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.