Clinical Use of MDMA, Part 2

Jan 25 2008 Published by under Drug Abuse Science, MDMA

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 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.

9 responses so far

  • I have concerns about the serotonergic dysregulation as well. But there is evidence that a potent dose of alpha lipoic acid taken before the MDMA will completely inhibit the negative impact on the serotonergic system. See this abstract.
    This chemical is too valuable to let go of, but prudent safeguards should be taken even with the lower therapeutic dosing.

  • daksya says:

    To follow up on the comment above, there's evidence that it's a metabolite likely that results in serotonergic axotomy. Of course, there's older & more tentative evidence that there are MDMA substitutes without the serotonin depletion. So, maybe there's some hope for a cocktail that can attentuate the risk of serious side-effects.
    The seizure threshold study you cite used doses of 5mg/kg in mice and between 2-6 doses within 1 to 3 days. For humans, that's neither "intermittent" nor "low-dose".

  • Casey says:

    Ya, but can anything Ricaurte publishes be trusted?

  • DrugMonkey says:

    "Ya, but can anything Ricaurte publishes be trusted?"
    Since the link you provide is to the avowed advocates of the complete legalization of MDMA one might as well turn this critique on their critique of Ricaurte. This is why argument by ad hominem gets us nowhere.
    But do explain if you would. We have a considerable body of work from Ricaurte which has indeed been replicated in other laboratories. We have the 2002 Science paper debacle. On the box score for now, he's more likely to have published a replicable result than not. Are all those other (competing) labs fakers too? How do you address this part of the story?
    The more interesting question is: How should we view those contributions he's made where there simply is not any direct replication available to date? That is indeed a valid question. And the only way to answer it truthfully is to insert your own biases into the equation. Basically to state "I think he's a scummy cheater and always has been, just, er, because". Or to state "Gee, I'm a wide-eyed naif who thinks no scientist could ever intentionally do wrong". or....pick your opinion-based interpretation. But be clear in your own mind that this is where your belief is coming from. Alternately, sack up and provide some evidence based thinking, that's cool too...
    My biases stem from my general experiences with the way things actually work in science labs, the occasional professional interaction with various drug abuse scientists and the like. All of which add up to my gut feeling about this body of work. Some of which I've blogged about on the old site and will again here.

  • Casey says:

    The link was simply the first one Google gave me when I queried *Ricaurte retraction* (asterisks omitted).
    So forgive the bias of the link I sent. It does not reflect an agenda on my own part. I was simply too lazy to care about finding another link that illustrated the retraction in a less "ad hominem" fashion. I am a published scientist with only a very distal knowledge of neurochemisty. I was asking you for your expert opinion.
    So again, can anything by Ricaurte be trusted? Since you referenced his 1988 Brain Research paper might I presume you trust that study at least. Do you trust all Ricaurte's work other than the retracted science paper? I am actually not aware of any published studies supporting Ricaurte's other work (because I'm not keeping up in your field). So if you tell me that such supporting studies exist I'm just going to have to take your word for it. Are those validated studies numerous enough to salvage his trustworthiness (in your opinion)?
    Just curious.

  • DrugMonkey says:

    Sorry Casey, I went off a bit half-cocked there.
    I am not one who assumes everything Ricaurte has published is falsified, no. I do think he is one of those that trends towards the hype-the-data approach. I do think he's firmly convinced that MDMA results in lasting detrimental insult to the brain and is at times driven by defense of this position more than simply following whatever data wherever they lead. In this he has plenty of company from scientists working in other areas, not to mention MDMA tox.
    The 2002 Science paper debacle stinks to high heaven and we will never know what happened. It tells me a little something about his judgment and arrogance at that time, certainly. I have no reason from subsequent papers to suspect anything dodgy.
    Okay, so you don't have to take my word for the MDMA tox stuff. For one thing, the MAPS archive link on the blogroll to your left gives anyone access to the papers. or most of 'em.
    but to briefly outline, sorry, without links or direct refs. If you reach to the rat data, there are copious findings from at least two dozen labs showing the essentials. That a "repeated high-dose, short course" exposure to MDMA leads to lasting reductions in markers for serotonin axon integrity. I really don't see how this particular finding can be dismissed.
    In Ricaurte's squirrel monkey studies, this regimen broke down to 5 mg/kg MDMA, twice a day for four days with the intervals no shorter than 6 hrs. There were two main confirming groups back in the day. The Battaglia/Insel/De Souza crowd from NIDA intramural and the Slikker/Ali/Paule crowd from the National Center for Toxicological Research (an FDA outfit). rhesus versus squirrel monkey, a bit of back-n-forth on dose, significant diff in 5 brain regions/ no 7 regions, sure. but the essentials were consistent. This part of his work one therefore has assertive reason to believe is good. Ricaurte also did tissue analyses, one might assume, for at least three groups (Gold, Fantegrossi, Winsauer) who I would assume did the dosing themselves. These might therefore qualify as partially-independent replications although one might wish to know if tissues were sent blinded to treatment or not.
    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.
    Of course, this question of where the threshold lies is THE question in the minds of some people. the reasons why there are not copious amounts of data on this are fodder for at least a couple of posts on the way science functions sometimes...

  • DrugMonkey says:

    And on it goes. 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/kg 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? hmmm.

  • a reader says:

    When thinking about a threshold for toxicity in people, it is useful to keep in mind how widely the thresholds vary in rats. Some rat strains, like Dark Agoutis seem to get depletions after around 10 mg/kg MDMA dose but other strains show nothing at 40 mg/kg.
    Humans probably vary by that much in their sensitivity as well. Even if you did PET scans and measured SERT, a dose that looks safe in your first ten people might cause changes in some of your next fifty (if you kept collecting data).

  • meme says:

    i love all of what has been said but does any one know hot to make it?

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