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H. Schwabedissen

Role of serotonin transporter and receptor gene variations in the acute effects of MDMA in healthy subjects

December 27, 2018 / MDMA, Neuroscience, Papers, Publications / By / , ,

Abstract

Methylenedioxymethamphetamine (MDMA; ecstasy) is used recreationally and has been investigated as an adjunct to psychotherapy. Most acute effects of MDMA can be attributed to activation of the serotonin (5-hydroxytryptamine [5-HT]) system. Genetic variants, such as single-nucleotide polymorphisms (SNPs) and polymorphic regions in 5-HT system genes, may contribute to interindividual differences in the acute effects of MDMA. We characterized the effects of common genetic variants within selected genes that encode the 5-HT system (TPH1 [tryptophan 5-hydroxylase 1] rs1800532 and rs1799913, TPH2 [tryptophan 5-hydroxylase 2] rs7305115, HTR1A [5-HT1A receptor] rs6295, HTR1B [5-HT1B receptor] rs6296, HTR2A [5-HT2A receptor] rs6313, and SLC6A4 [serotonin transporter] 5-HTTLPR and rs25531) on the physiological and subjective response to 125 mg MDMA compared with placebo in 124 healthy subjects. Data were pooled from eight randomized, double-blind, placebo-controlled studies that were conducted in the same laboratory. TPH2 rs7305115, HTR2A rs6313, and SLC6A4 5-HTTLPR polymorphisms tended to moderately alter some effects of MDMA. However, after correcting for multiple comparisons, none of the tested genetic polymorphisms significantly influenced the response to MDMA. Variations in genes that encode key targets in the 5-HT system did not significantly influence the effects of MDMA in healthy subjects. Interindividual differences in the 5-HT system may thus play a marginal role when MDMA is used recreationally or therapeutically.

Vizeli, P., Meyer zu Schwabedissen, H. E., & Liechti, M. E. (2018). Role of serotonin transporter and receptor gene variations in the acute effects of MDMA in healthy subjects. ACS chemical neuroscience., 10.1021/acschemneuro.8b00590
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Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects

January 20, 2017 / MDMA, Papers, Publications / By / , , , ,

Abstract

In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.

Vizeli, P., Schmid, Y., Prestin, K., zu Schwabedissen, H. E. M., & Liechti, M. E. (2017). Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects. European Neuropsychopharmacology, 27(3), 232-238. 10.1016/j.euroneuro.2017.01.008
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