Methylenedioxymethamhetamine, the compound used in the drug Ecstasy, was developed in Germany in 1914 as an intermediary substance to pave the way to alternative therapeutic medicines. Presently, MDMA is used for a subculture in America and all over the world of "ravers" who spend their weekends taking this unique drug because of its seemingly mind- expanding properties. The truth about this drug is that it fools the body's senses by releasing too much serotonin and possibly permanently damaging important nerve cells in the process. Many studies claim that MDMA cannot be considered a narcotic because they believe it to be non-addictive.

The body becomes accustomed to a substance, a criterion for addiction, so that the body requires ever-increasing amounts of the drug to maintain similar pharmacological effects when used (Encarta 99). Another form of addiction, called habituation, is defined as a psychological urge to use the substance, even when the dependence has worn off. According to the World Health Organization, becoming dependent requires at least: "a strong desire to take the drug; difficulties controlling the behavior; a withdrawal state; tolerance; progressive neglect of alternative pleasures and persisting with use despite evidence of harm" (Jansen). A study by Karl L. R. Jansen shows three distinct cases where these criteria are met.

One subject, age 19, spent his entire disposable income on MDMA. Despite a seizure caused by use of this and other drugs, the subject "was unable to stop using MDMA without external assistance" (Jansen). Another subject exhibited an extremely high tolerance to the drug so that he was able to take 250 mg with almost no effect. "Despite severe depression, he was unable to stop using MDMA although he believed that this was a cause." The third subject suffered from post-traumatic stress disorder after witnessing a combined murder-suicide.

He took MDMA an felt feelings of attachment for the first time since the incident and thus, continued using the drug heavily. "Despite evidence of harm to himself, his use of both MDMA and alcohol continued." In all of the preceding cases, the subjects admitted to using other, more potent drugs such as amphetamines and cocaine. The subject's dependence to MDMA may have been a result of combining with these harder drugs, but Jansen still contests that, "With repeated, high frequency use, the effects of MDMA may become gradually less empathy-generating and more like amphetamines" (Jansen). The science of MDMA has to do primarily with the release of the neurotransmitter serotonin from the axon terminals in brain cells. The brain contains billions of cells, consisting of a cell body which stores the DNA, dendrites that receive chemical signals from other brain cells, and an axon, a long cylindrical body which relays electrical signals from the cell body to the axon terminals (Sferios). Most serotonin cells begin in a part of the brain called the "raphe nuclei." The serotonin cells are much longer and thicker than other brain cells, and they branch off from the raphe nuclei to all other parts of the brain.

The brain communicates within itself by the use of the brain cells. The neurotransmitter is released from nerve terminals found at the axon base. When they diffuse across the synapse, they are then recognized by receptors on the receiving cell with which they attach themselves. The major function this bond performs is it, "induces, inhibits or modulates currents of electrically charged particles (ions) across the cell membrane" (Aertes). Serotonin is a neurotransmitter, synthesized by the amino acid tryptophan and tryptophan hydroxylase (TPH).

The amino acid 5 Hydroxy-Tryptophan (5 htp) comes in contact with the enzyme decarboxylase when it diffuses through the brain cells' membrane. 5 htp is synthesized from tryptophan, which is found in a diet high in proteins, however, tryptophan must go through a number of metabolic changes before it turns into 5 htp (Sferios). After being synthesized, it is stored in pre-synaptic or membrane vesicles (Leon van Aertes, PhD). Serotonin's main functions are to control mood, appetite, and sleep. There are other neurotransmitters in the brain that function along with serotonin.

Serotonin and dopamine are the two that are closely related to accepted hypotheses about the neurotoxicity of MDMA. The normal function of serotonin in a neuron is much different from the actions that take place once MDMA is taken into the system. Normally, the molecules of serotonin remain in the axon terminal until an electrical signal from the brain tells the molecules to be released. Transport vesicles in the axon terminal take up the serotonin and then bond with the cell surface membrane and bud off into the synapse to release serotonin (Sferios). There are two specialized parts of the neurons that function in this serotonergic system.

First, the receptors, at the ends of the dendrites, which have the specific function of absorbing the serotonin into the cell and beginning its transport, down the axon to the next terminal. When normal amounts of serotonin are released, the number of these receptors remains small, because serotonin is a neurotransmitter that takes a lot of time to be synthesized and, thus, not much is used at any given time. The second part of the system is the reuptake transporters on the membranes of the axon terminals. Usually, when serotonin is released into the synapse, there are not enough receptors to accept all the transport vesicles secreted.

When this happens, some are accepted back into the axon terminal by these reuptake transporters, where they are stored for later use, or destroyed by certain enzymes called monoamine oxidase, to be discussed later. "Abnormal (serotonin) levels have been associated with clinical depression, anxiety disorders, and psychosis in humans who have not experimented with illicit drugs" ("Effects... ." ). MDMA affects the brain in such a way that serotonin is released in extremely high amounts without needing the normal electrical signal to start the reaction. This explains the feelings of euphoria someone would feel if they were taking MDMA.

