How Mdma Works In The Brain

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Jessica E. Malberg, Ph.D., and Katherine R. Bonson, Ph.D.

The pharmacology of MDMA primarily involves two brain chemicals: serotonin and dopamine. These neurotransmitters help nerve cells communicate with each other (as described below) and each of them have their own complex neural systems and behavioral responses. MDMA acts in the brain through three main neurochemical mechanisms: blockade of serotonin reuptake, induction of serotonin release, and induction of dopamine release. With these actions, MDMA is essentially a combination of the effects of fluoxetine (Prozac), the serotonin reuptake inhibitor and antidepressant; fenfluramine (Pondamin), the serotonin releaser (and the "fen" in "fen-phen"); and amphetamine, a dopamine releaser. Additionally, MDMA can directly interact with receptors in a variety of neurotransmitter systems and can act as a monoamine oxidase (MAO) inhibitor. This chapter will explain how each of these different mechanisms function at the cellular level with an eye toward how these actions can ultimately affect behavior and mood.

How Neurotransmitter Systems Function in the Brain

Before we attempt a complicated discussion of the neurochemical effects of MDMA, readers may benefit from a basic orientation to the way that the nervous system functions in the brain. Nerves communicate with each other by electrical and chemical means. When an electrical signal reaches the end of one neuron, there is a gap before the start of the next neuron. This space is known as a synapse. A synapse cannot be bridged with an electrical signal;

communication between neurons continues with the release of a chemical from the presynaptic neuron. This chemical, called a neurotransmitter, is synthesized and stored in this presynaptic space. Once released, the neurotransmitter floats across the synapse and can bind postsynaptically on the next neuron to protein structures known as receptors. When the receptor is occupied with the chemical, it causes the induction of a new electrical signal, and nerve cell communication continues. Neurotransmitters also can bind to presynaptic receptors, which function in a negative feedback mode to reduce the release of more neurotransmitter.

The normal functions of the presynaptic neurotransmitter cell are storage, release, and reuptake of its neurochemical. We can explain this concept using the example of serotonin (5-hydroxytryptamine, or 5-HT) neurons. Storage simply means that 5-HT is stored inside the cell, in one of two forms. Single molecules of 5-HT floating in the cytoplasm (the fluid in the cell) are characterized as either free-floating or cytoplasmic. 5-HT also can be found sequestered within the cell in storage packages called vesicles. Release of 5-HT occurs when a neuron is activated, causing the presynaptic terminal to release stored 5-HT into the synapse. The released serotonin then can bind to any of fourteen currently known serotonin receptor subtypes. These receptors are located both postsynaptically and presynaptically and are concentrated by subtype in particular regions of the brain. For instance, the 5-HT2 receptor, which is stimulated by hallucinogenic drugs, is found in high concentrations in the frontal cortex, an area of the brain responsible for higher cognitive processing.

After a certain amount of time, 5-HT will stop binding to the receptor and will become free again in the synapse. At this point, 5-HT can do one of three things: (1) It can be recycled into the presynaptic neuron through a reuptake mechanism (transporter) so that it can be stored for future release.

(2) It can be degraded by an enzyme such as monoamine oxidase subtype A (MAO-A), which metabolizes 5-HT into 5-HIAA (5-hydroxyindoleacetic acid).

(3) It can diffuse away out of the synapse. All of these actions terminate the effect of the neurotransmitter.

The serotonin reuptake mechanism is sometimes called the transporter protein. The 5-HT transporter is located on the outside membrane of the presynaptic cell, facing the synapse. Reuptake begins when the 5-HT in the

synapse binds to the 5-HT transporter. Once a molecule of 5-HT is bound to the transporter, the transporter changes shape (or configuration) and moves the 5-HT to the inside of the cell, where the 5-HT "falls off' and is released into the cytoplasm of the cell. The transporter then reorients itself toward the outside surface of the presynaptic membrane to continue its uptake function for the next molecule of 5-HT. The net effect of the action of the 5-HT transporter is removal of 5-HT from the synapse. There are many transporters on presynaptic serotonin membranes throughout the brain, so the reuptake mechanism does not rely on a single site at a time, working to recycle serotonin molecules. Drugs that "block" the reuptake mechanism occupy the site that would normally be occupied by 5-HT. This prevents 5-HT from binding to the transporter, so it is left out in the synapse, where it can reattach to a postsynaptic receptor. Thus, a drug that causes reuptake inhibition essentially prolongs the effect of any released serotonin. This is the mechanism of action of many antidepressants known as selective serotonin reuptake inhibitors (SSRIs).

