A Primer on MDMA and “Neurotoxicity”
Yesterday (June 4th) the FDA advisory committee voted almost unanimously to recommend against the adoption of MDMA (3,4-Methylenedioxymethamphetamine) as a legal treatment for PTSD. This has presented a major roadblock on the decades-long journey to get the drug approved as a medicine in the United States. Although there is compelling evidence (both officially published and collected from hundreds of underground therapy case studies) that MDMA assisted therapy can be effective, there are concerns about its safety profile, both during the acute effects of the drug and in the long-term. It was this concern for safety, coupled with procedural objections to the study design of the clinical trials that resulted in the FDA committee’s decision.
The therapeutic appeal of MDMA lies in its ability to induce a powerful state of equanimity and positive self-regard, one which enables the user to compassionately and calmly re-examine past events in their lives. For many individuals who have experienced traumatic events, the intensity and pain of the traumatic experience and associated memories makes it difficult to normally process and integrate after the fact. The promise of MDMA is that it is capable of opening a few hour window of time in which that necessary processing, done with the aid of a trained psychotherapist, can take place.
Although MDMA’s capacity to induce a state of psychological safety and wellbeing is relatively well validated, the physical safety profile of the drug has been a topic of much more debate. In particular, the history of MDMA research is marked by the specter of potential neurotoxicity. This was catalyzed by an early study which supposedly found that MDMA caused visible brain damage in monkeys who were administered a large dose. This would indeed have been cause for concern, if it wasn’t for the fact that it was later discovered that the monkeys had been given a large dose of methamphetamine, not MDMA.
Thankfully, it is now well established that MDMA does not create holes in the brain. There are, however, genuine concerns about the long-term effects of MDMA on the brain and its potential to induce different subtler forms of neurotoxicity. These concerns were strong enough for the FDA advisory committee to recommend against approving the drug, so they seem worth taking seriously. In this article I describe three levels at which MDMA might be considered neurotoxic, and what can be done to mitigate these negative effects. I have also tried to include diagrams wherever possible to make the underlying neural mechanisms clearer. I hope that they are helpful.
(Quick disclaimer: I am a cognitive neuroscientist, not a molecular biologist. The level of detail presented here is also simplified for the sake of communication with a wider audience. If you are an expert in this area and notice that I got a detail wrong, please let me know, and I’ll be happy to update the article accordingly.)
Basic Pharmacology of MDMA
Before turning to how MDMA changes brain function, it is useful to understand the basics of how the monoamines such as serotonin and dopamine function to transmit signals in the brain. Because it is central to the effects of MDMA, I will use serotonin as the running example. Under normal circumstances, serotonin is packaged into vesicles and released from a presynaptic cell into the synaptic cleft once an action potential is reached. From there, the serotonin moves towards the postsynaptic cell and binds with specialized serotonin receptors to trigger signal processing in the postsynaptic cell. The serotonin then detaches from the receptor and is reabsorbed back into the presynaptic cell by the serotonin transporter, where it is recycled and later reused.
MDMA disrupts this process in multiple ways. Once in the brain, MDMA enters presynaptic serotonin, dopamine, and norepinephrine cells through the transporter reuptake mechanism. Again we can focus on serotonin as an example. Once inside the presynaptic cell, MDMA disables the normal vesicle release process and also reverses the flow of the serotonin transporter. This means that rather than bringing serotonin into the cell, the transporter now allows it to be released. Because this release is the effect of the MDMA and not the typical action potential of the cell, it takes place continuously for the duration of the drug effect. On top of that, because the transporter is reversed it no longer acts to effectively reuptake serotonin back into the cell. These two effects combined produce a significant and persistent signaling effect on the postsynaptic cells, which collectively produce the psychoactive effects of the drug.
Level One: Neurotransmitter Depletion
MDMA causes the continuous release of serotonin and dopamine without proper recycling to take place for several hours. This results in the depletion of the brain’s natural reserves of these important molecules. Because of this depletion, in the aftermath of MDMA use, individuals sometimes experience a period of lethargy, sadness, and overall malaise that can last anywhere from 12 to 36 hours. This phenomenon is sometimes referred to as the “come-down.” It isn’t indicative of any lasting brain damage, but only of a temporary state of disequilibrium which the body is well equipped to handle.
Proper sleep, a balanced diet, and adequate hydration are typically sufficient to restore neurotransmitter levels naturally within a day or so. Ensuring good health practices before, during, and after MDMA use can significantly mitigate the severity of this depletion and enhance recovery. Some users turn to supplements like 5-HTP (5-Hydroxytryptophan), which is a precursor to serotonin, for use the day after taking MDMA in an attempt to speed this process up. While this may provide some marginal benefit, it isn’t necessary as long as other aspects of personal health are taken care of.
Level Two: Receptor Downregulation
The brain (and body at large) strives to maintain homeostasis, a state of balanced function. When an excess of serotonin or dopamine is suddenly released from a presynaptic cell, the brain compensates by downregulating, or reducing, the number of postsynaptic receptors available to bind with those molecules. A useful analogy can be made to listening to music on a pair of speakers. If suddenly a song begins to play which is much louder than you were expecting, your natural reaction would be to turn the volume down. We do this because we are most interested in “receiving the signal,” and it is actually more difficult to make out fine details from excessively loud music. A similar mechanism is present in the brain. In the case of MDMA, postsynaptic cells reduce the number of serotonin, dopamine, and norepinephrine receptors in response to their excessive activation during the acute drug effects.
