Clinical MDMA Brief (09 Mar 2009)

Mar 09 2009 Published by under MDMA

There is a short Perspective piece on clinical MDMA published in the pre-publication queue at Journal of Psychopharmacology today that is of interest to me. The authors of this piece take a shot at answering a question I asked in a comment to one of my prior posts in which I noted one of the many revisions to the clinical protocols to permit more MDMA be administered. One commenter claimed "acute MDMA effects are sometimes too brief to achieve sufficient therapeutic effects and that an additional dose extends the drug's duration.". To which I responded:

And therein lies one of my problems. What's the hypothesized mechanism/mode/psychodynamism/whatever of action?
What do they hypothesize? Why is staying high for another hour so much better than coming back in a month and having another shorter session? What neurochemical properties does MDMA confer at, say, 3 or 5 mg/kg that it does not confer at 1 mg/kg?
If they had hypotheses, then why start with a lower dose? Were they in fact predicting that lower dose would be ineffective all along and were just demonstrating safety and lack of efficacy at the most common entry recreational dose? Was this made clear up front?

Well, Johanson and Krebs1 take a stab at answering the mechanistic question in the Perspective.


The Eureka alert indicates that this paper will enjoy free access [Publisher Link] for "a limited time" so you should be able to grab it for yourself.
First, a bit of background reading:
Those of you new to my thoughts on the utility of MDMA as a clinical adjunctive therapy for Post-Traumatic Stress Disorder might want to start with:
Clinical Use of MDMA, Part
Clinical Use of MDMA, Part 2
These will give you my launch into the topic and provide you with some links back to the advocacy side.
You may also wish to review a couple of posts that will get you started on the most obvious adverse effect of concern, death.
Repost: MDMA Case Reports
Recreational Ecstasy User Dies, Responses Typical: How about publicizing the tox screens?
One of the fine points of scientific interest in this is how we assess risk to humans from the available animal research literature. It sort of melds these two topics together into the critical question. I've touched on one aspect of this melding in a few places but you can start here:
Letter to the Editor as a mechanism of post-publication scientific discussion

Clinical MDMA Brief (23 Jan 2009)

Let me also draw your attention to the Psychedelic Research blog.

Three Testable Hypotheses

Okay, back to Johanson and Kreb's speculation. They advance three hypotheses for the putative mechanism which may underlie a potential therapeutic effect of MDMA.
Oxytocin: This is based on literature showing that MDMA increases oxytocin release as well as that drawing a connection between oxytocin and human affective constructs of trust, empathy and (anti)anxiety. The money cite is to Thompson et al. (2007) who found that pharmacological blockade of oxytocin receptors in rats blocked MDMA-induced huddling
Ventro-medial prefrontal cortical / amygdala circuitry: Although this circuitry is well established as being critical in fear conditioning, the link here is tenuous. One cite for altered activity in these regions in PTSD subjects and one imaging study showing acute effects of MDMA on brain metabolism in these regions.
Norepinephrine and cortisol: A tangled web, here. MDMA does release norepinephrine and cortisol but the relationship between these neurotransmitters/neuromodulators/hormones and stress or fear is complex. Teasing apart the direction of causality is not going to be easy.
Not a bad first step although my identifying this as "three testable hypotheses" is quite generous. It is of course disappointing that this is a thinly cited Perspective bit instead of a comprehensive review. At the very least this effort gives the casual reader the impression that the mechanistic support for these clinical trials is very thin indeed. The overall rationale for trials is good on the theoretical/psychodynamic scale based on "just thinkin'" about the subjective properties of MDMA, sure. I can get behind that one myself. But I would like to see some more meat about the neurobiology. That would allow a whole bunch of things to take place.
First, some better targeted scientific investigations in humans as well as nonhuman models to further explore which neurobiological properties of MDMA might have the therapeutic effect. This would lead, second, to a more convincing argument that there is something "there" in the clinical setting (the advocates would be all over this, right?). Of course, third, this would entail the risk of showing the clinical effect to be bogus. Nevertheless, fourth, if it were a real effect additional studies might lead to better shaping of the dosing to produce (and evaluate) the desired neurobiological effect (oxytocin release? fronto-amygdalar activation? norepinephrine? cortisol?) in individual subjects. Finally, fifth, this might bring us to non-MDMA alternative medications (or combinations of medications) that have the desired clinical effect without any of the drawbacks of MDMA.
And of course this last would be enthusiastically received by the advocates of clinical MDMA for PTSD and other psychiatric disorders, right? 'cause their primary motivation is helping with the disorder rather than with promoting use of MDMA isn't it....?
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1Johanson, PØ and Krebs, TS. How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale
J Psychopharmacol OnlineFirst, published on March 9, 2009 as doi:10.1177/0269881109102787