MDMA and the 5-HT Transporter

How does MDMA fit into the function that we have just described? Although we have previously discussed the two mechanisms of 5-HT release and blockade of uptake separately, MDMA is unusual pharmacologically, because it can produce both of these effects at the same time. MDMA functions similarly to the antidepressant fluoxetine in that both drugs occupy the 5-HT transporter site and prevent 5-HT from binding to the transporter. In contrast to fluoxetine, MDMA also is taken up by the transporter after it is bound and is deposited into the presynaptic cell. This action does not occur with fluoxetine because of its relatively large size, which allows it to occupy the 5-HT transporter site but prevents its entry into the presynaptic cell. MDMA is closer in size to 5-HT than fluoxetine and therefore is able to enter the cell as if it were 5-HT.

Once inside the presynaptic cell, MDMA induces the release of 5-HT into the synapse. This is a four-step process:

1. MDMA is released from the transporter into the cell when the transporter undergoes a change in "configuration" (shape) and the MDMA falls off.

2. The transporter then has the correct configuration to bind cytoplasmic 5-HT (the serotonin in the neuron, not the synapse).

3. The bound 5-HT is transported out of the presynaptic cell, and when the transporter changes configuration again, the 5-HT falls off into the synapse.

4. The transporter is then in the correct configuration to bind more MDMA that is available in the synapse and repeat the process.

[For diagrams to help explain this process, please refer to the Ecstasy slide show on the Web site www.dancesafe.org]

MDMA's ability to induce 5-HT release is common to all substituted amphetamines, including methamphetamine and fenfluramine. Under normal circumstances, 5-HT is not released in large amounts but is tightly regulated in the brain. Thus, the main effects of MDMA—inhibition of 5-HT reuptake and release of 5-HT from the presynaptic neuron—flood the synapse with atypically large amounts of 5-HT. Within three to six hours after MDMA administration, so much 5-HT has been released that there is a temporary depletion of 5-HT in the presynaptic cell. Additionally, MDMA inactivates the enzyme (tryptophan hydroxylase) that is necessary for synthesis of new 5-HT, so that cells cannot make enough 5-HT to reach baseline levels. Since low levels of serotonin are associated with depression, this may account for the transient mood swings that follow MDMA use in humans. Within twenty-four hours, however, new serotonin can be synthesized, and 5-HT levels return to normal (Schmidt 1987). Longer-lasting depletions of 5-HT have been seen only when high doses of MDMA are given repeatedly for long periods of time. Similar depletions of 5-HT also are seen with long-term administration of fenfluramine [see "Does MDMA Cause Brain Damage?"].

Scientists have created a mouse that does not have the 5-HT transporter in its brain—this is known as a "transgenic mouse" or "knockout mouse," because the genes that are responsible for the transporter have been knocked out of the genetic makeup of the mouse. This mouse is useful scientifically to test how the absence of a transporter affects a living biological system, especially when it is challenged with drugs. In regular mice, MDMA will produce an increase in the amount of movement that mice make around a cage. But when 5-HT transporter knockout mice were given MDMA, there was no increase in their locomotion (Bengel 1998). This suggests that without a 5-HT transporter, MDMA could not get into the cell and cause its various effects. In contrast, when amphetamine was given to regular and knockout mice, both groups showed an increase in locomotion (this is thought to be because of increased dopamine). Thus, it was concluded that the 5-HT transporter is required for MDMA to exert its effects.

MDMA and Dopamine

MDMA also causes the release of dopamine (DA), but to a lesser extent than release of 5-HT. The release of DA appears to rely on the previous release of 5-HT, since blockade of the 5-HT transporter with fluoxetine suppresses the increase in DA after MDMA administration (Nash and Brodkin 1991). This principle also has been borne out in genetically altered mice that lack a 5-HT transporter, in whom MDMA does not cause hyperactivity (a measure of dopamine action). Conversely, giving drugs that increase 5-HT synthesis before the administration of MDMA causes an even greater increase in DA release (Gudelsky and Nash 1996). It should be noted that the effect of 5-HT on DA release involves the DA transporter as well, since inhibition of the DA reuptake mechanism also will prevent DA release in response to MDMA.

