Yes, it really is the MDMA that killed him

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.
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.

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

  1. nails Says:

    This issue is something new for me so I don’t have a strong opinion either way, but I have some questions about this.
    Does MDMA cause hyperkalemia? Because that can cause cardiac problems for sure.
    I don’t know how booze combined with extacy can effect the outcome, but it says that the patient drank alcohol with the drugs.
    I don’t really see how the lack of other drugs makes the MDMA cause so definite, from what I read in your post it seemed like the patient’s concentration of MDMA fell below what is considered to be a leathal level. I also wonder if other things were overlooked because of the drug use, like prior medical conditions or questioning about symptoms of any sort previous to the drug use. I am comfortable thinking that it is pretty likely that the drug played a big part in the death (or maybe it is the sole cause). But its not quite a “take that!” to anyone who thinks that it is not lethal by itself. They can speculate on a variety of different things.


  2. I would guess that if he’d dropped 3 pills, his friends probably did too, no? In my experience (anecdote warning) it’s unusual to triple-drop at the beginning of a night, the lag-time involved with E means most people will wait an hour and see how they feel before modifying their dose. However, while “double dropping” was once a big deal, it isn’t worthy of mention these days in the UK, as concentrations of MDMA in E can be so low. Finally, Ecstasy seems to have vastly different affects on different people – some will be gurning all night on a single pill, others can sleep on a bellyful of the same pills. My impression here is that the poor guy had a sensitivity to MDMA – tip of the bell curve stuff, and unfortunate.


  3. Must write one hundred times: affect is a verb. Damn me and my stupid non-linear composing.


  4. Matthew Says:

    Yes, and peanuts are deadly too.
    I think Frank hit the nail on the head here.


  5. DrugMonkey Says:

    Yup, as I mention repeatedly on this blog, the incidence of MDMA-associated medical emergency and fatality is far too low to be a simple effect of MDMA alone. There are other contributors which we do not yet understand and those have to do with individual physiology.
    What I do with posts like these is knock down the arguments (and they are plentiful) that it “has” to be other obvious environmental or circumstantial contributors such as, e.g., non-MDMA tablet constituents, dancing, high ambient temperature, dehydration, etc and MDMA cannot possibly have a causal role.
    If you all are willing to abandon those, then we are making some serious progress on the topic…
    Now Frank, as far as the guy having a sensitivity, yes, by some ways of looking at it this is true. We’d need more information, however, to determine if there was evidence for a constitutive condition with this chap or possibly an acquired one- think, sensitization mechanisms. Me, I find it unlikely that these people who get into trouble with the reasonably hefty (compared to what might be seen as the starter dose) intake are taking Ecstasy for the very first time. Sometimes interesting human outcomes sound very much like what would be a stimulant sensitization regimen in animal models.


  6. Tom Says:

    As with many prior posts, I appreciate the breakdown. While nails did ask the interesting (to me) question of prior medical history to see if the MDMA complicated something else, I was profoundly struck in a prior entry of yours that medical clinical drug trials clearly define high mortality rates at what is a statistically very low number (well under 1% if I recall correctly). Therefore if MDMA is complicating so many possible medical issues to cause so many deaths, then it should be labeled the cause of death. Even if it was dancing, dehydration, etc, MDMA would still have been a major factor. I’ll agree there is some wonkiness to how the numbers are derived, but like cigarettes, there is no questioning the deleterious health effects leading to death. So, again, thanks for the breakdown so I can continue to pass this on to friends and family and hopefully get someone to think before they dose (so they don’t).
    On the other side of the fence, do you happen to know what the doses were back when MDMA was used for marriage therapy or in other legal ways back in the day? I am curious what the mg/kg rate actually tested in humans has ever been. Also, what, if any, effect would the alcohol have played? It’s a downer so shouldn’t that have actually lowered heart rates and temperature? Or would the combined pressures on the liver caused an even worse scaling of the non-linear aspects of the dosage of MDMA?
    Finally, I think we’ll have to agree to disagree about the legality etc. People will kill themselves one way or another no matter what we do. But the war on drugs causes too much incidental harm to otherwise innocent bystanders and today a large, large number come from the law enforcement side of the war. Further, by having such a confrontational standpoint, people do not seek help. I would much rather see something like what Portugal has done (not legality, but decriminalization) to de-escalate the law enforcement side and allow a return to the days when people considered the police helpful instead of fearing them.


