Last Updated on Friday, 10 July 2009 22:11

Each image progresses from basic to more advanced. The advanced images should not be too difficult to understand if you have gone through the previous ones. The second part of this slideshow is all about MDMA neurotoxicity, including up-to-date research and current theories.

1) The Human Brain

This is a model of a typical human brain, showing some of the basic brain areas. You don't need to memorize them all. This is just a warm-up to get you started.

2) An Individual Brain Cell



This is a model of a typical brain cell, or neuron. Your brain contains billions of brain cells. A brain cell consists of a cell body, which stores the DNA, dendrites which receive chemical signals from other cells, and an axon, which carries an electrical signal from the cell body to the axon terminals. The axon terminals contain chemicals, called "neurotransmitters," which are released in order for the cell to communicate with nearby cells. Serotonin is a neurotransmitter, and some brain cells have axons that contain only serotonin. These are called "serotonin neurons." Other brain cells produce and release different neurotransmitters, like dopamine or norepinephrine, and some produce and release more than one neurotransmitter. However, your serotonin cells only produce and release serotonin.

3) Neurons, Dendrites and Axon Terminals

Here you can see how the axon terminals, which contain serotonin, lie very close to the dendrites of other, nearby neurons. Notice the gap between the axon terminal of the serotonin neuron and the dendrites of the next neuron. This gap is called the "synapse" and is where the serotonin gets released. Soon we will look at the synapse up close, and see what happens when ecstasy causes large amounts of serotonin to be released there. But first, let's look at how serotonin cells are distributed throughout your brain.

4) Seratonin Cells in the Brain

Most serotonin cells (in red) begin in a specific area of the the brain stem called the "raphe nuclei." Their dendrites and cell body's are located here, and they have very long axons that extend into every other part of the brain.

Most people think of brain cells as shorter and confined to particular brain regions (in blue). While some brain cells are like this, this is not the case with serononin cells. No wonder serotonin plays such an important role in so many brain functions, such as the regulation of mood, heart-rate, sleep, appetite, pain and other things.

Ecstasy causes your serotonin neurons to release large amounts of serotonin, which are stored in the axon terminals. This massive serotonin release is responsible for the primary subjective effects of MDMA.

6) Axon Terminal Close-Up

Inside the axon terminal are small vesicles that contain serotonin molecules. When an electrical charge comes down the axon, these vesicles merge with the outer membrane of the axon terminal and release serotonin into the synapse.

7) Axon Terminal (Artists Rendition)

This is an artists rendition of the view inside a serotonin axon terminal. The vesicles float around scooping up serotonin, and when directed to by an electrical current coming down the axon, they merge with the membrane and release the serotonin into the synapse.

8) Close-Up of Synapse

Moving in a little closer to the synapse, we can see some serotonin molecules floating around. We also see some serotonin reuptake transporters on the membrane of the axon terminal, as well as receptors on the dendrite of the nearby neuron. In order to understand how MDMA works in the brain, and why it produces the effects it does, you need to know what these reuptake transporters and receptors do. But first, just for the fun of it, let's look at an actual photograph of a synapse...

9) Photo of Seratonin Axon

This is an actual photograph of a serotonin axon terminal (top), a dendrite (bottom), and the synapse in between. Notice the serotonin-filled vesicles inside the axon terminal. You can't actually see serotonin molecules in this picture, nor the reuptake transporters or receptors. This is because they are so small. You can, however, imagine serotonin molecules floating around inside the gray area. Also, notice that some other dendrites are visible even though they haven't been stained like the bright one.

10) Vesicle Releasing Seratonin

This is a closer view of a vesicle releasing serotonin into the synapse. Serotonin Receptors: The primary reason for Ecstasy's subjective effects. On the other side of the synapse, attached to the membrane of the dendrite, are these things called receptors. There are receptors for many neurotransmitters. Let's say the magenta-colored ones are serotonin receptors and the green ones are for dopamine. Notice how a serotonin molecule can easily fit into the serotonin receptor, but not into the dopamine receptors (or any other type of receptor for that matter). This is because serotonin recepters are designed specifically for serotonin molecules. When a serotonin molecule attaches to a receptor, which is called receptor binding, the receptor sends chemical information down the dendrite to the cell body of the neuron. The cell body then decides, based on the information from all its recepters put together, whether or not to fire an electrical impulse down its own axon. If a critical amount of receptor binding occurs then the axon will fire, causing the release of other neurotransmitters into other synapses. This is how your brain communicates, and something like this is happening in your brain at a normal pace all the time.

