MDMA for PTSD: The first peer-reviewed clinical trial report

July 23, 2010

ecstasypills.jpgMy readers will recall that I have blogged now and again about ongoing efforts to get 3,4-methylenedioxymethamphetamine (MDMA), the psychoactive compound preferentially sought as Ecstasy in recreational users, approved as a medication to be used in psychotherapy. The initial attempts have focused on the treatment of Post-Traumatic Stress Disorder. PTSD is a seriously debilitating condition and we may not have sufficient resources and knowledge to deal with, e.g., an anticipated uptick due to the current wars that the US is prosecuting.
I introduced the MDMA/PTSD Phase I clinical trials here, noting

The short version of the theory is that the subjective properties of MDMA (empathic, inhibition lowering, etc) are consistent with helping people in difficult psychotherapeutic situations (such as for post-traumatic stress disorder (PTSD) and, supposedly, end stage cancer anxiety) make therapeutic breakthroughs during a limited number of treatment sessions of talk therapy. This is not proposed as a chronic medication like a selective serotonin reuptake inhibitor (SSRI). The funny thing is, I approve of the concept of moving forward with clinical trials based on the available evidence.
Why not? I mean PTSD can be a very devastating psychological issue and if there are treatment-resistant cases that can benefit from a limited number of MDMA exposures, great.

I concluded that particular post with this observation.

As is general practice in medicine, sometimes there are going to be risks associated with therapy. Sometimes quite substantial risks can be acceptable if the alternative is bad. However we get ourselves into a world of trouble, sometimes even losing a perfectly helpful medication, if we are not as honest as possible, up front, over the actual risks.