  7. DrugMonkey Says:

    On the other side of the fence, do you happen to know what the doses were back when MDMA was used for marriage therapy or in other legal ways back in the day? I am curious what the mg/kg rate actually tested in humans has ever been.
    As I allude to in the post there are human laboratory studies in which humans are given doses of MDMA for purposes of investigating the pharmacokinetics. There have also been studies on the cognitive and subjective effects. Generally the doses are somewhere around 1-1.6 mg/kg but may go as high as 2 mg/kg. I’m unaware of lab studies going any higher. If you click the sidebar link for the MAPS article database and type some obvious search terms you can get started on those papers.
    The clinical picture from back in the day is not well known to me but I have some observations on the currently-running clinical trials that focus on the dosing.
    It’s a downer so shouldn’t that have actually lowered heart rates and temperature? Or would the combined pressures on the liver caused an even worse scaling of the non-linear aspects of the dosage of MDMA?
    Not necessarily, ditto and interesting question. Actually all are interesting questions. there are just starting to be some combined-drug-challenge stuff appearing in the animal literature but I’d have to take a look. perhaps I’ll blog some of those eventually.
    I think we’ll have to agree to disagree about the legality
    Since I don’t express any views in either support or opposition on the legal status of recreational drugs I doubt you know whether you agree or disagree with me. I believe firmly that the best possible starting point for policy discussion (and personal decisions for that matter) is to make sure we understand the available evidence as clearly as possible.


  8. Rogue Epidemiologist Says:

    Okay, I know the neurochem behind E, but how does it shred one’s kidneys?


  9. DrugMonkey Says:

    how does it shred one’s kidneys?
    This is not really my area but my understanding is that in the cases of death involving kidney failure we are talking about downstream effects of the seizure activity and rhabdomyolysis, not a direct effect of MDMA.


  10. Gray Gaffer Says:

    I know how you hate anecdotal info – not data – and I have no doubt the MDMA component was causal in this case. The anecdotal part is that I have observed consistently that taking alcohol with any other drug enables/amplifies all the negative results of both. A pleasant pothead get obnoxiously belligerent if alcohol is added to the mix, even if not normally a belligerent drunk. I have never known anybody who mixed their highs with alcohol to not become at the least unpleasant to be around. I even knew two who died from mixed intoxication. Couple that with the unfortunate but typical social meme that drugs must be consumed in overdose quantities if you want to have a good time and the surprise is there aren’t more fatalities. I guess when one is under that level of neurological disorganization you just don’t know how messed up you really are.
    Observation but not personal experience. I guess I was lucky enough to observe before I tried that I never tried. Certainly my few alcohol-only forays during College had most unpleasant outcomes that I never did that again.


  11. DrugMonkey Says:

    GG, true they could have considered this a little better and at least reported a blood alcohol level. I would tend to assume it was negligible or they would have made more of it but..who knows. There is a very small scientific literature looking at combined effects of MDMA and alcohol, one of interest is this one (similar to a cannabis/MDMA paper I blogged):

    Co-administration of ethanol with MDMA did not affect cardiovascular function compared to the MDMA alone condition, but attenuated the effects of MDMA on fluid retention and showed a trend for attenuation of MDMA-induced temperature increase. In conclusion, co-administration of ethanol and MDMA did not exacerbate physiologic effects compared to all other drug conditions, and moderated some effects of MDMA alone.


  12. Gray Gaffer Says:

    DM: of course, I have zero insight into the chemical and pathological effects internally, I can only observe behavior. That reference suggests the depressive effect of alcohol is predominant in the pathology, neh? Does it also reduce cogitation capabilities? The root for the behavioral changes I’ve seen seems to be a failure in evaluating and suppressing undesirable or inappropriate actions before their expression, coupled with loss of or reduced motor control. I don’t know the details inside their systems, but I would hazard a guess that things are not as co-ordinated as they should be. Like heartbeat response to activity demands.


  13. Thanks for posting this.
    Speaking only for myself, my support for the decriminalization of drugs is based on minimizing the harm caused by those drugs to both individual users, and society as a whole. My concern is that the benefits of the war on drugs (Reduced drug use and availability) are overshadowed by the consequences (use of state resources and revenue, human rights violations in prosecution and imprisonment of users, funding organized crime, lack of quality or dosage control).
    Understanding the real dangers posed by recreational drugs can help craft a policy that can minimize the number of deaths, disabilities, and psychological damage caused by recreational drug use, without creating the network of social ills caused by a militaristic zero-tolerance policy.


  14. JThompson Says:

    Most of the regular recreational drug users I’ve ever known weren’t the brightest bulbs in the box and it wouldn’t shock me in the least if they took far more than that.
    The line of ‘reasoning’ typically goes “If one pill will get me high, I bet five pills will get me totally smashed!”
    I suspect they’d also crush them up and snort them, as they claim it’s the best way to take pills. That or “plugging” them.
    Before I’m accused of being an anti-drug crusader, I’m in favor of the legalization of absolutely everything. I’d just prefer people know the actual facts of what they’re taking instead of what some random idiot in a club told them.


