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:

[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.

 

Water Pick Experimental Results

Since my last dental appointment (3 months ago), I’ve cleaned one half of my mouth with a water pick (in addition to brushing on both sides), with the goal of determining if it actually did anything useful. I was inspired by my dentist’s insistence that I Do Something despite not noticing when I consistently used the pick. I pre-registered on Facebook that if the hygienist spontaneously commented that one side looked better, or some objective measure like # of cavities was different, I would consider it evidence in favor of the water pick. Today was the appointment.

Final results:

  • Hygienist didn’t comment either way.
  • No new cavities on either side
  • Gum pocket measurements were worse on the water picked side.

Obviously one trial isn’t conclusive, but I’m giving up on the water pick. Next step: test flossing.

Bullshit Job Notes

Scott talks about a bit of medical theater, in which companies demand doctors notes to allow people to bring in their own chairs to work; he is often the person in best position to provide that note, despite being a psychiatrist who usually works remotely. He’s knows little about back pain and nothing about chairs. His compromise has been to write out a note saying “[Patient] reports back pain that would be improved by a chair they have chosen.” This shouldn’t work because he’s not adding any additional information to the patient’s complaint, but it does.

I had my own experience with this in my first real-world programming jobs. The overhead lights in my office gave me a headache, so I turned them off. Someone noticed and didn’t think it was fair my roommate be forced to work in the dark (although he told me it was fine). I indeed had to go to the doctor, who dutifully wrote out “Elizabeth says the lights give her headaches…”. Luckily I had fabulous health care insurance and flexible hours at my job, so this was a minor annoyance.

I really disliked the way the company handled it though. Their solution was a lamp, which was fine, but there was a lot of pressure to say either “yes, the problem is entirely solved” or “no, it is definitely not solved.” “Can I take a week to see if I develop a headache?” was not an option. I don’t think I even got to pick out my own lamp.

Several years later I had a similar problem at a different large tech company you have definitely heard of, one known for being an amazing place to work. I hated working in an open office and tried to leverage my post-dental-surgery fragility into a private office or the right to work from home. In retrospect, this was not a reasonable accommodation: despite having offices in 50 countries and running much of the world’s telework infrastructure, that company’s workflow was set up for in person communication. But they couldn’t just say that, so they tried to find ways to meet the letter of my doctor’s note without actually giving anything up. This was a problem because what I really wanted was control over my environment, and that was the exact thing they didn’t want to give me.

I think a thing that’s going on with the notes is that gatekeeping makes sense in some circumstances (substantial changes in job duties), and it was no skin off the decision-maker’s nose to make that a universal rule. “Protection from lawsuits” factors in, but if companies were paying the cost of the note they would draw the line in a different place. As it stands, it’s worth infinite amounts of your time and money to avoid risk of a lawsuit that might cost them either.

Today in Horrifying Systems

Recently I listened to Econtalk’s episode on the doctor-patient relationship, which was primarily about a study showing that hospitalized patients did better when their care was supervised by their primary care physician. The study shows what it shows (although pilot studies are prone to not replicating), but implicit in the discussion was the idea that continuity of care was important because doctors remembering things is better than writing them down. This may be true, and the podcast in fact cover some of the problems with medical records*, but if so that is a profound failure of medical record keeping. Human memory is the last thing you want to trust your life to. I pay extra for the kind of doctors that spend actual time talking to me, and I still have to remind the one that that drug she loves has unacceptable side effects for me, every time I see her. I in no way trust her to remember something as dense and detailed as test results. That’s why she writes them down.

My understanding is that many people do understand this, but fixing medical record keeping involves a huge government entanglement that stifles all progress. So we’re stuck with human memory as the thing keeping us alive.

Note that there are good reasons to have your PCP supervising your hospital stay even if everything is properly written down, which is hospitals are full of specialists who aren’t even trying to coordinate care. You benefit immensely from someone thinking “how are these things going to interact?” In theory this should be done by a hospitalist, but they only have so much time and not doing it is much faster. But let’s not pretend we’ve proved human memory is in any way a good solution to any problem ever.

