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?
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?