MDMA-assisted therapy for PTSD: A randomized, placebo-controlled phase 3 trial

https://www.nature.com/articles/s41591-023-02565-4

by beefman • 3 years ago

99 104 3 years ago

notamy2• 3 years ago

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.

prashp• 3 years ago

But also

Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)).

notamy2• 3 years ago

Yep! I do wish they clarified what exactly that means; perhaps I just missed it in my quick read.

carimura2• 3 years ago

2 in the placebo group.

RadixDLT• 3 years ago

dupe: https://news.ycombinator.com/item?id=37524353

dang• 3 years ago

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.

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.

mountainriver• 3 years ago

Overall seems positive, some interesting pieces:

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.

Alupis10• 3 years ago

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.

andrekandre• 3 years ago

  >> 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?

rexpop2• 3 years ago

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.

Thoreandan• 3 years ago

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....

akhosravian• 3 years ago

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.

theptip4• 3 years ago

You are aware of intersex/chromosomal conditions and “gender assignment” treatments at birth right? “Sex assigned at birth” is a well-defined empirical label.

tmpX7dMeXU4• 3 years ago

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.

singingfish2• 3 years ago

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

johndhi2• 3 years ago

Not really. Research almost entirely paused until the last few years.

singingfish2• 3 years ago

aah research impeded by morality police, understand now, thanks

samdcbu• 3 years ago

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.

randomNumber712• 3 years ago

Even as someone who has used this recreational, I'm very sceptical about mdma for medical treatment.

I have seen smart people needing professional help for a very long time after using this too often. And too often is already every second weekend, because the body needs so long to restore the serotonine.

But maybe they are using very little doses? I can still not believe that taking this regularily is a good idea.

Edit: Sry for not reading it carefully enough to find the dosage.

Still 120-180 mg with only one month in between is a lot.

ethanbond6• 3 years ago

If only there were some mechanism by which we could separate people's personal vibes and anecdata from actual scientific understanding... perhaps a series of clinical trials?

History will look unkindly upon people who kept these substances out of the hands of people who need them because "I knew a guy once who did too much street MDMA and went stupid."

Honestly, adopting that position in the face of a well-designed Phase 3 RCT showing such strong results is pretty much actively evil as far as I'm concerned. People are suffering. People are blowing their brains out after combat; people are afraid to get in their cars after accidents, or walk outside or have sex after being raped, and you're like "ehh Idk I knew a guy." Come on.

carimura2• 3 years ago

rave massage circles?

randomNumber712• 3 years ago

Its not like "I know a guy". Its like common knowledge for people who do this stuff that it seriously fucks you up if you do this too often. Its like 100% guaranteed.

I would not take this every day for a month even if you offer me a years salary.

Every medic who thinks this is a good idea should do the self test in my opinion. The same goes for giving ritalin to kids, but that is a different story...

nhod• 3 years ago

MDMA-AT is definitely not taking it regularly. It is done only a handful of times, with pharmaceutical-grade MDMA and no other adulterants, in controlled doses, in a controlled setting. Very different than a Tesla pill at a rave every other weekend.

randomNumber712• 3 years ago

Ok, not regularly already makes more sense. Still the dosage would be very interesting, and the time interval. I didn't talk about tesla pills, but mdma crystals dosed with a high precision weight according to body mass.

That a tesla pill with 0-300 mg can be harmful is obvious^^

bbatha• 3 years ago

And too often is already every second weekend, because the body

The intended therapy is taken several times in a guided sessions, 3 for this study, with a therapist. They aren't just sending people home with a bottle of mdma to take before bed.

hinkley3• 3 years ago

Yeah my impression of a therapeutic setting would be an asymptotic progression of a few doses in short intervals with an exponential back-off ending in no further uses or perhaps once a year.

Resets are not a recurring situation. I'd take it as a sign of using the treatment in bad faith.

yieldcrv• 3 years ago

nobody knows the correct dose because nobody could do the trial

it could be anything in any interval or nothing

we have FDA approved treatments that say “don’t do this for more than 2 years” and at the very least we can make objective choices because the side effects are listed… because those also occurred to an actual human being in a controlled environment

I can’t advocate for ignorance like this

Glench• 3 years ago

As other commenters have noted, this is MDMA-assisted therapy. Controlled dose, setting, with supportive professionals.

But one interesting thing to note:

Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was −23.7 (−26.94, −20.44) for MDMA-AT versus −14.8 (−18.28, −11.28) for placebo with therapy (P < 0.001, d = 0.7).

The placebo group got better, too! What this means is that therapy for PTSD actually works! It just works better on average with MDMA assistance.

gchamonlive• 3 years ago

You cannot really compare the two use cases. It's like banning morphine because if people used that in parties they would have a heart attack.

randomNumber712• 3 years ago

I'm not against banning anything. Just considering the side effects you need very hard evidence to justify this.

