Single oral dose MDMA neurotoxicity revisited

I have been awaiting this paper since I saw the poster a few meetings back, Dear Reader. It contributes to an ongoing theme of posts on MDMA (Ecstasy) that I have neglected for some time. Some of you may recall the topic of my third blog post which noted the current attempts to get MDMA approved as adjunctive treatment during PTSD psychotherapy. I have been somewhat critical of their approach, mostly because of my understanding of the MDMA-associated neurotoxicity literature in animal species.

To overview, very briefly, if you administer MDMA twice per day at approximately 6-12 hr intervals for four days to rats, monkeys and a few other species, you produce lasting decrements in many markers for serotonin neurons / serotonin function in the brain. Lasting as in, as long as 7 years in a monkey (Hatzidimitriou, 1999). There is a parallel literature identifying lasting affective and cognitive alterations in human consumers of MDMA / Ecstasy and some imaging evidence of similar serotonergic changes.

It is tempting to associate at least the affective disruptions with the lasting serotonergic alterations. (Three monkey studies failed to connect these serotonergic patterns to substantial changes in cognitive behavior so that one is a little more tenuous...you can find some hints in the rat literature and some mother's eye stuff in the monkey studies but the gun ain't smoking very much.) However, as you are aware DearReader, the human studies of drug users are fraught with complications. One doesn't know anything about pre-existing differences (depressives more likely to use MDMA?), the precise dose and pattern folks exposed themselves to, the environmental conditions, co-administered psychoactive substances and even the identity of the drugs being consumed as "Ecstasy".

This cycles the discussion back to the controlled animal models. The MDMA enthusiast is frequently found to contest the relevance of the animal models, primarily on the grounds of the dose. The typical animal model features 10-20 mg/kg of MDMA per injection in rats and 5-10 mg/kg in monkeys. Again, these are repeated twice daily for four days. In addition, the route of administration is typically intraperitoneal (rat) and either intramuscular or subcutaneous in monkeys. Naturally, the majority of human use is oral which Pharm101 tells us should reduce the peak brain exposure as well as the rapidity with which peak levels are attained compared with the injected routes. So there has been vigorous debate, including between animal-research and human-research scientists, as to whether the animal data should be taken as relevant to the human condition.

As I blogged before, there is another concept from Pharm101 that relates to this discussion, i.e., that of species-scaling of drug doses. The short version is that you need higher per-kilogram-of-bodyweight doses in smaller species to produce similar outcome on parameters such as peak plasma levels, Area Under the Curve as well as toxic outcomes for various body systems including the brain. That prior post lays out data which show that a 1.6 mg/kg oral MDMA dose in a human produces peak plasma levels similar to 2.8 mg/kg in a squirrel monkey but an AUC similar to 5.7 mg/kg in a squirrel monkey (with a higher peak, obviously).

All well and good but the evidence of lasting serotonin changes on the low-end of the dosing spectrum has not been all that good. There was an old Ricaurte paper from the early days that found serotonergic changes in a handful of brain regions after a single oral dose of 5 mg/kg MDMA in squirrel monkeys. The trouble is, it was never replicated by any other papers and it was only in 3 subjects. So...not quite as convincing as the data on the higher-dose, injected, repeated models which come from multiple labs, in several species of laboratory animals and in many (total) animals per species.

A new paper from the Ricaurte group,

Mueller M, Yuan J, McCann UD, Hatzidimitriou G, Ricaurte GA. Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations. Int J Neuropsychopharmacol. 2012 Jul 24:1-11. [Epub ahead of print] [PubMed]

provides a long-past-due update on their prior report (Ricaurte et al, 1988; PubMed).

The study tested single oral doses of 5.7 (N=8), 10.0 (N=6) and 14.3 (N=4) mg/kg MDMA and the brains were collected one week later for analysis. As with prior studies, significant reductions in brain content of serotonin and its major metabolite 5-HIAA were observed in multiple brain regions including frontal, temporal, parietal and occipital cortex, the hippocampus, caudate nucleus, putamen and thalamus. Importantly, these reductions were dose-dependent in magnitude with some differences from the vehicle control group (N=8) failing to reach statistical significance. The lowest dose, however, did produce significant reductions of serotonin in frontal and temporal cortex, hippocampus and caudate.

This last is the most critical contribution because it replicates the prior study in a larger sample.

The one oddest thing about the design was the collection of brains at one week instead of two. For the vast majority of studies in this area, two weeks seems to be the modal time for brain harvest. I think the choice of one week here is going to muddy the waters because there will be those that claim this is reflective of acute depletion of serotonin stores rather than the classic neurotoxicity profile. Concerns are partially alleviated by some serotonin transporter binding data provided suggesting reduced expression, but only a single brain slice per treatment group was shown. It would have been nicer if this had been a completed study with quantification from all animals. They authors have left some daylight for their critics and it is not really clear why they would have done this.

