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Treatment With MDMA

A theme that I return to every so often on the blog is the degree to which we don’t understand the molecular mechanisms of psychiatric syndromes. I’ve found that many people outside of the biomedical world are surprised by this – depression, for example, is something that’s distinctive enough, widespread enough, and certainly has enough of a presence in most people’s consciousness as something real (as it should). And there are even pop-pharmacology  explanations that many people have heard of (“not enough serotonin!”), so it can come as a surprise to find out that we really, really don’t have a handle on it on that level at all. And the same goes for all the other diagnoses with similarly high profiles, such as schizophrenia, PTSD, and more.

Confusion is sort of built in with these, because it is certainly true that all of these fragment into more-or-less distinct subtypes on closer examination. In depression, for example, there is manic depression, which is a very different thing than the classic major depression, and there’s post-partum depression, and so on. Anxiety disorders, attention disorders. . .all of these similarly can be (and are) subdivided into various other syndromes, each having greater or lesser overlap with its neighbors. It seems quite likely that there are shared molecular and cellular pathways between such related syndromes, but at the same time it’s also likely that some of them are quite different from each other and just manage to land in the same rough phenotype. With both the “splitting” and the “lumping” classification schemes being plausible, it’s no wonder that these areas are (so far) difficult to systematize.

An extra layer of confusion is also baked in to any discussion of these topics, because they bang right into the philosophical problems of consciousness and of its relationship to physical reality. At the extreme, you get the less-than-useful “It’s all in your head” comment directed at sufferers of these things, which invites the response of “What isn’t?” Dialed back a notch, you get the somewhat more common attitude that “OK, yeah, I understand that some people have really crippling depression or anxiety, but you don’t, so why don’t you just try not thinking about that stuff – ever tried that?” That’s no help either, of course, not that it slows some people down. People have different ideas about what it means to say that something is “real”.

Look at post-traumatic stress disorder. When someone has had an overwhelming traumatic experience and continues to feel effects from it months or years later, the original stimulus is obviously not there any more. A combat veteran doesn’t wake up in the middle of the night because there’s a real battle going on. What real beyond doubt, though, is that such a person’s central nervous system has truly been affected by that earlier experience. This would be a good point to note that we don’t understand that much about the molecular and cellular mechanisms of memory, either. And when the effects of that trauma get re-stimulated, there is real cortisol and real adrenaline in their blood system with all the very real physical correlates in the rest of the body (heart rate, sweating, muscle tremors and more).

All this leads up to this new paper (open access) in Nature Medicine. It presents the result of a randomized placebo-controlled trial for PTSD sufferers. 45 of them got placebo medication plus integrative psychiatric therapy, and another 45 got the same psychiatric therapy after doses of MDMA. The results very strongly indicate a positive effect for the latter, as assessed by widely-accepted ratings scales administered by independent (treatment-blinded) observers. These results appear to be better than any of the drugs actually approved for PTSD therapy, namely sertraline and paroxetine.

An obvious confounding variable is that the objectives of the study (MDMA effects on PTSD) were of course stated at the beginning of the trial (you have to do that!), and that it may well have been obvious pretty quickly to the patients which group they were in. The authors note this problem, but mentioned in the follow-up unblinding interviews that there were at least 7 people in the placebo group who thought that they were getting MDMA, and at least two patients in the MDMA group who had thought that they were getting placebo, for what that’s worth. The paper also notes that follow-up is so far limited to two months past the last experimental session, but they’re planning on continued checks. The coronavirus epidemic also made the overall study group smaller than they had planned.

I would have liked a third arm of “therapy without placebo” to really see what the expectation effect might be in a trial like this, but I’m not sure how that would fly with a review board. But the differences between the two study arms we have, coupled with the good safety profile noted, seem to me to make a strong argument for MDMA therapy. Another trial is underway (similarly sized), and the organization behind these (MAPS) is planning to try for FDA approval if that one is also positive. I certainly hope it is – around half of PTSD sufferers don’t respond to current therapy at all, it seems, and it can obviously be a crippling thing to live with.

As the discussion that started this post should make clear, the question of “how does it work” is not yet answerable past a certain point. The MAPS authors believe that the drug makes it more possible for patients to approach the traumatic memories without setting off as many associated symptoms, and that this along with the therapy gives a person experience in encountering these memories without going then down the same pathways as before. Just seeing that it’s possible to do that at all must mean quite a bit, you would think. But that’s about as far as explanations can go for now, and I hope that in years to come the ones we currently have will seem vague and primitive. By that point the use of MDMA itself may seem primitive as well, but for now it’s looking like a real advance on what we have.

