Human pharmacology of mephedrone in comparison with MDMA

This trial (n=12) compared the effects of MDMA (100mg), mephedrone (200mg) and placebo with respect to the physiological, subjective, psychomotor, and pharmacokinetic parameters amongst healthy male volunteers. Mephedrone induced stimulant-like effects, which included enhanced euphoria, well-being, feelings of pleasure, and mild changes in perceptions, as well as sympathomimetic effects (hypertension, tachycardia, and mydriasis), but with faster, less intense, and shorter duration compared to MDMA.

Abstract

“Mephedrone (4-methylmethcathinone) is a novel psychoactive substance popular among drug users because it displays similar effects to MDMA (3,4-methylenedioxymethamphetamine, ecstasy). Mephedrone consumption has been associated with undesirable effects and fatal intoxications. At present, there is no research available on its pharmacological effects in humans under controlled and experimental administration. This study aims to evaluate the clinical pharmacology of mephedrone and its relative abuse liability compared with MDMA. Twelve male volunteers participated in a randomized, double-blind, crossover, and placebo-controlled trial. The single oral dose conditions were: mephedrone 200 mg, MDMA 100 mg, and placebo. Outcome variables included physiological, subjective, and psychomotor effects and pharmacokinetic parameters. The protocol was registered in ClinicalTrials.gov (NCT02232789). Mephedrone produced a significant increase in systolic and diastolic blood pressure, heart rate, and pupillary diameter. It elicited stimulant-like effects, euphoria, and well-being and induced mild changes in perceptions with similar ratings to those observed after MDMA administration although effects peaked earlier and were shorter in duration. Maximal plasma concentration values for mephedrone and MDMA peaked at 1.25 h and 2.00 h, respectively. The elimination half-life for mephedrone was 2.15 h and 7.89 h for MDMA. In a similar manner to MDMA, mephedrone exhibits high abuse liability. Its earlier onset and shorter duration of effects, probably related to its short elimination half-life, could explain a more compulsive pattern of use as described by the users.”

Authors: Esther Papaseit, Clara Pérez-Mañá, Julián-Andrés Mateus, Mitona Pujadas, Francina Fonseca, Marta Torrens, Eulàlia Olesti, Rafael De La Torre & Magí Farré

Summary

INTRODUCTION

In recent years, new/novel psychoactive substances have become increasingly popular in Europe and the United States. These substances may pose a public health threat. Mephedrone is a beta-keto analog of phenethylamine related to cathinone, the active stimulant present in khat leaves (Catha edulis). It has been used recreationally in the UK and other European countries and was involved in 4100 cases of intoxication resulting in death during the period between 2009 and 2013.

Mephedrone use is highest among club drug users, where the prevalence ranges from 13.8% to 35.2%. It is taken predominantly by nasal insufflation, although oral use has been promoted.

After a recreational oral dose of 200 mg (50 – 300 mg), users report effects lasting 2 – 3 h.

Preclinical studies have shown that mephedrone has a different pharmacology from amphetamines, but is structurally related to them. It has been shown to increase dopamine and produce more serotonin increase (5-HT) than MDMA.

Mephedrone has a complex metabolic disposition in humans and CYP2D6 is involved in oxidation reactions. It is unknown whether CYP2D6 polymorphism could have an important role in modulating the risk of mephedrone toxicity.

Subjects

Twelve healthy male subjects were recruited by word of mouth. They were recreational users of amphetamines, ecstasy, mephedrone, and cathinones, and drank an average of 1.4 units of alcohol per day.

The volunteers underwent a general medical examination, urinalysis, 12-lead electrocardiogram, and psychiatric diagnostic examination prior to their inclusion. Only CYP2D6 extensive metabolizers were included, and nine participated in the pilot studies and 12 in the present study.

Study Design

The study design was a double-blind, randomized, crossover, and controlled trial with placebo, MDMA, and mephedrone. The dose of mephedrone was 200 mg/day, and showed similar effects to MDMA.

Experimental Sessions

Participants completed a training session to familiarize themselves with procedures and questionnaires, and a urine sample was collected for drug testing. The drug was administered between 0815 and 0830 hours, and the experimental sessions had a duration of 12 h after administration.

Baseline measures were obtained at the beginning of each experimental session, and a psychiatric evaluation was performed 8 hours after dosing.

Physiological Measures

Noninvasive measurements were made at 45 and 15 min prior to predose, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after drug administration.

