How Does MDMA work? Is Combining MDMA and SSRIs Actually Dangerous?
Ahhh MDMA, one of the hall of famers of recreational drugs. A magical pill/powder that takes away your worries and replaces all your negative thoughts with overwhelming love, affection, euphoria, and contentness. A veritable love potion if one can even exist. Millions swear by this little compound, but few understand how it really works.
We’ve probably all heard numerous warnings about the dreaded Serotonin Syndrome and how combining MDMA and SSRIs is basically a death sentence.
Today we’ll go in detail about…
How Does MDMA work? Is Combining MDMA and SSRIs Actually Dangerous?
In short, the answer is that MDMA depends heavily on the serotonin transporter (SERT) to function, so SSRIs actually completely reduce the effects of MDMA and thus does not increase the risk of serotonin syndrome.
Serotonin
But let’s delve into the science of exactly what’s happening for more clarity.
SERT
Let’s talk first about SERT (SERotonin Transporter). This is a protein that operates within neuronal synapses (where signals between neurons are sent) and attaches to excess Serotonin molecules and takes them back into the cell for storage or recycling. This is a process known as “reuptake” and is how your body ensures careful levels of serotonin activity to make sure excess serotonin don’t overwhelm the system.
Frequently, SERT will bind to serotonin molecules and bring them back into the presynaptic neuron and store them in vesicles (basically a big bag within the cell) for future use.
SERTSource: https://en.wikipedia.org/wiki/File:SLC6A4.pngMDMA
Circulating to CNS
Now how does MDMA work? After you intake the MDMA, it circulates into your bloodstream and eventually makes its way into the brain. Once there, a MDMA molecule would simply float around arbitrarily until it happens to float into a neuronal synapse (Gap between two neurons where neuronal messages are sent).
Entering into the neuron
Once at the synapse, the MDMA molecule actually binds to the SERT. After binding, the SERT does its job and brings its payload back into the cell for future usage. In anthropomorphic terms: the MDMA disguises itself as a serotonin molecule and tricks SERT to reuptake the MDMA back into the neuron.
Inside the Presynaptic Neuron
Once the MDMA enters the presynaptic neuron, it can now do a variety of important actions:
1) MDMA attaches to VMAT2 (Vesicular Monoamine Transporter 2), and blocks its activity. This prevents VMAT2 from successfully packaging serotonin into the vesicles (where they are stored for future use), and instead causes it to release massive amounts of serotonin from the vesicles into the cell’s cytoplasm. This serotonin is now floating around in the neuron, but has not yet started having an impact on neurotransmission. They still require some mechanism to make it out of the neuron and into the synapse.
2) MDMA is also a TAAR1 agonist (trace amine associated receptor 1, which is a receptor that regulates the release of monoamine neurotransmitters such as serotonin). Activation of TAAR1 causes protein kinase A (pKA) and protein kinase C (pKC) to phosphorylate all monoamine transporters (DAT, SERT, NET) present in the neuron. pKA causes the transporter to internalize (come back into the cell, temporarily retiring from its duties) which leads to reuptake inhibition. On the other hand, pKC causes transporters to reverse the direction of their flow, bringing neurotransmitters out of the neuron and into the synapse instead causing neurotransmitter release.
3) The reversal of SERT is the primary direct mechanism whereby MDMA releases serotonin into the cleft. Normally, SERT works by taking excess serotonin from the synapse back into the vesicles. But once TAAR1 agonism starts the process of SERT reversal, these newly reversed SERT start transporting serotonin from the cell cytoplasm out in into the synapse. Since MDMA’s activity at VMAT2 has already caused a big release of serotonin out of storage vesicles into the cytoplasm, the reversed SERT has tons of serotonin to work with and causes a massive release into the synapse.
Despite being the primary mechanism of MDMA, the other SERT reversal would not be possible nor effective without VMAT2 reversal providing enough serotonin to work with and TAAR1 agonism allowing for the reversal of the transporter in the first place. So all 3 of these mechanisms discussed so far are equally vital in MDMA’s mechanism of action.
SerotoninFate of the Released Serotonin
In addition to large amounts of serotonin release, MDMA also serves to keep concentrations of already released serotonin elevated in the synapse. It achieves this by disrupting the normal functionality of SERT and preventing it from effectively recovering excess serotonin to place into storage.