And this work is of course part of a broader movement for the controlled use of psychedelics and other drugs largely known for recreation and for abuse. I’ve written about this before on the blog. Some people who know me personally will have encountered my own policy of no recreational drug use, which is pretty wide-ranging and of lifelong standing. But I’m all for these studies – given the state of knowledge in the field, I see absolutely no reason not to investigate a drug that might be useful just because other people want to take it for fun. It seems a ridiculous distinction to make. And even though I have no desire at all to experiment with my brain chemistry on a random Saturday night, if I suffered from something like PTSD – and I am overwhelmingly glad to say that I don’t – I would leap at the chance to alter my brain chemistry in order to lessen it.

66 comments on “Treatment With MDMA”

  1. Andrew says:

    This post surprised me. The author looks and writes like someone who would enjoy an occasional taste of the hippy lettuce.

    1. Derek Lowe says:

      Nope, this is what I’m like after decades of complete sobriety. . .

      1. miles says:

        Wild ideas like starving komodo dragons and chihuahuas come naturally to Derek without chemical assistance…must have been the lab time that made him bonkers

        1. Pedwards says:

          Nobody finishes grad school without a bit of madness. Usually it’s just a question of how much madness vs. how much they had when they started their PhD.

      2. The ether bunney says:

        Ahem… and the times spent TA-ing those labs with poor to no flume hoods were sobering experiences?….

        1. Derek Lowe says:

          You sound like someone who’s heard my “TA-ing the phenyl Grignard three times in one week” story, for sure. . .mind you, by partway through the second one I was mostly out in the hallway, because the smell of the ether was about to make me hurl.

          1. truthortruth says:

            Can you link to this story. Sounds lovely 🙂

          2. An Old Chemist says:

            @truthortruth: Here is the link to Derek’s story about phenylgrignard driving him out in the hallway:
            https://blogs.sciencemag.org/pipeline/archives/2020/02/06/the-good-ol-grignard

          3. Miles says:

            No, but I look forward to reading it. My first degree was Agricultural Botany, and selecting species and feed mixes to maximize yields, as in, getting cows to produce five gallons a day. That involved sampling stuff from various parts of the digestive tract. Sometimes things got a bit “gaseous”…and a fellow student was unfortunate enough to be in the firing line standing behind the moo, wearing a new jacket (city types wear new Barbours on the farm).

      3. Shazbot says:

        You may not like it, but this is what peak performance looks like.

  2. DRN says:

    Also psilocybin, kavalactones, tryptamine derivatives, and probably a dozen other compounds have great potential for mental health… but who cares…

    1. Doctor Memory says:

      Thankfully, the MAPS project cares rather a lot, and it’s rather a lot thanks to them that ketamine is basically the closest thing we’ve had to a breakthrough in the treatment of chronic depression ever. We’re finally starting to un-do some of the damage done by the blanket prohibition of research in this area, and I’m really excited to see what’s going to come next.

  3. BrainMostlyHealthy says:

    To answer the less than helpful comments our host mentions:
    “Have you tried doing tensor calculus? Why not? IT’S ALL IN YOUR HEAD. Or rather isn’t.”
    Learning andvanced maths is easier than learning to regulate ones neurotransmitter production.

    1. Riemann says:

      I can’t really parse Mr. MostlyHealthy’s disjoint comments; however, it does remind me of the time that the father of a former girlfriend told me, “You can’t possibly understand biology if you don’t know tensor calculus”. (a bit lordly, but he was ScD, ScD, FCGI, FRS)

      I get where he was coming from, in a tensor-like way…

      1. AVS-600 says:

        That seems pretty non-sensical to me. But I’ll give him the benefit of the doubt and assume that he was going for a vacuous truth, and his intended point was “You can’t possibly understand biology”.

  4. Tony says:

    Sure. Just as it’s possible to be against using narcotics for recreational purposes, while still recognizing that they are a godsend for someone with terminal cancer, or who shows at the ER with a finger ripped off by a drill press.

    Even if the psychedelics we know of don’t turn out to be directly useful, it is clear that these compounds have profound effects on the brain. One can’t help but wonder how much more advanced our understanding of psychopharmacology would be if psychedelics research hadn’t been effectively banned for 50 years.

    1. Carl Pham says:

      Or what it would be like if some subset of human beings weren’t shitheads who consistently abuse any new technology so badly that the rest of us develop defensive hostility towards it. Everything from the abuse of powerful — and potentially useful — drugs resulting in the general hostility that produces, enrtirely predictably, clumsy overreach by government, to the endless effort we all have to take now against e-mail and phone spam, or ransomware attacks.

