As with all of these studies, it’s important to remember that this isn’t evidence that taking MDMA by itself is therapeutic. The therapy sessions are the primary treatment in this study and the MDMA is being explored as an adjunct to therapy.
I don’t know who needs to hear this, but: Taking MDMA you bought off the street and hoping it’s going to cure whatever ails you isn’t even remotely similar to what’s being studied here. MDMA is also well known to produce depressive rebound effects in the following days that can worsen mental health problems if the patient isn’t properly monitored and prepared. (and no, taking some supplements and 5-HTP won’t save you from all the side effects no matter what that guy on the internet claims)
Importantly, both the MDMA-assisted therapy and the regular therapy groups improved over the course of this study. It should go without saying that regular old therapy is and will continue to be the first-line treatment for PTSD. People will debate the relative safety of MDMA all day long, but no matter how you look at it, MDMA will always be more risky than therapy alone. The MDMA group had a 1-in-10 incidence of treatment related adverse events, for example.
Another important piece of context is that true placebo control is impossible in these studies. Patients and caregivers will know which patients received MDMA due to the dramatic effects of the drug. This doesn’t negate the study, but you do have to consider the fact that these patients went into this study expecting to maybe get MDMA with the expectation that MDMA would help them. They would no doubt be either excited or disappointed after realizing which group they were in. This will, unfortunately, impact the results in ways that can’t be measured.
I hope future studies will compare against an active control group. It would be much better to compare, for example, therapy with placebo, therapy with SSRI, and therapy with MDMA. It’s easy to differentiate from placebo, but it’s much harder to find new treatments that outperform existing options.
Another alternative would be to trial an active placebo group. For example, if one group received MDMA and another group received a dose of amphetamine then both groups would know they had received a psychoactive drug with euphoriant properties, but if they were truly drug naive (as asked in the intake screener) then theoretically they wouldn’t be able to tell which group they were in. This would more effectively isolate MDMA’s unique properties, if any, without breaking the blinding as much.
I’m skeptical that a placebo control for MDMA can be valid. The effects of MDMA are pretty noticeable. The study actually asked participants if they thought they were on MDMA, and most answered correctly.
If the participants can tell, it somewhat defeats the purpose of having a placebo control group.
If you start with people who know what MDMA feels like, I suspect you're sunk for the reasons you state.
But if for instance the placebo were niacin... niacin makes most people feel funny. If you don't know what MDMA or a niacin flush feels like, you might just know something is happening but not what.
And then you test people who don't experience niacin flush with or without a placebo to make sure that niacin isn't a therapeutic chemical.
Blinding isn’t just about the patients - It’s about the therapy providers as well. We would like to think they’d provide the same treatment regardless of what the patient received but over-eager researchers tend to get more excited about the active group and provide them more attention and enthusiasm.
Niacin isn’t a great placebo these days because it’s not the 70s any more and people going into these studies will probably Google what to expect from the drug. Also Niacin is short acting and makes people itchy and uncomfortable, so it’s not really compatible with therapy.
Talked to a therapist at the MAPS conference who said that the way you know a patient is in the trial is about halfway through their therapy session, they inevitably say, "But enough about me, how are YOU doing??"
My understanding is that in trials like this they’ll usually use a benzodiazepine as the control. Not psychedelic, but psychoactive enough that a drug-naive person wouldn’t know for sure what they were on.
This was not an active placebo study. The placebo group did not receive any medication.
Benzodiazepines would not be an appropriate active placebo anyway as they are a sedative, not a stimulant. They would also be expected to interfere with the therapy because they impair memory and alertness, so that’s a no-go.
It's a control. A baseline. That's the whole point. And especially with the therapy trials they're running, its not like it'll hurt people to have been given a placebo (unlike if you were to say, trial an HIV antiviral with a placebo)
Yeah this is going to be hard with all the psychoactive substances, but really we shouldn't discard placebo effect as "not real," especially for disorders that we already know are highly mediated by beliefs (about the self or the world). Reliably and persistently mutating those beliefs toward an actually improved life seems perfectly fine to me.
