Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): The Influence of Gender and Genetics (CYP2D6, COMT, 5-HTT)

Abstract

The synthetic psychostimulant MDMA (±3,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75–100 mg) which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of MDMA pharmacokinetics following 1.4 mg/kg MDMA to the gender differences observed in drug effects appears to be negligible or even null. In contrast, 5-HTTLPR and COMT val158met genotypes play a major role.Trial RegistrationClinicalTrials.gov NCT01447472

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

“…The administration of a single dose of 100 mg of MDMA produced the previously described typical physiological (increase of SBP, DBP, HR, T, and PD) and subjective effects (euphoria, stimulation, feelings of well-being, disphoria, and mild changes in perceptions) (Mas et al, 1999;Camí et al, 2000;Hernández-López et al, 2002;Farré et al, 2004;Farré et al, 2007;Pardo-Lozano et al, 2012).…”

“…In humans, several single dose placebocontrolled studies have been reported (de la Torre et al, 2000a;Pardo-Lozano et al, 2012). In addition, some repeated dose placebo-controlled studies have been published (Farré et al, 2004;Kuypers et al, 2007;Kuypers et al, 2008;Peiró et al, 2013), including the therapeutic use of MDMA in post-traumatic stress disorder (PTSD) (Mithoefer et al, 2011, Oehen et al, 2013.…”

3,4-Methylenedioxymethamphetamine (MDMA) and metabolites disposition in blood and plasma following controlled oral administration

“…A recent study by Pardo-Lozano et al [36] demonstrated that individuals carrying two functional alleles (FA) for CYP2D6 produce significantly higher HMMA plasma concentrations relative to carriers with one FA. It is likely that the patterns observed in plasma would be reflected in blood; i.e., higher blood HMMA concentrations (and possibly increased MDMA clearance) would be observed in cases of extensive metabolizers.…”

Rodent models in neuroscience research: is it a rat race?

“…Interestingly, several other differences between the species in relation to the behavioural and biochemical effects of MDMA have been reported (Easton and Marsden, 2006), with some data suggesting that the effects are mediated mostly via dopamine in mice but predominantly via serotonin in rats (Kindlundh-Hogberg et al, 2007) and humans (Roberts et al, 2016). Although the relationship between serotonin-transporter polymorphisms and the reinforcing effects of MDMA have not yet been studied in humans, there is evidence that some of the characteristic behavioural effects are more prominent in humans with a genetic reduction in the serotonin transporter, similar to what has been described in rats (Pardo-Lozano et al, 2012). …”