      A shame we don’t just promptly eliminate those among us who act like internal viruses, exploiting whatever means there is at hand in pursuit of their narcissistic goals, heedless of any larger cost. After 50 generations we might be able to keep the nice things that science creates for us.

      1. aairfccha says:

        Along a similar line of thinking: Prohibition would have worked just fine if only people had stopped drinking.

        There is just one problem: IT DOESN’T WORK. People DO like to play with their bio- and neurochemistry and the pearl-clutching moralists should better learn from their failures, learn to live with that reality and not attempt to impose their world view on the rest of the world, messing things up worse than drugs on their own ever could.

      2. aairfccha says:

        A shame we don’t just promptly eliminate the prohibitionists who act like internal viruses, exploiting whatever means there is at hand in pursuit of their narcissistic goals, heedless of any larger cost. After 50 generations we might be able to keep the nice things that science creates for us.

  5. albegadeep says:

    I wholeheartedly agree with the “no recreational use of drugs but they’re good things to research” concept. The number of anecdotal stories of, for instance, CBD oil helping with various neurological issues definitely warrants research – but smoking pot for fun isn’t so good. (For one thing, SMOKING it is going to cause its own health problems.)

    In the end, I suspect some of the Schedule I controlled substances will eventually be found to have appropriate medicinal use, when administered in just the right quantities. While a ban on the general population using them is appropriate, don’t ban them for research!

    1. CET says:

      I’m reluctant to ask this, given the internet abyss that it tips toward, but does anyone with an a background in anth or sociology or history or poli sci have a good general resource for the history of the perspective that there is no difference between ‘I don’t think x is a good idea’ and ‘I don’t think other people should be allowed to do x’?

      It seem to me that the one does not necessarily follow from the other, but it is often assumed that is does (or should).

      1. En Passant says:

        … good general resource for the history of the perspective that there is no difference between ‘I don’t think x is a good idea’ and ‘I don’t think other people should be allowed to do x’?

        One useful book on the history of drug prohibitions (including alcohol and caffeine), is Thomas Szasz, Ceremonial Chemistry: The Ritual Persecution of Drugs, Addicts, and Pushers. Syracuse, New York: Syracuse University Press. 2003 [1974]. ISBN 978-0-8156-0768-7.

        It is well documented, and full of footnotes to source material.

        Ceremonial Chemistry offers insights into the reasons for peoples’ belief in drug prohibitions. The reasons are variations on “it’s for your own good”.

        C. S. Lewis wrote scathing commentary about the imposition of “for your own good” laws decades before, in God in the Dock: Essays on Theology and Ethics:

        My contention is that good men (not bad men) consistently acting upon that position [imposing “the good”] would act as cruelly and unjustly as the greatest tyrants. They might in some respects act even worse. Of all tyrannies, a tyranny sincerely exercised for the good of its victims may be the most oppressive. … To be “cured” against one’s will and cured of states which we may not regard as disease is to be put on the level of those who have not yet reached the age of reason or those who never will; to be classed with infants, imbeciles, and domestic animals.

        1. CET says:

          Thanks! I’ll have to check out the Szasz book, and the one by CS Lewis. His work is very hit or miss for me, but it’s always interesting.

          To be fair, I’m curious about the attitude well beyond it’s application to drug laws. I’ve been noticing it a lot lately in subcultures that didn’t used to think that way. I can’t tell if it’s just a side effect of the human tendency to hubris and reflexively assuming that our own positions are definitely the correct ones, or if there is actually a well developed set of arguments around ‘for your own good’ as a justification.

    2. Orange_Pills says:

      The argument made against prohibition does not question if the ban is appropriate (although that is still an issua to be discussed) but if it works.
      Any so called narcotic is just 2 clicks away and gets delivered by the mail man. Is it reasonable to assume that doubling the police budget changes that?

      1. Skeptical says:

        The counter-argument (which I’m sympathetic to in the case of strongly addictive substances, like opioids and cocaine) is “how much worse would the current problem be if these drugs were even easier to get?” I find it hard to believe that addiction wouldn’t be more widespread, even if it would be easier to treat.

        1. aairfccha says:

          With opioids, most problems are a result of (or strongly escalated by) prohibition rather than of the drugs.

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219559/

        2. JDK says:

          Places that have tried it (Portugal for one) have had great success in reducing addiction levels but the legal access was also paired with social policies as well. Any prohibitions make drug problems worse, one would have thought that Prohibition made that clear but obviously not.
          “Evidence … proves that prohibition only drives drunkenness behind closed doors and into dark places, and it does not cure it or even diminish it.” Mark Twain

    3. Gus says:

      So are you in favour of banning the recreational use of alcahol then? Without doubt one of the most dangerous drugs on the planet both physically and mentally. Your views are absurdly anachronistic, culture bound and certainly not based on science.