Right, but if you observe a high enough effect size, it’s in some sense irrelevant whether there was a placebo arm. If somehow there is a reliable d=0.4 placebo effect, then that is just as good as if the drug “really works”. To be clear on magnitudes, there was a something like 70% increase in the treatment effect vs. therapy+placebo.
Indeed what does it even mean for the cure to be “just in your head” or “a placebo” if condition is purely psychological, the trauma is resolved, and there is no remission? It’s a very different game vs. a mechanistic acting drug which either does or does not reduce cholesterol or whatever.
Rick Doblin has some talking points on this that I found fairly compelling... but now I can't find them. Basically that their trial is as good as you can do given that.
As effective as that might be in terms of a proper active control group, it does not seem terribly ethical to give amphetamines to patients with PTSD without any medically sound reason to do so.
> There were no deaths or serious TEAEs [treatment emergent adverse event]. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated.
I've been hearing about this for a long time - probably since the late 1990s, so I'm surprised to see that it seems only in the last couple of years that there are phase three trials. I would imagine that the safety profile of MDMA is already well understood / fairly well researched in the 1950s and 1960s
MDMA was first synthesized in 1912 by Merck. Merck and US Army did several animal trials in the 1950s, but by the end of the decade MDMA was shelved and thought to have no therapeutic benefit. It wasn’t until Sasha Shulgin rediscovered it in 1976 that its therapeutic benefits were discovered, at which point therapists and psychiatrists began quietly using it for psychedelic assisted psychotherapy. In July 1984 the DEA proposed making MDMA a Schedule I controlled substances, which led to outcry from practitioners who requested the DEA hold hearings to provide testimony on MDMA’s therapeutic benefits. While these hearings were ongoing, the DEA used its emergency scheduling authority in May of 1985 to place MDMA in Schedule I.
Animal efficacy and human safety trials of MDMA began in the late 1980s, and the first FDA-approved, placebo controlled, double blind phase I study was published in 1996.
> The only measured exploratory covariate with a significant interaction with treatment was lifetime history of SSRI use, which was associated with improved efficacy of MDMA-AT (P = 0.02; Supplementary Table 5). Covariates significantly impacting the main effect were sex assigned at birth and baseline Beck Depression Inventory (BDI)-II score; female sex assigned at birth and baseline BDI-II score ≥23 were both associated with improved outcomes irrespective of treatment assignment (P < 0.05).
This is an interesting outcome, particularly the SSRI usage
> Eight participants (MDMA-AT, n = 7; placebo with therapy, n = 1) experienced cardiac TEAEs, which included palpitations (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 1 (2.0%)) and tachycardia (MDMA-AT, n = 2 (3.8%)); all were mild.
Seems a bit concerning, but I have little to measure this against.
> superiority of MDMA-AT over SSRIs cannot be assumed without a direct comparison
I feel as though this should be done. Even though the results are promising they come with a significant safety risk for the participants who are essentially at the mercy of the administrator and could be easily subject to abuse.
That being said, for people with severe PTSD this is surely a godsend. Maybe we can mitigate the safety issue other ways.
> That being said, for people with severe PTSD this is surely a godsend.
This seems a bit of a premature statement. The long term usage affects of MDMA use can be very costly, and I suspect long term use of something that provides artificial "feel good" emotion will have a tremendous downside for people who are already struggling with normality.
> sex assigned at birth... female sex assigned at birth
As an aside - in a scientific article, this is insane language to use and really calls into question the assumptions and conclusions.
> in a scientific article, this is insane language to use and really calls into question the assumptions and conclusions.
Springer Nature would appear to disagree with your assertion.
"Authors should use the terms sex (biological attribute) and gender (shaped by social and cultural circumstances) carefully in order to avoid confusing both terms. Article titles and/or abstracts should indicate clearly what sex(es) the study applies to. Authors should also describe in the background, whether sex and/or gender differences may be expected; report how sex and/or gender were accounted for in the design of the study; provide disaggregated data by sex and/or gender, where appropriate; and discuss respective results. If a sex and/or gender analysis was not conducted, the rationale should be given in the Discussion. These guidelines apply to studies involving humans, vertebrate animals and cell lines."
