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Enzyme CYP2D6 and MDMA Pharmacology
by Erowid
Jun 25, 2002
It has been previously believed that the CYP2D6 liver enzyme may be at least partially responsible for some individuals' unusually strong reaction to MDMA. Although a small percentage of users seem to react with extreme sensitivity to MDMA and experience overly strong effects at normal doses, there is mounting evidence that CYP2D6 does not play a critical role in sensitivity or adverse reactions.

It is reported that between 3 - 10% of Caucasians are considered "poor metabolizers" and have lower levels of the liver enzyme CYP2D6.1,2 This enzyme is involved in the metabolization of many chemicals, including amphetamines and phenethylamines.3 Several articles and journal papers have suggested that these "poor metabolizers" may be at greater risk of adverse reactions, including papers by Colado et al in 1995, which stated "[Our results] indicate that in human subjects acute MDMA-induced toxicity may be exacerbated in poor metabolizer phenotypes."4 The theory grew out of the fact that for several years, CYP2D6 was the only known liver enzyme to metabolize MDMA, but now several others are believed to be involved (Kreth 2000).5

Further research has so far failed to confirm this hypothesis and it now appears that individuals of the low CYP2D6 genotype may not be at higher risk of adverse reactions to MDMA than normal metabolizers. Data from both published and unpublished research suggests that the CYP2D6 enzyme is quickly saturated (at doses less than 50 mg oral, perhaps as low as 10-30 mg), even in strong metabolizers. Each enzyme in the body can only metabolize a certain amount of a given chemical in a given period of time. If more of a chemical is present in the blood than an enzyme can break up, that enzyme "pathway" is considered 'saturated' (full). Pathways can become saturated because there are more things that it metabolizes that it can handle or because the enzyme activity is decreased. With MDMA the enzyme activity is actually decreased because MDMA or one of its metabolites binds to the CYP2D6 enzyme and forms an inhibitory complex which stops the enzyme from functioning normally for over a week.(Heydari et al 2002)

Because any therapeutically effective dose of MDMA will saturate this specific enzyme, all users are effectively 'poor metabolizers' of MDMA with this enzyme. CYP2D6 metabolizes MDMA into DHMA (dihydroxy-methamphetamine) and it is still possible that poor metabolizers would have decreased formation of DHMA compared to strong CYP2D6 metabolizers. However, because this pathway is overwhelmed (saturated) for all humans, it would not substantially affect the blood levels of the parent drug (MDMA).

In 1998, O'Donohoe et al. checked the CYP2D6 genotype for 7 patients who had visited hospitals after adverse reactions to ecstasy.7 They found that none of the 7 patients had the poor metabolizer genotype. While this is hardly conclusive, due to the small sample size and other limiting factors, it demonstrates that low CYP2D6 activity is not necessary for adverse reactions to MDMA.

Research from de la Torre, et al, has shown that MDMA metabolism seems to hit an important metabolic saturation point between 100 and 150 mg in most of their subjects, above which, peak blood levels increase non-linearly (in other words, an increase of 10% in the dose causes a larger than 10% increase in the blood levels). This research further suggests there are other critical metabolic pathways which are not yet fully quantified. See Kreth et al, 2000 for more discussion of other enzymes, which are thought to include CYP-1A2, CYP-3A4, & CYP-2bB.

In an unpublished commentary on the issue from mid 2002, Matthew Baggott, author of an extensive MDMA literature review,9 writes:
"Although it was fomerly hypothesized that genetic variations in CYP2D6 activity might influence the risk of MDMA toxicity, CYP2D6 activity now appears unlikely to be a major source of variance in adverse reactions. Several in vitro studies have shown that MDMA is not just a substrate for CYP2D6 but also binds to it, forming an inhibitory complex (Brady et al. 1986; Delaforge et al. 1999; Wu et al. 1997). Compelling in vivo evidence of enzyme inhibition was provided by de la Torre et al. (de la Torre et al. 2000a) who showed that plasma levels and 24-hour urinary recovery of HMMA [4-hydroxy-3-methoxy-methamphetamine, which is thought to be formed from DHMA - erowid] are dose-independent. This is likely the result of inhibition of CYP2D6-mediated DHMA formation.