  6. Tom says:

    Well, there are some clues out there as to how they work: https://www.cell.com/cell-reports/fulltext/S2211-1247(18)30755-1#secsectitle0025

      1. Tom says:

        I think it’s the durable plasticity effects that are most interesting to me. Maybe neurodegeneration experiments are worth a look here, too.

  7. McKenna says:

    Their training manual for therapists is quite curious. Obviously it adresses people without scientific background but they propose the concept of a “healing intelligence” that everyone has. Their treatment is just a mechanism to allow this to happen and does not need much (if any) intervention.

  8. Brian says:

    This is an ignorant but sincere question for the statisticians here. Is 45 patients receiving the MDMA therapy enough to believe that this works with this level of success using this mode of testing? If it was 90 or 120 patients with a positive result, would you believe it more?

    1. McKenna says:

      If the effect is large enough you don’t need large samples. If you want to test if parachute safe lives you wouldn’t need more than one bag of potatoes in each group to see a conclusion.

      In relation to this study. In the placebo group one third had improvements seen in their condition, while the verum group had two thirds with a response (and a larger effect too). This is different from statins where 140 patients taking it for a year yield 1 patient living a year longer.

      1. Brian says:

        Thanks.

      2. Skeptical says:

        That’s a larger effect than I expected of statins.

      3. Anthi says:

        Please dont write about Statins if you only write about efefcts after 1 year, evryone who is i this field than knows that you havend read the studies about simva an so on

    2. eyesoars says:

      What McKenna said. Often a large number of study subjects indicates that the treatment effect is real but may be nearly negligible. Conversely, e.g., studies of tart cherries/cherry juice on gout are quite small, because two dozen subjects is enough to conclusively prove effect.

  9. Oligodendrocyte expert says:

    A substantive, rather than “substance,” comment….hey, I think there’s a little science humor there somewhere! With the realization CNS myelin is dynamic, not static—and that that dynamism is in response to behaviorally-relevant neuronal activity—has arisen the concept of maladaptive myelination, i.e., “abnormal” (neuronal) activity-dependent myelination. It is likely the effects of stress on oligodendrocytes and their progenitors, NG2 glia—and MDMA’s capacity to dampen or counteract those effects, and the resultant maladaptive myelination—is a key element of MDMA’s mechanism of action in the PTSD studies Derek is highlighting.
    https://www.biorxiv.org/content/10.1101/2021.02.15.431176v1
    “Region-specific maladaptive gray matter myelination is associated with differential susceptibility to stress-induced behavior in male rodents and humans”

  10. Jonathan B says:

    The bottom line is that treatment of mental health disorders is hard. Despite enormous amounts of work researching brain function the understanding of mood and cognition is obscure. There is quite a lot to be said for a black box approach: if a chemical is known to be psychoactive and sufficiently safe why not look to see if it is effective in psychiatric conditions that are severe enough to justify that drug?

    As a scientist (not a doctor) who happens to have had some experience with sufferers from mental health problems, it seems to me that the standard diagnoses are based around symptoms rather than causes which makes categorisation difficult. For example patients with “depression” seem variously to respond best to a range of the available drugs (despite your recent post positing a common mechanism) or non-pharmaceutical interventions. Are those really the same illness, or different underlying problems with overlapping consequences? A unidimensional description of depression in terms of serotonin is almost certainly a cop-out.

    It is possible PTSD is somewhat more homogenous, in which case finding a known drug is beneficial will bring strong benefits.

    1. luysii says:

      Jonathan B: “it seems to me that the standard diagnoses are based around symptoms rather than causes”

      Exactly. But you need to know some history to see why this is so (and why it is actually an improvement on what came before).

      The following is a fairly extensive quote from a blog I write — https://luysii.wordpress.com/2013/05/02/the-dsm-again/

      Docs bring diseases into existence all the time simply by naming them. This is why the new DSM-V (Diagnostic and Statistical Manual of Mental Disorders) of the American Psychiatric Association (APA) is so important. Is homosexuality a disease? Years ago the APA thought it was. If your teenager won’t do what you want, is this “Adolescent Defiant Disorder”? Is it a disease? It will be if the DSM-V says it is.