In the discussion, the authors continue their thesis that 5.7 mg/kg is equivalent to 1.6 mg/kg for a human. Therefore, they conclude that they have shown that lasting serotonergic deficits can be produced at doses that are unarguable "typical human doses" of MDMA. I have previously argued that this is a dose range that is being used in the clinical protocols even if you leave off notions of species scaling. So overall, yes I would say I agree with their basic contention that they have shown the expected serotonergic effects with MDMA exposure that is 1) oral, 2) single-dose and 3) within the range of expected human single-use episodes.

This study should further convince those who have previously argued that the animal data has no relevance because of dosing issues. This shows that there is no magic threshold of protection that happens to coincide with notions of "typical human use".

24 responses so far

  • J Delphinki says:

    I hate to have to resort to muckraking, but I'm not sure I can trust much of anything coming out of Ricuarte's lab on MDMA after his 2002 Science retraction. Any competent and conscientious researcher, especially one with the experience he has with dosing amphetamines, should and would have noticed major red flags (not least of which is that two of his ten specimens died in the course of the study from their toxic doses of methamphetamine).

    He should have had the good sense to be cautious after the uproar he caused with the "holes in the brain" nonsense from his 1998 Lancet paper and the DEA's ad campaign, but he either disregarded objectivity or is incompetent. Neither gives me any pause in calling him a hack.

    For those ignorant of the infamous incident, here are a few links to get you up to speed.
    http://www.villagevoice.com/2004-03-02/news/the-ecstasy-factor/
    http://www.nytimes.com/2003/12/02/science/research-on-ecstasy-is-clouded-by-errors.html?pagewanted=all&src=pm
    http://www.maps.org/mdma/ricaurtefunding.pdf

    He had the clout to withstand the backlash, as you can see on RePORT by the fact that he still gets plenty of money from NIDA to provide the answers they want to hear. This report is more of the same.

  • Comrade PhysioProf says:

    Dude, I tripped out on dozens of 400-600 mg doses of pure ecstasy back in the 80s, and I'm fucken FINEish.

  • Isis the Scientist says:

    I was in elementary school in the 80s.

  • Grumble says:

    It's the -ish part that worries me, CPP.

  • Wiles says:

    the one week bit certainly leaves substantial daylight for critics. also, i don't think even the staunchest of mdma assisted psychotherapy proponents claim that mdma is completely risk free. no drug is. like all treatments, mdma for ptsd would have to be on a patient by patient cost benefit analysis. another thing to question would be whether these reductions in 5-HT markers have any clinical significance. Most studies i'm aware of on human users havent found any clinically significant deficits. Though i believe there was a statistically significant difference in a word recall test, i'd have to look to be sure. regardless a fraction of a second of word recall probably won't adversely affect anyone. at this point i feel comfortable saying that the side effects of 1-2 doses of mdma per year, in a controlled setting, are far less detrimental than living with severe treatment resistant PTSD. And that dose regimen may not need to be maintained after 1-2 years for most patients. further study will better elucidate that last bit.

  • drugmonkey says:

    Wiles- agreed that in treating disorders we are willing to risk adverse consequences because the disorder itself is so horrible. The majority of use is recreational, not therapeutic, you realize.

    JD- oh yes, clearly you just hate to muckrake.

    CPP- dude you are the posterboy for lasting cognitive deficits!

  • Jonathan says:

    First off, I'm also highly skeptical of anything coming out of Ricuarte's lab, let's not pretend he doesn't have a very real agenda.

    Secondly, look at the UK, which had a massive rate of MDMA use throughout the 1990s. Wouldn't we see great evidence of neurotoxicity in that population by now? Or did exposure to cow prions balance it all out?

  • drugmonkey says:

    There IS a great deal of evidence. Numerous studies testifying to lasting effects in users.Try PubMed.

    However, there are a few "translational" considerations....A few off te top if my head.

    -possible tolerance associated with a slow introduction, a few animal studies support this notion

    -threshold. By way of analogy it takes dopamine depletions on the order of 80% to see Parkinson's symptoms. For any given endpoint I human function that is related to serotonin this could also be the case

    -detection. A related issue but if behavioral/affective changes are still well within the norm it can be hard to know if one has changed. 10% impaired memory? What is that? Heck becoming a father put at least that big of a hit on my brain.

    -Coadministered substances which might be protective.

    Regarding Ricuarte, yes there was the big screw up with the Science paper. And yes, he has an "agenda" to the extent that he believes the numerous studies he's published and the results of others. How is any scientist any different? Nevertheless, the most important consideration is the replication within the field by other labs including ones that are antagonistic towards Ricuarte. If you read deeply in this literature you realize he is not essential to the fundamental understandings.