9 responses so far

  • TSK says:

    Hi DM,
    I'm really pleased that you have commented on our article. It would be excellent if you could add to this speculative framework with some experimental results from your lab. One of our main goals in writing this was to stimulate more neurobiology researchers to apply for state-funded grants on the potential therapeutic aspects of MDMA.
    - Teri
    (krebs at ntnu.no)

  • DrugMonkey says:

    Yes, well, it is true that review articles can be very helpful when it comes to making an argument for a line of work. So in that sense your piece is a positive way to advance your goal here. much more positive than, say, denying that animal research findings could ever have any relevance to human effects (unless of course they support the agenda, then they are kewl). so kudos on that.
    but let me ask you a question. do you really think that MDMA is ever going to be approved for medical use in the US? I just don't see it happening. You look at other therapeutic drugs getting stopped or pulled from the market for very rare adverse events and you have to wonder. Take "suicidal ideation" which is a big reason these days to get demonstrated useful drugs pulled from the market. It isn't even clear that the "ideation" is a good predictor of actual attempts! Compared with the established risks of MDMA, well, it isn't a good bet.

  • TSK says:

    Thanks, feel free to cite our article.
    Methamphetamine is an FDA approved medication for daily-use in children with ADHD. Serotonin reuptake inhibitors, benzodiazepines, even anti-psychotics are commonly prescribed for long-term daily-use to people with anxiety disorders. Clinicians understand that useful medications often have the potential for adverse effects or recreational use.
    MDMA, taken a few times in a medical setting, appears to have a risk profile similar to many other psychiatric treatments. Approval in the USA and other countries of MDMA for augmentation of psychotherapy will require large Phase III clinical trials showing benefit compared to placebo.
    Some interesting links...
    Risks of clinical use of amphetamines, including neurotoxicity: SM Berman et al. Potential adverse effects of amphetamine treatment on brain and behavior: a review. Molecular Psychiatry 2009, 14(2):123-42.
    Political history of MDMA in the USA:
    Ecstasy Rising
    , ABC News 2004.
    PTSD in the military: The Soldier's Heart, PBS Frontline 2005/2009.
    News item on continuing clinical trials of MDMA:
    Military.com
    , March 04, 2009.

  • timc says:

    "First, some better targeted scientific investigations in humans as well as nonhuman models to further explore which neurobiological properties of MDMA might have the therapeutic effect. This would lead, second, to a more convincing argument that there is something "there" in the clinical setting (the advocates would be all over this, right?). Of course, third, this would entail the risk of showing the clinical effect to be bogus."
    I'm afraid I fail to see your logic here. By this logic the clinical effect of SSRIs, lithium, timolol in glaucoma and countless other medications would be "shown to be bogus" because we don't really have that clear a picture of how they work for all indications. How exactly can a large, reproducible clinical effect over placebo be rendered "bogus" by a research plan failing to find a completely clear unambiguous mechanism of action? How long does the basic research have to be done before the clinical effect is declared "bogus"?
    It strikes me that you are applying a lot of logic to this that you do not apply elsewhere. You are going to put up a post telling us how the clinical effects of lithium and timolol are bogus, right? 'cause your primary motivation is informed disinterested skepticism, rather than biting MDMA on behalf of whatever dog you have in this race, isn't it....?

