Clinical MDMA Brief (20 June 2008)

June 20, 2008

In a prior post on the clinical trials evaluating MDMA as a medication to be used in psychotherapy for Post-Traumatic Stress Disorder I focused on the dose that was being administered. This is an interest of mine because it helps us to understand how the animal research might relate to human recreational and therapeutic use.

One of my conclusions from before is important for the present discussion:

A brief consideration will show that humans come in a range of sizes and in this case we must consider everything from the 110 lb woman (let us remember the Mithoefer study is for sexual assault Post Traumatic Stress Disorder; PTSD) to the 220 lb man (the other target population for that study is warfighter PTSD). So more like a 50-100 kg range for estimating the all important mg/kg dose for comparison with animal research studies. The 110 lb / 50 kg woman given 125 mg is at a 2.5 mg/kg dose and 3.75 mg/kg cumulative dose if the supplemental is administered. The equivalent numbers for a 220 lb / 100 kg man would be 1.25 and 1.88 mg/kg.

The latest dosing news from the MAPS tells us the Swiss PTSD trial has been approved for 150 mg initial dose with 75 mg supplemental for a 225 mg cumulative dose. For those keeping score at home we’re up to a 4.5 mg/kg cumulative dose for a 50 kg woman.
The newsletter I was recently forwarded indicates that up to 5 sessions will be permitted.
C’mon now. 4.5 mg/kg in a boosting regimen?
5 times?
As I noted in a comment:

The 88 Brain Research one is interesting because it purports to show the expected deficit (two brain regions only) after a single 5 mg/kg oral dose. This, to my knowledge, has never been replicated in a nonhuman primate. Negative results not published either. The only other thing we know about the lower threshold is a study by the Slikker group showing (if memory serves) that if you drop the dose to 2.5 mg/kg for each of the 8 hits, you don’t get serotonin reductions.

And the Giorgi et al, 2005 paper described effects of a 5 mg/kg, bid, 2hr X 2 consecutive day regimen of MDMA in mice that lowered seizure thresholds. For me this is instructive. First is the old pharmacology trope that a mouse is basically a liver wrapped in fur; they have startlingly high metabolic rates. (There are a couple of scaling equations used to estimate dose translations between species.) Suffice it to say that in this specific area of MDMA/lasting serotonin changes it typically requires at least twice the per-injection dose in a rodent to see similar effects compared with a nonhuman primate. Now the one caveat here is that the Giorgi results haven’t been replicated in rat yet and unfortunately, the mouse is the odd-species-out in MDMA-tox because it gets a dopamine hit that is not reported in rats or any of the three nonhuman primates that are typically studied.
Nevertheless, as I’ve alluded to at least obliquely, the current era of MDMA research is focusing to a greater extent on lower / less frequent exposures and reporting some lasting effects. The field seems to me to be moving very close to using mg/kg doses that are the same (not scaled with species-scaling equations) as the clinical trials are using in an apparent push to give more and more MDMA.
As I said before, this concerns me.
I realize part of the purpose of a Phase I clinical trial is to establish safety margins, which sort of requires pushing to an unsafe level in a way. No doubt this is why they keep pushing. But still, shouldn’t a rational assessment of ongoing animal laboratory results be part of the process?
The other problem, as we’ve seen in higher profile clinical trial situations, is that one needs to assess the appropriate endpoints. Are they? We don’t know. I’ve certainly never seen anything in the description of the studies which suggests they are using PET to monitor serotonin transporter levels or lumbar sampling of CSF for the serotonin metabolite 5-HIAA before and after treatment, for example. They may just not be making this public, but I would tend to doubt it.
And what about liability for seizure?

No Responses Yet to “Clinical MDMA Brief (20 June 2008)”

  1. a reader Says:

    They are probably upping the dose because they’re not getting good results (symptom reduction) in that study.
    I’m a little skeptical about the relevance of the rodent seizure study. If MDMA caused significant changes in EEG power around 4 Hz in people, I think we’d know about it by now.
    Do you think serotonergic endpoints (with the additional risks they add) are better than neurocognitive ones, such as memory and executive function? After all, there doesn’t seem to be a simple relationship between serotonin and neurocognition.