My subsequent attentions have been lavished upon what I see as a lack of recognition/admission of potential risk factors associated with intake of MDMA, particularly in context of the trend for pushing the doses ever upward as the clinical trials continue.
I have also been critical of what I saw as rather half-baked mechanistic theorizing for how MDMA might produce a therapeutic effect. After all, if this is neurobiologically real there should be a mechanistic explanation for why this drug is so special. How is it better than an antidepressant or stimulant? Or a traditional hallucinogen for that matter? MDMA shares pharmacological properties will all these drug classes, albeit in its own unique constellation of pharmacocomplexity.
In other posts I’ve covered issues related to drawing inferences about likely human outcomes from the doses used in animal studies here and here. These observations follow on from an earlier discussion of how we should view the doses of MDMA being used in the context of the likely range of human subjects-from an average sized adult woman to a large male warfighter.
ResearchBlogging.orgThis post was chosen as an Editor's Selection for ResearchBlogging.org
There was aready an interesting preview of the study to be found in a non-peer reviewed protocol made available by the research team. It is nice, however, to finally see the peer-reviewed article by Mithoefer and colleagues appear in the Journal of Psychopharmacology. This study is described in the Introduction as being a “pilot Phase II” trial. This means we are not merely looking at the safety and useful dose range (as with a Phase I trial) but are interested in efficacy. Does the proposed medication actually work? This is a “pilot” I suppose because traditionally 20-30 subjects would be a Phase I trial and a Phase II really expects 100 or more subjects.
The authors do speculate on the potential mechanism of action in the Introduction but it is unsatisfying, as with that prior paper. Yes, the indirect serotonin agonist properties are linked to the subjective properties- properties that seem to include empathy, openness to others, lack of fear, etc. A perfectly reasonable-sounding psychodynamic effect, no doubt, but then what is so special about MDMA? They speculate on the oxytocin enhancement that is a downstream effect of serotonin release and about fear conditioning circuitry of the ventromedial PFC and amygdala. Again, I’m not seeing why MDMA is so special.
The design of this study examined 20 PTSD patients who met DSM-IV-R criteria for crime- or war-related Post-Traumatic Stress Disorder and had a Clinician Administered PTSD Scale (CAPS) score of 50 or greater (moderate to severe symptoms). In addition, patients had to have had a minimum prior course of 6 mo of psychotherapy and 3 mo of treatment with either a Selective Serotonin Reuptake Inhibitor (SSRI; e.g., prozac) or Selective Norepinephrine Reuptake Inhibitor (SNRI) compound. Individuals visited the clinic on at six occasions- a baseline evaluation, two experimental therapy sessions, followup evaluation visits 3-5 days after each therapy session and a final evaluation 2 months later.
Twelve patients (10 F) were assigned to MDMA-treatment (125 mg initial dose; 4 rec’d 62.5 mg supplemental dose 2-2.5 hrs later) and 8 (7 F) to inactive placebo treatment conditions. The average age was about 40 years and all subjects were described as Caucasian. There was only a single individual whose index trauma was combat stress (assigned to MDMA) and the majority were sexual assault and childhood sexual or physical abuse.
Mithoefer10-Fig3.png
Figure3: Time 1: less than 4 weeks
before first experimental session;
Time 2: 3-5 days after first experimental
session; Time 3: 3-5 days after second
experimental session; Time 4: 2 months
after second experimental session
As depicted in Figure 3 from the article, the CAPS scores declined in both groups, however to a much greater extent in the MDMA-assigned group. Main effects of Time and Treatment Group, as well as the interaction, were reported in the statistical analysis.
So yes, this study shows efficacy of MDMA treatment in the course of a structured psychotherapeutic session for PTSD.
In terms of major limitations to this study, the first has to do with blinding of the treatment condition. I don’t really wish to go into expectancy, confidence in the efficacy of the therapeutic modality (ala E. Fuller Torrey), placebo effects and all that. Suffice it to say that for the highest confidence we would wish for successful blinding. It failed utterly in this study, perhaps unsurprisingly. The therapists identified the treatment condition for all subjects and 19/20 of the patients correctly identified the condition they were in. Not blinded in the least. This does not make the study useless, it just puts an additional consideration into our interpretation.
A second moderate limitation is that the subjects were treatment resistant and had previously been on SSRI medications. Since these chronic treatments induce some degree of plasticity of the serotonergic system, and a major effect of MDMA is on serotonin systems and indeed the Reuptake mechanism for which SSRIs are named, well, there are some things to think about. Throw in the original lack of response to SSRI and one wonders about the pre-therapy state of these patients’ serotonergic function relative to those who respond to SSRI therapy. Not a huge knock on this early stage study of course. I mean, if you are going to get a recreational drug with known neurotoxic and acute toxicity risk approved as adjunct it is going to have to beat existing medications in some way. Starting with the population that remains untreated despite the best current therapy is an obvious place to start. Still, from a neuropharmacological standpoint it makes this study less cleanly interpretable than otherwise.
One head shaking minor criticism is the inclusion of the single warfighter.[ * ] I can see where they are eager to go into this other index trauma but it just kinda looks like critique bait. Why bother?
There was one interesting thing I noticed in the paper. An outcome, not really a criticism or a kudos. I was critical before about the rational for “supplemental dosing”, i.e., giving half the original dose several hours into the session. This study reports that the 4 subjects who received a supplemental dose did no better or worse than those who received the single dose protocol. Great. So that should put paid to that part of the protocol in all of the additional trials this group is running (MAPS is a sponsor of this and several other similar trials worldwide). Right? Heh, I crack myself up sometimes. Somehow I bet they will find an excuse to keep on with the supplemental dosing.
The sleep aid zolpidem (Ambien) or a benzodiazepine were administered after a substantial number (40-60%) of sessions. Unsurprising that MDMA-treated patients would have difficulty sleeping and probably unsurprising that the psychotherapy-only group would have similar issues. Sort of complicates interpretation though. We can’t possibly know there are no interactions between the drugs, particularly when you harken back to the original theorizing about fear conditioning circuitry. If the effects of successful therapy (MDMA-assisted or not) have to do with conditioning, i.e., neuroplasticity…well, putting a benzodiazepine or a nonbenzodiazepine GABA modulator like zolpidem on board might just affect overnight consolidation, no? Again, no study can be perfect and this is not a fatal flaw it just makes things a little more complicated. We’d like to be able to connect some mechanistic dots as to how MDMA is supposed to be working to have full confidence that these effects are real. Real in the sense of being specific to the known pharmacological effects of MDMA.
There are more details in the study. As always, I encourage my readers to take a look for themselves. It can be found at the MAPS site if you do not have access from where you are browsing.
__
Mithoefer MC, Wagner MT, Mithoefer AT, Jerome I, & Doblin R (2010). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England) PMID: 20643699
*The original version contained this erroneous passage

The course of morbidity was a single month in comparison with durations of 232-273 mo for non-crime related and 8-11 mo for the crime related PTSD. (Hmm, come to think of it the warfighter couldn’t have met the criteria for failing 6 mo of prior psychotherapy and 3 months of pharmacotherapy.)

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44 Responses to “MDMA for PTSD: The first peer-reviewed clinical trial report”


  1. Those were very low doses. Instead of giving sleeping pills or benzos afterwards, they should have given the subjects beers and some fucken bong hits.

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  2. DrugMonkey Says:

    Very funny ding dong. These are most emphatically not “very low doses”. Not based on the consensus street availability at most times in the past few decades. Not based on controlled subjective report studies in human subjects. Not based on the modal intakes reported by human users.
    True, there are users, and plenty of them, who take much higher doses. This tends to develop over time in individuals with substantial use patterns and histories however.
    You know this because of course you’ve read every word I’ve written on the subject, including the posts linked in this overview.

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  3. mr. gunn Says:

    Fuckin threadshittin PhysioProf…
    Great review, DM. Glad to see some real research finally being done. The blinding of subjects will remain an issue, but overall this feels like progress.

