Repost: MDMA Case Reports

A recent post of Zuska's discusses the pejorative use of "anecdote" to dismiss personal accounts of gender bias. The generic argument will be well familiar to many scientists who are used to sneering at sources of insight that are limited to individual data points. I concur in many cases however I also value anecdotal observations much in the way that commenter Sanguinity identified a number of useful applications of the anecdote in science including the following:

- suggest a new direction for query/research.
...
In that last case, the anecdote is a potential source for a vast new amount of information, but only if you don't dismiss it out of hand as "just an anecdote."

This reminded me of a post I wrote previously on the value of anecdotal case reports describing MDMA-related fatality and medical emergency.


The singular of data is "anecdote".
We all know this hoary old scientific snark. Pure Pedantry ponders the utility of Case Reports following a discussion of same at The Scientist.
The Pure Pedantry Ponder identifies "rare neurological cases" as a primary validation for the Case Study, but the contribution goes way beyond this. Let's take YHN's favorite example, drug abuse science and MDMA in particular.


To summarize, when MDMA started coming to the attention of scientists in, oh, the early 80s the thought was "hmm, looks like an amphetamine, let's study it like an amphetamine". This is where the "neurotoxicity", "locomotor activity" and "drug discrimination" stuff came in. Bouncing forward, we can see the emergence of thermoregulation, ambient temperature, vasopressin as a relatively late interest. Where did this come from? The case reports of medical emergency and death. Which, while rare, are not of the singularly "rare neurological case" variety with which we are familiar from neurology101. Still, the MDMA Cases play a key role, I submit. Why?
The fact is, animal lab type drug abuse researchers get very far away from their subject matter in some cases. Understandably so. First, there is no guarantee they had much familiarity with the druggies in college in the first place and MDMA/Ecstasy likely postdated them. "Them" being the PIs who are sadly as of this writing very much not likely to be young enough to have been in college in the mid eighties. So they know all about the cocaine and the weed and the LSD but emerging drugs? Not so much. Their undergrads and even grad students could tell 'em but how often do the PIs listen? Then there's just the general trend that even by the post-doc days scientist are just moving away from the youth culture, don't you know? Finally, while scientists got to do a bit of tasting back in the 70s, those days are long gone.
So instead we have a bunch of out-of-touch old fogies who think MDMA is just another amphetamine, should be studied like just another amphetamine and can't see why there are different approaches needed. Case reports provide needed stimulus to new experimental approaches, needed support for the arguments that other things need to be investigated about this drug, etc. Don't believe it? Then why did NIDA have to come out with a Program Announcement in 2004 (yes, 2004!) saying in essence, "For God's sake will you please submit some proposals other than the mechanisms of so-called serotonin neurotoxicity?". [Current R01 and R21 versions of the PA].
Time will tell but the field may have missed the boat a bit by not paying enough attention to MDMA related Case Reports. Giorgi et al have reported a potential sensitization of seizure threshold following a particular regimen of MDMA in mice. Experimentally, this is relatively novel stuff. But reading the case reports with the hindsight, there are clear indications of seizure as possibly being a primary cause of medical emergency (it has been generally been assumed to be thermogenic seizure subsequent to the high body temperature). Time, and some additional experimentation, will tell if this was a missed foreshadowing from the case reports or not...
So yeah, I find a big role for case reports. Not just for the unique cases but also to lay down a record of some interesting phenomena that might bear looking into in a systematic way.



Another comment responding to Zuska's observations is also particular apt for the interpretation of MDMA case reports and well-controlled animal studies. This is so brilliant:

If it's 'science and stats', then deniers argue that it's just averages and impersonal statistics, and it doesn't speak to the experiences of an actual individual woman, who are presumably doing *just fine*. If it's anecdotes, then deniers argue it's not based in hard facts and on real distributions, and that that it doesn't speak to the experiences of an actual individual woman, who are presumably doing *just fine*. And thus we achieve a sort of Schroedinger's paradox for women's issues in science, in which any proof that women are having a shitty time is simultaneously neither quantitative nor anectodal enough. It's beyond 'moving goalposts', it's like a quantum singularity generating goalpost probabilities so indeterminate as to be inachievable.

This is exactly the way the MDMA advocates dismiss the anecdotal evidence on the one hand ("exceptionally rare congenital effect, musta' been the heat, dehydration, overdose, etc, etc") while denying the experimental science on the other ("animals are not humans, massive overdose, oral administration, etc").

