DrugFacts 2010 Repost: Yes, it really is the MDMA that killed him

November 10, 2010

This is Drug Facts Week, an effort of NIDA to promote understanding of the effects of recreational drugs. Although I’m slightly busy with other matters, I wanted to participate, partially, with a series of re-posts. This post originally appeared July 7, 2009.


I’ve taken the liberty of providing a title for a new case report on a fatality associated with consumption of Ecstasy which more accurately captures the tone of the article. In this case the authors go to some length to beat home a message that I have been known to blog now and again. The report is in the pre-print stage in the Journal of Emergency Medicine.
RHABDOMYOLYSIS IN MDMA INTOXICATION: A RAPID AND UNDERESTIMATED KILLER. “CLEAN” ECSTASY: A SAFE PARTY DRUG?
Herve Vanden Eede, MD, Leon J. Montenij, MD, Daan J. Touw, and Elizabeth M. Norris, MB, CHB. J Emerg Med. 2009 Jun 3. [Epub ahead of print], doi: 10.1016/j.jemermed.2009.04.057


The Case starts with this initial description:

A 19-year-old man presented to the Emergency Department (ED) in a coma with seizures and hyperthermia (temperature 42.5°C). Questioning of his friend revealed the patient’s intake of alcohol and three tablets of Ecstasy. The ingestion took place at home about 2 h before admission to the hospital. There was no physical exercise (dancing) during that period and there was good ventilation in the room. The patient was brought in by ambulance with the diagnosis of seizures.

Sounds very familiar. The current report emphasizes that the ambulance arrived about 6 min after the on set of seizure and the patient was in the Emergency Department 5 min after that. Pretty good for one of these case reports already. We get some idea of the time course after emergency services were contacted and indeed an estimate of timing from initial ingestion.
The report then goes on to summarize the treatment once in hospital with standard cooling/stabilization procedures, a cardiac arrest / resuscitation in the ED, movement to an Intensive Care Unit, subsequent second cardiac arrest from which the patient was not able to be recovered.
Blood panels taken at arrival in the ED and again in the ICU indicate hyperkalemia, rhabdomyolysis, myocardial damage and a syndrome of inappropriate antidiuretic hormone.
In summary, this Case Report is highly consistent with the general picture that can be obtained from a close reading of all the published Case Reports and indeed many of the popular media accounts that do not end up reported formally in the scientific literature.
So now we get to the usual denialist question/assertion that it must have been some other drug, not 3,4-methylenedioxymethamphetamine, that was the cause of death. The authors are clearly speaking to such an audience.

The serum toxicology screening showed an elevated level of MDMA (1.5 mg/L); no other amphetamines or other drugs were found. Urine was tested for party drugs (amphetamines, MDMA, cocaine, cannabinoids) using an
immunoassay (Architect, Abbott, Netherlands), and blood was screened for drugs using HPLC (high-performance liquid chromatography)-diode-array detection (I-Toxsystem, Agilent, Netherlands). The I-Tox system is able to screen and quantify more than 1000 common drugs and metabolites within one analytical run (1-3). The
results for the amphetamines were later confirmed by liquid chromatography-tandem mass spectrometry (lower limit of quantification for amphetamines 10 g/L).

