Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4h apart Human pharmacology of MDMA after repeated doses taken 4h apart

Farré, Magı́; Tomillero, Angels; Pérez‐Mañá, Clara; Yubero, Samanta; Papaseit, Esther; Roset, Pere-Nolasc; Pujadas, Mitona; Torrens, Marta; Camı́, Jordi; Torre, Rafael de la

doi:10.1016/j.euroneuro.2015.05.007

Cited by 23 publications

(26 citation statements)

References 45 publications

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“…With CYP2D6 being polymorphically expressed, substantial interindividual differences in MDMA and metabolite plasma concentrations are expected. Furthermore, MDMA is a mechanism-based inhibitor of CYP2D6 resulting in an irreversible inhibition of its own metabolism in high or after repeated doses (de la Torre et al, 2000aTorre et al, , 2000bShen et al, 2013;Farre et al, 2015). The dose of MDMA in this study corresponds to a common recreational dose.…”

Section: Discussionmentioning

confidence: 95%

“…Other studies were performed over 48 or even 143 (Kolbrich et al, 2008) hours with HMMA still being positive after 95 hours. Various racemic pharmacokinetic studies on MDMA and some metabolites after controlled administration are available (Kolbrich et al, 2008;Shen et al, 2013;Farre et al, 2015). The following discussion will mainly focus on enantioselective effects.…”

Section: Discussionmentioning

confidence: 99%

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Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

et al. 2015

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Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples from 16 healthy participants receiving 125 mg of MDMA orally in a controlled study were analyzed using liquid chromatography-tandem mass spectroscopy after chiral derivatization. Pharmacokinetic parameters of R-and S-stereoisomers were determined. Sulfates of 3,4-dihydroxymethamphetamine (DHMA), and sulfate and glucuronide of 4-hydroxy-3-methoxymethamphetamine (HMMA) were identified, whereas free phase I metabolites were not detected. Stereoselective differences in C max and AUC 24 were observed with the following preferences: R>S for MDMA and DHMA 4-sulfate; S>R for 3,4-methylenedioxyamphetamine (MDA), DHMA 3-sulfate, and HMMA glucuronide; and no preference in C max for HMMA sulfate. R/S ratios were >1 for all analytes after 24 hours, independent of the initial chiral preference. These are the first data on chiral pharmacokinetics of MDMA phase II metabolites in human plasma in vivo after controlled administration. The main human MDMA metabolites were shown to be sulfate and glucuronide conjugates.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

et al. 2015

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“…In rodents, exposure to MDMA repeatedly have been shown to produce deficits in the brain causing neuronal death or memory loss3132333435. Callahan and his colleagues found MDMA causes structural damage to axonal transport mechanisms in multiple brain regions36.…”

Section: Discussionmentioning

confidence: 99%

Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

Hsing

Liu

Weng

et al. 2016

Sci Rep

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3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

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“…The digit symbol substitution test scores were based on the number of correct patterns keyed in during 90 s (correct responses) (Peiró et al, 2013;Farré et al, 2015;Camí et al, 2000;de la Torre et al, 2000). The Maddox wing device measures the balance of extraocular muscles and quantifies exophoria as an indicator of extraocular muscle relaxation.…”

Section: Psychomotor Performance Measuresmentioning

confidence: 99%

“…The results are expressed in diopters along the horizontal scale of the device. These measures have been previously used in the evaluation of psychostimulants and MDMA effects (Peiró et al, 2013;Farré et al, 2015;Camí et al, 2000).…”

Section: Psychomotor Performance Measuresmentioning

confidence: 99%

Human Pharmacology of Mephedrone in Comparison with MDMA

Papaseit

Pérez‐Mañá

Mateus

et al. 2016

Neuropsychopharmacol

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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.

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Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4h apart Human pharmacology of MDMA after repeated doses taken 4h apart

Cited by 23 publications

References 45 publications

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

Human Pharmacology of Mephedrone in Comparison with MDMA

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