Mephedrone (4-methylmethcathinone)

Mephedrone is a psychostimulant and empathogenic substance, classified under the phenethylamine and β-keto-amphetamine families. It is closely structurally related to methcathinone and methamphetamine. Its effects have been compared to those of cocaine, amphetamine and MDMA (Winstock et al., 2011). These effects include:

Intense stimulation and alertness; euphoria
Empathy, closeness towards others and sociability
Intensification of sensory experiences
Sexual arousal
Perceptual distortions

Users described it, in terms of the subjective experience in produces, as a combination between the psychostimulant and empathogenic effects of cocaine and MDMA, respectively. Typical unwanted effects for mephedrone include loss of appetite, xerostomy, bruxism, tremors, tachycardia, temperature changes, agitation and irritability (James et al. 2011; Wood et al. 2009). Furthermore, mephedrone has been shown to elicit positive conditioning in rats and mice (Lisek et al., 2012; Karlsson et al 2014) and it has been reported that it could have comparable abuse potential to that of cocaine or MDMA (McElrath and O'Neill, 2011).

Mechanism of Action of Mephedrone

Until recently, little had been known as to the mechanism of action of cathinones. In 1999, Cozzi et al. published a comparative study on the ability to bind to monoamine transporters of MDMA, methamphetamine and their respective cathinone derivatives methylone and methcathinone. Nonetheless, mephedrone remained as an unresearched drug until the early 2010s.

Mephedrone is a substrate for both DAT and SERT with high affinity (López-Arnau et al., 2012), where it acts as a blocker (Simmler et al., 2012); it is internalized into the terminal, where it interacts with VMAT (López-Arnau et al., 2012), presumably promoting the release of vesicular dopamine and serotonin into the cytoplasm through the mechanisms discussed in the “generic mechanism of action of amphetamines” section (i.e. weak base and substrate hypotheses). Subsequently, monoamines are released into the synaptic cleft, via reverse transport. This mechanism resembles that of most amphetamine derivatives, as could be expected, due to the structural similarities. It is noteworthy to point out that mephedrone possesses a unique DAT/SERT blockade and dopamine/serotonin release profile, wherein the proportion of the degrees at which these phenomena take place is close to the unity (Simmler et al., 2012; Kehr et al., 2011). This translates into the characterization of mephedrone as a “nearly equally” dopaminergic and serotonergic drug, which explains the similarities in subjective effects to both cocaine and MDMA alluded to above.

Pharmacokinetics of Mephedrone

Mephedrone has a short half-life (25 min when administered intravenously), and presents low bioavailability, due to an extensive first-step effect (i.e. a large percentage of the compound is metabolized before reaching the bloodstream) (Martínez-Clemente et al., 2013). These properties account for users’ preference for the intranasal over the oral route of administration as well as their tendency to re- dose frequently.

Mephedrone has non-linear pharmacokinetics. With increasing oral doses, the bioavailability becomes higher, the half-life longer and total and hepatic clearance lower. This can be explained by a saturation of the hepatic function.

Furthermore, mephedrone presents a 20% protein binding and a low brain/plasma concentration ratio (1.85) when compared to other amphetamine derivatives (Chu et al., 1996), reflecting higher difficulty crossing from the bloodstream into the brain.

Mephedrone is N-demethylated, yielding the corresponding methcathinone metabolite. Mephedrone also undergoes different oxidative reactions including aliphatic and aromatic hydroxylation, leading to the corresponding 3’-hydroxy- methylmethcathinone or hydroxyl-4-methylmethcathinone metabolites. Finally, mephedrone can also suffer an allylic hydroxylation, generating 4- hydroxymethylmethcathinone, which can, in turn, be further metabolized into 4- carboxymethylmethcathinone, through oxidation.

Neurotoxicity of Mephedrone

Neurotoxicity of cathinone derivatives is a controversial matter. Angoa-Perez et al. (2012) and den Hollander et al. (2013) reported no damage by mephedrone to dopamine or serotonin systems when administered to mice, while more recent reports have shown the appearance of neurotoxicity when using a dosing schedule which better agreed with mephedrone pharmacokinetics and exploring cerebral areas others than striatum (Martínez-Clemente et al., 2014; Lopez-Arnau et al., 2015). In these studies, mephedrone induced a dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expressions one week after exposition. Furthermore, changes in oxidative stress markers point to the possibility that these changes could be due to increases in the presence of free radicals. This has been found to have deleterious consequences on memory, as measured by the Morris water maze test (López- Arnau et al., 2015).