Potencial de abuso y farmacología humana de la mefedrona (4-MMC, 4-metilmetcatinona)

Abstract

Mephedrone (4-methylmethcathinone, 4-MMC) is an analogue of cathinone the active natural psychostimulant present in khat leaves. Chemically it is a phenylethylamine similar to 3,4-metylenedioxymethamphetamine (MDMA, ecstasy) and others amphethamine derivatives. From 2008, the shortage of MDMA became mephedrone in one of the most popular novel psychoactive substances (NPS), and the legal alternative to ecstasy because its pleasurable and entactogen effects. The notification of clinical adverse events, severe intoxications and unexplained deaths related to mephedrone consumption contribute to its ban in most countries in 2010. At present, there is no human research available on its pharmacological effects in humans under controlled and experimental administration. Objectives. The objectives of this Thesis/Dissertation were to evaluate the clinical pharmacology of mephedrone and its relative abuse liability, determine basic pharmacokinetics of mephedrone and to compare the mephedrone pharmacological effects and pharmacokinetics to those of the MDMA. Methods. Design was unicentric, randomized, double-blind, crossover, and placebo (neutral comparator) and MDMA (active comparator) controlled clinical trial. The three treatment conditions consisted in the oral administration of 200 mg of mephedrone, 100 mg of MDMA and placebo. This dose of mephedrone was selected based on the results from a pilot study which evaluated increasing doses of 50, 100, 150 and 200 mg of mephedrone. It was selected the dose of 200 mg for its similitude to the dose of 100 mg of MDMA. Subjects. A total of 25 healthy male volunteers recreational users of psychostimulants participated (12 of them participated in the final study). Variables. Pharmacodymanics parameters including the measurement of physiological, subjective and emotional effects and psychomotor performance were evaluated. Blood samples were obtained to determine for mephedrone, MDMA and its metabolites. Essential pharmacokinetics parameters were calculated for both mephedrone and MDMA. Results. The administration of mephedrone produced an increase in arterial blood pressure, heart rate and pupil diameter. It induced subjective feelings of euphoria, wellbeing, pleasure, stimulant-like effects and mild change in perceptions. These effects started at 30-45 minutes and persisted during 2-3 hours. Mephedrone administration was well tolerated and no serious adverse events were presented. Maximal plasma concentrations values for mephedrone were 134.64 ng/ml (51.75-218.30) and peaked at 1.25 hours post-administration. The elimination half-life for mephedrone was 2.15 hours. The administration of MDMA produced its prototypical psychostimulant effects, physiological and subjective (started 45 minutes-1 hour and total duration 4 hours) and maximal plasma concentration values were consisted with those determinated in previous studies. The elimination half-life for MDMA was 7.89 hours. Pharmacological effects of mephedrone were similar to those produced by MDMA although with a more rapid onset and a shorter duration of effects. The shorter action duration is probably related to its short elimination half-life. These differences could explain, in real live conditions, a more compulsive pattern of use in order to prolong the duration of the desired effects and consequently an increased risk of toxicity. Conclusions. The results suggest that mephedrone could exhibit a high abuse liability as other amphetamines and MDMA but its shorter duration could explain a more compulsive pattern of use.

Date of Award	25 May 2016
Original language	Spanish
Awarding Institution	Germans Trias i Pujol University Hospital
Supervisor	Magi Farre Albaladejo (Director) & Oscar García Algar (Director)