Abstract
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a recreational substance also investigated as medication for posttraumatic stress disorder. Dopamine (DA) system stimulation likely contributes to the acute mood effects of amphetamines, including MDMA. Genetic variants, such as single-nucleotide polymorphisms (SNPs), and polymorphic regions of the DA system genes may in part explain interindividual differences in the acute responses to MDMA in humans. We characterized the effects of common genetic variants within genes coding for key players in the DA system including the dopamine D2 receptor (DRD2/ANKK1 rs1800497, DRD2 rs6277, and rs107959), the dopamine transporter (DAT1 rs28363170, rs3836790, rs6347, rs11133767, rs11564774, rs460000, and rs463379), and dopamine D4 receptor [DRD4, variable-number tandem repeat (VNTR)] on the subjective and autonomic response to MDMA (125 mg) in pooled data from randomized, placebo-controlled, crossover studies in a total of 149 healthy subjects. Plasma concentrations of MDMA were used as covariate in the analysis to control for individual pharmacokinetic (metabolic and weight) differences. None of the tested genetic polymorphisms within the DA system altered effects of MDMA when adjusting for multiple comparisons. Genetic variations in genes coding for players of the DA system are unlikely to explain interindividual variations in the acute effects of MDMA in humans.
Highlights
3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is widely used recreationally for its euphoric effects
The influence of polymorphisms within genes coding for the DA receptor D2 gene (DRD2), DAT1, and DRD4 on the maximal acute subjective and autonomic effects of MDMA is shown in Tables 1–3, respectively
Regarding the DAT1 rs3836790, MDMA produced a higher increase in Mean arterial pressure (MAP) in individuals homozygous for the 5 repeats (5R)-allele compared to 6 repeats (6R)-allele carriers (F1,144 = 4.31, p < 0.05)
Summary
3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is widely used recreationally for its euphoric effects. A few studies explored the role of genetic polymorphisms of the 5-HT, NE, and oxytocin systems and found only minimal influences on acute effects of MDMA [19,20,21,22,23]. The VNTR polymorphism within the gene coding for the subtype 4 of the DA receptors (DRD4) is frequently studied in relation to psychiatric disorders and personality traits [44,45,46,47]. The present study is the first to explore the influence of variants within genes coding for the DA system on the acute effects of MDMA in humans. Given the partially inconclusive pharmacogenetic studies in addition to the unclear degree to which MDMA effects are driven by the interaction with the DA system, we hypothesized that genetic mutations of the DA system would not influence cardiostimulant effects and have only minimal influence on the mood effects of MDMA
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