  • Jonathan says:

    I guess the question I'm asking is, has the UK cohort been compared to a population that didn't spend the 1990s eating cheap pills like they were M&Ms to see if they're a nation of drooling retards (beyond what we already know of the UK being a nation of drooling retards)?

  • Neuro-conservative says:

    New paper on memory impairment following MDMA use, with an interesting prospective design:

    They took a bunch of new users of MDMA, tested their memory, and followed them for a year. At the end of the year, they compared those who continued to use (>10 times) and those who didn't. The users showed declines in memory compared to the non-users, "suggesting serotonergic dysfunction in hippocampal regions as a consequence of MDMA use."

  • miko says:

    "First off, I'm also highly skeptical of anything coming out of Ricuarte's lab, let's not pretend he doesn't have a very real agenda."

    I wish people would stop questioning or criticizing people at Johns Hopkins. They can't help it if they're PASSIONATE. It's in the fuckin' water there! Or something!

  • drugmonkey says:

    I guess the question I'm asking is...

    Are you going to just keep making up more and more impossible experiments that will satisfy your intellectual rigor as a way to avoid grappling with the existing literature on this issue?

    It really doesn't take long to PubMed MDMA with a few key words like "cognition", "Anxiety", "Depression", "Affective", "memory", "attention" and the like. It is science. You aren't going to find a nice neat, airtight story suitable for 2nd year Med students.

  • Jonathan says:

    I would, but I keep forgetting.

  • Isis the Scientist says:

    I wish people would stop questioning or criticizing people at Johns Hopkins. They can't help it if they're PASSIONATE. It's in the fuckin' water there! Or something!

    Yeah, but have the cured cancer yet? Maybe they should give up on this meaningless bullshit and focus on that.

  • CPP- dude you are the posterboy for lasting cognitive deficits!

    Dude, I am cognitively ENHANCED!

  • Jonathan says:

    Hey Mr. Drugmonkey. Do you know the cartoons of Tim Kreider? Because I am reading some Tim Kreider, and I think he's pretty much your spiritual brother. http://www.thepaincomics.com/ If you need some credentials, it was I who recommended that Jim Knipfel book to you long ago, and you liked it. Hope you like this stuff too. Yours in scotch, Jonathan

  • Dude, are you gonna post some fucken shitte on this blogge, or what, dicke?

  • Eddie says:

    Drugs are fun. Drugs can be pretty bad for your short-term and kong-term health. I think most people can agree with that. Regardless of the consequences of drug abuse, people will continue to use drugs. That is an unfortunate fact. If evidence of health damage were enough to stop people from abusing drugs then crack would not have made it out of the late eighties. I got clean and sober with the help of a sober living called New Life House. Check out their site if you are looking for help. http://www.newlifehouse.com . I think having resources available to people who are in need of assistance is important.

  • KateClancy says:

    Hey Brother Drug, I wanted to ask you a question about this quote:

    "Naturally, the majority of human use is oral which Pharm101 tells us should reduce the peak brain exposure as well as the rapidity with which peak levels are attained compared with the injected routes."

    So, here's the thing. I have never taken any sort of Pharm 101 or have a pharm background... but I need to learn a bit about the pharmacokinetics of hormonal contraceptives for a book chapter I've been invited to write. If you remember any citations (or textbooks) off the top of your head that will explain this point a bit more (about peak brain exposure from oral versus other kinds of preparations) I would really appreciate it, since it relates to a broader point I'm trying to make about the more diffuse ways hormonal contraceptives affect women beyond reproduction. Thanks so very much!

  • drugmonkey says:

    hmm, you should bother Abel Pharmboy about that or maybe dr_leigh... I'll see what I can come up with when I get a chance

  • KateClancy says:

    Cool thanks! I'll bug Abel 🙂

  • NeuroChaz says:

    Ok so we all know mdma temporarily depletes serotonin. The question is, does it destroy the axons? and can the axons grow back? All this study shows is depleted serotonin after a week. Duh.

  • DrugMonkey says:

    7 years is "temporary"? Ok, if you say so.

    ...this research is not conducted in a vacuum, in other words. Do try to consider the entire body of work. One week is far out for this still to be the acute phase. I do wish they'd done the canonical 2 weeks - really strange choice.

  • Dariusz says:

    I see you only response when you like. Why you dont comment Delphinki? because he has right 7 years is "temporary"? Ok, if you say so. and author is ? George A. Ricaurte who do what? His fake study from 2002 was exosed so he wait few years and he try again. Look at Dr. David Nutt we’ve done many studies and cannot find any good evidence that MDMA damages serotonin neurons. I dont know if he has right but all studies showing neurotoxity show in higher dose example Cowen visual brain activity in higher-users seem more what he explain as loss of serotonin neuron but low-users have lower activation than controls. You get funding from NIH ? dont wrong me im not person who saying MDMA is safe but single dose is a propaganda, question is are you author or puppets who defend this "evidence"?

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