9 responses so far

  • DuWayne says:

    So instead we have a bunch of out-of-touch old fogies who think MDMA is just another amphetamine, should be studied like just another amphetamine and can't see why there are different approaches needed.
    Wow, this is stunning to me. I mean I can understand it to a certain extent, anecdotes are not all that useful in most research situations. But how exactly does someone who studies drugs and/or drug abuse and addiction, ignore mountains of anecdotes that lend themselves to the understanding that MDMA isn't just another amphetamine?
    Because I never had the opportunity to try MDMA that I was comfortable with, I cannot say entirely what it is like. It was my understanding early on, that MDMA is a tricky bugger to synthesize so I didn't want to try it unless I knew the chemist who made it and had confidence in their abilities. But I have observed many, many people on it over the years, including those who have done it in combination with something else besides marijuana (cannabis being a very common as a mixer with many drugs). I have also spent a fair amount of time around tweakers (though I have a low tolerance for speed freaks).
    There is just no comparison between most amphetamines and MDMA.
    I would also note that another factor that seams to me would be important, is that MDMA is rarely sold pure, with inert fillers. Whether it's ketamine, LSD, heroin, cocaine or something more obscure, it's almost never just MDMA. I can see this really being a complication for research, because it really works out as being several different drugs. It's probably complicated even more by the fact that mistakes are often made in synthesis, which sometimes make their way into directions that that chemist posts somewhere and that version of the drug can become relatively common.
    Oy, it's not a wonder I never tried the stuff. There are just way too many variables to be concerned about.

  • DuWayne says:

    I should also note that MDMA is largely responsible for my position on across the board legalization of drugs. I don't know of any drug that is more prone to inconsistency in manufacture and admixing. The problem with that being, the guy who's selling it to you, probably has no idea what it might have been mixed with and if it was made properly. I would suspect that this fact is largely responsible for MDMA related deaths, though I understand that it can be fatal in and of itself.

  • DrugMonkey says:

    Wow, this is stunning to me. I mean I can understand it to a certain extent, anecdotes are not all that useful in most research situations. But how exactly does someone who studies drugs and/or drug abuse and addiction, ignore mountains of anecdotes that lend themselves to the understanding that MDMA isn't just another amphetamine?... There is just no comparison between most amphetamines and MDMA.
    Okay, let me do a 180 on you here and point out that there are very good reasons for this state of affairs. Which of course I didn't really address in the post because I was making a narrow point.
    Chemically, meaning structurally, MDMA is very similar to other amphetamine class molecules. There is a consistent backbone structural motif from which a few dangly bits hang off. The dangly bits differ, thus creating different amphetamines. I'll try to round up an easily available version of the usual figure comparing these structures.
    Pharmacologically, MDMA fits in very well with the amphetamines in that they all tend to share affinity and reuptake blockade effects at dopaminergic, serotonergic and noradrenergic (collectively monoamine) transporters. Transporters are the "reuptake" mechanism of Selective Serotonin Reuptake Inhibitor (SSRI; Prozac/fluoxetine) fame; "Selective" being a critical (albeit relative) term because many drugs hit all three of the monoamine transporters. They also tend to facilitate the release of the monoamines so combined with blocking the reuptake mechanism, this potentiates and sustains the chemical signal.
    The newer Verrico et al 2007 and the classic Battaglia, 1989 are available from MAPS' database for the pharmacologists in the crowd. The difference between structurally related amphetamine-type compounds as far as the pharmacologist is concerned lies in a differing ability to affect the function of these three different monoamines (of course there are some primary effects on other neurochemical systems and downstream effects and metabolism effects that I am ignoring here, primary pharmacology is plenty complicated and suffices for the point).
    From a behavioral pharmacology position, well, the first thing to do is to dose some rats. And what do you know. The amphetamines all look very similar in rats. Not exactly the same and of course the more subtle your assay, differences can emerge. Nevertheless, MDMA in a rat looks similar to Meth or MDA...to a first approximation. It is a bit hard to appreciate with hindsight but when scientists were getting into this in the seventies and into the eighties, well, MDMA did look very much like an amphetamine. So there were good reasons to study it as if it were an amphetamine.
    At that point, typical scientific inertia took over. Scientists are, as a population, frequently taking "what works" experimentally and geeking out to the Nth degree within a narrowly described model. Less good, or so I submit, in messing around with hard-to-grapple problems.
    Like the issue of the threshold for lasting damage / toxicity. Like the issue of species differences- perhaps the rat is not a particularly good model for all things. For example the Verrico paper I link to is important precisely because it generates data from human monoamine transporters (expressed artificially in cells, of course) instead of only rodent ones (as with the classic Battaglia paper). The Fantegrossi, Taffe, Nader and (I think) Ferris/Myer groups have been identifying ways in which monkey responses to MDMA may differ considerably from the rodent and look in some ways less like an amphetamine. Even in rat, some interesting drug-discrimination work from the Glennon lab gets into some very simple procedural differences leading to a rat telling different stories about what a drug "feels like", depending on which drug you train it with.
    In overview, I defend and understand the starting point for scientists of examining MDMA as if it was just another amphetamine. I critique, however, the monomaniacal fixation and a sort of conservatism in approach sustained for far too long. as I said in the original post, more recently, NIDA has been soliciting a broader diversity of studies. Some of the most recent studies have been, to my mind, refreshingly diverse.

