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

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.

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.

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.

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.

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)

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??"

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.

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

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.

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%)).

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

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.

> 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.

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.

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.

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.

> 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.

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

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.

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.

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

Get some 5HTP in you.

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.

> 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.

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.

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.

• 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.)