Clinical Use of MDMA, Part 1

December 3, 2007

As most readers are likely aware, there are currently a number of clinical trials running with the explicit goal of obtaining governmental approval of use 3,4-methylenedioxymethamphetamine (MDMA, aka “Ecstasy”) for medical purposes. I’ve talked about the Slate and Time puff pieces on this before, and the Multidisciplinary Association for Psychedelic Studies (MAPS) which is pushing / sponsoring these trials lays out the whole thing here, if you are too lazy to Google. The short version of the theory is that the subjective properties of MDMA (empathic, inhibition lowering, etc) are consistent with helping people in difficult psychotherapeutic situations (such as for post-traumatic stress disorder (PTSD) and, supposedly, end stage cancer anxiety) make therapeutic breakthroughs during a limited number of treatment sessions of talk therapy. This is not proposed as a chronic medication like a selective serotonin reuptake inhibitor (SSRI). The funny thing is, I approve of the concept of moving forward with clinical trials based on the available evidence.

Why not? I mean PTSD can be a very devastating psychological issue and if there are treatment-resistant cases that can benefit from a limited number of MDMA exposures, great. For that matter, if a limited number of doses of one drug can replace chronic treatment with an SSRI, even better. And there have been various psychotherapists and clients, dating back to the legal days but also in underground recent practice, testifying to efficacy (really, go visit the MAPS page for the details). So there is a decent reason to launch some trials. Just so long as we understand the health risks properly. I don’t know that we do and that is the essence of my critique of the current clinical trials.

A few more media things are recently available including a 10-min segment on NPR’s “Tell Me More” that aired on Nov 26, 2007 (RealMedia here, WinMedia here). The NPR interview follows up a piece Tom Shroder wrote for the Washington Post Magazine entitled “The Peace Drug” (behind a registration wall but you can find the text here). (Neurophilosophy has a bland summary here, maybe the discussion will get interesting.) Shroder admits on “Tell Me More” that he is college buddies with Rick Doblin, head honcho of MAPS, and has followed his efforts over the years. Oh really. At one point the host asks if Shroder feels that “some people get too close” to the drug and Shroder has to quickly fuzz-on about how Doblin is coming from a “libertarian” perspective, blah, blah. Whatever. Doblin wants to legalize the drugs for unregulated recreational consumption. Period. Clinical trials are just a means to that end. It occurs to one that Shroder may not be the most disinterested reviewer of his old college bud’s life work which may explain the puffery.

This ties into the consistent problem I see with popular media reports that cover the MDMA science. They are more concerned with arguing a position than in communicating a Gestalt of what is known about this drug. Lately, the trend toward puffing the clinical trials has struck a denial-of-the-science tone that really ticks me off. In this, the media tends to echo the viewpoint of Doblin and MAPS that no animal science that illustrates a detrimental effect of MDMA on any aspect of health could possibly be relevant to clinical use nor to “responsible” recreational use. In this they pursue a “warfare” approach (as outlined by Thomas Robey in a different context) which polarizes the debate into the EvilScientists (tools of a right-wing, abolitionist, just-say-no, puritanical anti-freedom conspiracy) and the RationalLibertarians (who can see through obvious flaws in each and every research study). So beyond the denial of science business, the advocates are also engaged in ad hominem attacks against the scientists themselves.

Now, don’t get me wrong. There is much YHN loves about the MAPS. Not least is the fact that they have a very extensive collection of the MDMA-related scientific literature made available for public viewing. MDMA research isOpen Access” thanks to these folks! They should be lauded for this contribution to public communication of drug abuse science alone, even if the copyright infringement issue is a bit fuzzy. I will admit to a certain libertarian leaning in some areas so I’m at least sympathetic to the notion that individual adults should be able to make their own choices. Still, the clinical trials are a Trojan Horse and to this I object. MAPS wants drugs, including cannabis, MDMA and many other psychedelics legalized. Not just made into “medications” which is their most official position. Legalized for recreational use. Whether one agrees or disagrees on legalization for recreational purposes is beside the point. This position tends to compromise their authority on the medical side. And it makes one question their “reading” of the literature when they assert that MDMA is perfectly safe.

Importantly the abovementioned NPR interview also has Dr. Michael Mithoefer on board, he’s the director of the longest running clinical trial effort. (A podcast of the MAPS “communications director” interviewing Dr. Mithoefer is available here.) Mithoefer says some interesting things, including “Ecstasy can be dangerous in some situations” although there is “quite a bit of phase I safety data… using doses similar to those we’re using under medical supervision, pure MDMA, showing it can be safely administered“. Case reports show quite clearly that MDMA can result in death and that this is a relatively rare outcome against estimates of the number of human use episodes per unit time. There are a diversity of factors which are likely relevant to the etiology of a given MDMA-related fatality including the MDMA dose, sex and age of the user, genetic liabilities, co-administered drugs (intentional or non-MDMA pill contaminants), prior use history, ambient temperature of use setting, sustained motor activity (rave dancing), etc. On these essential facts the advocates and research scientists are likely in substantial agreement.