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  4. DrugMonkey Says:

    I believe, from reading the successive protocol updates on MAPS, that they are trying an active placebo condition and/or a dose-response type of strategy. The idea of the latter being if you get a low dose the patient feels high but it might be nonfunctional from a therapeutic standpoint. Then if the higher dose works but you have less certainty on the part of the patient and therapist about when the “active” dose was on board, you have the same blinding effect.
    Is it “real research”? I dunno dude. Some of the things they are doing with respect to pushing the dose ever upward, and continuing to repeat sessions, doesn’t really make much sense. They don’t really have a decent hypothesized mechanism of action. Without that it is really hard to know how to perform the appropriate controls to show that MDMA has some special properties.
    OTOH, this is coming at this from a psychodynamic psychiatric perspective. Not an organic disorder or so-called “medicalized” perspective. And it is indubitably the case that Ecstasy users report subjective results that apply if you believe in psychodynamic theories of psychiatry.
    I may have to rope in PalMD to think through the logic on this one.

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  5. Dirk Hanson Says:

    So the subjects had taken at least 3 month’s worth of SSRI’s beforehand–which can take a while to wash out, and which blunt or alter the intensity and effects of at least some psychedelics,as I understand it–and then they are also taking benzos or Ambien afterwards? I’m no research scientist, but that does seem to muddy things a bit.

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  6. leigh Says:

    glad to see your thoughts on this one, DM. i’ll contribute a few of mine here as well.
    1. the heavily female subject group.
    yes, PTSD tends to be more prevalent in females. and perhaps there is an effect of sex in the treatment-resistance criteria of the condition to begin with. who knows. it still seems unduly skewed to me.
    sex x treatment (specifically drug AND therapy, and combinations thereof) interactions, anyone?
    2. the one token combat veteran. ffs. [shakes head] … ffs. that is all.
    3. age of onset/age at traumatic experience is something i didn’t see addressed but could be an important factor- at least as important as duration of symptoms/treatment attempts. maybe i got irked and didn’t pay as close attention on that one?
    4. i’m not buying the mechanistic stuff. really. and this is a big blockade for me. i get the strategy in making the attempt, don’t get me wrong, but if making the attempt adds little to the argument? otoh, it is a notoriously difficult thing to model in preclinical research, and without that preclinical support it is going to be far harder to hypothesize anything.
    5. the confounds of non-uniform benzo/zolpidem treatment bugged me a lot. first of all, both of those drugs individually and in combination have their own modulatory effects upon PTSD symptoms. next, we have no idea what effects MDMA might be adding/subtracting/multiplying/etc when those particular pharmacological tools are used. and since the incidence/timing of “rescue” treatment was essentially uncontrolled for, there’s no way we can know from that dataset.
    6. i would have liked to see some straight-up basic physiological data in there as well. baseline, with MDMA on board, MDMA + therapy session, etc. particularly things related to anxiety/fear.
    i think this is an interesting piece of literature, and certainly groundbreaking stuff. but i don’t see how it rules in or rules out any one hypothesis here. i will be keeping an eye out for larger studies.

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  7. juniorprof Says:

    I’ll take a stab at mechanism. Correct me if I’m wrong but, doesn’t MDMA actually cause efflux at the 5HT transporter kind of like amphetamine does at the DAT (and 5HT transporter too I think). This would be quite a different pharmacological effect than either an SSRI or a 5HT agonist (nearly all of which have some subtype selectivity) in that it would saturate 5HT receptors of all subtypes, so long as they were synaptic.

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  8. Klem Says:

    Hopefully NIMH will now start funding clinical and pre-clinical mechanism studies of MDMA (and therapeutic trials)!
    Keep in mind, MDMA is being studied for PTSD primarily because of pre-1985 clinical experience. In 1986 a DEA Administrative Law Judge ruled that MDMA should be Schedule III (rather than Schedule I), based on expert testimony on clinical use and available safety data. The files from the hearing are interesting to read.
    Anyway, what is the therapeutic mechanism of SSRIs? I don’t think there is a consensus. (Also, regarding neurotoxicity, SSRIs can also cause SERT downregulation and, at high doses, neuron damage in rats (see a review by NIDA scientists on MDMA in rats, Baumann 2007) – but for some reason there does not seem to be much concern about SSRIs.)

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  9. Scicurious Says:

    Great post, DM!
    I agree with Leigh that I really don’t like the benzo post-treatment. Are there any studies on the effects of that alone?
    I also agree with her that they REALLY needed a control for onset of symptoms and length of time spent dealing with the disorder.
    Also Juniorprof, the release may be a factor, but there’s a lot more to MDMA than neurotransmitter release. It’s a much dirtier drug than most people give it credit for (5-HT1 and 5-HT2 weak agonist effects, effects on VMAT, etc). I don’t know that I’d be willing to guess at mechanism until I’d tried all the specific receptor and transpoters alone and in combination. But I’m really thorough like that.

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  10. I would think that mixing MDMA and benzodiazepines would be bad for your heart? Also I’m a little confused… was the benzo administered to smooth out the comedown?

