The preclinical pharmacology of mephedrone; not just MDMA by another name

Abstract

The substituted β-keto amphetamine mephedrone (4-methylmethcathinone) was banned in the UK in April 2010 but continues to be used recreationally in the UK and elsewhere. Users have compared its psychoactive effects to those of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'). This review critically examines the preclinical data on mephedrone that have appeared over the last 2-3 years and, where relevant, compares the pharmacological effects of mephedrone in experimental animals with those obtained following MDMA administration. Both mephedrone and MDMA enhance locomotor activity and change rectal temperature in rodents. However, both of these responses are of short duration following mephedrone compared with MDMA probably because mephedrone has a short plasma half-life and rapid metabolism. Mephedrone appears to have no pharmacologically active metabolites, unlike MDMA. There is also little evidence that mephedrone induces a neurotoxic decrease in monoamine concentration in rat or mouse brain, again in contrast to MDMA. Mephedrone and MDMA both induce release of dopamine and 5-HT in the brain as shown by in vivo and in vitro studies. The effect on 5-HT release in vivo is more marked with mephedrone even though both drugs have similar affinity for the dopamine and 5-HT transporters in vitro. The profile of action of mephedrone on monoamine receptors and transporters suggests it could have a high abuse liability and several studies have found that mephedrone supports self-administration at a higher rate than MDMA. Overall, current data suggest that mephedrone not only differs from MDMA in its pharmacological profile, behavioural and neurotoxic effects, but also differs from other cathinones.

Keywords: 5-hydroxytryptamine; MDMA; body temperature; cathinones; dopamine; drug metabolism; locomotion; mephedrone.

Figure 1

Structure of mephedrone and other β-keto amphetamines (cathinones) and their related amphetamine congeners.

Figure 2

The major metabolites of mephedrone and proposed pathways of their formation. [Reproduced from Dybdal-Hargreaves et al. (2013) with permission from Elsevier Press].

Figure 3

Locomotor response of individually housed male Lister-hooded rats following various doses of (±)-mephedrone HCl (4, 10 and 30 mg·kg⁻¹ i.p.) administered at time 0. Rats were habituated to the test arena for 60 min prior to injection. Data are shown as mean ± SEM infrared beam breaks in each 5 min bin. Mephedrone-treated groups different from control group (P < 0.01 or better) as follows: mephedrone (4 mg·kg⁻¹) at 10 min; mephedrone (10 mg·kg⁻¹) from 10 to 45 min; and mephedrone (30 mg·kg⁻¹) from 10 to 55 min.

Figure 4

Locomotor response of individually housed rats following the first and fifth doses of (±)-mephedrone HCl (10 mg·kg⁻¹) or (±)-MDMA HCl (5 mg·kg⁻¹), doses being given on 2 consecutive days on weeks 1 and 2, and the final dose 1 further week later. Rats were habituated to the test arena for 60 min prior to injection. Data are shown as mean ± SEM infrared beam breaks in each 5 min bin. Total beam breaks are first dose: saline 534 ± 74, mephedrone 1695 ± 300*, MDMA 1447 ± 181*; fifth dose: saline 467 ± 74, mephedrone 2742 ± 213*^†, MDMA 2629 ± 319*^†. *Compared with the respective dose of the saline injection; ^†P < 0.001 compared with the first dose of the same drug challenge injection.

Figure 5

Effect of MDMA and mephedrone on rectal temperature in individually housed male Lister-hooded rats (n = 5–6 per group). Compounds (4 or 10 mg·kg⁻¹ HCl salt) or saline vehicle (1 mL·kg⁻¹) were injected i.p. at 0 min and temperature assessed at 20 min intervals for the next 2 h. Data are shown as change in temperature (°C, mean ± SEM) from the baseline reading taken at the time of injection. [Reproduced from data presented in Shortall et al. (2013a)].