The point of these studies is that MDMA can improve the efficacy of talk therapy. I don’t think anyone in this space is thinking MDMA will replace traditional anti depressants as a thing you take regularly for an indefinite period of time.
Further, I’d speculate MDMA is not obviously harder on the body than adderall or other stimulants currently legal for ADHD.
>> sex assigned at birth... female sex assigned at birth
> As an aside - in a scientific article, this is insane language to use and really calls into question the assumptions and conclusions.
i'm not really familiar with scientific writing, but why would that be insane language to use? what would be better?
There are many social aspects to the "male" and "female" experience in society, it helps to separate those out from congenital physiology. For example, living as a woman often entails responsibilities of caregiving, housekeeping, and/or "social reproduction." Certain "emotional labors" are also relegated to women's roles, such as calendaring and keeping in touch, but none of these are safely assumed to have derived from congenital sex.
Expectations of eg emotional stoicism in men preclude eg certain platonic intimacies that are common among women. Gendered relationship norms significantly influence our mental and physical health. It would be unscientific to presume they were physiologically congenital. For that reason, it makes sense to refer to study participants by their "sex assigned at birth," rather than presuming any overlap between socialized gender and congenital sex. Remember, in scientific inquiry, precision is key.
Please don’t paint your obvious naivety re gender as scientific enlightenment. This is real populist Ben Shapiro reasoning and I’d really hope that this community is above it. The reality is that esp. when we are talking about mental health it is important to be specific about the nature of a sex/gender breakdown. Could it be a question of hormones? Socialisation? The author/s are using concise language in a scientific publication and because of your naivety and typical software developer undeserved sense of transferable expertise, you are claiming it as superfluous, when it isn’t. Please consider that maybe you are wrong, and not everyone else.
You are aware of intersex/chromosomal conditions and “gender assignment” treatments at birth right? “Sex assigned at birth” is a well-defined empirical label.
Thanks! but on HN, we don't count reposts as dupes if the story hasn't had significant attention yet. This is to give good stories multiple changes at getting attention.
Readit News
I don’t know who needs to hear this, but: Taking MDMA you bought off the street and hoping it’s going to cure whatever ails you isn’t even remotely similar to what’s being studied here. MDMA is also well known to produce depressive rebound effects in the following days that can worsen mental health problems if the patient isn’t properly monitored and prepared. (and no, taking some supplements and 5-HTP won’t save you from all the side effects no matter what that guy on the internet claims)
Importantly, both the MDMA-assisted therapy and the regular therapy groups improved over the course of this study. It should go without saying that regular old therapy is and will continue to be the first-line treatment for PTSD. People will debate the relative safety of MDMA all day long, but no matter how you look at it, MDMA will always be more risky than therapy alone. The MDMA group had a 1-in-10 incidence of treatment related adverse events, for example.
Another important piece of context is that true placebo control is impossible in these studies. Patients and caregivers will know which patients received MDMA due to the dramatic effects of the drug. This doesn’t negate the study, but you do have to consider the fact that these patients went into this study expecting to maybe get MDMA with the expectation that MDMA would help them. They would no doubt be either excited or disappointed after realizing which group they were in. This will, unfortunately, impact the results in ways that can’t be measured.
I hope future studies will compare against an active control group. It would be much better to compare, for example, therapy with placebo, therapy with SSRI, and therapy with MDMA. It’s easy to differentiate from placebo, but it’s much harder to find new treatments that outperform existing options.
Another alternative would be to trial an active placebo group. For example, if one group received MDMA and another group received a dose of amphetamine then both groups would know they had received a psychoactive drug with euphoriant properties, but if they were truly drug naive (as asked in the intake screener) then theoretically they wouldn’t be able to tell which group they were in. This would more effectively isolate MDMA’s unique properties, if any, without breaking the blinding as much.
If the participants can tell, it somewhat defeats the purpose of having a placebo control group.
But if for instance the placebo were niacin... niacin makes most people feel funny. If you don't know what MDMA or a niacin flush feels like, you might just know something is happening but not what.