Research has shown that your mood is influenced in part by the amount of serotonin receptor binding. When you are happy, it is likely that you have more serotonin receptors activated. Positive events in your life (like falling in love, perhaps) cause greater serotonin release, increasing receptor binding. So does taking ecstasy.

After a little while the serotonin molecule will detach ("unbind") from the recepter and float back into the synapse. When this happens, the receptor stops sending chemical signals to the cell body, and it waits for another serotonin molecule to come along. (Those yellow things on the membrane of the axon terminal are serotonin reuptake transporters. Don't worry about them just yet.)

11) The Peak Experience (About an hour or so after you take Ecstasy)

When you take Ecstasy, the vesicles release enormous amounts of serotonin into the synapse. This significantly increases serotonin receptor binding (more serotonin in the synapse means a greater chance for some of them to bind to the receptors). This increased receptor activity leads to significant changes in the brain's electrical firing and is primarily responsible for the MDMA experience (i.e. empathy, happiness, increased sociableness, enhanced sensation of touch, etc.). Notice also that there is some dopamine in the synapse as well (the blue things). MDMA also causes dopamine release (from dopamine cells), but lets not discuss that yet. Keep it in the back of your mind (no pun intended) because it will come up later when we get into neurotoxicity. For now, just notice that the dopamine receptors have also been activated.

The effects of a normal dose of ecstasy last about four to six hours. We will be looking at what happens in the brain during the various stages of an ecstasy experience, as well as some changes that may occur in the brain after long-term, frequent use. But now let's take a look at the "reuptake transporters" (those yellow "H" looking things). To understand how ecstasy works over time in the brain, it is important to know what these things do.  

12) Serotonin Reuptake Transporters

Along with binding to the dendritic recepters, serotonin molecules also bind to "reuptake transporters" on the axon's membrane. These transporters take the molecule and transport it back into the axon terminal. They are sometimes called "pumps" and can be thought of as a revolving door. The serotonin enters one side, and the door spins around pushing it out the other side. We have shown here four reuptake pumps in various stages of transporting serotonin. Imagine them spinning and transporting serotonin from the synapse back into the axon.

Reuptake transporters reduce the amount of serotonin in the synapse. Keep in mind that these are one-way doors. Serotonin doesn't go through them the other direction. It can only be released into the synapse from the vesicles. As the reuptake pumps are pulling the serotonin back into the axon, some of this serotonin makes its way back into the vesicles, where the MDMA may cause it to be released again. However, some of it gets broken down by Monoamine Oxidase. We show this in the next slide.

13) Monoamine Oxidase breaks down your serotonin

Approximately three hours into your ecstasy experience your serotonin transporters have removed much of the serotonin from the synapse, but there is still plenty around to activate the receptors, so you still feel the desired effects of the drug. Pretty soon, however, the reuptake transporters will remove most of the serotonin from the synapse, and you will start coming down.

We said in the last image that some of the serotonin finds its way back into the receptor where the MDMA causes it to be released again. This is true, but notice the hammers inside the axon. This is "monoamine oxidase" (MAO), an enzyme that breaks down serotonin (serotonin is a monoamine, remember). After your reuptake pumps remove the serotonin, MAO breaks most of it down. MAO doesn't really look like a hammer, but thinking of it as a hammer that smashes up serotonin molecules is a good way to remember what it does. Notice too that the dopamine receptors are also still activated as well.

14) When you start coming down

First, notice that the number of activated serotonin receptors has been reduced because there is less serotonin in the synapse. This means you should be starting to feel somewhat normal again. Also, the uptake pumps are still removing serotonin from the synapse, as usual, and MAO is still doing its job breaking it down. Notice that the dopamine levels in the synapse haven't lowered as much as the serotonin. This is because dopamine replenishes itself much more quickly than serotonin. Notice also that there is a lot less serotonin in your vesicles, and this is mainly why you come down. Simply put, there's no more serotonin left to be released. The MDMA may still be around trying to make your vesicles release more, but there isn't enough there. In about four hours, Ecstasy has used up most of your serotonin.

You could take more Ecstasy at this point, which a lot of people do. However, this usually doesn't work. You can't just take more ecstasy to regain the ecstasy feeling. Why? Because the ecstasy feeling is really a "serotonin feeling" and you currently don't have enough serotonin left. (It takes time for your brain to build up more, which we will be discussing soon.) Of course, if you took a lower-than-normal dose, you may not have released most of your serotonin, in which case you may feel the effects come on again if you take more. However, you cannot keep doing this repeatedly all night long. There will come a point (sooner rather than later) when you have depleted your serotonin levels so much that taking more Ecstasy will not work.

