Should We Buy the Idea of an “Allergy” to MDMA?

MDMA \(ecstasy\) pharmacokinetics in a CYP2D6 poor metaboliser and in nine CYP2D6 extensive metabolisers

Evidence that individuals possessing a compromise in CYP2D6 activity would be more susceptible to acute toxic effects of MDMA has been lacking. A previous metabolic bioactivation of MDMA, regulated partially by this enzyme, is needed to elicit neurotoxic effects in the central nervous system. It is postulated that the chemical species involved in serotonergic neurotoxicity are catechol thiol conjugate metabolites of the drug (HHMA) [8]. The functional polymorphisms in CYP2D6 could influence the development of MDMA neurotoxicity. During a trial designed to study the pharmacology of two consecutive doses of MDMA [3], one subject was found to possess the CYP2D6*4/*4 genotype and was classified as a PM. The objective of this paper was to compare the results of this subject with those of nine others previously published. Furthermore, the paper includes pharmacokinetic data on MDMA metabolites not previously published.

Temperature increases were more apparent in the CYP2D6*4/*4. The female Dark Agouti rat, a model of CYP2D6 poor metabolism, is more susceptible to the hyperthermic effects of MDMA [1]. It is hypothesised that the increase observed in the CYP2D6*4/*4 subject in this study is related to the higher AUC 0–24 h and C max 0–24 h values of MDMA in plasma; thus, CYP2D6*4/*4 subjects may be under increased risk of hyperthermia caused by MDMA.

There was a lack of prolactin response in the CYP2D6*4/*4 subject following both doses of MDMA (AUC 0–6 h 10.09 ng h ml and 11.21 ng h ml, respectively). Slight temperature increases were seen in all subjects, but temperature increased more in the CYP2D6*4/*4 subject than in the CYP2D6*1/*1 subjects with AUC 0–6 h values of 2.867C/h and 0.404C/h respectively.

Following the second dose of MDMA, differences in phenotype were no longer apparent as CYP2D6 was being inhibited and CYP2D6*1/*1 and CYP2D6*1/*4 subjects behaved similarly to the CYP2D6*4/*4 subject administered single doses. This suggests a tendency towards the phenomenon of phenocopying following repeated doses. Changes seen in MDMA metabolite AUC 0–24 h and C max 0–24 h values could also influence the risk of neurotoxicity. Higher AUC 0–24 h values of HHMA in the CYP2D6*1/*4 and CYP2D6*1/*1 may be translated to an increased risk of neurotoxicity for these subjects.

Using the term allergy is annoying. It's not an allergy. It's an enzyme expression difference. Regardless, the study did show poor CYP2D6 metabolizers were more susceptible to temperature increases after a single dose, but that re-dosing made the difference negligible. I think everyone knows that the most risk for damage with MDMA is with higher body temperatures and re-dosing. We know that the initial MDMA dose inhibits CYP2D6. So poor CYP2D6 metabolizers have higher AUC after a single dose, but the CYP2D6 inhibition of the initial MDMA dose brings normal metabolizers to the same level. Other studies have shown that the CYP2D6 inhibition of the first does of MDMA can take up to 10 days to return to normal. So while poor metabolizers do show higher AUC after a single dose, and do have to be more conscious of body temperature increases, re-dosing brings everyone to the same place. Re-dosing is always going to make things more risky.

I think the more likely explanation for the deaths are poor quality/fake MDMA, or predispositions to heart trouble with 5-HT2B agonism.