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....?
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