is this true? "sudden death syndrome" from MDMA

[ihavequestions]

swim read in a pretty respectable and unbiased book about drugs with good info on all ranges of drugs.

in the MDMA section it was said that there is a "sudden death syndrome" in some user who take MDMA.

it was said that 1 in 12 people lack the cytochrome enzyne P450-246 that metabolizes MDMA that can reult in a fatality.

is this true? cause that seems like alot of people who lack that enzyme.

[chinpokomaster]

If the inference is that 1 in 12 people who take MDMA are risking sudden death, then I'm not that inclined to believe it.

[RaverHippie]

I have never heard of an MDMA related death due to that cause. That fact is false. Think about it at a rave of 200 MDMA users 17 would have had to die...that doesn't happen in the real world. If SWIY is so worried about ingesting psychedelic substances before SWIY even takes them, then they would probably be a nervous wreck while on the substance. SWIM has noticed a trend in SWIY's posts...

[truth]

MDMA is pretty harmless compared to most things. Pure MDMA that is. When used responsibly in the right increments of time. Nothing Worse then playing a contact sport or taking a Tylenol. Everything has bad effects, but this is most likely untrue. imo

[notts.pirate]

as said its false, SWIM worked out that is this 1-12 were correct within a few months the population of the town SWIM parties in would be halved

[Paracelsus]

in the MDMA section it was said that there is a "sudden death syndrome" in some user who take MDMA.

it was said that 1 in 12 people lack the cytochrome enzyne P450-246 that metabolizes MDMA that can reult in a fatality.

It is true that CYP2D6 metabolizes MDMA and it is thought that lack of this enzyme results in more potent effects, which means higher risk of overdose. This does not mean that 5-10% of the population will die when taking MDMA.

[ihavequestions]

yeah, i thought that number was too high. in that same article swim read that approxamately 16% of all 12th grader had tried MDMA at least once in 1990 something. it also said that the number had significantly increased since then. that would be alot of dead people.

[snapper]

From Erowid :
Enzyme CYP2D6 and MDMA Pharmacology
by Erowid
June 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 50mg oral, perhaps as low as 10-30mg), 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 150mg 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 #
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.
Gonzalez FJ, Meyer UA. Molecular genetics of the debrisoquin-sparteine polymorphism. Clin Pharmacol Ther 1991 Sep;50(3):233-8.

The Worldwide Physiologist. CYP Isoforms.

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. http://www.erowid.org/references/references.cgi?ID=518

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. http://www.erowid.org/references/references.cgi?ID=391

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

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

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. http://www.erowid.org/references/references.cgi?ID=382

. Baggott & Jerome's MDMA Literature Review 2001, MAPS.org
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."
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.

Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition.
de la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J.
Unitat de Recerca en Farmacologia, Institut Municipal d'Investigació Médica, Barcelona, Spain. rtorre@imim.es

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is a widely misused psychostimulant drug abused among large segments of the young population. Pharmacologically it displays effects related to amphetamine-type drugs and a set of distinctive effects (closeness to others, facilitation to interpersonal relationship, and empathy) that have been named by some authors "entactogen" properties. MDMA is a potent releaser and/or reuptake inhibitor of presynaptic serotonin (5-HT), dopamine (DA), and norepinephrine (NE). These actions result from the interaction of MDMA with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. The most frequent effects after MDMA/ecstasy administration are euphoria, well-being, happiness, stimulation, increased energy, extroversion, feeling close to others, increased empathy, increased sociability, enhanced mood, mild perceptual disturbances, changed perception of colors and sounds, somatic symptoms related to its cardiovascular and autonomic effects (blood pressure and heart rate increase, mydriasis), and moderate derealization but not hallucinations. Acute toxic effects are related to its pharmacologic actions. The serotonin syndrome (increased muscle rigidity, hyperreflexia, and hyperthermia), among others, is characteristic of acute toxicity episodes. MDMA metabolism is rather complex and includes 2 main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The fact that the polymorphic enzyme CYP2D6 partially regulates the O-demethylenation pathway prompted some expectations that subjects displaying the poor metabolizer phenotype may be at higher risk of acute toxicity episodes. In this metabolic pathway a mechanism-based inhibition of the enzyme operates because the formation of an enzyme-metabolite complex that renders all subjects, independently of genotype, phenotypically poor metabolizers after the administration of 2 consecutive doses. Therefore, the impact of CYP2D6 pharmacogenetics on acute toxicity is limited. One of the interesting features of MDMA metabolism is its potential involvement in the development of mid- to long-term neurotoxic effects as a result of progressive neurodegeneration of the serotonergic neurotransmission system.
MID: 15228154 [PubMed - indexed for MEDLINE]



In other words, this is false and your reference is less reliable than you thought.

[KomodoMK]

Originally Posted by RaverHippie

I have never heard of an MDMA related death due to that cause. That fact is false. Think about it at a rave of 200 MDMA users 17 would have had to die...that doesn't happen in the real world. If SWIY is so worried about ingesting psychedelic substances before SWIY even takes them, then they would probably be a nervous wreck while on the substance. SWIM has noticed a trend in SWIY's posts...

I've also noticed this trend, it would really not be a good idea for SWIY to take a substance if you worry about what could happen so much as it's just asking for anxiety attacks. At the very least you will create a mental block dulling the experience. Just go into the experience with an open mind and no worries and you'll love every minute of it.