Literature Review: MDMA

Introduction

MDMA (popularly known as Ecstasy) is a chemical with powerful neurological effects. Some of these are positive- the Multidisciplinary Association for Psychedelic Studies (MAPS) has shown very promising preliminary results using MDMA-assisted therapy to cure treatment-resistant PTSD. It is also, according to reports, quite fun. But there is also concern that MDMA can cause serious brain damage. I set out to find if that was true, in the hope that it wasn’t, because it sounds awesome.

Unfortunately the evidence is very strongly on the side of “dangerous”. Retrospective studies of long term users show cognitive deficits not found in other drug users, while animal studies show brain damage and inconsistent cognitive deficits. The one bright spot is the MAPS study, which reported no drop in cognitive function after a therapeutic dose of MDMA, but we’ll talk about the problems with that later. There was a single study showing mitigations may be effective.

I was a little inconsistent with citing my sources in this post when I was relying on a number of studies to inform a general point. If you want to follow up or check my work, you can see my notes here.

Background

MDMA’s primary effect is to release massive amounts of serotonin at once. In particular it works on the 5-HT(2B) receptor, which affects the brain, appetite, gut motility and, in a nice bit of poetics, the heart.

MDMA also has significant hormonal effects, causing an increase in DHEA (a cortisol precursor), cortisol (the long-term stress hormone) and prolactin (best known for inducing lactation, but also a counter to dopamine and sex hormones). Curiously, higher cortisol correlates with higher enjoyment of MDMA. At first this surprised me because cortisol is thought of as indicating stress, but then I remembered that the only thing worse than cortisol is needing it and not having it (which may be the chemical underpinnings of burn out). It may be that cortisol contributes to an “energized” feeling, which is interpreted positively due to the flood of serotonin and dopamine.

The Damage

Retrospective Studies

Studies looking at the brains and behavior of long term recreational users are the least trustworthy to me, because it’s so hard to distinguish what else the subject might have taken, deliberately or mixed with their supposed MDMA. If you did want to listen to those studies, the news is awful, with participants showing problems with:

• Memory and learning.
• Increased impulsivity (especially likely to be a cause rather than effect of MDMA).
• A post-MDMA depressive crash.
• Word recognition.
• Attention.

[Note that some of those links are to the same study and should not be taken as independent confirmation]

In some cases, MDMA-users were compared to users of other street drugs and performed worse, providing something of a control. In other cases, only a combination of MDMA and alcohol inhibited performance.

Controlled Animal Experiments

It’s abundantly clear in autopsies that MDMA changes neurochemistry and damages nerves. But only some studies showed this to translate to any actual cognitive deficit. My best guess is this is either because some studies give their rats way more drug than is reasonable, or because the brain is able to work around deficients. I worry that these work arounds are temporary, and as age does its work it will reveal damage done long ago.

Most of the animal studies used very high doses of MDMA, or many repetitions in a short period. I think this is a reasonable shortcut to determining the effects of long term use, but it does leave the possibility the brain is able to heal from damage, if given enough time.

Controlled Human Experiments

These are thin on the ground, and the ones I did find often didn’t do cognitive tests, focusing instead on things like serum levels and temperature (which MDMA raises). The one exception was a study by MAPS, which reported no “significant” cognitive deficits, but declined to share the actual scores on the RBANS test they used. This makes me extremely suspicious.

Is it worth it? This meta-analysis found only ⅓ of MDMA-for-PTSD studies demonstrated statistically significant improvements. This study didn’t even find an improvement in mood. I was going to make fun of this study for specifying that “subjects liked MDMA”, but actually very few studies bothered to note the subjective enjoyment effects, so good on them for getting it on the record.

Mitigations

Folk wisdom has a number of remedies for the post-MDMA crash, including 5-HTP, tryptophan, and SSRIs. These are all aimed at the depletion of of serotonin that occurs after MDMA wears off; if that depletion is the primary cause of brain damage, they might reasonably intervene. If on the other hand the damage is primarily caused by the initial flood of serotonin I would expect them to have no effect.

This very small study (treatment groups of size 8) nonetheless found that single treatments of 5-HTP and tryptophan prevented large drops in serotonin and its metabolite 5-HIAA, and large drops in the number of binding sites. 5-HTP and tryptophan actually increased serotonin or sensitivity in certain brain areas. This is a smaller study than I want to trust my brain to, but nonetheless very interesting.

Conclusion

These studies are likely heavily biased by the US government’s hatred of fun. They’re often quite small, so it would be easy for publication bias to sweep positive reports under the rug. To really answer this question I’d need to do similar literature reviews for other substances and see how they compared. I don’t have that kind of time (if you would like to buy the time for me, contact me at elizabeth at this domain name), but I did find MDMA’s wikipedia page much scarier than LSD’s or marijuana’s. On the other hand, all of the evidence points in one direction, and it would not be shocking if a sudden massive release of neurotransmitters, followed by a prolonged deficit, was damaging.

MDMA is risky, and you probably shouldn’t use it, although a handful of times with the right therapeutic environment might be worth it if your problems are bad enough. There are promising but unproven mitigations. If you do decide that MDMA is worth the risk to you, at least be careful to hydrate properly, in a cool environment to prevent overheating, and definitely don’t mix it with anything else. In other words: a rave is the last place you should be doing E.

 

This post supported by Patreon. Thanks to Justis Mills for copyediting.