  • MattXIV says:

    First, there is no guarantee they had much familiarity with the druggies in college in the first place and MDMA/Ecstasy likely postdated them. "Them" being the PIs who are sadly as of this writing very much not likely to be young enough to have been in college in the mid eighties. So they know all about the cocaine and the weed and the LSD but emerging drugs? Not so much. Their undergrads and even grad students could tell 'em but how often do the PIs listen? Then there's just the general trend that even by the post-doc days scientist are just moving away from the youth culture, don't you know? Finally, while scientists got to do a bit of tasting back in the 70s, those days are long gone.

    This doesn't follow from the facts. You'd have to have hung around a hell of a lot of raves to finally see someone have a serious adverse reaction to an ecstasy dose and the same issues with impurities and concurrent use of other substances that make interpreting the case reports difficult means it would be anybody's guess what actually caused it.

    To summarize, when MDMA started coming to the attention of scientists in, oh, the early 80s the thought was "hmm, looks like an amphetamine, let's study it like an amphetamine".

    There isn't a good structural reason for barking up the amphetamine tree either. There are lots of other phenethylamines out there that have just as much in common with MDMA as it does with amphetamines. Indeed, a good clue that impact on seizure thresholds may be worth looking into for MDMA is that it has a electronegative R3 substitution, (-O-CH2-O-and back to the 4 in MDMA, -Cl in buproprion). Given the wide variety of physiological effects of phenethylamines and the fact that many of these affects are impacted by R2 through R5 substitutions, and ampehtamine doesn't have any R2 through R5 substitutions, it doesn't take a lot of imagination to consider that it and MDMA may not have all that much in common. The main thing they do have in common relative to other phenethylamines is their CH3- Ralpha, but methylphenidate doesn't have the Ralpha and it seems to be closer to amphetamine.
    One clue as to why the comparison to amphetamine and it's RN-substituted friend may have been emphasized is that they have by far the most well-known negative side effects of the phenethylamine family. Could it be that the funding priorities emphasized finding MDMA to be as dangerous as possible in service of supporting it's regulatory status? No, perish such thoughts suitable solely for those dirty hippie "advocates", for there is nothing to see here and we should all just move along.

  • DrugMonkey says:

    You'd have to have hung around a hell of a lot of raves to finally see someone have a serious adverse reaction to an ecstasy dose
    I was trying to make a much more general point here. Any specificity had to do more with the subjective effects, as in "Ahh, this may look kinda like an amphetamine but it sure as heck feels completely different". That may have put people onto different directions from the get go. Or not. Since it is a single historical blip, we can't really test it.
    and the same issues with impurities and concurrent use of other substances that make interpreting the case reports difficult means it would be anybody's guess what actually caused it.
    Righto. You do realize that this sort of situation is a clarion call for well-controlled research studies? Don't you? My point here is that an anecdote is a starting point or launching pad for new investigations. Not proof in and of itself. A generator of hypotheses rather than a test of hypotheses.
    Given the wide variety of physiological effects of phenethylamines and the fact that many of these affects are impacted by R2 through R5 substitutions, and ampehtamine doesn't have any R2 through R5 substitutions, it doesn't take a lot of imagination to consider that it and MDMA may not have all that much in common.
    Not being a chemist I'll beg off any strong statements as to what was obvious or not at what point in time to any given scientists. In some senses one might have to go back to Shulgin just before he first took some MDMA and ask "What do you predict this is going to feel like?".
    Could it be that the funding priorities emphasized finding MDMA to be as dangerous as possible in service of supporting it's regulatory status?
    As usual, this betrays a fundamental misunderstanding of the way scientists actually operate. As I've noted before, it is vastly more likely that the experimental literature is hugely dominated by toxic effects is because a lack of effect is uninteresting (in the sense that it doesn't lead anywhere) and difficult to prove (there are many ways to not get an effect). Furthermore, if you actually read the papers you will understand that there are no-effect studies or findings. They are just typically combined with positive effect findings. Note that these no-effect results were generated by NIDA (and FDA) funded scientists who continued to get funded just fine.
    True, NIDA is not in the business of reporting beneficial effects of recreational drugs. Actually all of NIH is prohibited from promoting recreational drug use by Congressional mandate although there is a big window exception for potential medically-relevant beneficial effects.
    True, those that shape public policy were more than happy to trumpet adverse findings and ignore neutral or lack-of-effect findings. However there is little evidence other than conspiracy thinking that all scientists were somehow engaged in an agenda to only report adverse consequences of MDMA.
    Given your apparent familiarity with chemistry I would assume that you understand the fundamental truism of pharmacology that every thing is toxic. The only question is the dose and endpoint. This is the realm many, if not most, pharmacology and toxicology type scientists inhabit. Finding out what are the dangers of a given compound. This is what happens with drugs of abuse as much as it does with environmental toxins or potential therapeutics. No doubt your "dirty hippie" types validate this for the latter two categories and in fact levy precisely the opposite attack against government funded scientists!
    Could it be that recreational drug legalization advocates engage in chronic bad faith denial of science and ad hominem attacks against the scientists themselves in pursuit of their political agenda? Naaah, perish the thought...

  • MattXIV says:

    Given your apparent familiarity with chemistry I would assume that you understand the fundamental truism of pharmacology that every thing is toxic.

    But this doesn't explain the emphasis on the amphetamine mechanisms of toxicity for MDMA. Other phenethyamines can do pretty nasty stuff as well - the effects of buproprion on seizure threshold were clear enough to take it off the market temporarily in the mid '80s before it was reintroduced at a lower dose and fenfluramine was found to damage heart valves and got pulled entirely in the late '90s - they'd been on the market since the mid '80s and '70s respectively. Both these compounds were able to demonstrate that they did not pose the same risks as amphetamines despite structural similarities to the satisfaction of regulators in a timely manner and the issues that came up with them were distinct from those that make amphetamines problematic.

    However there is little evidence other than conspiracy thinking that all scientists were somehow engaged in an agenda to only report adverse consequences of MDMA.

    But that is not what I said; I'm saving my accusations of bad faith for the ONDCP. To clarify - my claim is not that the particular studies or the people executing them are consciously biased, but that the funding process exists to provide a backing for a particular point of view; it's designed to provide the best arguments for predetermined policy positions by providing funding for sincere research programs that are most likely to result in conclusions that can buttress the argument. As you note, the results are more important than the strength of the study in determining what gets publicized. What you seem to be avoiding recognizing is that if the desired results aren't produced it often just results in the funding of another round of studies. This is re-enforced by a regulatory process where drugs without a recreational use go through the FDA process and get the chance for phase I study to determine the safe dosage; drugs with a recreational use get schedule I and go to limbo, where they are to be studied in animal models indefinitely. This disparity in treatment doesn't even serve the purpose of assessing the risk of recreation drugs well; the amphetamine link was chased after for years in animal studies instead allowing human studies that would have validated whether a psychoactive dose would be safe across the full range of potential side effects like the normal drug trial process; meanwhile MDMA use became increasingly widespread without a strong understanding of the consequences. You may see this as just how the process works, but compared to the treatment of other phenethylamines that don't have any recreational use, I cannot help but see a process designed to avoid funding anything decisive enough that it may lead to the recognition that a therapeutic dose may be safe (or even safer than comparable amphetamine doses) because of the implications of such a conclusion for the recreational dose.