Where I am in disagreement with the clinical trials advocates and much of the science (as represented in the papers, anyway) is the degree of confidence we have regarding what the actual risk factors are. No one single factor is explanatory! If it was hyperthermia cased by dancing in a crowd or hot room, if it was dehydration, if it was hyponatremia caused by water chugging, if it was a factor of high dose or drug contamination or drug combinations, etc, etc. we would have a higher rate of emergency and/or mortality! This suggests to me that we do not know enough about the things that cause medical emergency. I fear that a willingness to underplay the safety will hinder attempts to figure out exactly what combination of events and genetic liabilities does indeed lead to medical emergencies.

Here’s the thing. Read over the more recent papers from people doing research in rats, mice and monkeys with a very close eye to the details in the methods and discussion sections. (We can discuss why science has a tendency to go along in certain tracks ignoring or minimizing unusual events and which is the baby and which is the bathwater but that is another post.) Scientific meeting presentations and conversations with the researchers reinforce this impression. (Of course not everyone is privy to this information but since the MAPS type folks do go to scientific meetings and the clinical trials types should, I hold them responsible for this type of professional engagement.) You will find a number of direct and indirect references to animals in their studies going into serious medical emergency or even dying after MDMA administration, at doses that are far below the Hardman et al. 95% CI lower limits and at or below doses that were, reportedly, safe in the prior “neurotoxicity” work. These findings are in controlled conditions in which one can start to rule out consistent effects of dehydration, sustained locomotor activity, other drug exposure and perhaps even ambient temperature. They suggest that we need to start taking a closer look at individual genetic differences, precise MDMA exposure history, factors such as liability for seizure, etc. This seems particularly important to me when the clinical population has to have failed to respond to prior treatment which in many cases will have involved chronic psychoactive drug treatment. Treatment that might be predicted to cause some lasting alterations in brain systems affected by MDMA.

To finish up on this part I need to emphasize where I started. I think the concept for MDMA as adjunctive therapy has merit and even sufficient evidence in support. As is general practice in medicine, sometimes there are going to be risks associated with therapy. Sometimes quite substantial risks can be acceptable if the alternative is bad. However we get ourselves into a world of trouble, sometimes even losing a perfectly helpful medication, if we are not as honest as possible, up front, over the actual risks.

8 Responses to “Clinical Use of MDMA, Part 1”

  1. physioprof Says:

    What’s the consensus on long-term delayed neurotoxicity from MDMA? Is there any good evidence that people who ingested a lot of MDMA as young adults without apparent adverse effects will be subject to neurological problems later in life?


  2. drugmonkey Says:

    The “good evidence” is the constant drumbeat of studies showing neuropsych problems in long abstinent users. Unfortunately these are flawed by the usual caveats, most specifically the near-universal cannabis smoking. However the question of long-term effects of cannabis alone is a whole ‘nother issue that complicates.

    Beyond that, my reading is that the situation is highly similar to other situations of looking at effects of drug exposure. Likely the majority of casual users (and even not so casual users) of drugs are not going to notice specific long term consequences. Some are and they are going to have various confidences in attributing it to their use of any particular drug. Or for that matter attributing a fraction of their problem to drug exposure. (by way of example, those with a family history of alcoholism score worse on certain neuropsych tests that abstinent alcoholics do poorly on. take a family history positive alcoholic and ask what fraction of his impairment is due to the genetic risk and what fraction to the actual alcohol exposure). This is why we need step by step animal research studies to test the hypotheses. but you knew that…

    with respect to “long-term delayed neurotoxicity” there’s probably someone else around here (ahem) who can give you a better read. The stereotypical “serotonergic neurotoxicity” paradigm data suggest that the simple hypothesis (massive serotonin disruption) isn’t the answer to the lasting cognitive problems.
    Although the Ricaurte 2002 debacle was technically fubar, the underlying principle of “partial depletions putting one down the road to disaster” still has merit and is basically untested to date. even in a rat a full aging study is not fun. ain’t nobody going to do this in one of the usual primate species with decades-long lifespans.
    I find Giorgi et al 2005 of interest because it gets into a new area for MDMA, found no monoaminergic effects and the idea of temporal lobe regions being altered in a way that influences seizure threshold leads to some rather obvious hypotheses about cognition. memory in particular. the prior obsession with “serotonin neurotoxicity” as the animal model has delayed branching out into other areas. the focus was on what “worked” rather than what might really address the underlying clinical problem, if there was one. don’t get me started…


  3. Thomas Robey Says:

    Very nice post. I look forward to the next installment.


  4. […] particularly for those that may be skeptical of either psychological experimental methods or what may be viewed as druggie “science”. This type of attitude may also be why the paper was accompanied by an editorial and four […]


  5. […] Stress Disorder. If you haven’t been following along some of my prior observations are here, here, here. If you want everything I’ve opined on this drug, click the MDMA link under the […]


  6. In all treatments there is a risk/reward balance. unless trials are conducted we will never know where the balance is.


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