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  11. Vaughan Says:

    Excellent analysis although wanting a ‘decent hypothesized mechanism of action’ seems a little churlish given that this is absent from a whole list of psychiatric drugs widely in use and on the market, and many other medications besides.
    Clearly, understanding the mechanism of action is an important scientific goal, and as you say, useful for understanding adequate controls and the like, but as we can see from the history of psychopharmacology, it is not necessary to develop effective treatments.
    By the way, the study is by not coming from a psychodynamic perspective. You no more need to believe in Freudian or Neo-Freudian ideas to accept these findings than you do to accept research on how SSRI medication facilitates psychotherapy for depression or that CBT facilitates pharmacotherapy for psychosis.

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  12. DuWayne Says:

    I don’t think the lack of a mechanistic hypothesis is problematic, in and of itself. The problem for me is throwing psychodynamics into the picture. The bottom line, I am sorry to say, is that psychodynamic therapy is pretty much bullshit. While there are elements of it used in evidence based cognitive therapy, it is not the psychodynamics that Freud or Jung knew and loved. Psychodynamic psychiatry is even more of a load of shit, being the same theory that brought us the therapeutic use of cocaine and LSD by clinicians who should be locked up.
    That is not to say that cocaine, LSD and MDMA might not have their therapeutic uses. Cocaine in particular, as a short lived anti-depressant, would likely be useful as an adjunct to cognitive therapy for depression. It could make it easier to explore the thought processes driving a person’s depression, without causing a spiral and making it worse.
    Understanding what little I do about PTSD (mood disorders and addiction are what I geek on), I would imagine that cocaine would be useful there, for much the same reason. I would assume that is also why MDMA would be particularly useful. In essence, MDMA would allow a person to explore the cause(s) of their PTSD very vividly, while preventing that exploration from becoming a major stressor. This would also be really easy to fuck up – suggestion is a huge problem with PTSD (or in general) without MDMA. MDMA would very likely open a patient up to suggestion even more.
    The problem of course, is that MDMA also causes the very symptoms of PTSD. My guess would be that that is why the participants were given benzos or Ambien after. I am really not sure what else could be done, as it would be unethical (at least in my opinion) to leave someone with PTSD to suffer the come down from MDMA without a cushion of some sort. I am not sure what could really be done to remove any potential confounders, without causing potentially very serious problems. Honestly, were I a psychiatrist, I don’t know that I would be comfortable using MDMA therapy (at all really, but assuming I would) without also having the patient on an SSRI – especially if the patient is supposed to take the MDMA more than two or three times.
    EPM -
    I hope not. There are enough similarities between MDMA and my ritalin, that such a problem (if serious) would be rather bad for me. I think that taking large doses of both together would probably not be a good idea, but taking reasonable, therapeutic doses would not be so problematic.

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  13. DuWayne Says:

    Vaughn -
    By the way, the study is by not coming from a psychodynamic perspective.
    Yes it is. Not to the extent that I think the results should be discounted. But if they were following Grof’s protocols (or an approximation of them), then there was a significant amount of bullshit interspersed with useful therapeutic discussion.

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  14. yogi-one Says:

    It all sounds so ‘drug du jour’ to me, sorry to say.
    It all sounds so ‘drug du jour’ to me, sorry to say.
    I think PTSD treatment would be better without drugs. You would need a quite good therapist however, and a patient who was very serious and focused on overcoming their PTSD. To be able to raise emotional contact and guide them through those emotions without them either supressing the emotion or becoming over-identified with it (and thus re-traumatized) is not a trick for beginners. Meditation is a good technology towards developing this skill.
    I’m against it because once they start clinically, it’s all too easy for them to justify using it casually away from therapy. PTSD people can get in real backspins with uncontrolled drug use, and that possibility increases if in their minds, they think their doctor justifies drug use for their condition.
    I think if you want to use the recreational drug approach, Physioprof was right, even though he was joking. I bet you could get just as good results from having them attend group sessions where they shared a few bong hits and a couple of beers. Nobody gets addicted to anything, and nobody has to go through an amphetamine-style “crash”.
    Seriously.
    I think PTSD treatment would be better without drugs. You would need a quite good thrapist however, and someone who was very serious and focused on overcoming their PTSD. To be able to raise emotional contact and guide them through those emotions without them either supressing the emotion or becoming over-identified with it (and thus re-traumatized) is not a trick for beginners. Meditation is a good technology towards developing this skill.
    I’m against it because once they start clinically, it’s all too easy for them to justify using it casually away from therapy. PTSD people can get in real backspins with uncontrolled drug use, and that possibility increases if in their minds, they think their doctor justifies drug use for their condition.
    I think if you want to use the recreatyional drug approach, Physioprof was right, even thought he was joking. I bet you could get just as good results from having them attend group sessions where they shared a few bong hits and a couple of beers. Nobody gets addicted to anything, and nobody has to go through an amphetamine-style “crash”.
    Seriously.

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  15. yogi-one Says:

    Apologies for the double-post! Please edit!