      There are a lot of things wrong with what the DSM has become (297 disorders in 886 pages in DSM-IV), but the original impetus for the major shift that occurred with DSM-III in the 70s was excellent. So it’s time for a bit of history. Prior to that time, it was quite possible for the same individual to go to 3 psychiatric teaching hospitals in New York City and get 3 different diagnoses. Why? Because diagnosis was based on the reconstruction of the psychodynamics of the case. Just as there is no single way to interpret “Stopping by Woods on a Snowy Evening” (see the previous post), there isn’t one for a case history. Freud’s case studies are great literature, but someone else would write up the case differently.

      The authors of the DSM-III decided to be more like medical docs than shrinks. In our usual state of ignorance, we docs define diseases by how they act — the symptoms, the physical signs, the clinical course. So the DSM-III abandoned the literary approach of psychodynamics and started asking what psychiatric patients looked like — were they hallucinating, did they take no pleasure in things, was there sleep disturbance, were they delusional etc. etc. As you can imagine, there was a huge uproar from the psychoanalysts.

      Now no individual fits any disease exactly. There are always parts missing, and there are always additional symptoms and signs present to confuse matters. The net result was that psychiatric diagnosis became like choosing from a menu in a Chinese restaurant, so many symptoms and findings from column A, so many from column B. (Update 2013 — Having been to China for 3 weeks this year, restaurant menus over there aren’t like that).

      This led to a rather atheoretical approach, but psychiatric diagnoses became far more consistent. Docs have always been doing this sort of thing and still do (look at the multiple confusing initial manifestations of what turned out to AIDS back in the 80s). Different infections were classified by how they acted, long before Pasteur proved that they were caused by micro-organisms. Back when I was running a muscular dystrophy clinic, we saw something called limb girdle muscular dystrophy , in which the patients were weak primarily in muscles about the shoulders and hips. Now we know that there are at least 13 different genetic causes of the disorder. So there are many distinct causes of the same clinical picture. This is similar to the many different genetic causes of Parkinson’s disease I talked about 2 and 3 posts earlier. At least with limb girdle muscular dystrophy it is much easier to see how the genetic defects cause muscle weakness — all of the known genetic causes involve proteins found in muscle.

      Where DSM-IV (and probably DSM-V — it’s coming out later this month) went off the rails, IMHO, is the multiplicity of diagnoses they have reified. Do you really think there are 297 psychiatric disorders? Not only that, many of them are treated the same way — with an SSRI (Selective Serotonin Reuptake Inhibitor). You don’t treat all infections with the same antibiotic. This makes me wonder just how ‘real’ these diagnoses are. However in defense of them, you do treat classic Parkinsonism pretty much the same way regardless of the genetic defect causing it (and at this point we know of genetic causes of less than 10% of cases).

      There is a fascinating series of articles in Science starting 12 Feb ’10 about the new DSM-V. The first is on pp. 770 – 771. One of the most interesting points is that 40% of academic inpatients receive a diagnosis of NOS (Not Otherwise Specified — e.g. not in the DSM-IV — clearly even 297 diagnoses are missing quite a bit).

      But insurance companies and the government treat this stuff as holy writ. Would you really like your frisky adolescent labeled with “prepsychotic risk syndrome” which is proposed for DSM-V. Also, casting doubt on the whole enterprise, are the radical changes the DSM has undergone since it’s inception nearly 60 years ago. We’ve learned a lot about all sorts of medical diseases since then, but strokes and heart attacks back then are still strokes and heart attacks today and TB is still TB. Do these guys really know what they’re talking about, and should we allow them to reify things?

      That being said, cut psychiatry some slack. Regardless of theory, there are plenty of mentally ill people out there who need help. They aren’t going to go away (or get better) any time soon. Psychiatrists (like all docs) are doing the best they can with what they know.

      1. Jonathan B says:

        Thanks luysii, an interesting history. Actually what gets me is not so much charactersing psychiatric conditions by symptom (which definitely has a logic) as the consequent assumption they can all be treated the same way.

        Are clinical researchers following up the different successful treatments of (say) depression achieved by trial and error, to see whether it is possible to identify second order features of their presentation that would enable the best therapy to be identified quicker?

        1. Mad Hatter says:

          I have a bit of experience in this area. Major depression is mostly treated with SSRIs or SNRIs. All of them primarily hit serotonin and dopamine receptors at varying levels, and the tailoring of one’s treatment is really trial-and-error unfortunately but generally successful after a couple drugs. There are a lot of options and doctors tend to favor certain ones based on success in their practice. Maybe genotyping patients can flush out more successful outcomes.

