most areas it is legal, so long as it is not sold for human consumption and therefore retailers describe it as 'bath salts'.

As of September 7, 2011, The United States Drug Enforcement Administration (DEA) is using its emergency scheduling authority to temporarily control the synthetic stimulant mephedrone. This action was considered necessary to protect the public from the imminent hazard posed by this chemical. Except as authorized by law, this action will make possessing and selling Mephedrone or the products that contain it illegal in the U.S. for at least one year while the DEA and the United States Department of Health and Human Services further study whether these it should be permanently controlled.