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  16. DuWayne,
    That’s why I figured it would be dangerous, actually, because MDMA is so similar to drugs like ritalin. I know that kids will mix benzos (usually clonazepam or alprazolam IIRC) with Adderall (sort of the same effect as speedballing), and it’s supposed to be very dangerous, but then again I don’t know the dosages involved. I can’t imagine that mixing stimulants and depressants is exactly safe at any dosage, but then again what do I know.

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  17. …actually now that I think of it I think most of the danger comes from when these kids are using phenazepam that they order off of the internet. There’s no way to dose that stuff using household items and they wind up taking extremely high doses without knowing it.

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  18. DuWayne Says:

    I think PTSD treatment would be better without drugs. You would need a quite good therapist however, and a patient who was very serious and focused on overcoming their PTSD.
    Bullshit. While it is important to have a decent therapist and relatively committed patients, drugs help bridge the need to deal with what happened and not spiraling. You can argue that something that is primarily a recreational drug might be a bad idea, but to try to deal with the cause, without losing control is a lot easier with medication.
    To be able to raise emotional contact and guide them through those emotions without them either supressing the emotion or becoming over-identified with it (and thus re-traumatized) is not a trick for beginners.
    Crock of horse shit. There is absolutely nothing wrong with suppressing emotions, when extreme emotional reactions are the problem. The therapists job is to help the patient accept what happened and let go of the emotional reaction they are carrying around because of it. Going into the cause with the depth necessary is going to be exactly like being re-traumatized. Observing that with some forced detachment makes it easier to let it go.
    That is not to say that there aren’t behavioral methods that don’t require medication, but they also don’t fuck around with reliving shit either. There you are dealing with a very different approach, that focuses almost entirely on the behavior itself, rather than the cause.
    On top of that, what you are saying here is only useful for some number of people who meet your criteria for motivation and can only be used by therapists who are sufficiently spiritually aware.
    Meditation is a good technology towards developing this skill.
    While I won’t argue that meditation isn’t good for a lot of things, becoming a better therapist isn’t one of them.
    Seriously.
    I’m against it because once they start clinically, it’s all too easy for them to justify using it casually away from therapy. PTSD people can get in real backspins with uncontrolled drug use, and that possibility increases if in their minds, they think their doctor justifies drug use for their condition.
    Ok, first of all, a good doctor is going to make sure that they are not going to be a justification for substance abuse. That isn’t even all that hard to do. So let’s just throw that out right off the bat. Likewise, a good doctor is going to hammer down the notion that a little in therapy, justifies more outside of therapy. While there are people who are capable of selectively ignoring what their doctors say about it, when doctors are extremely clear and repetitive with their admonitions, such selective ignorance is exceedingly hard to manage.
    As for substance abuse and PTSD in general, a decent therapist will be aware of and monitoring potential problems. Substance use contracts aren’t unheard of, neither are requests for regular call ins to the clinic – if there is reason to suspect a given patient may have problems. There is always a risk of pushing an idea to the point that the patient decides “what the fuck? Other people like me do it.”
    But this is another place that drugs can come in handy. It is a lot easier to avoid fucking around with shit, when you already feel relatively stable.
    There are always tradeoffs to consider and there are always risks – no matter what the therapy. But what you are suggesting has absolutely no evidence to back it up. It is complete and utter bullshit through and through. It is the same sort of fucking bullshit that woo peddlers like to throw out there, along with claims that most of psychology is bullshit.

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  19. Gloria Says:

    EcoPhysioMichelle, how is MDMA similar to Ritalin?

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  20. DuWayne Says:

    EPM -
    It is also important to recognize that alcohol is also often a factor in kids getting hurt with prescription drugs. That is not to say that it isn’t happening with the drugs themselves, it does. And what you are describing is often a part of that. But as far as most fatalities and hospitalizations go, alcohol is usually a factor.
    Although this is an all around bizarre phenom, a major anomaly in drug use and abuse in children. I have written about it some, but could probably do with some more. It is because if prescription drugs that the SAMHSA National Survey of Drug Use and Health, is apparently going to lower the age of the survey from twelve, to ten. Mind you, kids as young as seven or eight have been discovered trading pills with friends, or ended up in the ER because of it.
    Click my name and scroll down a couple of posts, for info on substance use and kids. Having at least one kid with a lot of risk factor, I have a very strong interest in the topic.

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  21. Gloria, I was referring mainly to their effects on the heart at high dosages, not implying that they have similar psychological effects.

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  22. Horrible Clarity Says:

    Off the top of my head and a bit out of left field, but I just recently read a paper by Weaver in Nature Neuroscience (2004,7, 847-854) where they showed that poor maternal care causes changes to the methylation state of a promoter for glucocorticoid receptors, permanentley messing up the HPA axis and stress responses in rats. I’m pretty sure a 5-HT based mechanism was propesed to explain the maternal care actions.
    A similar action could be at play, powerful emotional event = severe PTSD due to changed fear responses, MDMA = massive 5-HT release and allows changing of methylation state of stress related genes.
    I’m surprised that MAPS doesn’t fund any animal work if they are really serious about this work, finding a plausible mechanism is important to legitimizing this.