Exactly. MDMA was causal. It wasn’t dancing or dehydration or PMA or methamphetamine or anything else. It was the drug 3,4-methylenedioxymethamphetamine which is what most people intend to consume as “Ecstasy”. And what do you know? The constellation of symptoms are exactly the same as in the other cases in which there may be less certainty about the identity of the drug consumed, multiple drugs consumed or putative threatening environmental circumstances like presence of the user at a rave party.
Okay, now to get to the next obvious question, what does 1.5 mg/L of MDMA in the blood mean? Is it consistent with the report (presumably from co-users of the deceased) of three tablets consumed?
Returning to a prior post on MDMA pharmacokinetic comparisons between human and squirrel monkeys, the first thing we note is that we need to do some conversion as that paper gave plasma levels in ng/ml instead of mg/L as seems to be the usual practice for Case Reports in humans. Never fear, Google is your friend. You can start with a conversion site such as this one to find that 1 mg = 1,000,000 nanograms. So the deceased had 1,500,000 nanograms (ng) of MDMA in each L(iter) of serum. (For our purposes the difference between serum and plasma is essentially irrelevant.)
Next we need to convert the volume of assessment. Again, if you are really forgetful, the Web can help. 1 liter is equal to 1,000 milliliters (ml). So if the deceased has 1,500,000 ng of MDMA in each liter of serum, he had 1,500 ng in each milliliter of serum. So we now have a comparison dose of 1,500 ng/ml to compare with the PK paper I previously discussed. In that paper, the humans were given a 1.6 mg/kg dose (112 mg of MDMA for a 70kg/154lb person) and the average peak concentration was 255 ng/ml, observed at 2.4 hrs after ingestion. This latter indicates that the deceased in the current Case Report was very likely close to peak levels when they drew blood at initial arrival at the Emergency Department, btw. I will note that if you look at several of the other MDMA pharmacokinetic studies, mostly by the de la Torre group, a peak plasma level of somewhere between 150-250 ng/ml is pretty typical for a ~1.5 mg/kg or fixed 100 mg oral dose of MDMA.
Beyond this we are into uncertainty because if anyone has given humans doses that result in plasma levels of about 1,500 ng/ml I sure haven’t seen them*. And although it might be tempting to do some simple arithmetic this would very likely be inaccurate because it appears that MDMA inhibits the liver enzymes responsible for metabolizing it, leading to a so-called non-linear dose-effect function. The Case Report at hand, of course, indicated that the individual was reported as consuming 3 tablets . The authors also repeat 75 mg/tablet as a typical content in their area but also refer to data suggesting that this content may have been increasing in the past few years- “even 200 mg/tablet” seems a bit of a stretch to assume given that that was probably the peak observed ever. Still it gives us a possible (if highly unlikely) upper bound of 600 mg and a (more likely) lower bound of 225 mg as the amount consumed by this individual. Thus depending on where the guy fell in a 70-100kg bodyweight range (the one critical bit missing from the Case Report) we’re talking anywhere from 2.25-8.5 mg/kg consumed.
What else can we deduce from the animal literature? Well, certainly the so-called serotonin “neurotoxicity” studies very frequently administered repeated 5 mg/kg doses (twice per day for 4 days) to squirrel monkeys and there were a few studies on the effects of 10 mg/kg doses (twice per day for 4 days) in macaque monkeys. For the most part no medical emergency/fatality has been reported therefore we must conclude that single 5-10 mg/kg doses (even injected intramuscularly or subcutaneously) are not inevitably lethal in monkeys. (Do keep in mind that whether you look at peak plasma level (2.8 mg/kg ~= 1.6 mg/kg) or Area Under the time/concentration Curve (5.6 mg/kg ~= 1.6 mg/kg) doses in monkeys are likely to be higher than humans to produce an equivalent effect.) One prior paper from Bowyer and colleagues reports peak plasma levels of MDMA (in this case the d/+/S stereoisomer only) of ~1,200-2,500 ng/ml (individual differences) after a single 10 mg/kg dose in macaque monkeys.
Given these bits of information anyone is free to speculate what dose the subject of the Case Report actually ingested. I’d still bet that 8.5 mg/kg is pretty unlikely. It could have been 2.25 mg/kg but that doesn’t seem likely to have produced such high plasma levels either. Something in between would be my call.
As a final note, we can return to the supposed three-tablet ingested dose. I would find that totally consistent with the above analysis. Maybe they contained a little more MDMA than average but the distribution seems to be pretty broad in the 75-125 (150?) mg/tablet zone so we shouldn’t make any firm assumptions there.
It is up to those experienced with recreational use practices to decide of somebody taking three tablets of Ecstasy is far outside the norm. Everything I’ve ever seen, from formal surveys to user reports, suggest such practices are common enough.
__
*no legitimate IRB should ever approve such a thing, btw.

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No Responses Yet to “DrugFacts 2010 Repost: Yes, it really is the MDMA that killed him”

  1. Matthew Says:

    No doubt. There is risk involved with consuming psychoactive compounds.

