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

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.

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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.
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*no legitimate IRB should ever approve such a thing, btw.