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Mephedrone

Mephedrone, also known as 4-methylmethcathinone, 4-MMC, or 4-methylephedrone, is a synthetic stimulant drug belonging to the amphetamine and cathinone classes. It is commonly referred to by slang names such as drone, M-CAT, white magic, meow meow, and bubble. Chemically, it is similar to the cathinone compounds found in the khat plant, native to eastern Africa.

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 lengths 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, insufflate, inject, smoke or use rectally. 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. 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. 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 An unpublished study of six samples also ordered off the internet in the UK in 2010 found they contained very few organic impurities.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==
Adverse effects
Short-term effects The EMCDDA reported mephedrone can cause various unintended side effects including dilated pupils, Although some studies in animal models reported no damage to dopamine nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in serotonin transporter (SERT) and dopamine transporter (DAT) function. Although mephedrone has been found to be a monoaminergic neurotoxin, in one study, moderate doses of MDMA produced serotonergic neurotoxicity in rodents whereas mephedrone and methylone did not do so, suggesting that cathinones like mephedrone may be less neurotoxic than their corresponding amphetamine counterparts like MDMA. Reinforcement disorders There have been reports of users craving mephedrone, suggesting it may be addictive. ==Overdose==
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, intramuscularly 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. 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 the 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 methadone, a synthetic opioid. According to Fiona Measham, a criminologist who is a member of the Advisory Council on the Misuse of Drugs, 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==
Pharmacology
Pharmacodynamics Mephedrone acts as a potent substrate for monoamine transporters, including the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). It inhibits the reuptake of these neurotransmitters and promotes their release. The drug induces a rapid and significant increase in extracellular levels of dopamine, serotonin, and norepinephrine. This effect is more pronounced for serotonin compared to dopamine, which distinguishes mephedrone from much of the other psychostimulants. The pharmacodynamic profile of mephedrone is often compared to MDMA and methamphetamine. Like MDMA, it has a greater effect on serotonin than dopamine release. Similar to methamphetamine, it causes rapid dopamine release. Mephedrone is a potent and near-full agonist of the serotonin 5-HT2A receptor, whereas it was inactive as an agonist of the serotonin 5-HT2B receptor. Mephedrone administration leads to increased extracellular dopamine in the nucleus accumbens, elevated serotonin levels in the frontal cortex, and alterations in brain temperature. The drug crosses the blood-brain barrier easily, with a brain-to-plasma ratio of approximately 1.85 in rats. The absolute bioavailability of mephedrone is relatively low, at about 10% in rats, suggesting a significant first-pass effect. The main phase I metabolic pathways include N-demethylation, reduction of the ketone moiety, and oxidation of the tolyl group. Based on the analysis of rat and human urine by gas chromatography and mass spectrometry, mephedrone is thought to be metabolised by three phase 1 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). Both 5 and 6 are thought to be 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 causes of side effects and potential for toxicity. of mephedrone (1) based on the analysis of rat and human urine ==Chemistry==
Chemistry
Appearance and odour Mephedrone is a white substance. It is sold most commonly as crystals or a powder, but also in the form of capsules or pills. Detection in body fluids Mephedrone may be quantitated in blood, plasma or urine by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalised patients or to provide evidence in a medicolegal death investigation. Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/L in persons using the drug recreationally, >100 μg/L in intoxicated patients and >500 μg/L in victims of acute overdosage. ==History==
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 semisynthetic substances such as methylhexanamine. These drugs are primarily developed to avoid being controlled by laws against illegal drugs, thus giving them the label of designer drugs. David Nutt reports the re-popularization story of mephedrone in a way that can be cross referenced with a report by Chemistry World in an article. Fiona Measham, a criminologist at the University of Lancaster, thought 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 ecstasy 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, with mephedrone being detected in 20% of ecstasy tablets by mid-2009. The decrease of MDMA was thought to be partly 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 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 Services (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 incorrectly reported 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. The story was later shown to be an online joke posted on mephedrone.com, later included in a police report with the caveat that it could be unreliable. The police report was used as a source for the story in The Sun. Other myths the media often repeated during 2010 were that mephedrone had led to the deaths of over 20 people, teachers were unable to confiscate the drug from pupils and 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 its increased usage. Jon Silverman, a former BBC Home Affairs Correspondent, has written two articles discussing how the media had a strong influence over the UK government's drugs policy, particularly in that the government wished to demonstrate they were being "tough" on drugs. A survey of 1000 secondary school pupils and university students in Tayside conducted in February 2010 found 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 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 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 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 former 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 no vote was required. In an interview conducted in July 2010, when he was no longer a minister, Johnson admitted the decision to ban mephedrone was sped up after widespread reporting of deaths caused by the drug, and 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 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 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 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, after mephedrone was made illegal, a street trade in the drug emerged, with prices around double those prior to the ban, at £20–£25 per gram. In September 2010, Druglink reported the ban had a mixed effect on mephedrone use, with it decreasing in some areas, remaining similar in others and becoming more prevalent in some areas. In an online survey of 150 users after the ban, 63% said they were continuing to use mephedrone; of those, half claimed unchanged usage amounts (as to dosage and frequency) and half claimed decreased usage. Compared to previous surveys, more users purchased it from dealers, rather than the internet. The average price per gram was £16, compared to around £10 before the ban. The 2010 Mixmag survey of 2,500 nightclubbers found one quarter had used mephedrone in the previous month, the price had roughly doubled since it was made illegal, and 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, users were more likely to have concerns about it. Interviews with users in Northern Ireland also found 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 knew there was still demand for mephedrone, but were aware the supplies may be exhausted in the future. Secondly, the dealers perceived customers were likely to be willing to pay more for an illegal substance. Professor Shiela Bird, a statistician at the Medical Research Council, suggested 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 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, some products branded as Ivory Wave possibly 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. A Drugscope survey of drugs workers at the end of 2012 reported that mephedrone use was still widespread in the UK and that there increasing reports of problematic users. It was being taken as not only a "poor man's cocaine" but also amongst users of heroin and crack cocaine. Cases of intravenous use were also reported to be on the increase. ==Society and culture==
Society and culture
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 its possession, sale and manufacture illegal. It was first made illegal in Israel, where it had been found in products such as Neodoves pills, in January 2008. The importation of mephedrone into the UK was banned on 29 March 2010. In May 2010, the Republic of Ireland made mephedrone illegal, Mexico, by decree, outlawed mephedrone as a substance "with low or no therapeutical use which pose[s] a serious threat to public health" in 2014. 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, A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities. Usage 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 (five days per month compared to three days per month). An Irish study of people on a methadone treatment program for heroin addicts found 29 of 209 patients tested positive for mephedrone usage. Harm assessment Professor David Nutt, former chair of the Advisory Council on the Misuse of Drugs (ACMD) in the UK has said in 2009, "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 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." == See also ==
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