  15. MadScientist Says:

    I would give absolutely 0 credence to the claims of the dead dope’s buddies. I’d want any remaining pills to be assayed for dosage and the uniformity of dosage; I don’t even think the number of pills claimed by his buddies has the least relevance to any publication. Time of call, arrival of ambulance, arrival at hospital are all fairly reliable figures, but once again we have the time at which the victim collapsed to the time the call was made and I wouldn’t trust most eyewitness reports on that.
    To all those who deny the toxicity of the drug: please take it – a damn lot of it – the world can do without you.


  16. Andrew Dodds Says:

    MadScientist –
    Yes, MDMA is toxic, but given the sheer number of doses taken, plus the fact that these doses are illegal and unregulated, the number of deaths is tiny. So ‘Not very toxic’, or ‘Very slightly toxic’ would be more appropriate.
    If you are in the ‘no one should do anything fun if it involves the slightest risk’ camp, then I assume you are also against extreme sports, alcohol in practically any dose, etc, etc..


  17. Lab Lemming Says:

    I’ll come out against extreme sport when cave divers and mountain climbers start denying the danger inherent in their activities, and start blaming fatalities on dancing, or allergies, or lack of ventilation.


  18. Andrew Dodds Says:

    Most people I’m aware of who use drugs do acknowledge some danger; I think the analogy you are looking at (especially as regards caving or climbing) is that often lack of preparation is cited more than inherent danger.
    The problem is with the massive overplaying of the risks; people look at a peer group who take drugs with minimal side effects, then see hysterical propaganda that pretty much implies drugs=death, so tend to regard all warnings as false.


  19. E Says:

    I am an experienced MDMA user. I am a petite 5’4″ 110 lb. college-aged girl, and on many occasions have taken 400 mg (sometimes more) of pure MDMA in a night. I always smoke plenty of marijuana when I do MDMA, take bupropion (my normal medication, raises seizure threshold), have taken it with SSRIs, have taken it with cocaine, and as of late, prefer to take it with a hefty dose of the anti-convulsant gabapentin to lower the seizure threshold. I drink plenty of fluids and do not dance, however, sometimes I spend hours in a hot bath. The worst that has happened to me was some lingering depression a couple weeks after using.
    I do not, however, consume alcohol with MDMA (or ever)…the case said that this patient also consumed alcohol, and while you emphasized that no other party drugs were found in his blood, you didn’t talk about the interaction with alcohol – don’t you think this is significant? It wasn’t just MDMA, it was MDMA and alcohol, a lethal drug. A bad combo, surely.
    Also, I wonder if this was his first time or if someone like me could all of a sudden have a bad reaction to MDMA after using it safely many times.


  20. DrugMonkey Says:

    Fascinating, E. The fact that you manage to survive this is, of course, not particularly informative. As I say repeatedly, most people don’t get into trouble. What I don’t say that often is that even people who do some seemingly really stupid mixing of drugs survive. Sure.
    What on Earth persuades you that alcohol is somehow worse than what you are doing? There’s minimal street evidence, given that probably more MDMA is taken in the context of alcohol exposure than any other single compound. There’s minimal lab evidence, I cite something above in this thread. And there is little in the way of pharmacological rationale to suggest that alcohol is specifically a problem.
    In the Case, sure, another glaring problem is the failure to report exactly how much the guy was supposed to have consumed and a blood alcohol level upon arrival at the ED. Nothing is perfect.
    But again, my continued point on this issue is this. Why, o, why when you look at all of the case reports of medical emergency and death is the single most consistent factor the presence of MDMA in the body? Why is the constellation of symptoms amazingly consistent across the cases in which different drugs and environmental circumstances apply? Why are those symptoms consistent with what happens in animal models when one knows that the only drug was MDMA, what the dose was and what the environmental factors were?
    My point is that you have to go to remarkable evaluative gymnastics to avoid admitting that MDMA causes the symptoms.