15) When you come down some more

Depending on how much MDMA you took, you may end up depleting so much of your serotonin that fewer receptors are activated than before you took ecstasy, when you were in a normal brain state. This is what causes the "ate up" feeling that a lot of users experience when they come down. You can become very depressed at this point, feeling extremely non-social, tired and irritable.

Some people at this point are tempted to take more Ecstasy, because the contrast between how they were feeling an hour earlier and how they feel now is so extreme. But when they take more, it doesn't work. While it may give the user a little more energy (i.e increase the speediness), they won't recapture the empathy and other desirable MDMA effects. Remember, Ecstasy releases (and then depletes) the serotonin that you already have. It doesn't cause more serotonin to be created.

Your brain needs time in order to rebuild its serotonin levels. This could take up to two weeks. As expected, the larger the dose the greater the serotonin depletion and the longer it takes for your brain to replenish it.

Can these lowered serotonin levels cause depression? Yes. There are a few pharmacological reasons why MDMA use can lead to temporary yet prolonged periods of depression. Perpetually low serotonin levels resulting from weekly MDMA use is one of these reasons. If you take ecstasy on a regular basis, you may be releasing and depleting your serotonin before it has a chance to fully replenish itself. This means you will be operating on lower-than-normal serotonin levels most of the time, and this can lead to depression.

Another reason you can get depressed has to do with "receptor downgrading," which we will be discussing soon. How does your brain make serotonin in the first place, and why does it take so long for it to replenish its stores after they have been depleted by MDMA? Let's take a look . . .

16) Producing New Serotonin

Your serotonin brain cells produce serotonin when an amino acid called 5-Hydroxy-Tryptophan (5-htp) enters the cell and comes into contact with an enzyme called decarboxylese. The 5-htp enters the cell directly through the cell's membrane. It does not have to go through the reuptake transporters, the way previously-released serotonin must. Once in the axon, decarboxylase turns the 5-htp into serotonin, where it enters the vesicles (the vesicles are not shown in this diagram). In other words, after the serotonin is made inside the cell, it moves to the terminal where it is stored in the vesicles ready to be released into the synapse when the time comes.

There's usually plenty of decarboxylase in your cells, but the amount of 5-htp you have can vary depending on your diet. 5-htp is synthesized in your body from another amino acid called tryptophan, which is contained in many foods. A diet high in tryptophan-containing proteins can increase the amount of 5-htp in your brain, and thus help your brain build serotonin more quickly.

Normally it takes a long time for your brain to build serotonin. Why? One reason is that tryptophan must go through a number of metabolic changes before it is turned into 5-htp. Another reason is simply that your brain was not made to make serotonin very quickly. Normally, it doesn't need to, because serotonin is not usually released in very large quantities. As a comparison, dopamine is released in larger quantities under normal circumstances, and your brain is thus built to replenish dopamine much more quickly. Researchers say that the dopamine system is "robust" in this sense, while the serotonin system is "delicate."

17) Down-regulation of Receptors: The most probable cause of ecstasy-related depression.

The brain is built to adapt to changing circumstances. One of the ways your brain adapts is through the up-and-down regulation of receptors. What this means is that if your serotonin receptors get hyper-activated by serotonin molecules, they may retreat into the membrane of the dendrite, essentially shutting themselves down for a while. One theory says they do this in order to avoid getting damaged from over-stimulation. Another theory says that it is just a way for your brain to maintain a balanced, normal state. Whichever one of these theories is true, it has been proven conclusively that serotonin receptors will down-regulate over time if bombarded with large amounts of serotonin.

This may lead to depression, even after your brain serotonin levels have been restored, because the serotonin cannot bind to downregulated receptors. Many ecstasy users we have interviewed have reported periods of depression lasting months or even a year or more following a period of heavy use. Keep in mind, however, that most evidence of MDMA-induced depression is anecdotal, based on reports by MDMA users. Since many people experience depression it is difficult to know for sure whether the depression experienced by MDMA users is really related to their MDMA use. While MDMA is known to reduce serotonin levels, serotonin levels varies greatly among healthy, non-depressed, non-MDMA users. Until more research is done, we cannot know for sure whether MDMA users actually have a greater risk of experiencing depression than non-users.  Let's now turn to the issue of neurotoxicity . . .

This next section deals with MDMA neurotoxicity. If you have understood everything so far, you should have no trouble with this section.

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