The fact that CYP2D6 is apparently easily saturated makes this possible source of individual sensitivity appear less significant. In fact, there currently seems to be little evidence that the poor metabolizer genotype is by itself a major risk factor for acute MDMA toxicity. Kreth et al. (2000) reported that the poor metabolizer trait did not lead to significant alteration in maximal drug plasma concentrations in an individual participating in a clinical study of the MDMA analogue, MDE. This provides further evidence that the role of CYP2D6 in MDMA metabolism is sufficiently limited that it is not a major risk factor in healthy individuals in a clinical setting."
Another point of data is that for other related psychoactives, CYP2D6 has been shown not to be related to adverse reactions. For example, SSRI use can lead to hyponatraemia. Stedman and colleagues found that the poor CYP2D6 metabolic status was not significantly associated with hyponatraemia in those receiving SSRIs.10

While it is still possible that low CYP2D6 levels could shift risks slightly, this appears to be a minor or potentially irrelevant issue. Several other related enzymes are implicated in MDMA's metabolism and it is more likely that some other enzyme, system, interaction, or behaviour is responsible for most variations in reactions to this chemical.

It is important to note that the issue is not yet completely resolved and additional human pharamcokinetic research may be able to answer some of the outstanding questions. Detailed work in Spain, by de la Torre et al, showing higher levels of DHMA than previously thought may indicate that CYP2D6 is more important than the above analysis would suggest.

References #
  1.   Kimura S, Umeno M, Skoda R, et al. The human debrisoquine 4-hydroxylase (CYP2D6) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Human Genet 1989;45:889-904.
  2.   Gonzalez FJ, Meyer UA. Molecular genetics of the debrisoquin-sparteine polymorphism. Clin Pharmacol Ther 1991 Sep;50(3):233-8.

  3.   The Worldwide Physiologist. CYP Isoforms.

  4.   Colado MI, Williams JL, Green AR. The hyperthermic and neurotoxic effects of 'Ecstasy' (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype, Br J Pharmacol, 1995; 115(7):1281-9.

  5.   Kreth KP, Kovar KA, Schwab M, Zanger UM. Identification of the Human Cytochromes P450 Involved in the Oxidative Metabolism of 'Ecstasy'-Related Designer Drugs, Biochem Pharmacol, 2000; 59:1563-1571.

  6.   Not yet published. Heydari A, Rostami-Hodjegan A, Lennard M S, De La Torre R, Tucker GT, Farre M. Molecular Pharmacology and Pharmacogenetics.

  7.   MDMA toxicity: no evidence for a major influence of metabolic genotype at CYP2D6, O'Donohoe A, O'Flynn K, Shields K, Hawi Z, Gill M Addiction Biology, 1998; 3(3):309-314

  8.   Non-linear pharmacokinetics of MDMA (`ecstasy') in humans, de la Torre R, Farré M, Ortuño J, Mas M, Brenneisen R, Roset PN, Segura J, Camí J Br J Clin Pharmacol, 2000; 49(2):104-9.

  9.  . Baggott & Jerome's MDMA Literature Review 2001,
    From this review:
    "The dose-dependent metabolism of MDMA is at least partially due to inhibition of some metabolic pathways. Several in vitro studies have shown that MDMA is not just a substrate for CYP2D6 but also binds to it, forming an inhibitory complex (Brady et al. 1986; Delaforge et al. 1999; Wu et al. 1997). Compelling in vivo evidence of enzyme inhibition was provided by de la Torre et al. (2000a) who showed that plasma levels and 24-hour urinary recovery of HMMA are dose-independent. This is likely the result of inhibition of CYP2D6-mediated DHMA formation."
  10.   Stedman CAM, Begg EJ, Kennedy MA, Roberts R, Wilkinson TJ. Cytochrome P450 2D6 genotype does not predict SSRI(fluoxetine or paroxetine) induced hyponatraemia. Hum Psychopharmacol Clin Exp 2002; 17: 187-190.