This effect of 5-HT on DA release may occur though the 5-HT2 receptor, since activation of this site in the abserVc^MjMDMA is known to increase DA release. To test whether the 5-HT2 is involved in MDMA-induced DA release, 5-HT2 antagonists were given before administration of MDMA. These antagonists were found to block the increase in DA from MDMA, but they did not affect the resting levels of DA before MDMA (Schmidt et al. 1991). Given the connection between MDMA neurotoxicity and DArelease [see "Does MDMA Cause Brain Damage?"], 5-HT2 antagonists might be useful in the prevention of any possible damage from highdose MDMA.

MDMA and 5-HT Receptors

Although the primary effects of MDMA are on the transporter sites in 5-HT and DA systems, there is evidence of direct interactions between MDMA and other receptors. The most intriguing work in this area has shown that MDMA has a slight affinity for the 5-HT2 receptor. This is interesting, because the hallucinogenic response from the classic psychedelics (such as LSD) has been correlated to activation of the 5-HT2 site.

MDMA often is characterized by users as having some psychedelic properties (despite the lack of hallucinations); it is therefore not surprising that the site associated with the psychedelic experience is activated to a small degree by MDMA. However, when rats are trained in drug discrimination studies to identify when they have received MDMA by pressing a certain lever, they do not press that lever when LSD is given to them instead. This suggests that the internal experience of classic hallucinogens is different from that of MDMA, in agreement with results from studies of human beings, which report a distinction between these drugs.

Additionally, the increased body temperature that is seen after MDMA ingestion may be the result of 5-HT2 activation, since stimulation of this receptor with other drugs is known to cause hyperthermia. This conclusion is strengthened by the fact that pretreatment with fluoxetine does not block MDMA-induced hyperthermia, suggesting that preventing 5-HT release by occupying the reuptake sites is not sufficient to inhibit the body temperature effects of MDMA.

Another receptor that may play a role in the action of MDMA in the brain is the 5-HT1b site. This receptor is thought to be important in producing feelings of calmness, and drugs that activate this site are known in psychiatric research as "serenics." Exploration of this receptor with MDMA has shown that there is a similar pattern of increased locomotion in rats when MDMA or 5-HT1b agonists are given. In contrast, the pattern of locomotion with 5-HT1a or 5-HT2 agonists is not similar to that from MDMA.

When rats are given repeated doses of MDMA and become tolerant (that is, they do not respond behaviorally to a dose of MDMA at the same level as they did before drug administration), they also fail to respond to the effects of a 5-HT1b agonist—this is known as cross-tolerance. Cross-

tolerance also happens when rats are made tolerant to repeated administration of the 5-HT1b agonist and are subsequently given MDMA. This suggests that MDMA shares a common mechanism of action with 5-HT1b agonists. Finally, drug discrimination studies have shown that rats trained to identify MDMA will press the MDMA lever when they are given trifluromethylphenylpiperazine (TFMPP), a drug with 5-HT1b properties. TFMPP has been promoted on underground drug information Web sites as being similar to MDMA when combined with a stimulant.

MDMA and Interactions with Other Drugs

Selective Serotonin Reuptake Inhibitors (SSRIs)

It has been shown that people who have taken fluoxetine or other SSRIs, like paroxetine (Paxil) or sertraline (Zoloft), for at least three to four weeks for depression have a reduced response to LSD and other hallucinogens (Bonson 1996a, 1996b). Our new research has found that a similar effect exists with MDMA. Most (but not all) people who take SSRIs for a long period of time report a reduced or completely eliminated response to MDMA. This decrease in response to MDMA in people who have taken SSRIs occurs because SSRIs occupy the same site on the 5-HT transporter that MDMA uses. Because an SSRI was there first, MDMA has nowhere to bind on the transporter and cannot be taken up into the presynaptic serotonin cell. Since all the SSRIs that are used as antidepressants have extremely long durations of action, MDMA simply diffuses away out of the synapse without ever having any psychoactive effect.

People who are not under treatment for depression also take fluoxetine in single doses before ingestion of MDMA. This practice is based on familiarity with neurotoxicological studies using rodents and monkeys that suggest that fluoxetine can blunt the serotonin-damaging effects from repeated high doses of MDMA when it is taken either before or three to four hours after MDMA. As expected, when fluoxetine is taken immediately before (in one dose) or concurrently with MDMA, it can decrease the MDMA response in humans. But since the effects of MDMA have dissipated by four hours after ingestion, taking fluoxetine after the effects of MDMA have worn off will not interfere with the response to MDMA and may still produce the desired protective effects.