*EHRs simultaneously have too much information, taking a long time to complete and read, and don’t have space for information off the beaten path.

The Longevity Research Institute

A theme on this blog is “there isn’t enough good information.” Anti-aging research is worse than most topics at this, perhaps even worse than nutrition. There are several reasons for this: time/money requirements of research, the FDA’s focus on pathology rather than health, and science as a whole disincentives the kind of replication you need to truly trust a result. But there’s a new organization, the Longevity Research Institute, aiming to fill this gap. (Full disclosure: I’m on the board).

To run a longevity experiment, you have three choices: research something with a short life cycle (limited applicability to humans), research something with a long life cycle but track biomarkers instead of actual lifespan (risks goodharting the biomarker while not affecting or even hurting lifespan), or wait. Even a mouse experiment can take four years for your subjects to die. And the more successful your treatment, the longer (and thus more expensive) the experiment.

This would make lifespan-increasing treatments more expensive, but that’s hardly the end of the world. What could be more worth paying for than life? Unfortunately, the FDA takes another view. To get FDA approval, a drug must show effectiveness treating a specific disease, and aging is not considered a disease. This has been challenged recently, with the TAME trial, but has been a fact of life for a very long time and there’s no guarantee TAME will win the fight.

Finally, science in general is bad at replication. Repeated studies are necessary to have any confidence in a treatment, but glory goes to the original discoverers of a treatment and their funders, not to replicator three of ten. So we end up with a list of promising treatments that no one can trust because no one has any incentive to test them again.

All together, this leads to a lot of low-hanging fruit in longevity research; there’s a ton of promising molecules out there that only need money to be tested. The Longevity Research Institute aims to pick that fruit. It has a very targeted mission: take compounds already shown promising in at least one trial and fund replication trials where you actually wait to see how long the mouse lives. That’s it. Yes, it should worry you that this isn’t already being done.

The LRI is run by Sarah Constantin, who writes the blog this blog wants to be when it grows up. You can see her past work in e.g. treatment-resistant depression, STD transmission, and chronic fatigue syndrome. Because there are very few fixed costs (Sarah’s salary, some legal consulting) and studies are so expensive, there’s lots of room for more funding. You can see the LRI’s roadmap here and an initial list of promising compounds here. LRI’s first trial, of the synthetic pineal peptide epitalon, launched just last month.

For more information, you can follow the blog or Facebook group. If you feel so moved, you can donate to LRI here. I’m happy to talk to anyone considering donating (elizabeth-at-this-domain-name), and for larger amounts Sarah herself is available.

In Robert Kegan’s In Over Our Heads, he says “it is a poor school whose favorite students are the ones it does not have to teach.” (page 171). I get what he’s going for, but having lived it, I can also say it’s a poor school whose least favorite students are the ones it does not have to teach. It tends to lead to things like resentfully insisting you do have something to teach the student and forcing them to go through the motions of learning it, or standing in their way when they try to do something they’ll actually learn from. Or an intrusive focus on their personal life.

I feel like the whole concept of favorites is leading people astray here, which is a very Kegan thing to say.

Self Help Epistemic Spot Check Results

In a word: ¯\_(ツ)_/¯

I reviewed several self-help books with a wide range of scientific backing. For posterity:

Polyvagal Theory
The Tapping Solution/EFT
Full Catastrophe Living/Mindfulness
Exercise for Mood and Anxiety
A Guide to Better Movement
There were a few others I never published because I didn’t get very far into.

As a reminder, epistemic spot checks are checking a book’s early claims for truth/scientific validity/coherent modeling, to determine whether it’s worth continuing. After a few books I concluded that scientific backing didn’t seem that predictive of a book’s helpfulness, and started focusing on modeling. But that wasn’t predictive either.

I never officially decided to quit this project, but I can no longer get excited about checking out a new book, because nothing short of trying it seems to have any predictive ability of whether or not it is helpful. This leads me to believe that most of the effects are placebo effect, not in the sense of  “imagined” as people usually use the word, but in the sense that it’s your own brain doing most of the work, and people just have to try things until something clicks for them, starting with the cheapest. I find this answer deeply unsatisfying, but what are you gonna do?