  21. jj Says:

    pleasant pothead get obnoxiously belligerent if alcohol is added to the mix, even if not normally a belligerent drunk

    I’ll have to disagree with you on this one. I’ve seen the exact opposite, many many times. Guy is drunk and obnoxious, takes a toke, and they calm right on down. Now this isn’t always the case, if the guy is black-out-I-don’t-give-a-shit-drunk, the only way to get that guy shut up is wait until he passes out (then chief ’em)


  22. going anon Says:

    I’ve done E exactly once. Anecdote, not data, of course, but here it is.
    My wife and I were struggling, some big issues between us, and so fearful and untrusting around the issues that we were unable to feel and trust our love for each other and to get to dealing with the issues. We took E together, and spent an evening just doing that with each other.
    The drug was remarkable – it didn’t fix the problems, of course. But it did allow us to open up what we felt for each other, to feel the love and fear and pain and most important, be able to express it from a completely open and loving place. It has put is back into a place of being able to work on our problems while knowing and being able to express and receive our love for each other. Pretty amazing.
    We were told by the friend who gave it to us that the dose was 100 mg/ tablet, but who knows how accurate that is. We each did one tablet to start, and then a half tablet 2 hours later. We also took B6 and 5-HTP before and just after, and then through the next two days. We reminded each other throughout to drink water, and to pee as necessary – because it was easy to forget to do either. I was buzzed and very awake, but easily disoriented, dizzy when I moved, and slightly hallucinatory at this dose.
    The most obvious thing I noticed was that the next day, I felt like I was running at half speed, and a little sad, but still full of love. The effect lasted a little bit through the next day as well.
    I get why some people want to do a lot of this, and often. It’s an amazing feeling experience, and a lot of people do a lot of ecstacy in a lot of places in front of a lot of people with none of them seeing any problems. I’ve got friends who go to Burning Man each year, and there are thousands of people wandering around the desert eating ecstacy for days straight.
    Your analysis is pretty convincing that there is a rare, really dangerous, occasionally fatal constellation of symptoms in some people. It would be really good to know how rare.It would be even better to get some handle on why – is it random, is it sensitization is it some constellation.
    Because I’d’ really like to do this again, in the right setting, with my wife or with one or two other people – but I’d also really like to know what’s going on with these cases. Or at least, what the probability of serious outcome is.


  23. Aj Says:

    3+ pills in a night is not unusual in an of itself; but (and it’s not really clear from the report) if this guy did drop three pills at once – that is not something I wouldn’t expect from a (fellow) recreational user.
    Speculating, I’d wonder if this person either (ab)used MDMA a lot, or if they had never done it before (hey it’s not working – I know I’ll take some more).


  24. Elyse Says:

    Whenever I read about anyone dying from MDMA, it seems (though one can’t be sure) that it was the person’s first time trying it, and for some reason their body just wouldn’t tolerate it. And the risk is very low, like someone said, like the risk of someone dying from eating peanuts!
    I didn’t say alcohol is worse than what I used to do, but it’s certainly less safe than MDMA alone, in terms of lethality, addiction potential, and potential to cause violent/unsafe behavior.
    Yes, drugs can be dangerous. Yes, there is a risk. But there is a risk in everything we do, whether it’s driving a car, eating a bacon cheeseburger, or popping 3 pills of XTC.
    Your writing is quite sensationalist…why don’t you provide some statistics so people can be informed on the (un)safety of MDMA, not just frightened. It’s stuff like this that fuels the Drug War zealots, whether you state a political position or not.


  25. DrugMonkey Says:

    Whenever I read about anyone dying from MDMA, it seems (though one can’t be sure) that it was the person’s first time trying it
    This is frequently the initial suggestion in media reports. Often enough as the story develops this turns out to be not true. The recent Australian case I blogged about was an example of where the initial reports took a tone of “oh, poor little innocent waif led astray by evul boyfriend and/or ‘those dealers'”. Later it turned out the mom knew she had been injecting ‘amphetamines’ iv in the past… So I view such claims with suspicion. The fact that this guy took three tablets and the Edmonton group of youngsters also were taking multiple tablets…well, I tend to bet against it being the first time ever. Could be wrong and we’ll never know for sure in many cases…up to everyone to decide for herself what makes logical sense in such cases.
    it’s certainly less safe than MDMA alone, in terms of lethality, addiction potential, and potential to cause violent/unsafe behavior
    as a general point, I fail to comprehend what comparative risk analysis tells us about whether there is or is not risk associated with MDMA. You bring this up as if it does so…how?
    lethality- I’d dispute that anyway. On what basis? How are you going to equate starter dose, average recreational dose and wackaloon extremes?
    addiction potential- we’re probably in agreement on this one.
    Your writing is quite sensationalist
    Really? Please explain how so.
    why don’t you provide some statistics so people can be informed on the (un)safety of MDMA, not just frightened.
    What “statistics” are you after? I blog about papers and findings, i.e., data. I direct people to the same sources I use and they are free to do their own legwork to come to an understanding of the health effects of MDMA. Luckily, as I point out repeatedly there is an advocacy group that (probably somewhat illegally) makes a very large amount of the primary literature available at a click (or three). Heck, I even put that link in our sidebar.
    If you think you have a better read on the literature and other available evidence than I do…by all means bring it. What I fail to have any patience for are people who insist that all of the available information is bogus, bullshit (hi isabel), biases or flawed simply because they don’t like the conclusions. or, worse, can’t even be bothered to read any papers at all.