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  23. DrugMonkey Says:

    By the way, the study is by not coming from a psychodynamic perspective. You no more need to believe in Freudian or Neo-Freudian ideas to accept these findings than you do to accept research on how SSRI medication facilitates psychotherapy for depression or that CBT facilitates pharmacotherapy for psychosis.
    It Is though. If you look at the explanations of the team, it is very heavy on the ideas of openness, dealing with affective “pain” and the alleviation thereof and other concepts that are based in what we might call psychological constructs. This is not to say that those constructs might not map on the neurophysiological and neurochemical processes, it is just that these folks do not make those connections. Or at least don’t lean on these anywhere near to the extent that they prefer talking about the constructs.
    EPM and Gloria, MDMA has stimulant like, i.e., indirect dopamine agonist, properties as well. affinity at the dopamine transporter, inhibition and reversal of that transporter..resulting in increased dopamine efflux. Just like ritalin has indirect dopamine agonist properties so in one neuropharmacological aspect, they have similarities.

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  24. DuWayne Says:

    …finding a plausible mechanism is important to legitimizing this.
    Ok, this just bugs the shit out of me. Why exactly do we need to find the mechanism for this drug and not, say, Welbutrin? Or Prozac? I am not trying to speak defensively about MDMA, but what the hell is the deal with singling this out, when we don’t know the mechanisms behind a hell of a lot of psych drugs – or even non-psych drugs?
    DM -
    Seriously, all you need to see is that they were following Grof’s protocols, altered slightly. Grof explains his own work as psychodynamic exploration of the soul – or some mystical life force, using LSD. And it is. I read about his work years ago, when I believed in spiritual duality. I had a lot of mixed feelings about it then, because while it confirmed my thinking about hallucinogens, I was already seeing psychodynamics as being so much nonsense. Not because I wanted to, but because the evidence suggested it is. I was fighting serious confirmation bias on that one, a I had also been a huge Jungian.
    I would suggest you read up on Grof sometime, I am absolutely certain you would have something to say about him. My abnormal instructor was went on a bender about him, when someone asked about him in class. Even a lot of people who are big believers in psychodynamics find him worse than laughable.

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  25. Craig Says:

    I’m with DuWayne on this: the thing that I’d be most inclined to object to in this study is the lack of any attempt at a negative control or placebo for the talk therapy aspect. What evidence do they have that MDMA plus talk therapy works better than MDMA alone (or MDMA plus a long chat with a supportive friend)?

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  26. Horrible Clarity Says:

    Why exactly do we need to find the mechanism for this drug and not, say, Welbutrin? Or Prozac?
    Because Welburtin and Prozac aren’t potentially drugs of abuse (at least I’ve never heard of people getting high on anti-deppresants). I’m not saying its ‘fair’ but the standards of evidence that people are going to want before this is truly accepted are going to be higher beacuse of the stigma associated with drugs.
    Also I think its an incredibly interesting question, if MDMA is making such a massive positive impact on a (usually) intractable condition like PTSD finding out how is really important and could revoltionise psychopharmacology.
    Hell, finding biological explanations for why a drug that makes you feel really good and empathic helps with treatment resistant PTSD (it makes sense psychologicaly but we don’t have a good story as to what is happening neurologically) is a major step in working out more complicated levels of the whole brain-mind question. Especially with your stated distaste for psychodynamic interpretations (which I largely argree with) finding biological pathways to explain these effects is how we are going to get more satisfying explanations.

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  27. DuWayne Says:

    Craig -
    You misunderstand me entirely, I am not averse to talk therapy and actually think it would be reckless to do this without some sort of talk therapy. It is the type of talk therapy that is problematic here. Honestly, I am not a big fan of using drug therapies without some kind of talk therapy, with the possible exception of maintenance for mood disorders.
    I would rather they used cognitive behavioral therapy. There is actual evidence that it works reasonably well in general and that it works better than other therapies for PTSD. By addressing not only the root problem, but also addressing both the internal cognitive behaviors and the external world behaviors, you basically address everything. It is important to confront and address the the actual stressor(s) that caused the PTSD and if done properly, that may allow the patient to address the rest. But if you also address the thoughts – the rationality of the thoughts, the circumstances in which those thoughts occur and hit on the behaviors that follow those thoughts, you aren’t leaving the patient alone to work that on their own.
    Perversely, a strict behavioral approach isn’t out of the question either, though while antidepressants or antianxiety drugs might be part of the patients general maintenance, they are not at all part of the talk therapy. It is also rather difficult to use this therapy for PTSD, but there are some advantages to this approach, one of them being that the patient can apply the principles to other problems or problem behaviors. The disadvantage is that it wouldn’t likely work so well for people with more serious cases of PTSD.
    Horrible Clarity -
    I don’t buy it and it isn’t because of “fairness.” Nor, to be clear, do I like not understanding the mechanisms. What I do like, is to see people with serious mental/emotional problems get better. As such, I really don’t give a fuck why something works, in the face of using it to help people.
    That isn’t to say that finding out how these drugs work isn’t important to me, it is and largely for the reasons you state in your last para. I also think it’s important, because MDMA, like a lot of accepted psych drugs has serious, antithetical side effects. I want to understand why MDMA causes an oppositional reaction. I want to understand why a lot of antidepressants can make a person suicidal. I think these are extremely important questions.
    But that doesn’t mean I want to wait until we understand those mechanisms to use them. If the results of this study can be generalized, you can fuckingwell bet that I want to see MDMA used to help treat serious cases of PTSD. I would prefer they use evidence based talk therapy, as that would be far more efficient than throwing nuggets of actual useful therapy, in with a ton of bullshit. But given the difficulties related to treating PTSD in a more traditional fashion and the scope of the cases we have to deal with, I am all for going through more clinical studies and approving the therapy if they work out.
    Don’t get me wrong, I am not interested in reckless bullshit. I want to see this get the same scrutiny that other drugs get, and some. I just think it is fucking ridiculous to get all up in arms about mechanisms, when we don’t understand the mechanisms of a hell of a lot of other drugs, including other potential substances of abuse.

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  28. Craig Says:

    DuWayne: I’m not averse to talk therapy, as long as it is proven by evidence to be efficacious. And not just in a general “well, CBT seems to work a bit in some conditions, so it isn’t quite as useless as older psychodynamic therapies” way either.
    It needs to be proven to be effective at treating this particular condition, in conjunction with this particular drug. The talk therapies should be held to the exact same standard or proof as the drug therapies, for the same reasons. Hence, the need for negative and placebo controls.

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  29. Craig Says:

    “Standard or proof” was meant to be “standard of proof”, obviously. Too many 12hr days in the lab lately…

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  30. DuWayne Says:

    Ummm, Craig, there is actually a great deal of evidence to support CBT. Not just a little and not just indicating that it helps a little for some disorders. CBT has been studied more than most any other therapy, though ironically, an exception would be pyschodynamic bullshit. When you are dealing with severe, induced (ie. triggered by a stressor) psychological disorders, CBT is the gold standard.
    CBT has been studied and proven to work more effectively for treating PTSD, than anything else, including drugs alone. Because of the nature of PTSD in particular, it would be extremely reckless to offer a patient a drug like MDMA without also providing talk therapy. We know enough about the effects of MDMA, to know that it is more likely that a patient is going to wander off into her or his own little escape, than it is that they are going to confront something so unpleasant. And that is the fucking point of the whole exercise.
    Without adjunct talk therapy, it is no different than giving someone a recreational dose of ecstasy. And regardless of whether this ends up working out or not, MDMA isn’t something to fuck around with like that.
    Given the problems that drug therapies can cause – the known potential and common side effects, and the very serious questions that have arisen recently about evidence for the efficacy of a lot of psych drugs, I am going to stand very firmly on the side of adjunct talk therapy. The entire theory of “chemical imbalances” that can be compensated for with drugs alone has pretty well been decimated by decades of failure.
    What there is actual evidence for, is that drugs, in conjunction with evidence based talk therapy, can help those with debilitating, permanent mental illnesses function. And there is evidence that drugs can help people get through evidence based talk therapies that will actually help them get better (ie. eventually need neither drugs nor talk therapy), without making things worse (ie. confronting the negative thoughts that, for example, feed depression and cause a spiral).
    This is not only supported by a hell of a lot of studies of several disorders, this is also supported by what we have learned about the brain in the last couple of decades.

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  31. JayVee Says:

    I’m wondering what was used as the placebo. Ecstasy causes a euphoric high (for a few hours), which is caused by MDMA, right? Doesn’t that strong effect make it obvious to the patients whether they had the real thing (MDMA) or a placebo? Or did they use another drug to “simulate” the high for the placebo? Or maybe they didn’t tell the patients that MDMA was the substance they were studying?

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  32. Craig Says:

    DuWayne:
    Hmmn…you quite likely have a point. I was under the impression that CBT had only really convincingly demonstrated efficacy in the treatment of phobias, but it looks like I was mistaken.
    I’m going to have a dig through Bisson J, Andrew M. Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane Database of Systematic Reviews 2007, Issue 3. as soon as I get a break from the lab and catch up on my sleep (last perfusion day tomorrow, thankfully…).
    Are there any other key sources you’d recommend?

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  33. DuWayne Says:

    For sources on PTSD and CBT, the best I could recommend now, would be a few lit reviews, as they list studies and allow you to look more closely, while providing a decent explanation of aggregate conclusions. I will list them here, so this comment doesn’t get held for moderation.
    I would like to clarify something, before you check those out – something that a couple of the reviews actually mention. EMDR is basically a form of CBT, with some specific additions that I quite honestly don’t understand. It is also important to recognize that there are different ways to consider a given psychological disorder. Like I said above, I am not nearly as familiar with PTSD, as I am with substance use disorders and mood disorders. But given teh efficacy of CBT with those, I am very familiar with many of it’s other uses.

