No major role of norepinephrine transporter gene variations in the cardiostimulant effects of MDMA

Genetic variants of the norepinephrine transporter gene (SLC6A2) weakly influence the acute cardiovascular response to MDMA (ecstasy). In a pooled analysis of eight double-blind, placebo-controlled studies involving 124 healthy subjects, carriers of the GG genotype of the rs1861647 SNP showed higher increases in heart rate and rate-pressure product after MDMA than those with one or no G alleles. Subjects with a C allele in the rs2242446 SNP had greater heart rate elevations compared with the TT genotype. The AA genotype of the rs36029 SNP was associated with higher increases in mean arterial pressure and rate-pressure product than carriers of the G allele. Two other SNPs (rs168924 and rs47958) did not alter MDMA responses. These genetic factors may play a minor role in adverse cardiovascular events during recreational MDMA use.

Study at a glance

Abstract

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 α 1 -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. We 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. Carriers 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. Genetic 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.