  26. Klem Says:

    Some statistics, comments, and recommendations from a recent UK government-sponsored advisory report (emphasis mine):
    MDMA (‘ecstasy’): a review of its harms and classification under the Misuse of Drugs Act 1971 (Advisory Council on the Misuse of Drugs, Feb 2009)
    (4.17) It is particularly difficult to estimate the risk of taking any given MDMA dose due to the lack of information on the average level of consumption and dose-response relationship between tablet intake and increased risk of overdose, as well as uncertainty surrounding the number of ‘ecstasy’ users. For example, in 1995/96 a 25-fold range was estimated for ‘ecstasy’-related death among 15 to 24-year-olds of between one in 2,000 and one in 50,000 users (Gore, 1999). Equally, if we assume that there are 1.2 million adult ‘ecstasy’ users and that approximately 60 million tablets are consumed annually (Home Office, 2006a) then the risk of death per person and per tablet is: one in 39,000 and one in 1.8 million respectively, if all deaths mentioning ‘ecstasy’ are included; and one in 76,000 and one in 3.5 million respectively, if only those deaths solely mentioning ‘ecstasy’ are included.
    (4.19) A study of all drug-related deaths in Scotland during the 1990s found that every death where MDMA was involved was reported in the newspapers (Forsyth, 2001). Deaths due to other drugs were much less likely to be reported; for example, only one in 50 were reported for diazepam and for amphetamine it was one in three. The skewed reporting of ‘ecstasy’ against the landscape of other drug-related harms and deaths is a real phenomenon and may heavily impact on public perception.
    (10.2) Use of MDMA is undoubtedly harmful. High doses may lead to death: by direct toxicity, in situations of hyperthermia/dehydration, excessive water intake, or for other reasons. However, fatalities are relatively low given its widespread use, and are substantially lower than those due to some other Class A drugs, particularly heroin and cocaine. Although it is no substitute for abstinence, the risks can be minimised by following advice such as drinking appropriate amounts of water (see Annex E).
    (11.9) Recommendation 6: MDMA should be re-classified as a Class B drug.
    (11.15) Recommendation 12: Consideration should be given to developing a national scheme for the purpose of testing MDMA with a view to providing harm reduction advice and developing monitoring data.
    (11.16) Recommendation 13: Research into the medicinal use of MDMA should not be disadvantaged by the legislation and the position of MDMA in Schedule 1 of the Misuse of Drugs Regulations 2001.


  27. Klem Says:

    More statistics:
    The content of black market ecstasy tablets varies quite a bit. In the Netherlands in 2006: minimum 0mg MDMA, maximum 173 mg, average 74.1 mg. This is confusing and dangerous for the public.
    Consider alcohol, a blood alcohol concentration of 0.08% is the legal driving limit in the US and UK, but a blood alcohol concentration of 0.40% is often fatal. That’s only a 5-fold difference between threshold and overdose, possibly only a 2-fold difference between vomiting and death.


  28. Elyse Says:

    My boyfriend and friend took xtc last night and they tried to peer pressure me into it but I said no….just munched my pot brownie and popped some benzos and gabapentin…Because I started an SNRI I decided it wouldn’t be good to make my body into a walking chem lab….I thought of your article!
    I meant the tone of your writing is sensationalist…seems like you’re trying to show that MDMA is a really dangerous drug from single cases, when the reality is that ecstasy is a rather safe drug. (anecdotal)My boyfriend took 700mg of MDMA in a night and didn’t know where he was for a little while, but nothing bad happened at all. It’s not like if you take three pills you will die – it is a very rare occurrence.
    As someone commented earlier…when kids see literature
    telling them that drugs=death all the time, but observe otherwise in their peer groups, they tend to distrust any anti-drug education.


  29. Elyse Says:

    Thanks Klem, exactly the info that is needed to accompany this kind of article. Thank you for that contribution.