Psychomotor Performance Measures

The psychomotor performance battery included the digit symbol substitution test and the Maddox-wing device. The results were expressed in diopters along the horizontal scale of the device.

The psychomotor performance battery was administered at 0, baseline, 1, 2, 3, 4, 6, 8, and 10 h after drug administration.

Subjective Effects

Subjective effects were measured using a set of 23 visual analog scales, the Addiction Research Center Inventory, the Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire, and a pharmacological class identification questionnaire.

The Spanish validated version of the ARCI short form is a questionnaire that measures the effects of a variety of drugs of abuse.

The pharmacological class identification questionnaire asks about the class of drug the participants believe they have been given.

VASs were administered 30 min, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after drug administration.

Pharmacokinetics

Mephedrone and MDMA were determined in blood and urine at various periods until 48 h after drug administration.

Effects

Values from physiological, psychomotor performance measures, and subjective effects were transformed to differences from baseline and analyzed by one-way repeated-measures analysis of variance with drug conditions as factor. Time course of effects was analyzed using repeated-measures two-way ANOVA with drug condition and time as factors.

Pharmacokinetics

Mephedrone and MDMA plasma concentrations over time were determined using Pharmacokinetic Functions for Microsoft Excel and SPSS 18.0. A value of po0.05 was considered statistically significant.

Global Results

Table 1 presents the physiological, psychomotor, and subjective effects of mephedrone and MDMA, and Figure 1 summarizes the most relevant physiological effects, psychomotor performance, and subjective effects.

Physiological Effects

Mephedrone 200 mg and MDMA 100 mg increased systolic blood pressure, diastolic blood pressure, heart rate, T, PD MAX, and PD MIN as compared with placebo, but only mephedrone produced a higher peak effect on pupil size.

Mephedrone and MDMA produced similar effects, but mephedrone produced greater effects earlier and MDMA produced greater effects later.

Psychomotor Performance

Mephedrone and MDMA produced esophoria in the Maddox wing device, but there were no significant differences between active conditions.

Subjective Effects

Mephedrone and MDMA produced significant changes in subjective drug effects compared to placebo, although no significant differences were observed in peak effects or AUC after comparing the two drugs.

Mephedrone subjective effects appeared at 0.25 h, peaked at 0.75 h, returned to half-maximum at 1.5 – 2 h, and were close to predose values at 2 – 3 h after administration.

Mephedrone and MDMA increased all the subscales of the ARCI questionnaire compared with placebo, but mephedrone produced higher peak effects, AUC, and T-C points than MDMA.

Regarding the VESSPA-SEE questionnaire, mephedrone and MDMA increased all subscales compared with placebo, but there were no statistical differences in peak effects or AUC between the two active substances.

In the pharmacologic drug class identification questionnaire, 10 out of 12 subjects correctly identified mephedrone as a designer drug, one as a stimulant, and one as a placebo.

Pharmacokinetics

Mephedrone was quickly absorbed and rapidly eliminated after administration, with a mean Cmax of 134.6 ng/ml. MDMA concentrations peaked at 202.8 ng/ml after administration, with a mean t1/2 of 7.89 h.

DISCUSSION

This is the first controlled human study of mephedrone. It showed that mephedrone induces stimulant-like effects, euphoria, well-being, feelings of pleasure, and mild changes in perceptions, similar to those produced by MDMA, but with shorter duration.

Mephedrone at a dose of 200 mg induces marked, but short-lived, cardiovascular effects in comparison with MDMA, including hypertension and tachycardia. Moreover, mephedrone consistently results in mydriasis.

Although the profile of response attributable to mephedrone is common to the sympathomimetic effects of stimulant-like drugs, its faster and shorter-lasting response is specific.

Mephedrone produced stimulant-like effects and euphoric-like feelings in humans. These effects peaked at 0.75 – 1 h and returned to baseline levels at 3 h after administration.

Mephedrone showed a similar profile to MDMA when administered by the oral route, with peak concentrations and effects observed between 0.5 – 1 h and returned to baseline 2 – 3 h after drug administration. Its short half-life may explain the briefer duration of its pharmacological effects in comparison with MDMA.

Our study had some limitations, but it demonstrated that mephedrone presents an abuse potential profile similar to MDMA, but with some differences, such as a more rapid onset and a shorter duration of effects.

FUNDING AND DISCLOSURE

EP and CP-M have received funding from the Instituto de Salud Carlos III, the Red de Trastornos Adictivos, and the European Commission.