Ecstasy (MDMA)-induced hyponatraemia is associated with genetic variants in CYP2D6 and COMT.
We hypothesised that genetically determined poor metabolism of 3,4-methylene dioxymetamphetamine (MDMA) due either to the presence of CYP2D6 genotypes giving absent or low CYP2D6 enzyme activity, or a COMT genotype predicting low COMT enzyme activity would be associated with a greater degree of MDMA-induced reduction in plasma sodium and osmolality than other genotypes at these genes following consumption of 'ecstasy' tablets by clubbers. Of the 48 subjects who returned to the test site post-clubbing, 30 provided samples for measurement of vasopressin (AVP), plasma sodium, urea and plasma and urine osmolality. Genotyping was performed for functional variants in CYP2D6 (n = 29) and COMT (Val158Met, n = 30). In subjects with urinary MDMA detected post-clubbing, there was a significant association between change in plasma osmolality (p = 0.009) and in plasma sodium (p = 0.012) and CYP2D6 genotypic category. Individuals with the low-activity but readily inhibitable CYP2D6 extensive metaboliser/intermediate metaboliser (EM/IM) genotype showed greater reductions in these measures than all other CYP2D6 genotypic categories. COMT low-activity genotypes (Met/Met and Val/Met) were also significantly associated with reductions in plasma osmolality (p = 0.028) and in plasma sodium (p = 0.003). On conservative Bonferroni correction for two independent genes, the CYP2D6 and COMT plasma sodium findings remain significant. The relatively high frequency of the low-activity CYP2D6 and COMT genotypes in the population warrants further attention, since consumption of free water following ingestion of MDMA in these individuals may trigger dilutational hyponatraemia and increased risk of syndrome of inappropriate antidiuretic hormone secretion.
MRC Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK. kaitchis@ualberta.ca
Katherine J
KJ
Aitchison
Evangelia M
EM
Tsapakis
Patricia
P
Huezo-Diaz
Robert W
RW
Kerwin
Mary L
ML
Forsling
Kim
K
Wolff
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D001711:Biotransformation; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007010:Hyponatremia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000652:urine; D013287:Illicit Drugs / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D007177:Inappropriate ADH Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000652:urine; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D014882:Water-Electrolyte Balance / Q000187:drug effects; D055815:Young Adult
D013287:Illicit Drugs; D019389:Cytochrome P-450 CYP2D6; D002394:Catechol O-Methyltransferase; D018817:N-Methyl-3,4-methylenedioxyamphetamine