  30. DrugMonkey Says:

    And how did that Home Report turn out politically, Klem?
    As I’ve said on more than one occasion, ranting about how evul are nicotine and alcohol (and horseback riding) in comparison with MDMA is almost as irrelevant politically as it is scientifically.
    Consider alcohol, a blood alcohol concentration of 0.08% is the legal driving limit in the US and UK, but a blood alcohol concentration of 0.40% is often fatal. That’s only a 5-fold difference between threshold and overdose, possibly only a 2-fold difference between vomiting and death.
    So what is the “threshold” for MDMA? Because my threshold for alcohol is one drink, maybe another one 40 min or an hour later. I’m not hitting 0.08 BAC, I assure you. Given the PK data we’ve been discussing the difference between usual practices and medical emergency/death could very well be only a 5 fold difference. You can also ask how likely it is that someone who is not a seriously tolerant alcoholic gets enough alcohol on board to hit 0.40 BAC versus dropping three Ecstasy tabs. In the context of all use episodes of each substance, of course. And finally, the point about vomiting is apropo. Are you taking this as the danger sign? Because from what I can tell, the danger sign for MDMA is “found unresponsive” or “collapsed” or “seizure”. And this seems to be at 100% of the dose that leads to serious medical emergency and fatality in some cases.
    I’m happy to be informed though- is there a scenario where co-users of MDMA start some sort of harm-reduction and care of their buddies? Akin to telling obviously drunk dude to stop drinking, helping to not aspirate vomit, etc?
    seems like you’re trying to show that MDMA is a really dangerous drug from single cases, when the reality is that ecstasy is a rather safe drug.
    I suggest this is more about your knee jerk perceptions than it is about what I write. “dangerous” and “safe” are interpretations and comparisons. I don’t make those for you. I explore the data and facts and particularly I am fond of drilling down on the evidence about whether or not MDMA is a causal agent in medical emergency, fatality and, once in awhile, other nonfatal but clearly adverse outcomes (such as lasting affective disorder).
    when kids see literature
    telling them that drugs=death all the time, but observe otherwise in their peer groups, they tend to distrust any anti-drug education.

    gee, really?
    The flip side of this problem is that if they listen to people like you who insist that MDMA itself is “safe” is not a problem and could not possibly be the cause of medical emergency and fatality they do really stupid things like take ever increasing doses. They might even ignore warning signs about their own idiosyncratic responses to MDMA (this is speculation). Eventually some of them die (not speculation).
    Perhaps you think this is worth it in the pursuit of whatever agenda you may have (legalization, may I assume?). Even if harm-reduction were your goal, if kids “trust” information that is wrong I fail to see how we are better off.


  31. James Says:

    Terms specialist have used to describe mdma
    ‘Taking ecstasy is no more dangerous than riding a horse’
    ‘killer drug E is actually safer than aspirin or alcohol’
    This is how ‘safe’ MDMA


  32. Klem Says:

    Elyse, I’m glad you found my comments helpful. Please take care of your health, it sounds like you and your friends are doing a lot of drugs. You might want to discuss this with a medical doctor.
    Some more links about MDMA risks:
    MAPS MDMA literature review – submitted to the FDA, etc for clinical trial approval.
    MDMA User’s Guide – Anonymous internet advice, follow at your own risk.
    Ask Dr. Shulgin – MDMA (Ecstasy) Tolerance?


  33. Klem Says:

    If you went to a college drinking party and switched the vodka (40% ethanol) for everclear (95% ethanol), someone could easily die from alcohol overdose.
    In the same way it is dangerous that “ecstasy” pills have such a wide range of contents and dosages.
    In this case report, as noted by DM, the patient had a blood MDMA level over 5x that typically seen in MDMA clinical trials, and he had an extremely high body temperature of 42.5 °C (that’s 108.5°F!!).
    High temperature (hyperthermia) is common in MDMA-related medical emergencies (but not in MDMA clinical trials). Note, rats and other animals seem more susceptible to MDMA-related hyperthermia than humans, and most harms from high doses of MDMA in lab animals can be prevented by maintaining normal body temperature (Baumann 2007 [PDF]).
    Basic safety practices at dance clubs, aimed at preventing hyperthermia, include ventilation, drinking water, and “chill-out” areas. DM, if you want to know more about dance parties, try asking a harm-reduction organization (like Safety First or DanceSafe).


  34. Klem Says:

    Some more comments and links on ecstasy-related fatalities…
    Rogers et al. 2009: This is a recent systematic review of harms from illicit ecstasy use, including fatality case reports, prepared for the UK ACMD report on MDMA. Conclusion, “Ecstasy is associated with a range of acute harms but appears to be a rare cause of death in isolation.”
    Note, many (most?) of the harms from ecstasy are directly attributable to prohibition (e.g. uncertainty about dose and purity, lack of safety education (abstience-only), fear of asking for medical help, police/prison).
    Before MDMA was criminalized in the US in 1985/1986 there were few reports of health problems – perhaps in part because MDMA pills had standardized doses.
    Consider the official findings and decision of a DEA Administrative Law Judge after 18 months of court testimony (May 22 1986): There were a total of two “questionable” reports of MDMA-related deaths (Fact 85), and from 1972 to Sept 1983 the DAWN emergency room survey noted only 8 MDMA-related ER visits out of roughly 2 million mentions of other drugs (Facts 83,84).
    The conclusion from the DEA judge: “We have already seen that it cannot be placed in Schedule I, because it does have ‘a currently accepted medical use in treatment’ and it does not ‘lack… accepted safety for use… under medical supervision.‘”… “The administrative law judge concludes that the evidence of record requires MDMA to be placed in Schedule III.
    The entire process around MDMA becoming a Schedule I drug (despite the above decision) is quite fascinating. More links:
    The Politics of Medicine: the Scheduling of MDMA – Quick summary.
    Archive of related documents – From MAPS.
    Letter from Hoffman-La Roche Pharmaceuticals [PDF] – Argues that allowing the DEA to place MDMA in Schedule I without evidence would “negatively affect” all medical research because of increased time, paperwork and administrative delays.