And I couldnt find exact information about dosage and regularity in the paper...

derefr2• 3 years ago

And too often is already every second weekend, because the body needs so long to restore the serotonine.

Get some 5HTP in you.

randomNumber712• 3 years ago

Nice to learn s.th. xD. I'm probably a bit too old now anywas. I just knew bananas and nuts are good, but not why^^

OkayPhysicist• 3 years ago

The proposed use is MDMA-assisted therapy. Take a dose, talk to a therapist. Wait a month, repeat. You seem to be imagining people popping the stuff like SSRIs.

Intuitively, this makes a lot of sense. MDMA is a fun drug because of the fact that it makes it basically impossible to feel negative emotion under its effect. PTSD is characterized by extreme negative emotion around a particular trauma, to such an extent that it becomes disruptive to living a normal life. Just talking about the traumatic inducing experience can lead to uncontrolled emotional responses, making it difficult to approach therapeutically. The MDMA acts as a shortcut around that last bit: by blocking the patient from feeling negative emotion while they talk about their trauma, they can re-evaluate it in a more removed way.

Combine that with theories about how we edit memories when we recall them, and you've got a pretty obvious method of action.

It's not intended to be a chronically taken treatment. But the results were pretty massive. That CAPS-5 score they talk about the reduction by 24 points versus therapy alone's 15 is on an 80 point scale, with the bare minimum for PTSD diagnosis at a 12, and "moderate" PTSD being in the 23-35 range.

Compared to most results coming out of the mental illness treatment field, MDMA's looking like a silver bullet.

randomNumber712• 3 years ago

Yes that makes more sense. I can imagine that could work. Do you know how it compares to therapy with hypnosis?

There are multiple psychologist in my family, so maybe thats why im opposed to doing therapy with drugs unless physically necesarry.

d1lanka2• 3 years ago

I'm very sceptical about mdma for medical treatment.

Data disagrees with you.

I have seen tremendous improvement in quality of life of veterans with PTSD with just a few MDMA assisted therapy sessions.

randomNumber712• 3 years ago

I couldn't find information about dosage and regularity in the paper.

If it really is just a few sessions with enough time between then im ok with that.

But there should be enough scientific evidence that anything more is very dangerous.

fshbbdssbbgdd• 3 years ago

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.

ethanbond6• 3 years ago

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.

johndhi2• 3 years ago

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.

TylerE• 3 years ago

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.

Aurornis3• 3 years ago

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.

hinkley3• 3 years ago

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.

Aurornis3• 3 years ago

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.

MAGZine• 3 years ago

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)

chadd• 3 years ago

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??"

tmpX7dMeXU4• 3 years ago

That is the most MDMA thing ever.

tysam_and3• 3 years ago

I would be surprised if that wasn't a glaring point for them, but you do control as best as you are able to.

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.

staticautomatic• 3 years ago

Why not use another group taking an amphetamine in addition to one taking an inert placebo?

InSteady3• 3 years ago

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.

theptip4• 3 years ago

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.

DrKavorkian• 3 years ago

Nature is the mecca of all science. MDMA will be approved by FDA, that's inevitable. Likely would require special licensing. Clinics will pop up all over the country and it won't be long before “off label” prescriptions will appear. The incidence of PTSD will suddenly rise and before we have a chance to quell the opioid epidemic another epidemic will replace it on the front pages of the news. Meanwhile the smart ones will invest in whichever pharmaceutical company will be the first to patent an SSRI/MDMA combination drug. “The only thing that we learn from history is that we learn nothing from history.” Hegel

tysam_and3• 3 years ago

If you're talking about pairing an SSRI with MDMA, then perhaps you would perhaps be well-served by adding some reticence to the confident assertions made.

That pairing would be like a Clorox + Bleach pairing of the psychotropic world.

There is significant interest in the drug, and the culture largely is focused on appropriate administration measures. This is not a half-baked solution, MAPS has worked on this for decades.

hollerith• 3 years ago

That pairing would be like a Clorox + Bleach pairing of the psychotropic world.

Clorox is bleach. I think you mean ammonia + bleach.

sowbug• 3 years ago

MDMA isn't physically addictive. Could be psychologically addictive the way the lottery or Netflix is, but I doubt it's going to be giving oxycodone much competition.

derefr2• 3 years ago

• MDMA is almost anti-addictive — the more often you take it, the less fun it is. MDMA acts on the brain almost as if it by "using up" some scarce resource inside the brain, that only gradually builds back up when not taking MDMA. If you try to take MDMA again the very next day after taking it, you just get a headache. There's a reason you don't hear about "MDMA junkies" the way you hear about heroin junkies.

• SSRIs and MDMA are counteractive; being on SSRIs suppresses the effect of MDMA. (And also, due to this, you can end up with serotonin syndrome on the come-down from MDMA.)

Aurornis3• 3 years ago

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.

MDMA-assisted therapy for PTSD: A randomized, placebo-controlled phase 3 trial

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