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  34. DuWayne Says:

    Ack – all fancy and shit, then I forget to post the link…Here;
    http://dbraytonkvcc.blogspot.com/

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  35. Craig Says:

    DuWayne: thanks for that. However, that link requires an invite to access, which apparently I don’t have.
    Any chance you could email it to craigm[at]psych[dot]usyd[dot]edu[dot]au?

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  36. DuWayne Says:

    Shit – if anyone else actually wants the links, let me know.

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  37. Idealist Says:

    Using drugs to treat PTSD, particularly when it is resulting from the battlefields of war allows us to conveniently avoid consequences, and to devolve our thinking toward social acceptance for conditions we should not be tolerating.
    It’s a shortcut, a convenience, as much so for allowing society to tolerate the sufferer as it is a fast fix for the sufferer, while the causes in society go unchecked.
    wars; violent crimes; domestic violence, rape; natural or manmade disasters…
    What pill for these?

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  38. jack Says:

    When you say that the authors do not provide a satisfying potential mechanism of action, I doubt that you have ever taken a psychedelic drug. The authors provide an extremely obvious and convincing explanation for the mechanism of action, that is, enabling patients to directly confront their memories and discuss them with the therapist without shutting down and having their defense mechanisms and fears block the therapy. To anyone who has done LSD or ecstasy, it will be obvious that this therapy will be effective. I had no doubt the results of this study would be spectacular, as they would be with LSD and psilocybin as well, for appropriate conditions.
    Two problems hold up these therapies: (1) Pharmaceutical companies have no interest in off-patent drugs that will be administered only one or two times to a patient. In fact, they’d prefer this research be suppressed as it threatens to bite into their billions-of-dollars-a-year psychiatric medication revenues. (2) Brainwashed warriors in the war on people who choose to use some drugs that are not sold by pharmaceutical concerns can’t get over their bigotry against those who say yes, and their prejudice against the substances themselves. Oh, yes, and (3) $50-billion a year drug war has bureaucratic momentum. Wouldn’t want any of it getting defunded, would we? Well, the DEA wouldn’t want that. So we have to tow the line – drugs is bad. M’kay?

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  39. DrugMonkey Says:

    The authors provide an extremely obvious and convincing explanation for the mechanism of action, that is, enabling patients to directly confront their memories and discuss them with the therapist without shutting down and having their defense mechanisms and fears block the therapy.
    This is a psychodynamic “mechanism” of action however the authors are trying to connect neurobiology to such cognitive constructs. It may be an “obvious” explanation but it falls far short of being convincing. We have other drugs that manipulate these systems..and don’t have the abuse potential. So why is MDMA so unique then?
    Brainwashed warriors in the war on people who choose to use some drugs that are not sold by pharmaceutical concerns can’t get over their bigotry against those who say yes, and their prejudice against the substances themselves.
    Brainwashed legalize-eet fans who can’t separate their desire for unfettered personal drug use for recreational purposes from assessment of what science is telling us about the properties of those drugs.

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  40. I definitely feel that most of the MDMA “related” deaths have been labeled wrongly as direct use of MDMA in its pure form, taken in safe environments is shown to not cause harm. People are dying either from bad pills/ powder or drinking too much or too little water. Aside from recreational use there is definitely room for therapeutic & scientific use of MDMA just as there is with Marijuana.

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  41. DrugMonkey Says:

    I definitely feel that most of the MDMA “related” deaths have been labeled wrongly as direct use of MDMA in its pure form, taken in safe environments is shown to not cause harm.
    HAHAHA, and why pray tell do you “feel” this way when it is so demonstrably untrue? Unless you conveniently define “safe” environment as one which has not been shown to date to result in death?
    People die from MDMA only, taken in “recreational” amounts and in the quiet of their own home too, you know.

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  42. bryan Says:

    HAHAHA, and why pray tell do you “feel” this way when it is so demonstrably untrue? Unless you conveniently define “safe” environment as one which has not been shown to date to result in death?
    People die from MDMA only, taken in “recreational” amounts and in the quiet of their own home too, you know.
    links?

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  43. DrugMonkey Says:

    Click on Archive link in header. Click MDMA. Read. All of it. …if you are interested instead of being after easy dismissals that is….

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  44. What is molly Says:

    I know multiple people who take the drug (tested and in pure form, from direct from the source) multiple times a week in upwards of 400mg per dose and have little to no adverse effects. I’d just like to see some proper scientific research done using actual MDMA and not METH. I would love to have a study conducted where a handful of non MDMA (OR other drugs) users took MDMA in a lab and see how many of them die. It would be nice to know what it would take to determine the median lethal dose (LD50) of the substance.

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