  35. DrugMonkey Says:

    switched the vodka (40% ethanol) for everclear (95% ethanol), someone could easily die from alcohol overdose.
    “could” yes. Question is, how often does stuff like this happen in the context of all alcohol use episodes, versus similar heroic-dosing practices with MDMA in the context of all MDMA use episodes? You want to do relative risk in a comment, fine, but you have to be reasonable, not just dream up rosy scenarios for one and the worst case scenario for the other. especially when the general audience is so much more familiar with the scope of alcohol drinking practices. your point about unknown/ranging doses is absurd on two counts, first that most alcohol use is with at least approximately known concentrations and amounts. second, most drinkers have *some* ability to ball park the amount / concentration from sensory cues and subjective response. You have to gate on the highly unusual case of extremely rapid consumption of large amounts before your “swap grain neutral spirits for vodka” scenario gets very similar to the unknown content situation with *all* street Ecstasy.
    he had an extremely high body temperature of 42.5 °C (that’s 108.5°F!!).
    right…..and your point is? This is not a warning sign since people are not very good at objectively determining their body temp and the signs of this are not going to be as readily detected by friends. Furthermore, it quite likely is the case that this highly common finding in medical emergency and death may be subsequent to seizure-like activity generating muscular contraction and therefore heat. The theories (and swine model) about malignant hyperthermia syndrome are useful to review here.
    rats and other animals seem more susceptible to MDMA-related hyperthermia than humans, and most harms from high doses of MDMA in lab animals can be prevented by maintaining normal body temperature
    False and false. The venerable Malberg and Seiden 98 paper shows that even at the 24-26 deg C ambient conditions where rat body temperature did not diverge from normal they still observed evidence of neurotox in some brain regions. Bowyer et al 03 reported no change in body temp in monkeys, but the whopping reductions in brain markers of serotonin function were observed (reported in the prior Frederick et al 98). At best you can say that there is *some* evidence that maintaining stable body temp is somewhat protective for some outcomes. Beyond that we really don’t know. So given that the evidence is mixed (and quite scanty on either side when it comes down to it), going around insisting that people are “safe” if they don’t get elevated body temp is just not supported.
    I’d like to know what your evidence is for the first statement. The kinds of disruption of body temp that is seen in the ED is just not done experimentally with humans and not too much in rodents or other animals models either. Referring to the doses in the Malberg and Seiden 98 and the resulting mean effects on body temp…are you suggesting that humans dosed with those 20-40 mg/kg doses (or would you suggest some sort of dose scaling :-)) are not going to have body temp changes? unknown, I’ll admit but I know which way I’m betting.
    With the more tractable types of body temperature responses (within say a deg or two C) that are studied in the lab..evidence is mixed within both humans and animal studies. The most technologically refined and temp-dedicated human study reported temp disruptions at 2 mg/kg. Some other lab studies report no change but use less than optimal temp monitoring. The swine studies are minimal but one shows elevation of temp after 1 mg/kg. The nonhuman primate folks are fighting this out with some showing body temp changes at the 1-2 mg/kg range and some not. You’d have to go toe to toe with opposing findings over methodology in both human and animal studies.
    Rodents, of course, are a different matter. You do realize that the mech of cooling under normal conditions is totally different, right? And that the thermoregulatory neutral range is very much smaller? So it is a vastly more complicated matter to translate between rats/mice and humans when it comes to this stuff. Not impossible, just not as simplistic as it would be with larger mammals and especially Old World primates. Get both rats and humans in approximately the same parts of the thermoneutral range and they start looking more similar. Then, of course, you get right back to fighting over dose-equivalence to ask which is more sensitive to temperature disruption.
    Basic safety practices at dance clubs, aimed at preventing hyperthermia, include ventilation, drinking water, and “chill-out” areas.
    Sure but these have nothing to do with managing acute responses in an individual user do they? That was the question in #30 responding to you point about the vomit/death ratio with alcohol exposure. Unless you are telling me that there are frequently pre-morbid signs of trouble, the friends tell the person to use those reduction practices, this happens frequently, otherwise those people would proceed to medical emergency in high numbers and therefore my estimation of the warning sign / emergency ratio is way off.
    The contrasting points are the acute situational harm recognition and reduction practices one deploys with friends who are into the danger zone with alcohol.
    Final note- the drinking water advice is of unknown protective value given that the loss of sweating is unlikely to be due to dehydration of the body. Also, since hyponatremia is a frequent observation in fatal cases and excess water consumption may interact with a pharmacological effect of MDMA to disrupt anti-diuretic hormone function…well that may be one of those bits of advice from “trusted sources” that isn’t so good.


