Methylone

Abstract: Background and purpose: Designer beta-keto amphetamines (e.g., cathinones, "bath salts," and "research chemicals") have become popular recreational drugs, but their pharmacology is poorly characterized. Experimental approach: We determined the potencies of cathinones to inhibit dopamine (DA), noradrenaline (NA), and serotonin (5-hydroxytryptamine [5-HT]) transport into transporter-transfected human embryonic kidney 293 cells, DA and 5-HT efflux from monoamine-preloaded cells, and monoamine receptor binding affinity. Key results: Mephedrone, methylone, ethylone, butylone, and naphyrone act as nonselective monoamine uptake inhibitors, similar to cocaine. Mephedrone, methylone, ethylone, and butylone also release 5-HT, similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and other entactogens. Cathinone, methcathinone, and flephedrone act as preferential DA and NA uptake inhibitors and DA releasers, similar to amphetamine and methamphetamine. Pyrovalerone and 3,4-methylenedioxypyrovalerone (MDPV) are highly potent and selective DA and NA transporter inhibitors but unlike amphetamines do not release monoamines. The non-beta-keto amphetamines are trace amine-associated receptor 1 ligands, whereas cathinones are not. All cathinones showed high blood-brain barrier permeability in an in vitro model. Mephedrone and MDPV exhibited particularly high permeability. Conclusions and implications: Cathinones have considerable pharmacological differences that form the basis for their suggested classification into three groups. The predominant action of all cathinones on the DA transporter is likely associated with a considerable risk of addiction. (c) 2012 The Authors. British Journal of Pharmacology (c) 2012 The British Pharmacological Society.

Abstract: Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood–brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines—amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.