  • DrugMonkey says:

    timc, I suppose what I was getting at with this comment was the potential that there is nothing particularly magical or unique about MDMA on the one hand, and the idea that the more you know about mechanism, the better you can do in designing your clinical trials to ensure you are seeing what you think you are.
    As one issue, think about what the placebo should be in an efficacy trial. Currently the protocol is for low-dose MDMA. Is this the right one? A testable mechanism would allow greater focus on what the control conditions should be to prove that MDMA has uniquely advantageous properties that justify the risks over other less-risky alternatives.

  • Science and health vs. politics and profitt says:

    What are the less risky alternatives your refer to? Do you regard daily and long term use of SSRI or Benzodiazipines as less risky than 1 or 2 administrations of MDMA?
    Why should anybody belive you are independent of the industry and the war on drugs?

  • DrugMonkey says:

    What are the less risky alternatives your refer to?
    current accepted practices and the pool of potential other approaches including pharmacotherapeutics. Did you read the post? And the review it is describing? The focus of the authors Johanson and Krebs suggests that as far as drugs go alternatives would be oxytocin drugs and, presumably, noradrenergics.
    Do you regard daily and long term use of SSRI or Benzodiazipines as less risky than 1 or 2 administrations of MDMA?
    It's an empirical question but this is a bad comparison. If you track back to one of my very first posts you'll see me commenting that this contrast of 1 or 2 administrations against chronic SSRI treatment is one of the greatest reasons to take this seriously. You will also find in my prior posts my reasons for thinking that there is a potential for risk of lasting detrimental effects (including serotonin alterations, seizure sensitization and acute medical emergency-assuming good emergency medical care is available death is probably unlikely).
    Nevertheless, specific to my point about alternatives, we are in the zone of considering pharmaceutical alternatives which have a similar acute effect (the purported MDMA one) on one or two administrations. So raising chronic meds is a bit of a red herring.
    Why should anybody believe you are independent of the industry and the war on drugs?
    I make no protestations or assertions about my "independence" or bias or any of that. I have a disclaimer linked in the top bar and you would do well to read it. You are entirely free to make what you will of my "motivations" for blogging. I certainly speculate frequently that science-denialist advocates of recreational drug use are really all about legalizing their own preferences and that many of their higher-minded efforts are nothing more than Trojan horses. Nevertheless, this is never my main point and the focus is on the statements which I think tend to express denial or ignorance of the science. So if you think I am in denial or ignorant of some scientific findings which make a different case, have at it. I don't even mind if you speculate about my biases when you are doing so.

  • Science and health vs. politics and profitt says:

    Do you think based on the current evidence that 1 or 2 administrations of MDMA in a controlled setting, with medical precautions are more risky than daily medication with Benzo or SSRIs? It says without telling that my question is an empirical one.
    Do you know about any serious adverse events from RCTs, or are you thinking about the recent report from the UK?
    I appreciate that you dont even try to defend that your position is independent from industry and the war on drugs. Yes, I think you are in denial or biased.

  • DrugMonkey says:

    I appreciate that you dont even try to defend that your position is independent from industry and the war on drugs. Yes, I think you are in denial or biased.
    apparently your fervor or fondness for cognition-impairing drugs is hindering your reading comprehension. If you got reasons, have at it. I enjoy discussing evidence and heck, I'll even put up with some anecdotal blather if it is interesting and liable to move the discussion forward. If you think I am biased because you simply don't agree with me and keep re-asserting that, well, that's just namecalling.
    I dunno wtf RCTs means but I'm referring to the litany of MDMA-related emergency department visits which are accumulated in the epidemiological databases (e.g.), the Case Report literature and the popular press (I just blogged one of these as it happens).
    Since I doubt you are familiar with these I'll summarize. In many cases the plasma tox reports and/or the alleged consumption is consistent with the individual in trouble having consumed one or two of the usual street tablets of Ecstasy. (and to head off a typical complaint, even in those cases where there are other intoxicants- most frequently alcohol - the mode of medical emergency is frequently more consistent with the MDMA as the problem, not the other intoxicants.)

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