And then you test people who don't experience niacin flush with or without a placebo to make sure that niacin isn't a therapeutic chemical.
Niacin isn’t a great placebo these days because it’s not the 70s any more and people going into these studies will probably Google what to expect from the drug. Also Niacin is short acting and makes people itchy and uncomfortable, so it’s not really compatible with therapy.
Benzodiazepines would not be an appropriate active placebo anyway as they are a sedative, not a stimulant. They would also be expected to interfere with the therapy because they impair memory and alertness, so that’s a no-go.
Indeed what does it even mean for the cure to be “just in your head” or “a placebo” if condition is purely psychological, the trauma is resolved, and there is no remission? It’s a very different game vs. a mechanistic acting drug which either does or does not reduce cholesterol or whatever.
This should be the second of two Phase III studies, which are pretty rigorous. Some drugs are just very hard to make a valid control for.
Some studies also use a drug placebo and a control group with a combination of interventions, or little to none at all, as best as I understand.
One can use statistics afterwards to help bolster claims of efficacy if a sham/placebo group is difficult to source.
This is my best understanding of the matter.
> Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)).
Animal efficacy and human safety trials of MDMA began in the late 1980s, and the first FDA-approved, placebo controlled, double blind phase I study was published in 1996.
> The only measured exploratory covariate with a significant interaction with treatment was lifetime history of SSRI use, which was associated with improved efficacy of MDMA-AT (P = 0.02; Supplementary Table 5). Covariates significantly impacting the main effect were sex assigned at birth and baseline Beck Depression Inventory (BDI)-II score; female sex assigned at birth and baseline BDI-II score ≥23 were both associated with improved outcomes irrespective of treatment assignment (P < 0.05).
This is an interesting outcome, particularly the SSRI usage
> Eight participants (MDMA-AT, n = 7; placebo with therapy, n = 1) experienced cardiac TEAEs, which included palpitations (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 1 (2.0%)) and tachycardia (MDMA-AT, n = 2 (3.8%)); all were mild.
Seems a bit concerning, but I have little to measure this against.
> superiority of MDMA-AT over SSRIs cannot be assumed without a direct comparison
I feel as though this should be done. Even though the results are promising they come with a significant safety risk for the participants who are essentially at the mercy of the administrator and could be easily subject to abuse.
That being said, for people with severe PTSD this is surely a godsend. Maybe we can mitigate the safety issue other ways.
This seems a bit of a premature statement. The long term usage affects of MDMA use can be very costly, and I suspect long term use of something that provides artificial "feel good" emotion will have a tremendous downside for people who are already struggling with normality.
> sex assigned at birth... female sex assigned at birth
As an aside - in a scientific article, this is insane language to use and really calls into question the assumptions and conclusions.
Springer Nature would appear to disagree with your assertion.
"Authors should use the terms sex (biological attribute) and gender (shaped by social and cultural circumstances) carefully in order to avoid confusing both terms. Article titles and/or abstracts should indicate clearly what sex(es) the study applies to. Authors should also describe in the background, whether sex and/or gender differences may be expected; report how sex and/or gender were accounted for in the design of the study; provide disaggregated data by sex and/or gender, where appropriate; and discuss respective results. If a sex and/or gender analysis was not conducted, the rationale should be given in the Discussion. These guidelines apply to studies involving humans, vertebrate animals and cell lines."
https://www.springernature.com/gp/policies/book-publishing-p....
Further, I’d speculate MDMA is not obviously harder on the body than adderall or other stimulants currently legal for ADHD.
Expectations of eg emotional stoicism in men preclude eg certain platonic intimacies that are common among women. Gendered relationship norms significantly influence our mental and physical health. It would be unscientific to presume they were physiologically congenital. For that reason, it makes sense to refer to study participants by their "sex assigned at birth," rather than presuming any overlap between socialized gender and congenital sex. Remember, in scientific inquiry, precision is key.
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This is in the FAQ (https://news.ycombinator.com/newsfaq.html) and there are past explanations at https://hn.algolia.com/?dateRange=all&page=0&prefix=true&que... if interested.
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