Abstract
PurposeMethylenedioxymethamphetamine (MDMA, ecstasy) is used recreationally and frequently leads to sympathomimetic toxicity. MDMA produces cardiovascular and subjective stimulant effects that were shown to partially depend on the norepinephrine transporter (NET)-mediated release of norepinephrine and stimulation of α1-adrenergic receptors. Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the NET gene (SLC6A2) may explain interindividual differences in the acute stimulant-type responses to MDMA in humans.MethodsWe characterized the effects of common genetic variants of the SLC6A2 gene (rs168924, rs47958, rs1861647, rs2242446, and rs36029) on cardiovascular and subjective stimulation after MDMA administration in 124 healthy subjects in a pooled analysis of eight double-blind, placebo-controlled studies.ResultsCarriers of the GG genotype of the SLC6A2 rs1861647 SNP presented higher elevations of heart rate and rate-pressure product after MDMA than subjects with one or no G alleles. Subjects with a C allele in the SLC6A2 rs2242446 SNP presented higher elevations of the heart rate after MDMA administration compared with the TT genotype. Subjects with the AA genotype of the SLC6A2 rs36029 SNP presented higher elevations of mean arterial pressure and rate pressure product after MDMA administration than carriers of the G allele. The SLC6A2 rs168924 and rs47958 SNPs did not alter the response to MDMA.ConclusionsGenetic polymorphisms of the SLC6A2 gene weakly moderated the acute cardiovascular response to MDMA in controlled studies and may play a minor role in adverse cardiovascular events when MDMA is used recreationally.
Highlights
Methylenedioxymethamphetamine (MDMA, ecstasy) is used recreationally and frequently leads to sympathomimetic toxicity
We evaluated whether the SLC6A2 rs168924, rs47958, rs1861647, rs2242446, and rs36029 single-nucleotide polymorphisms (SNPs) influence the cardiovascular and subjective stimulant effects of MDMA
To account for differences in plasma concentrations of MDMA that were caused by differences in body weight, dosing, or metabolizing enzymes [9, 10], the area under the MDMA plasma concentration-time curve from 0 to 6 h (AUC) was included as a covariate in the analysis of variance (ANOVA), and we report the corrected statistics
Summary
Methylenedioxymethamphetamine (MDMA, ecstasy) is used recreationally and frequently leads to sympathomimetic toxicity. MDMA produces cardiovascular and subjective stimulant effects that were shown to partially depend on the norepinephrine transporter (NET)-mediated release of norepinephrine and stimulation of α1-adrenergic receptors. Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the NET gene (SLC6A2) may explain interindividual differences in the acute stimulant-type responses to MDMA in humans
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