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1. J Psychopharmacol. 2012 Feb 1. [Epub ahead of print]

Ecstasy (MDMA)-induced hyponatraemia is associated with genetic variants in
CYP2D6 and COMT.

Aitchison KJ, Tsapakis EM, Huezo-Diaz P, Kerwin RW, Forsling ML, Wolff K.

MRC Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry,
King's College London, London, UK.

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.

PMID: 22303032 [PubMed - as supplied by publisher]