  36. Zac Pearsall Says:

    MDMA is most defiantly a deadly drugs. No questions asked about that. I was addicted to MDMA for a long period of time. And resulting from the addiction I now have many health issues.


  37. ourcellardoor Says:

    XTC is unpredictable and you never know what it is cut with. It can be a very harmful drug if you don’t know what you’re doing…which it sounds like what happened to this poor fella. Very interesting points brought up, but bottom line no one will ever know for sure what killed this young chap except for the coroner and the chap’s family, so purely speculating does no one any good. Moral of the story=Drop acid not bunk x pills.


  38. DrugMonkey Says:

    no one will ever know for sure what killed this young chap except for the coroner and the chap’s family, so purely speculating does no one any good
    I beg to differ. The coroner said quite clearly what the cause of death was in this particular case.
    More generally, I go to some length in my discussions of Ecstasy-related fatalities to point out that while there may be a number of possibilities when it comes to the precise causal mechanism of death they do not come with the same probability. It is a classic anti-science technique to throw up the rhetorical hands and pretend that all outcomes are equally plausible. They are not.


  39. Anonymous Says:

    Those 3 pills that that 19 year old died from could have been laced(or mixed with) with a dangerous chemical, like bleach or sometimes even chlorine or the chemist could have fucked up on a batch. The reason why volatile chemicals like bleach are put into pills is because the drug dealer doesn’t care and he just wants to make money or where they are getting/making it are inexperienced chemists.The use of these chemicals are to basically form the pill, different pills have different mixtures of shit safe ones usually contain a very minimal amount of mdma(better/more expensive pills have more mdma in each pill). The fillers (stuff that sticks the mdma into pill form) of safe pills have a range from caffeine, mda, sometimes vitamins are used, rare pills that contain ajax cleaner (if you can handle your hallucinogens it is generally safe if you are not stupid- increases heart rate more as well as the chance of death increasing),ritalin, acid, or meth which isn’t good for you are in some pills but it definetely won’t kill you. Some people’s bodies cannot handle as much drugs in their body than others which is also a huge factor. The way to avoid getting bad pills or to be safe is to go to a person who u trust and they actually know what is in their pills (if they don’t, don’t risk it), slowly work on your tolerance by increasing your dosage by a little bit each time, to see if you can handle the drug start with a quarter pill if it doesn’t do anything in about 40 minutes increase the amount each time in quarter intervals, try to find what your body can handle, and stay hydrated. In Conclusion: I have done 15 pills all in one night a couple of years ago and I’m still here typing, I guarantee that the pills that the 19 year old took had dangerous chemicals in them or his body could not handle them. As I said get it from a trusted person and know what you are getting. Also pure mdma is a lot safer if you could attain it because it isn’t cut with anything but mdma (expensive though)and you know what you are getting if you know what pure mdma looks like (check the internet).


  40. DrugMonkey Says:

    I guarantee that the pills that the 19 year old took had dangerous chemicals in them
    Well, yeah. totally circular. MDMA being a chemical and being dangerous and all….
    but with respect to “bleach”, again, I ask anyone of your logic to explain why the symptoms are consistent with those where MDMA is confirmed?
    or his body could not handle them.
    Right. Again, totally circular argument. It does nothing to exclude a causal role of MDMA itself.
    and stay hydrated
    sigh. It. Is. NOT. About. “Dehydration”! Dehydration is bad, yes. But this not what is reported in the cases of medical emergency and death. It is far more common that individuals are hyponatremic, i.e., over hydrated. In part because of an effect of MDMA that releases vasopressin and causes the kidneys to retain water. Perhaps (this has not been specifically tested AFAIK) because of an interaction with recommendations to “stay hydrated” from well meaning but scientifically uninformed peers.


  41. PalMD Says:

    There is no end to denialism when it comes to drugs, legal and otherwise. Folks, it’s not a moral judgment.


  42. […] 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 […]


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