Dextromethorphan (DXM)

It has recendy been reported that what is sold as Ecstasy can sometimes contain only dextromethorphan (DXM), instead of MDMA (Baggott et al. 2000). When users discover that these tablets do not produce the desired MDMA effect, they might be inclined to purchase Ecstasy from another dealer in hopes of obtaining real MDMA. In a situation where a person ingests both DXM and MDMA, it is possible that this drug combination could produce what is known as the serotonin syndrome. This behavioral condition is characterized by muscle spasms, gastrointestinal problems and diarrhea, confusion, agitation, incoordination, shivering, fever, and sweating.

The serotonin syndrome can be brought on by any combination of drugs that increase serotonin availability in the brain. It seems to be especially likely with combination of SSRIs from different sources. Although DXM is primarily thought to be an NMDA (N-methyl-D-Aspartate) antagonist, it also has SSRI properties. This means that there can be an extra increase in serotonin when MDMA is also in the body. It is noteworthy that the liver enzyme that metabolizes MDMA (cytochrome P450 isozyme 2D6, or CYP2D6) can be inhibited by the continued presence of MDMA. Since DXM also relies on CYP2D6 for its metabolism, if this enzyme is not functioning, both MDMA and DXM may continue to act in the brain for extended periods and increase the risk of serotonin syndrome.

MAO Inhibitors

It is well known that the combination of a MAO inhibitor and an amphetamine can induce a dangerous increase in blood pressure known as hypertensive crisis. During this hypertensive reaction, the heart will race at life-threatening levels, and if medical attention is not sought immediately, unconsciousness and death are possible outcomes. Since MDMA is an amphetamine, it should never be taken by someone who is taking an MAO inhibitor. The medical literature has reported severe reactions to MDMA in persons taking MAO inhibitors since 1987, and several people have died. It should be noted that there are two types of MAO inhibitors—those that block the A form and those that block the B form of MAO. MAO-A inhibitors are typically antidepressant agents, such as phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). It is these drugs that are dangerous in combination with MDMA, leading to the excessive increase in blood pressure.

Many hallucinogen enthusiasts are also familiar with natural forms of MAO-A inhibitors, such as those found in the plants Syrian rue or pegnalum (Peganum harmala). It is important, however, to appreciate that no MAO-A inhibitor, natural or synthetic, should ever be taken with MDMA because of the risk of hypertensive crisis.

There are also MAO-B inhibitors—selegiline (deprenyl) is the most commonly known. These drugs are not thought to have the same risk factors as MAO-A inhibitors when combined with other drugs or certain foods. However, to be on the safe side, it is advisable not to take MAO-B inhibitors with MDMA.

Hallucinogens

The practice of combining MDMA with LSD is known as "candy flipping." Although some people take both drugs simultaneously, others take them at separate times. When the drugs are taken at different times, it is more common for LSD to be ingested first, since it has a longer duration of action (eight to twelve hours) than MDMA (two to four hours). MDMA is ingested after the LSD has begun to take effect. The candy-flipping experience has been described as "mellowing out the effects of tripping on acid," without eliminating the experience of LSD. Taking MDMA after LSD-induced hallucinations have subsided has been reported to bring back hallucinatory effects. The interpersonal "entactogen" qualities of MDMA can merge with the colorful aspects of LSD to create what has been described as "psychedelic brandy." A related experience is reported when MDMA is combined with hallucinogenic mushrooms—this interaction is known as an MX missile. There are currently no reports in the medical literature or in the underground press of adverse physical or psychological effects of combining MDMA with LSD or mushrooms. Caution is advised, though, since each person's biological and psychological makeup is different and some people may be predisposed to untoward effects after certain drug combinations.

Summary

It is unclear at this stage in scientific research just how the distinct psychoactive effects of MDMA relate to the various pharmacological mechanisms of action. Since drugs that mimic the individual actions of MDMA (such as fluoxetine at the transporter, fenfluramine in releasing serotonin, amphetamines in releasing dopamine, LSD at the 5-HT2 receptor and 5-HT1b agonists) do not produce the full MDMA response by themselves, it can be concluded that each of these actions must occur simultaneously for the unique effects of MDMA to emerge.

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