    On the other hand… doesn’t the frequency of an event such as this suggest that MDMA may be about as dangerous as something like, say… peanut oil?

    Like

  2. Charlie Says:

    Interesting post and above my head but based on this and the linked article, is it possible that the victim took MDMA the day before, thus depleting the required liver enzymes and resulting in a stronger dose response?

    Like

  3. drugmonkey Says:

    doesn’t the frequency of an event such as this suggest that MDMA may be about as dangerous as something like, say… peanut oil?

    Not really. At present we have a fairly defined understanding of the fact that people have peanut allergies. If you don’t have one, you are unlikely to die from peanut exposure.

    We do not have this understanding for MDMA at present. We don’t have defined individual warning signs, nor evidence of life-long immunity to adverse consequences.

    this, in my view, should change the risk calculation for a given individual.

    We also do not have, to my awareness, a firmly committed set of peanut-allergy denialists who pop up to minimize the risks and deny current scientific understanding of how some people may be harmed by peanut exposure. This factor is also related to calculating, on a population basis, how “risky” something is and provides an avenue for doing something about it. Letting people know there is such a thing as a peanut allergy, that their kid might have one if X, Y or Z occurs permits them to alter their behavior in such a way as to reduce risk. If you had people out their believing that there was no possible way the peanuts were at fault then risk from peanut allergy would be higher.

    The analogy is far from perfect but it hopefully gives you some flavor of why I blog these issues and why I think it is idiotic for the drug fans to constantly harp on about relative risk in a denialist tone. In your case, perhaps you are not one of those that thinks that it can never be the MDMA that is at fault. But if you go through comments on new media accounts of MDMA-related fatalities you will find the head-in-sand attitude that I would like to correct.

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  4. drugmonkey Says:

    is it possible that the victim took MDMA the day before, thus depleting the required liver enzymes and resulting in a stronger dose response?

    Possible…but I think unlikely. The reason is that medical emergency is relatively rare an there are lots of individuals taking this and much higher doses, even on repeated days or several hours apart. If it was a simple dose effect, we’d be seeing a lot more problems and with proportions that matched the doses ingested a lot better.

    At best a metabolic inhibition effect interacts with whatever other individual differences exist. Those differences may be innate (genetic) or acquired (plasticity of neurochemical systems due to repeated exposure to MDMA would not be hard to fathom). Very likely both.

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  5. drugmonkey Says:

    And if anyone needs a recent example of the MDMA-denialist comments (that manage to really misstate the science and/or pull sheist out of the behind)

    http://latimesblogs.latimes.com/lanow/2010/08/coroner-confirms-ecstasy-overdose-caused-death-of-15-year-old-who-attended-massive-rave.html#comments

    Like

  6. mcdermott Says:

    Almost twenty years ago, I interviewed the first known case of this to survive in the UK. (The ER team treated him symptomatically — packed him with ice and just tried to cool him.) Was in a coma for six weeks after the incident and then appeared to make a full recovery.

    He’d taken a single tablet that was known to be MDMA. He’d taken the drug before, frequently, and hadn’t mixed it with any other drugs.

    The weird thing was, it wasn’t even the last time he took MDMA. Despite this incident taking him as close to death as it’s likely to get, he took another pill about six months later (taking half at a time) and reported no apparent adverse consequences.

    Like

  7. RG Cooley Says:

    Freedom is intrinsically dangerous..just driving a car can and if driving fast enough likely will injure or kill you..people ski and die running into trees and off cliffs…but that’s ok…a person..an adult can… indeed they have to learn… to know their limitations….if not we all would have to live in a cage…not all drugs are equal and some do not allow second chances and should be well researched..ecstasy has been researched quite a bit and does have medical uses…however in a world where adults are treated like children and children like adults …well… a gigantic nanny state occurs….education and moderation will keep all with any sense firmly in a safe place…able to live life with as much exploration and risk as they can handle…legalize all drugs..for adults and deal harshly with anyone that sells or gives adult level concepts.. this includes sex and drugs to children…let children be children and let adults live their life’s in peace…

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