As a follow to the prior post on MDMA clinical trials, I wanted to delve down into the MDMA dosing specifics. One major problem I have with the MAPS efforts to pursue clinical trials is the expansion of dosing as the trials continue. As mentioned in the prior post, the director of the longest running clinical trial Dr. Michael Mithoefer seems to be under the impression that MDMA has been proven to be safe in the clinical setting and refers to other risky "settings" as if environmental conditions were the sole source of an interactive risk. MAPS honcho Rick Doblin has rather consistently argued that the likely threshold for lasting serotonergic dysregulation is considerably above "recreational" doses. I don't know whether they have read the single study showing (limited) lasting brain disruption associated with a single oral 5 mg/kg dose of MDMA, the human PK studies showing MDMA autoinhibits it's own metabolism or the paper suggesting intermittent low dosing can sensitize seizure threshold, but it would appear not.
What is the clinical dose, anyway?
The clinical dose started off at a flat 125 mg of 3,4 methylenedioxymethamphetamine ("MDMA") , taken orally. Whether this refers to the HCl salt or base MDMA weight I am unable to determine from the protocols; the animal studies almost universally refer to the HCl salt weight when calculating dose. We also have to assume the racemate, i.e. an approximately even mixture of "right-hand" and "left-hand" mirror molecules...this is a whole 'nother story. I may have just missed this information in the MAPS protocols. (For reference, if a 1.5 mg/kg dose refers to the salt, this is equivalent to about 1.26 mg/kg base. Alternately if the base, this would be equivalent to about 1.79 mg/kg of the salt.) Subjects were to receive two active treatment sessions scheduled three to eight weeks apart. Later, they added a supplemental dose of 62.5 mg administered two hours after the first dose and the number of possible treatment sessions was increased from two to three. No big deal right? This is close to the recreational dose, isn't it? Well maybe.
What is the recreational dose?
Although published analyses of street MDMA are not as common as one might like, the available data report contents from about 50 mg to 125 mg per tablet. The most recent data seem to show a big majority coming in around the 60-75 mg range. [See papers here, here, here; brief review at the end of this one. As a sidebar the MAPS database has a very large and freely available collection of the MDMA lit. I bag on them a lot but for this promulgation of the science, kudos.] One will go broke betting on what "typical" human usage is since cutting pills in half and "stacking" (taking 2 or more at one time) are reasonably common practices. Examination of per-episode consumption self-reports in the human reports examining cognitive outcomes in now-abstinent Ecstasy users shows some pretty whopping numbers at the top end but they may be presumed to have developed some degree of tolerance.
On realistic grappling with "typical dose"
Getting back to the clinical trial dose, Pharmacology-101 uses a standard 70 kg (154 lb) person in a situation like this- I find this idiotic. 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.
As a bit of a necessary sidebar here let us recognize that even mg/kg estimates are imprecise. The whole point of talking about dose or even dose per unit bodyweight is to estimate the drug concentration where it counts, i.e., in the brain or for that matter at the respective receptors and transporters that MDMA acts upon. Comparisons across species require some additional handwaving, the short version being that smaller animals tend to metabolize drugs more quickly than large animals (actually the accepted scaling functions have to do with mass and surface area). Bodyweight within species can be a useful tool but you can get some large individual differences which should keep us focused on the concept that these are only estimates. Even the exact same dose in two 110 lb / 50 kg women may not lead to exactly the same brain levels of drug! This is an area I think the scientists could work at a little harder, btw. Pharmacokinetic data for MDMA used to be totally missing, are now only infrequently provided and actual brain levels are very hard to find indeed. Not all my critique is for the advocates you know.
What, me worry?
So this brings us to toxic thresholds. The thing we all most want to know and the murkiest thing to discover. There are different kinds of "toxicity" so it helps to be clear on the variety under discussion. Let's start with the most important "toxic" effect, i.e., death. In toxicology one standard reference is to the dose of a compound after which 50% of the animals will die, known as the LD50. The most complete data on the LD50 for MDMA is in Hardman et al, 1973 J. Toxicology and Applied Pharmacology 25:299-309. Examining results for Substance VIII we find LD50 of 49 mg/kg iv (95% CI 46-52) in rat and 22 mg/kg iv in monkey (95% CI 17-28). Doses are expressed as the HCl salt but frustratingly the species and strains of the animals are not specified, I generally assume the "monkey" means a macaque genus was used. [The study, btw, is even older than it appears. It is supposed to be a declassification of work conducted in the 50's. So they get a pass on the incomplete Methods.] The Mechan et al 2006, suggests that a cumulative (t.i.d., 3 hr interval) oral dose of 25.8 mg/kg in squirrel monkeys is close to the LD50 as well. This latter finding, btw, is highly pertinent to whether we should consider the clinical trial protocol dose as the cumulative dose across the entire session or as independent dosings or some hybrid of the two. From this limited information we would have to conclude that we should lean more toward considering it a cumulative dose across a 3-6 hour period. Not too surprising, given the human pharmacokinetic data.
Moving right along, we next reach the consideration that the LD50 is in fact irrelevant because nobody is going to be using doses that kill half of the humans in treatment! What we really want is the LD1. Or even the LD0.5. In other words, at what dose are we going to start seeing any deaths (or at least significant medical emergencies)? That is really the question and as yet a real unknown. Human deaths are almost always going to be under somewhat rare, obscure or undetermined circumstances. As I discussed in the prior post, there are plenty of underexplored MDMA-related phenomena emerging.
Where will the clinical trials stop? I'll draw from to clinicaltrials.gov since I'm not a real expert on human clinical trials.
In Phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.
In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
So in some senses they are doing what they are supposed to in Phase I, i.e. to "determine a safe dosage range". So they apparently should be "pushing it". And Your Humble Narrator is being unduly alarmist.
On Disclosures: As the profile states YHN is funded by the NIH. It will come as no surprise that many of the topics I discuss are those that I have previously held, currently hold or am actively seeking to hold NIH funding to investigate. In other words, I have dogs in the hunt. It will not hurt my feelings if you read what I write on science-related topics with this in mind. If you are one of those paranoid types I encourage you to do so.