While a couple of hours of excess neurotransmitter release can cause rapid downregulation of receptor populations, it can take much longer for those receptors to up-regulate and return to baseline after the fact. Receptor downregulation accounts for the decreased effectiveness of MDMA with repeated use, as there are fewer serotonin or dopamine receptors for those neurotransmitters to bind to when released. Because of this, it takes more of the drug to achieve the same effect, and tolerance has been developed. Unlike neurotransmitter depletion, which resolves in a few days, the effects of downregulation can take anywhere from weeks to months to resolve. In more extreme cases, it can also lead to longer-term negative effects on mood and anxiety as the postsynaptic cells now “expect” much higher levels of serotonin and dopamine release than what is possible under normal circumstances.
The duration of receptor downregulation can vary. With very infrequent use receptor populations can return to baseline levels in a matter of weeks. On the other hand, if MDMA is repeatedly used while receptors are already downregulated, it can lead to more permanent changes that take place through alterations in genetic transcription factors. This can set a “new baseline” which is lower than what was the case prior. Concern for long-term downregulation underlies the common recommendation that individuals who choose to use MDMA recreationally should do so with a maximum frequency of once every three months.
There are hypothetical ways to speed up the process of upregulating receptor populations. Certain drugs, such as N-acetylcysteine (NAC), have been shown to aid in the process of upregulating dopamine receptors. NAC works by improving the body’s ability to capture and break down dopamine when it is not being used. This lowers the quantity of dopamine available to bind to postsynaptic receptors. In our music analogy, this is akin to playing quieter songs, which naturally prompts the slow increase of the volume on the speakers.
Level Three: Damage to Serotonin Cells
Thus far we have considered relatively superficial and temporary changes to the brain’s functioning. At its most severe, MDMA use can lead to actual structural damage to neurons in the brain. In particular, excessive levels of MDMA are believed to be capable of damaging serotonin-releasing neurons. This damage can result in long-term negative changes in mood and cognitive function. Damage to serotonin neurons is hypothesized to be due to the oxidative stress caused by dopamine, which can be harmful if not properly regulated within the cell. MDMA’s metabolites, particularly MDA (3,4-methylenedioxyamphetamine), play a significant role in this oxidative stress, as it causes much more dopamine release than MDMA itself.
Why does excessive dopamine release pose a problem? This particular form of neurotoxicity comes from the unique combination of simultaneous serotonin and dopamine release. Unlike presynaptic dopamine cells, serotonin cells lack the necessary mechanisms to adequately manage dopamine, leading to potential cellular damage if dopamine enters these cells. Normally this wouldn’t be an issue as the serotonin transporter would only open for a brief time and would typically not open at the same time as there were large quantities of dopamine in the synaptic cleft. Under the effects of MDMA however, both transporters are kept in an “open” state for the duration of the drug effects. This makes it possible for excess dopamine to enter the presynaptic serotonin cell and wreak havoc.
Thankfully there are multiple ways to mitigate the potential damage. The body’s natural MAOI and antioxidant systems exist to clean up molecules such as dopamine to prevent them from causing harm. While large doses of MDMA overwhelm that system, smaller doses are less likely to do so. Indeed, it seems that single therapeutic-level doses of MDMA do not cause long-term damage to the brain. These cleanup systems of the brain can also be enhanced through external means. Supplements such as Alpha Lipoic Acid (ALA) act as strong antioxidants and have been shown to prevent the neurotoxic effects of MDMA in studies using rodents. It has also been demonstrated that taking MDMA alongside the antidepressant bupropion can reduce the level of the metabolite MDA which enters the bloodstream, thus potentially reducing oxidative stress from the dopamine release which it would cause.
Unfortunately, once damage to serotonin neurons has taken place it is unlikely that these neurons will be able to naturally repair themselves in any short time span. One potential therapeutic avenue is to attempt to stimulate or speed up the neuro-regenerative process. A class of drugs which may help in this area is the psychedelics, many of which have been demonstrated to promote neurogenesis, the growth of new neurons, and can specifically aid in the regeneration of serotonin neurons. While it is uncontroversial that psychedelics can induce neurogenesis, it isn’t clear yet that the neurons being regrown are the same as the ones which would be damaged from excessive MDMA use. As such, more research is required before this can be worth recommending.
Summary
MDMA neurotoxicity is a legitimate concern, but it is not an insurmountable one. By understanding the mechanisms through which MDMA can affect the brain, recreational users and future clinicians can take proactive steps to mitigate these risks. Neurotransmitter depletion, receptor downregulation, and potential cellular damage each present unique challenges, but they can be managed with proper precautions. Most important is ensuring good overall physical health through proper rest, hydration, and nutrition before, during, and after using MDMA. Furthermore, the smallest therapeutically viable dose should always be used, and the drug should be consumed no more than once every few months.
Given the FDA advisory committee’s recommendation against approving MDMA, it is also worthwhile to consider how similar therapeutic effects might be possible with other safer drugs. One promising candidate is MDAI (5,6-methylenedioxy-2-aminoindane). Unlike MDMA, MDAI acts solely as a serotonin releaser without affecting dopamine levels. By avoiding the dopamine release, MDAI significantly reduces the risk of oxidative stress and the associated neurotoxicity. This represents a potential avenue for developing a safer PTSD therapy, but this line of work is still in its infancy, as there have been no studies of MDAI conducted with humans so far. Outside of MDAI, there are other novel drugs which act as serotonin releasers that may make promising therapeutic candidates.
Widespread use of a safe and effective MDMA-like substance in clinically supervised settings has the potential to dramatically improve how we relate to and treat trauma, both on a personal and societal level. The recent FDA committee decision presents a setback to that dream, but one which is reasonable, given the presented causes for concern. The long and winding approval process for MDMA has highlighted the necessity of not only focusing on maximizing and “proving” the benefits of the drug, but also of ensuring that the potential negative effects are also minimized or eliminated.