Once at the synapse, these serotonin bind to postsynaptic serotonin receptors, causing MDMA’s subjective effects. In addition to inducing large release of serotonin, MDMA also facilitates the serotonin to stay in the synapses for far longer, continually activating serotonin receptors for the entire duration of the MDMA experience. It does this via reuptake inhibition in 3 main ways: MDMA itself competitively occupies SERT to transport into the neuron, TAAR1 agonism (pKA induced phosphorylation) causes internalization (temporarily disabling) of a large number of SERT, while TAAR1 agonism (pKC induced phosphorylation) also reversal of SERT. Any SERT protein that has been impacted by either of these 3 processes would lose its ability to reuptake serotonin back into the neuron and thus the body’s primary process of reducing synaptic serotonin concentrations is significantly inhibited. This means that MDMA not only releases a bunch of serotonin, it also keeps it there for a long time leading to a continuous level of effect for the drugs duration.
Note on the ratio of monoamine released from this process:
TAAR1 agonism is not selective for one specific transporter and would cause internalization and flow reversal of all 3 monamine transporters (DAT, SERT, NET). However, because MDMA relied on the serotonin transporter SERT to make it into the neuron in the first place, this means that MDMA has a far easier time making its way into neurons with a high number of available SERT to use. Neurons typically specialize in the production of a few neurotransmitters each, so neurons with a high number of SERT tend to have comparably lower numbers of other transporters. This means that despite TAAR1 agonism signaling all transporters to start dumping neurotransmitters into the synapse, since MDMA is has the easiest time making their way into serotonin producing neurons, the end result is a high ratio of serotonin release compared to dopamine and norepinephrine.
A diagram of how a trace amine (such as phenethylamine or amphetamine) activates TAAR1. This is a bit similar to how MDMA does it (I couldn’t find a more relevant diagram)SSRIs
SSRIs stand for selective serotonin reuptake inhibitors. This is a class of drugs that work primarily by attaching to SERT and making it impossible for serotonin to bind to it. This reduces the amount of serotonin reuptake that occurs, which means that fewer serotonin molecules are being “cleaned up and recycled away”, leading to a higher concentration of serotonin in the synapse.
Note: Despite SSRIs typically being called antidepressants, the “serotonin hypothesis” of depression has since been heavily debunked. The heightened level of serotonin does not directly lead to an improvement in depression. The latest hypothesis is that serotonin mediated downstream changes allow for an increase in neuroplasticity (via glutamatergic pathways and production of BDNF). But this is off topic for this article.
SSRI + MDMA
Now, typically, when you combine two compounds that both release serotonin, the risk of Serotonin Syndrome can be extremely high and the combination is highly discouraged. Now, looking at the above explanations, both SSRIs and MDMA can massively raise serotonin levels, so it might stand to reason that the combination is a huge serotonin syndrome risk right?
Wrong!
(kinda)
MDMAThis is actually an outdated but prevalant myth which sounds good on the surface but does not survive scientific scrutiny.
If we look back to the section on how MDMA works. We quickly realize that both Entering into the neuron stage and part 2 of the Inside the Presynaptic Neuron stage BOTH require SERT to accomplish.
If a subject was already on a regiment of SSRIs, a large portion of their SERT proteins would have been inhibited already. This makes it very difficult for the MDMA to make their way into the presynaptic neuron. Even if it does, it would have yet another difficult job finding a SERT molecule that’s not yet disabled to be able to force it to reverse its flow and release serotonin.
Because of this fact, taking MDMA while an individual is on SSRIs leads to a profound and noticeable dulling of the MDMA’s effects. Even massive dosages of MDMA would only provide a mild dopaminergic stimulation but almost zero serotonergic activity.
Fluoxetine aka Prozac (A common SSRI)So… is it safe?
No! Just because we explained that SSRIs + MDMA does not raise the risk of serotonin syndrome, that doesn’t mean this combo has no other potential risk factors. Some reasons to avoid it are:
1) Taking dangerously high dosages of the MDMA out of frustration that you don’t feel it
2) Intense strain on the heart
3) If SSRI is a short lasting one, and if it wears off, your high dosage of MDMA might end up kicking in leading to an OD
4) Overheating and neurotoxicity can still potentially occur
5) Just beacuse it doesn’t necesarily raise the chance of Serotonin Syndrome does not mean that Serotonin Syndrome is impossible. It is still a risk!
6) It is a massive waste of drugs.
Combining MDMA and SSRI can still be very risky and we do not recommend it. But not because of Serotonin Syndrome!
Is it safe though?NahSources and extra reading:
Liechti, M. E. (2015). Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signaling. Swiss Med Wkly, 145, w14043. This review discusses the pharmacology of MDMA and its effects on monoamine signaling, including its action on SERT and VMAT2.
Simmler, L. D., & Liechti, M. E. (2018). Pharmacology of MDMA- and amphetamine-like new psychoactive substances. Handbook of Experimental Pharmacology, 252, 143-164. This chapter provides an overview of the pharmacology of MDMA, including its effects on serotonin, dopamine, and norepinephrine release.