          Now for illnesses like Bipolar, which I happen to have, is really a black box and one’s treatment plan is normally different from others in either dosage, combination, and drug. For instance, lithium is the gold standard and well studied as a mood stabilizer and works fairly well to quell an episode of either pole. It’s tolerated well enough but need constant blood work to thread the needle on clinically helpful and toxicity. It wasn’t until 2003 that lamotrigine (which I’m on) expanded indication from anti-convulsant to mood stabilizer that’s particularly helpful on preventing depression, and is tolerated well with minor side effects once you get pass the very slow dose titration up to a therapeutic level. Mind you it takes about 2+ months to know if it actually works for you, so yeah fun times. Then you have antipsychotics that can help both poles and there is no knowing what is going to work for you. They affect a whole bunch of things including dopamine and serotonin (like SSRIs), but are clinically different than SSRIs. Some can be prescribed SSRIs but more often than not, in just a couple doses will throw you into a manic state which occurred to me.

          Any drug repurposing or research is absolutely welcome to help treatment of any mental disorder. There are plenty of treatment resistant people who will try anything.

      2. Gus says:

        Yes but now thanks to dsm there’s plenty of children on psychiatric drugs too who may now have permanent brain damage because there simy aren’t any long term studies on what some these drugs will do to a child’s brain (the drugs haven’t been around long enough in some cases) . Dsm is a disgrace and the worst form of pseudoscience and quackery masquerading as medicine in our midst. It’s a terrible joke with potentially terrible consequences.

  11. Wallace Grommet says:

    Surprised that prazosin isn’t mentioned as a PTSD treatment drug.

  12. Marjorie says:

    In the adverse effects section, they should take into account the consequences of a study showing the benefits of MDMA on it’s public image.
    The out of protocol recreational use of the same substance has already enough dramatic consequences with long-term use.

    1. aairfccha says:

      One of those consequences being that the prohibition on those substances is increasingly indefensible? Bad news for prohibitionists and moralists, they had their way for about half a century and for some strange reason their Utopia is somewhat in absence.

      1. Marjorie says:

        I agree with you for THC or even LSD, but I think MDMA it’s another story.

  13. C_B says:

    For folks interested in the philosophical considerations mentioned in the first half of this post, I very strongly recommend the “Ontology of Psychiatric Conditions” series at Lorien Psych (very easy to read, intended for a lay audience):

    https://lorienpsych.com/2020/10/30/ontology-of-psychiatric-conditions-taxometrics/

    https://lorienpsych.com/2020/11/11/ontology-of-psychiatric-conditions-dynamic-systems/

    https://lorienpsych.com/2021/02/10/ontology-of-psychiatric-conditions-tradeoffs-vs-failures/

  14. Carl says:

    As someone with a long list of diagnosed mental health issues, (Sleep Disorder, Anxiety, Autism Spectrum Disorder, Dyslexia, Dyspraxia), i allways welcome anything that focuses on mental health. It a sadly underappreciated and often misunderstood area that needs more focus. Though at least in my personal case i think the biggest thing that needs to be talked about is how much many people don’t even realise somthing is badly wrong with them. You think your just a little odd or a little anxious, when in reality your really far off the beaten track.

  15. Charles H says:

    FWIW, it’s my expectation that most things that are identified only by symptoms will turn out the be syndromes rather than have any single cause. So you can’t have a simple explanation of, say, depression, because different broken things in different people result in the same observable symptoms. You’ll need better diagnostic methods or a sheaf of potential treatments that you try one after another until one of them works. Obviously the “better diagnostic methods” is preferable, not only because it allows faster treatment, but also because many of the treatments will come with unpleasant side effects.

    Bodies are complicated, and often the same (readily observable) symptoms will arise when different parts are broken in some particular way.

  16. LeeH says:

    Derek –

    Although you start your post discussing the complex mechanisms of CNS drugs, you later seem to imply that the potential PTSD effects of MDMA are due, or otherwise connected, to the psychoactive effect of MDMA. It might be true, but I think it would be a mistake to assume that the two are inextricably linked. Most drugs used in psychiatry have a pretty dirty pharmacological profile, and I suspect that MDMA is no different.

    1. Aaron says:

      There’s also been research into psilocybin and psilocybin mushrooms (isolate, instead of powdered mushrooms), for end-of-life as well as PTSD. More out of the UK I think, MAPS I belive is focusing more on MDMA first, then moving on.

      But there is some positive results, I don’t remember specifics. I personally know someone who was in the US Army, and after he got out had symptoms, and treated with mushrooms. I think a lot of the theory with the psychedelics goes that it helps disassociate the memory of the traumatic event from the physiological reactions that come with those memories that the brain triggers. Which that’s what psychedelics do, generally, is help our brains change their perceptions and ways of thinking.

