Pharmacology
The pharmacology and toxicology of mephedrone had not been studied in detail until well after its sale as a designer drug and its addition to controlled drug lists in many countries. Writing in the British Medical Journal, psychiatrists stated, 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 mephedrone is expected also to act 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, so exists in two forms, called enantiomers; the S form is thought to be more potent than the R form, because 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 we know nothing about" and "Who knows what's in 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 is probably as harmful as ecstasy and amphetamines and wait until we have some better scientific evidence to support that."
Several articles published near the end of 2011 examined the effects 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.
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