  • DuWayne says:

    DM -
    I critique, however, the monomaniacal fixation and a sort of conservatism in approach sustained for far too long.
    That is actually what I meant, more or less. I understand that research into new drugs (or really, new anything) can start off miles away from the reality of the situation. I can even understand that the inertia can keep things going in the wrong direction for a long time. What I have a hard time with, is the notion that scientists in a field like illicit drugs can get stuck in the wrong direction for so long.
    At that point, typical scientific inertia took over. Scientists are, as a population, frequently taking "what works" experimentally and geeking out to the Nth degree within a narrowly described model. Less good, or so I submit, in messing around with hard-to-grapple problems.
    This is an issue that has bothered me for a very long time, though for my own part, I have seen it more in psychology than anywhere else. I think that in large part it bothers me the most, because I was/am told by all sorts of people, from HS science teachers, to Carl Sagan (whom I had the pleasure of getting ice cream with when I was eleven, after seeing him speak at UoM), that science is self correcting and that most scientists would much rather find the flaws in their reasoning than allow a mistaken paradigm to persist.
    Could it be that recreational drug legalization advocates engage in chronic bad faith denial of science and ad hominem attacks against the scientists themselves in pursuit of their political agenda? Naaah, perish the thought...
    Hey now, some of us legalization advocates are interested in learning as much as possible about the hazards associated with various drugs, so that when they are legalized we can reasonably regulate them. I.e. we can set standardized dosages, present accurate warning labels, educate the public and learn to deal with addiction/dependency in a reasonable fashion. Add standardized production techniques, as I understand that there are a number of drugs that can be synthesized wrong and produce a drug that may be similar, but is not in fact what it is presented as. And of course, we can't forget admixing.
    And really, I am all for presenting the ugly side of recreational drugs. From addiction and dependency, to dangerous side effects, up to and including death. That I am prolegalization, does not mean that I want people using dangerous drugs. I just believe that a) legalization would make it a little safer and b) it would also be a huge boost to dealing with addiction, dependency and other recreational drug related public health issues, related violence being a huge one.
    I realize that you were making a generalization that is all too accurate a descriptive of most decriminalization advocates and even many legalization advocates. I just wanted to be clear that many of us want more studies about the dangers of various drugs and support a critical approach to recreational drug use. I fall more in line with those who believe in a harm reduction approach, than those who just want this or that legal so they can get high (though in all honesty, I would like to be able to go into a party type store to buy cannabis for recreational use).
    As usual, I have a lot of thoughts on this that I really need to mull over. I really enjoy reading your blog because you always make me really think about things. Unfortunately I don't have the background to easily explain things and ask the right questions, so I really appreciate your willingness to let me muddle through and help me get it.

  • Mr. Gunn says:

    I really get your point about case reports pointing out the direction for things to go, despite the utter and complete muddying of the waters by mixing of various additional drugs and overheating and dehydration.
    I despair of any real progress being made, though, until we can get past the "what kind of toxicity is this causing" mentality. It's kinda like the old "have you stopped beating your wife" thing, assuming that "normative" brain function is somehow the ideal.
    Don't you just know that there are some fascinating things to be learned from this chemical, provided someone with the right perspective can start asking the right questions?

  • DuWayne says:

    Mr. Gunn -
    I despair of any real progress being made, though, until we can get past the "what kind of toxicity is this causing" mentality.
    and then you follow;
    Don't you just know that there are some fascinating things to be learned from this chemical, provided someone with the right perspective can start asking the right questions?
    Even given the assumption that we already know that there can be therapeutic uses for MDMA, we would most certainly not ignore toxicity issues. We don't do that for any drug on the market.
    There are a lot of therapies that utilize drugs that are illicit outside that context. Adderall is not a whole lot different than methamphetamine. As I have been led to understand, cocaine is still used in the place of novacaine, for people who are allergic to novacaine and I believe that it is still used as a treatment in psychiatry, though I recall it's efficacy being rather controversial.
    Indeed, researchers have looked into potential uses for MDMA as a pharmaceutical and I would presume they still are. The same was true of LSD. This doesn't change the fact that studies into the toxicity and dependency of MDMA are an important place to focus. The same is true of virtually every pharmaceutical on the market. Doctors will talk about the different stages of studies into new drugs. In reality, the last phase of study is after it's release on the market, because only there can we actually see the results of long term use and only then do we discover side effects that are rare enough that they didn't come out in the limited human studies.
    What you seem to be advocating is just bypassing legitimate study and going right to "seeing what happens." That would be unethical, not to mention illegal.
    That said, I actually agree with you, that it would be interesting to see what can come from MDMA. I also tend to question the assumption that "normative" brain function is ideal. That doesn't change the importance of toxicity studies and simply adds a new dimension to the issue of dependence, rather than negating the importance of studying that.

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