MDMA for PTSD: The first peer-reviewed clinical trial report

My readers will recall that I have blogged now and again about ongoing efforts to get 3,4-methylenedioxymethamphetamine (MDMA), the psychoactive compound preferentially sought as Ecstasy in recreational users, approved as a medication to be used in psychotherapy. The initial attempts have focused on the treatment of Post-Traumatic Stress Disorder. PTSD is a seriously debilitating condition and we may not have sufficient resources and knowledge to deal with, e.g., an anticipated uptick due to the current wars that the US is prosecuting.
I introduced the MDMA/PTSD Phase I clinical trials here, noting

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.

I concluded that particular post with this observation.

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.

My subsequent attentions have been lavished upon what I see as a lack of recognition/admission of potential risk factors associated with intake of MDMA, particularly in context of the trend for pushing the doses ever upward as the clinical trials continue.
I have also been critical of what I saw as rather half-baked mechanistic theorizing for how MDMA might produce a therapeutic effect. After all, if this is neurobiologically real there should be a mechanistic explanation for why this drug is so special. How is it better than an antidepressant or stimulant? Or a traditional hallucinogen for that matter? MDMA shares pharmacological properties will all these drug classes, albeit in its own unique constellation of pharmacocomplexity.
In other posts I’ve covered issues related to drawing inferences about likely human outcomes from the doses used in animal studies here and here. These observations follow on from an earlier discussion of how we should view the doses of MDMA being used in the context of the likely range of human subjects-from an average sized adult woman to a large male warfighter.

There was aready an interesting preview of the study to be found in a non-peer reviewed protocol made available by the research team. It is nice, however, to finally see the peer-reviewed article by Mithoefer and colleagues appear in the Journal of Psychopharmacology. This study is described in the Introduction as being a “pilot Phase II” trial. This means we are not merely looking at the safety and useful dose range (as with a Phase I trial) but are interested in efficacy. Does the proposed medication actually work? This is a “pilot” I suppose because traditionally 20-30 subjects would be a Phase I trial and a Phase II really expects 100 or more subjects.
The authors do speculate on the potential mechanism of action in the Introduction but it is unsatisfying, as with that prior paper. Yes, the indirect serotonin agonist properties are linked to the subjective properties- properties that seem to include empathy, openness to others, lack of fear, etc. A perfectly reasonable-sounding psychodynamic effect, no doubt, but then what is so special about MDMA? They speculate on the oxytocin enhancement that is a downstream effect of serotonin release and about fear conditioning circuitry of the ventromedial PFC and amygdala. Again, I’m not seeing why MDMA is so special.
The design of this study examined 20 PTSD patients who met DSM-IV-R criteria for crime- or war-related Post-Traumatic Stress Disorder and had a Clinician Administered PTSD Scale (CAPS) score of 50 or greater (moderate to severe symptoms). In addition, patients had to have had a minimum prior course of 6 mo of psychotherapy and 3 mo of treatment with either a Selective Serotonin Reuptake Inhibitor (SSRI; e.g., prozac) or Selective Norepinephrine Reuptake Inhibitor (SNRI) compound. Individuals visited the clinic on at six occasions- a baseline evaluation, two experimental therapy sessions, followup evaluation visits 3-5 days after each therapy session and a final evaluation 2 months later.
Twelve patients (10 F) were assigned to MDMA-treatment (125 mg initial dose; 4 rec’d 62.5 mg supplemental dose 2-2.5 hrs later) and 8 (7 F) to inactive placebo treatment conditions. The average age was about 40 years and all subjects were described as Caucasian. There was only a single individual whose index trauma was combat stress (assigned to MDMA) and the majority were sexual assault and childhood sexual or physical abuse.

Figure3: Time 1: less than 4 weeks
before first experimental session;
Time 2: 3-5 days after first experimental
session; Time 3: 3-5 days after second
experimental session; Time 4: 2 months
after second experimental sessionAs depicted in Figure 3 from the article, the CAPS scores declined in both groups, however to a much greater extent in the MDMA-assigned group. Main effects of Time and Treatment Group, as well as the interaction, were reported in the statistical analysis.
So yes, this study shows efficacy of MDMA treatment in the course of a structured psychotherapeutic session for PTSD.
In terms of major limitations to this study, the first has to do with blinding of the treatment condition. I don’t really wish to go into expectancy, confidence in the efficacy of the therapeutic modality (ala E. Fuller Torrey), placebo effects and all that. Suffice it to say that for the highest confidence we would wish for successful blinding. It failed utterly in this study, perhaps unsurprisingly. The therapists identified the treatment condition for all subjects and 19/20 of the patients correctly identified the condition they were in. Not blinded in the least. This does not make the study useless, it just puts an additional consideration into our interpretation.
A second moderate limitation is that the subjects were treatment resistant and had previously been on SSRI medications. Since these chronic treatments induce some degree of plasticity of the serotonergic system, and a major effect of MDMA is on serotonin systems and indeed the Reuptake mechanism for which SSRIs are named, well, there are some things to think about. Throw in the original lack of response to SSRI and one wonders about the pre-therapy state of these patients’ serotonergic function relative to those who respond to SSRI therapy. Not a huge knock on this early stage study of course. I mean, if you are going to get a recreational drug with known neurotoxic and acute toxicity risk approved as adjunct it is going to have to beat existing medications in some way. Starting with the population that remains untreated despite the best current therapy is an obvious place to start. Still, from a neuropharmacological standpoint it makes this study less cleanly interpretable than otherwise.
One head shaking minor criticism is the inclusion of the single warfighter.[ * ] I can see where they are eager to go into this other index trauma but it just kinda looks like critique bait. Why bother?
There was one interesting thing I noticed in the paper. An outcome, not really a criticism or a kudos. I was critical before about the rational for “supplemental dosing”, i.e., giving half the original dose several hours into the session. This study reports that the 4 subjects who received a supplemental dose did no better or worse than those who received the single dose protocol. Great. So that should put paid to that part of the protocol in all of the additional trials this group is running (MAPS is a sponsor of this and several other similar trials worldwide). Right? Heh, I crack myself up sometimes. Somehow I bet they will find an excuse to keep on with the supplemental dosing.
The sleep aid zolpidem (Ambien) or a benzodiazepine were administered after a substantial number (40-60%) of sessions. Unsurprising that MDMA-treated patients would have difficulty sleeping and probably unsurprising that the psychotherapy-only group would have similar issues. Sort of complicates interpretation though. We can’t possibly know there are no interactions between the drugs, particularly when you harken back to the original theorizing about fear conditioning circuitry. If the effects of successful therapy (MDMA-assisted or not) have to do with conditioning, i.e., neuroplasticity…well, putting a benzodiazepine or a nonbenzodiazepine GABA modulator like zolpidem on board might just affect overnight consolidation, no? Again, no study can be perfect and this is not a fatal flaw it just makes things a little more complicated. We’d like to be able to connect some mechanistic dots as to how MDMA is supposed to be working to have full confidence that these effects are real. Real in the sense of being specific to the known pharmacological effects of MDMA.
There are more details in the study. As always, I encourage my readers to take a look for themselves. It can be found at the MAPS site if you do not have access from where you are browsing.
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Mithoefer MC, Wagner MT, Mithoefer AT, Jerome I, & Doblin R (2010). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England) PMID: 20643699
*The original version contained this erroneous passage

The course of morbidity was a single month in comparison with durations of 232-273 mo for non-crime related and 8-11 mo for the crime related PTSD. (Hmm, come to think of it the warfighter couldn’t have met the criteria for failing 6 mo of prior psychotherapy and 3 months of pharmacotherapy.)