      Serioud meditation practices can take people into similar states, but that takes years of time and serious practice.

      And while MDMA does have some potential long term issues from regular and especially closely spaced use, LSD/Psilocybin doesn’t seem to have any of those issues. And in fact doesn’t seem to be physically addictive at all, and with rare/uncommon mental/emotional dependency.

    2. aairfccha says:

      Alternatively, the dirty pharmacological profile of many official psychiatric drugs might be at least in part a consequence of the prohibitionist’s factual exclusion of substances which would be usable recreationally because it eliminates numerous substances which obviously do something in the CNS and are well enough tolerated to consume them without hard need.

  17. Thoryke says:

    Just about all the research described here is a huge leap beyond “does this substance inspire a depressed rat to swim towards the dry platform in the middle of the testing pool, or do they just float in “despair”.”

    I used to work down the hallway from a lab that did these rat tests, and it did not inspire great confidence in me, though I knew it was the best model they had at the time…

    1. LeeH says:

      Forced swim is still a standard in-vivo pharmacology test.

  18. Gus says:

    Firstly we have to competely let go of the idiotic concept that our minds and emotions are just machines that can be fixed with chemicals alone. I’m not saying chemicals don’t have an effect, but situations can cause the release of certain chemicals so in “some cases” its the situation that needs to change not the chemicals. Add to this the problem that “sometimes” a chemical imbalance is the problem, so it’s not black and white. But in general thinking you can fix a human mind with chemicals alone is as absurdly reductionist as thinking you can fix the plot of a terrible movie by changing the transistors in your television. As for mdma, of course it will help in the shorter at least for very obvious reasons, and may even help a bit in the longterm, basically, because it makes you feel extremely good, and feeling like that, even for a moment will give a spark of hope to any troubled soul. Without a course of therapy and changing the life and opportunities of that person though it may not help longterm. I find it extremely unlikely that anyone taking mdma would think they were having a placebo unless this was a “micro dose”

    1. Aaron says:

      MDMA doesn’t have a “micro dose”, it’s threshold dose or no real affect/effect AFAIK.

      As for can’t be fixed by chemicals alone, in general I strong agree with you. But short term chemical use _in combination_ with other things, especially in this case carefully laid out psychological therapy sessions, it can help significantly. For this, as I said above, it can help put the brain in a state where you A) feel more like you can talk about your emotions and you feel more connected, and B) help the brain re-wire to remove the trauma fight or flight reaction from occurring when the memories come up. And it’s not a one-and-done, or “here’s a prescription, get out of my hair”.

      So I agree with your premise, just throwing chemicals often is not truly the solution, it’s just treating the symptoms. These studies are designed differently, to use chemicals in a combined treatment plan to try and fix the underlying issues, rather than treat symptoms.

      1. Gus says:

        Yeah ive known a few people for whom medication probably saved their lives. One friend was basically visually hallucinating and couldn’t do anything, so I am not saying medication has no use. However compare this to my nephew who at 12 years old started playing up and having thr occasional tantrum because his parents got divorced and to my horror was put on medication when the issue was his situation not his brain chemistry. That made me extremely angry to be honest. The drug he was put on had only been around for a few years, and there is simy no possible way we can no what it could to his brain chemistry longterm. As for the mdma, you can take varying amounts before you “break through” so to speak its not an all or nothing drug. I’ll be honest I used to enjoy it when I was younger as did nearly. every other student in campus. There’s no way anyone would take a “full dose” and think they are on a placebo.

        1. Aaron says:

          Ugh, sorry to hear about your nephew. That’s just being excessively lazy I’d say, when you have perfectly good cause and effect that you can work through, preferably without any sort of medication at all.

          My micro-dose comment is that from friends that do it (micro-dose in general), there isn’t any real effect like people experience with microdosing mushrooms/LSD, for example. And IMO that sort of long term use is excessively dangerous for MDMA. Might be worth a good double-blind study with monitored health, but I suspect we won’t see significant positive results, and probably some negative brain chemistry signs.

  19. Oligodendrocyte expert says:

    Consistent with the thrust of my earlier comment that MDMA’s MOA in PTSD likely involves dampening neuronal activity-dependent maladaptive myelination, the authors of this 2014 rodent study demonstrated that, in chronic stress-exposed rats, MDMA treatment leads to downregulation of genes (in hippocampus) involved in “axon ensheathment” and “myelin sheath (formation)” relative to the expression of such genes in unstressed rats treated with MDMA, or chronic stress-exposed rats NOT given MDMA. The authors interpret these MDMA effects as deleterious. I would disagree, at least in the context of chronic stress.
    https://www.hindawi.com/journals/bmri/2014/141396/
    “Effects of Stress and MDMA on Hippocampal Gene Expression”

  20. JR says:

    I must admit this is not my area of expertise, but I did get a PhD in neuroscience and my wife is a psychiatrist in a major Boston-area hospital – and we talk about this subject a fair amount.

