Note: This post is 7 years old, so it’s both out of date and written by someone less skilled than 2025!Elizabeth. I wish I’d quantified the risks more, and some more data has come out on MDMA therapy since I published.
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:
Increased impulsivity (especially likely to be a cause rather than effect of MDMA).
[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.
If you’d like to support more work like this, I am currently fundraising for a more quantified review of long term ketamine therapy.
The recommendations I hear for MDMA usage are like, not much more than 200mg, wait at least a month and preferably three months between rolls, take the supplements recommended by https://rollsafe.org, have lots of water and electrolytes, don’t overheat.
Following this advice, it’s maybe given me a headache, but definitely not the terrible crashes some people report—but I may be unusually lucky in that regard.
It’s definitely the drug I’ve had where I would be the most concerned about disregarding cautious safety procedures.
I feel like the summary in the introduction is somewhat at odds with the content? You say
But then you also say that
Retrospective user studies look bad but results seem pretty confounded. The studies comparing MDMA users to users of other street drugs give inconsistent results, as some say MDMA users do worse than other drug users and some say they only do worse if they also combine the use with alcohol.
Only some animal studies show actual cognitive defects and the ones that do use doses that are crazy high. Possibly this works to simulate long-term use but it’s also possible that it doesn’t because the brain will heal between doses.
Controlled human studies don’t show much, MAPS claims no significant cognitive defects though it’s suspicious that they don’t share some of their data.
I do agree that this is reason to be concerned and that you might want to avoid MDMA because of this, but this sounds to me like “suggestive but inconsistent and often low-quality evidence” rather than “very strong evidence”.
Did the studies specify the dosage, frequency, and duration of use in the long-term users they studied? I would not be surprised if they show that taking MDMA e.g. once a week for months on end caused significant damage, but I would be much more surprised if there were significant long-term deleterious effects from reasonable doses spaced months or years apart.
I’ve been writing a short book called “Open MDMA: An Evidence-Based Synthesis, Theory, and Manual for MDMA Therapy Based on Predictive Processing, Complex Systems, and the Defense Cascade,” available here: https://osf.io/preprints/psyarxiv/aps5g. I have a large section on all the different risks, but here is the bit about cognitive/serotonin-system effects, in case anyone is interested in another assessment of the issue:
Some observational human studies and controlled high-dose animal studies have found that MDMA use is associated with neurotoxcicity (oxidative stress in this case) or cognitive problems (The History of MDMA by Torsten Passie). However, these problems have not been found in controlled studies in humans (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053129/pdf/nihms-247953.pdf). The human observational studies that find problems usually fail to adequately control for multiple-drug use, a significant risk factor. Notably, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053129/pdf/nihms-247953.pdf ruled out high levels of long-term cognitive issues from recreational MDMA use in a population that had exceptionally low lifetime use of other psychoactive substances. Unfortunately the study didn’t have the statistical power to rule out low-moderate levels of cognitive issues. One small randomized study of MDMA therapy also did not find any significant cognitive effects (https://journals.sagepub.com/doi/10.1177/0269881110378371). The animal studies that found problems typically used extreme doses, extreme frequencies of use, or injected the medicine, a more potent method of administration than swallowing a pill (The History of MDMA by Torsten Passie). It’s also not clear that humans respond the same way as rats to an equivalent dose. It’s possible that replicating these conditions of extreme doses or frequency of use could cause harmful neural oxidative stress in humans. Some studies have found serotonin system changes in humans, but the studies use a poorly controlled cross-sectional observational design (https://onlinelibrary.wiley.com/doi/abs/10.1002/hup.2811). So it’s not clear that MDMA, rather than other drug use or population difference, causes these changes, that the changes are bad, or that the changes are even clinically significant. The changes appear to decrease with abstinence. Fear and misinformation about MDMA is widespread due to the War on Drugs, sensationalized of poor quality research, and misattribution of MDMA-related deaths as an inherent risk of MDMA instead of its interactions with certain medications and health conditions, and the risks of heat illness or hyponatremia at raves (The History of MDMA by Torsten Passie). See chapter “The Toxicity Debate” in The History of MDMA by Torsten Passie for a comprehensive review of the topic.
High doses of certain antioxidants, including alpha-lipoic acid, ascorbic acid, and acetyl-L-carnitine, administered shortly before and during the session, prevent oxidative stress in rats (10.1097/00001756-199911260-00039, https://onlinelibrary.wiley.com/doi/abs/10.1002/1098-2396%28200104%2940%3A1%3C55%3A%3AAID-SYN1026%3E3.0.CO%3B2-O, 10.1016/j.neuroscience.2008.10.041). Some companies bundle these antioxidants together in commercially available products, but we are not aware of them having been rigorously tested for usefulness in humans (Rollkit).
For the sake of comprehensiveness here is MDMA researcher Matthew Baggott’s somewhat-disagreeing take:
https://old.reddit.com/r/MDMA/comments/4wyjd9/mechanisms_of_mdma_tolerance_and_loss_of_magic/
https://old.reddit.com/r/MDMA/comments/3r09sg/thoughts_on_taking_supplements_with_mdma/
https://old.reddit.com/r/AskDrugNerds/comments/10udz3u/is_there_any_scientific_basis_to_the_3month_rule/j7bvxsb/
Seems like a very useful animal study would be to compare high-dose or rapidly-repeated-low-dose MDMA with and without various common mitigations and supplements, and look at autopsied brain damage—I assume none of these have been done yet?
Not that I found in 2018, at least.
I asked Claude to research it and looked at some of the studies it turned up.
Ma et al administer (nothing, MDMA, DXM 5 minutes before MDMA) to 3 monkeys each and use radioisotopes to look for sertonergic abnormality 24 and 30 months after administration. The DXM sure looks like it helps but also there are literally just three monkeys in this image, maybe the middle guy just didn’t have very many serotonin transporters to start with?? Maybe I can email the authors and get the raw data.
(Also they give these monkeys a lot of DXM—these are not cough suppressant dosages, the monkeys are probably tripping balls even without the MDMA. And DXM+MDMA is generally considered a dangerous combination—if you look up trip reports on Erowid they reliably describe having a bad time that lasts for days—so I would not try this on humans.)
Malberg et al find that after giving rats high-dose MDMA (recreational dose would be like 1mg/kg and they do 20 or 40) and autopsying brains 2 weeks later, serotonin levels were much lower on the rats who spent their MDMA trip in a high-temperature room than in a low-temperature room. 8 rats for each of the 18 experimental conditions.
Aguirre et al find that alpha-lipolic acid cuts serotonin decrease in half a week after administration, though they used a temperature-controlled room at 22ºC which the above study claims doesn’t decrease serotonin, so idk. They also use 8 rats per experimental condition, but they only have 4 such conditions so I trust them a bit less.
Shankaran et al find that vitamin C substantially decreases 2,3-DHBA during the trip but don’t look at effects afterwards.
As far as Claude could tell, no one’s ever done human RCTs for MDMA mitigations and looked at cognitive or neurochemical effects afterwards.
Before trusting the rat data, I’d want to investigate how similar their reaction to MDMA is to humans. When I did the comparison with ketamine I found out there is no known anesthetic dose of ketamine in mice and rats, you always combine it with another drug, which makes me think rats+mice are not useful models of ketamine’s effects in humans.