of mephedrone, compared to the similar drugs mdma and amphetamine in the nucleus accumbens of rats, as well as examining the reinforcing potential of mephedrone. 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 about a 500% increase in dopamine, and about a 950% increase in serotonin. they reached their peak concentrations at 40 minutes and 20 minutes, respectively, and returned to baseline by 120 minutes after injection. in comparison, mdma caused a roughly 900% increase in serotonin at 40 minutes, with an insignificant increase in dopamine. amphetamine administration resulted in about a 400% increase in dopamine, peaking at 40 minutes, with an insignificant increase in serotonin. analysis of the ratio of the auc for dopamine (da) and serotonin (5-ht) indicated 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 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 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 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. proposed scheme for the metabolism of mephedrone (1) based on the analysis of rat and human urine 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. 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. it can have a distinctive odour, reported to range the smell of vanilla and bleach, stale urine, or electric circuit boards. synthesis mephedrone can be synthesised in several ways. the simplest method, due to the availability of the compounds,: 17 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 nonaqueous ether. finally, hcl gas is 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.: 17 mephedrone synthesis scheme from 4-methylpropiophenone 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, mephedrone consisting of only one enantiomer can be produced. the danger associated with this method is it may cause manganese poisoning if the product is not correctly purified.: 17 analysis mephedrone does not react with most reagent testing kits. the exception is the liebermann reagent, which gives a bright yellow reaction. history mephedrone. "not for human consumption. for technical use only. purity: 99+ %" 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. 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",: 17 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, registered to a portuguese ip 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 consuming it, the user had a "fantastic sense of well-being that i haven’t got from any drug before except my beloved ecstasy." after the initial description of mephedrone's qualitative effects by kinetic, the drug was commercially introduced in israel by a mathematician named ezekiel golan or "dr. z". 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 suggested the drug first became available to purchase on the internet in 2007, made available through british contacts, contact unknown, when it was also discussed on internet forums. mephedrone was first seized in france in may 2007, after police sent a tablet 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 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 they became aware of it in 2008, after it was found in denmark, finland and the uk. the drug enforcement administration noted it was present in the united states in july 2009. by may 2010, mephedrone had been detected in all 22 eu member states that reported to europol, as well as in croatia and norway.: 21 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 it only cost a "couple of hundred pounds" to synthesise a kilogram of mephedrone, the same month, the daily telegraph reported manufacturers were making "huge amounts of money" from selling it. in january 2010, druglink magazine reported 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 the wholesale price of mephedrone was £4000 per kilogram. in march 2011, the international narcotics control board published a report about designer drugs, noting mephedrone was by then being used recreationally in europe, north america, southeast asia, new zealand and australia. united kingdom the number of samples analysed by the forensic science service of seized mdma, piperazines and cathinones between the third quarter of 2005 and the first quarter of 2010: mdma seizures in blue, piperazine seizures in orange and cathinone seizures in purple 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 it was the fourth most popular street drug in the united kingdom, behind cannabis, cocaine, and ecstasy. the drug was used by a diverse range of social groups. whilst the evidence was anecdotal, researchers, charity workers, teachers and users reported widespread and increasing use of the drug in 2009. the drug's rapid growth in popularity was believed to be related to both its availability and legality. in a book about 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.: 11 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 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