  2. DrugMonkey Says:

    They are probably upping the dose because they’re not getting good results (symptom reduction) in that study.
    I agree with you that this is probably why. Given that their original dose was clearly psychoactive and perhaps even on the high end of the stereotypical recreational starter dose (i.e., one street tablet)…what does this tell us? Perhaps that MDMA doesn’t actually work and that there is no effect to be detected? What I have not seen a very good rationale for is why supplemental dosing and increased dosing is hypothesized to work better. Mostly because the only described rationales for the MDMA effect, i.e. on the reported affiliative, introspective, anxiety-lowering, etc prperties, are described as being present in recreational users without any indication that boosting or heroic doses are necessary to produce the effect.
    Now, it could be the case that the screened patients who must have failed prior treatment, might have either pre-existing or prior pharmacotherapy-induced serotonin abnormalities that would be consistent with a requirement for higher than recreational doses. The don’t talk about this in the web-published and popular media-published descriptions, though.
    I’m a little skeptical about the relevance of the rodent seizure study. If MDMA caused significant changes in EEG power around 4 Hz in people, I think we’d know about it by now.
    You are joking right? The population of users does not get exhaustively sampled on all outcome measures and we know already we are talking about 1) often subtle (albeit detectable under the right circumstances) effects that are 2) limited to some subset of the population of users resulting perhaps from 3) some unknown interactions of dosing conditions with individual liabilities.
    After I read the Giorgi et al study I went back through the case reports with a new eye. It is really interesting to see that many cases of medical emergency were marked by “patient found unresponsive, friends called emergency services”. Some organic seizure conditions in humans are marked by the individual passing out after seizing. Case reports of toddler ingestion frequently involve seizure-like responses. And then there is a very interesting case report from Carmody and Delanty 2005 which might very well be an interaction of ecstasy use with an idiopathic condition.
    These observations are suggestive but far from definitive. I am going to be very interested to see some additional work in this area to see if the Giorgi et al result holds up.


  3. a reader Says:

    Yes, we already know of a link between acute MDMA consumption and seizures from case reports. That pretty much settles that. Among other mechanisms, hyponatremia can cause seizures. And you’re right that rare toxicities are hard to detect.
    But the Giorgi study isn’t merely predicting rare toxicity, it is predicting frequent EEG changes. Some EEG changes have been reported in MDMA users, by Dafters for example, but they seem unlike what Giorgi et al report in mice.
    I believe the rationale of the MAPS people for boosters is that the acute MDMA effects are sometimes too brief to achieve sufficient therapeutic effects and that an additional dose extends the drug’s duration.
    Thanks for the ever-fascinating blog!


  4. DrugMonkey Says:

    acute MDMA effects are sometimes too brief to achieve sufficient therapeutic effects and that an additional dose extends the drug’s duration.
    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?


  5. reader Says:

    You’re thinking like a scientist, not like a drug company. We scientists love mechanisms, but the FDA (and thus drug companies) couldn’t care less.
    Lower doses were almost certainly necessary, even if they thought they wouldn’t work. You should always start low in studies in (drug-naive) patient populations.
    A legitimate question is whether they are looking hard enough for toxicity. MAPS does seem to design studies to fail sometimes. Check out the power analysis and sample size justification for their Swiss LSD study. One wonders whether it is designed to find nothing in order to quiet potential funders who think money should be spent on psychedelics with lower toxicity than MDMA.


  6. Hyperion Says:

    With regards to the mouse study showing lowered seizure threshold, it’s entirely possible that the abnormally large dopaminergic effect in that species could be responsible, since other dopaminergic drugs (ie bupropion) are known to lower the seizure threshold.
    On the other hand, plain old amphetamine can lower the seizure threshold, so it wouldn’t be completely off-the-wall to imagine that MDMA could as well. However, wouldn’t you also expect to see similar results from SSRI/tricyclic antidepressants as well since they also affect serotonin (and to a lesser extent catecholamine) reuptake?


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