    We both experimented a fair amount in grad school including trying many of the drugs now being used in these serious clinical studies. We experimented with moderate doses of MDMA/LSD/psilocybin/ketamine at parties/clubs/raves 20+ years ago – they were super fun to do and (being drug naive at the time) I still remember each of my first experiences vividly and with great affection, even decades later.

    Most of the medical establishment personnel I know are very straight-laced and never experimented themselves, so don’t have any first hand experience with positive drug experiences.

    As people who tried and enjoyed these club drugs (in moderation) we are not surprised by the results and laugh that the medical establishment is getting people high and saying what any club kid in the 1990s would have told you – high quality drugs in moderation are fun to do and leave you with warm, positive experiences. Is it really a coincidence that the medical community is finding success with all the best club drugs?

    1. Gus says:

      Exactly, I also have a PhD and fondly remember by drug experiences. It’s no surprise at all to anybody who has taken mdma that it can help people with these problems. I actually think therapist who use these chemicals (psilocybin, lsd etc) without having tried them themselves are quite dangerous.

  21. /df says:

    Regarding PTSD, the recent interesting result (that I no longer have a reference for) was that a potential sufferer does better to have fun-time after the stress instead of counselling, *before going to sleep*. The interpretation was that the relieving activity displaced the stress in overnight memory processing. Presumably an appropriate narcotic experience could have the same effect.

  22. Yosef says:

    I’m a disabled combat veteran with Major Depressive Disorder, Severe PTSD, Degenerative Disc Disease, AS, Fibromyalgia, as well as calcification in my hips. So chronic pain, fatigue, anger issues, ETC make life not worth living at times.

    I figured I’d share some first hand anecdotes.

    I have taken a myriad of prescriptions for 9 years now with little success, Indocin has been the only help, minimally.

    I don’t do recreational drugs, outside of alcohol which I am stepping away from. I’ve never even smoked weed, nor do I want to.

    The only thing I’ve had before that helps my depression is the supplement Alpha GPC which mostly helps suppress my Suicidal Ideations, very well.

    Yesterday, my wife asked me to try MDMA since she used to love it in high school. I’m not a drug guy, but prescriptions are drugs and risk/benefit is something I consider with everything. I HATE taking opioids. I always stretch my prescription and only take it before bed because of how awful it makes me feel. The pain relief is also meh.

    So I tried it yesterday, one capsule, not sure the exact mg. It was an interesting experience.

    I didn’t get the “I love everything and want to touch everything!” E-tard experience.

    What I can say is I have not felt this well since before I ruined my body in Afghanistan and a post workout endorphin high.

    My anxiety, depression, and rage could not break through all day. My mood wasn’t boosted, I was able to feel happy because I wasn’t feeling so easily triggered with rage and other negative feelings.

    My pain relief was AMAZING, better than Dilaudid. I have a buldging disc in my neck which still hurt, but was very minimal.

    My chronic fatigue wasn’t noticeable. I had energy all day, but not gittery. I was able to rest and nap just fine, even better since my pain was under control.

    I felt like I could actually get up and contribute to my family. I could get up and clean, lift and hold my baby daughter without my back flaring, actually be me again with some side effects that are tolerable compared to the alternative of physical pain, fatigue, and unstable mood.

    I am researching the long term side effects and will be trying it as a daily schedule, every other day, every three days, and as a PRN.

    I have no interest in getting high and I want to find the best benefit for the lowest possible dosage and frequency because everything I’ve ever been prescribed has been garbage. I wanted to kill myself MORE on SSRIs and SNRIs than not on anything at all.

    I am disgusted that I cannot get a prescription for something that may actually help improve my quality of life. Nonsensical prohibition that doesn’t work and selective government permission slips to keep big pharma capital flowing.

    Side effects short and long term are inherent with all forms of drugs.

    This disabled combat veteran wants the choice of a managed care plan and MDMA so far, after 9 years of suffering, is the best thing I have come across that may actually help improve my quality of life with chronic pain, chronic fatigue, and PTSD.

    But I have to be paranoid about legalities because prohibition still exists to help fund big pharma and government coffers.

    If anyone is interested in my personal testing, then I’d be happy to share.

    I’m the furthest thing from an addict and don’t want to take any types of drugs. But I’m willing concede to be better for my family.

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