The serotonin is bonding with so many receptors and making the body feel all the pleasurable feelings that go along with serotonin release, in higher doses than normal. MDMA makes the neurons release much of their stored serotonin at one time, and while the receptors of the dendrite continue to absorb the serotonin in the synapse, the amount left in the axon terminal and going into the reuptake transporters to be broken by MAO dwindles. The drug also inhibits the reuptake of any serotonin that maybe left in the synapse (Cloud). This is one of the adverse effects of MDMA. It takes a long time for the body to synthesize serotonin from tryptophan as compared to the synthesis of other neurotransmitters like dopamine and norepinephrine.

This is because serotonin replenishment is not needed so quickly in normal circumstances, because usually there are not so many active receptors on the dendrites. Without these stores of serotonin, the body goes through a period of depression after the use of MDMA (Sferios). These periods of depression are especially common with those who take the drug regularly. There is no way to illicit the feelings that MDMA gives without any serotonin, and the synthesis required to return to a normal level may take up to 2 weeks. "Low serotonin levels are associated with suicidal and impulsive behavior" (Coveney).

All of these changes in your brain cause certain adaptations of the brain itself in relation to coping with these changes. One way the brain accomplishes this is by down-regulating the receptors on the dendrites. This process makes over-worked receptors retreat into the cell membrane of the dendrites. When this happens there, it is another cause of depression associated with MDMA.

These down-regulated receptors are not necessarily up regulated when serotonin returns to normal, causing a lack of binding sites for the serotonin and a lack of its normal effects (Sferios). However, it should be noted also that up and down regulatory marking is not necessarily caused by MDMA as the body also, by genetics, can undergo this process to balance the flow and uptake of serotonin, so as not to damage the dendrites. Toxicity is defined as, "a substance's ability to disturb the physiological balance of an organism to such a degree that the organism can no longer be considered healthy" (Aertes). The two types of toxicity that are important to understand concerning MDMA are acute systematic toxicity and neurotoxicity. The effects on the organism being highly visible define acute systemic toxicity. There have been many animal studies that display possible acute systemic effects.

The first studies were performed in Michigan University where the L 50 (dose at which 50% of the animal die) doses were tested on guinea pigs, mongrel dogs, and monkeys. The L 50 doses showed that MDMA is almost 2 to 6 times as deadly as drugs like mescaline. Some symptoms associated with high doses of MDMA in the tested monkeys were "lack of movement control, convulsions, muscle rigidity and tremors, vomiting and difficulties with breathing" (Aertes). There are further, more serious systemic toxicity effects displayed in humans. (Note: Because of the inability to perform truly accurate testing of human subjects, most of the following symptoms are highly anecdotal. ) "Cardiovascular stimulation, broncho dilation, mydriasis, hypodipsia, respiratory stimulation and hyperthermia" (Seiden) are just a few of the effects also including, "convulsions, disseminated intravascular coagulation (DIC) (blood clotting in the blood vessels), rhabdomyolysis (dissolution of skeletal muscle), and acute renal (kidney) failure" (Aertes).

Cardiac arrhythmia is also a possible side effect from taking MDMA, since the drug raises blood pressure; the irregularities in heartbeat could be fatal for people who are predisposed to heart conditions. Hyperthermia, the over-heating of the body causing it to lose function, is the most prevalent of these symptoms, which supporters of MDMA contest could be caused by dancing in the hot clubs where much ecstasy use takes place. However, in controlled situations, body temperature is raised without dancing (Aertes). Hyperthermia can cause other adverse effects on the body.

There have been cases where users of the drug suffered from acute liver failure, precipitated from the hyperthermia condition and not directly from the effects of MDMA (Aertes). Even while alleviating the hyperthermia, the body could be in serious risk of certain types of attacks. While lowering the body temperature, consuming lots of water could cause a lowering of salt concentration in the fluids. The hypertonic condition of the body fluids as a solution would cause the cells to swell, and sometimes could lead to water intoxication and death. Two cases studied were shown in postmortem autopsies that after they took MDMA and drank too much water they, "developed mild oedema (abnormal accumulation of fluid in brain tissue) " (Aertes). There are other systemic effects of MDMA that are observed, which are not particularly dangerous, but still play a part in its biological effects.

The feelings given by the bombardment of serotonin can cause effects like, "muscle tension... rapid eye movement, faintness, and chills" ("Ecstasy." ). Dr. Aertes points out some other effects of MDMA and calls them "mild unpleasant side effects." These include, "loss of appetite, trismus (jaw clenching), bruxism (teeth grinding), nausea, muscle aches, stiffness, ataxia (impairment of motor control), blurred vision, increased sweating, anxiety, tachycardia (increased heart rate), insomnia (sleeplessness), and fatigue." Neurotoxicity is the more dangerous of the two toxic effects that have to do with MDMA.

Neurotoxicity occurs when aspects of the brain are damaged so that their function is lost or inhibited. For a time, Ecstasy was thought to be harmless because, when taken in small doses, the only isolated effects were the acute systemic toxicity, which were shrugged off as people who "couldn't handle" the drug. Well, the truth is that too much MDMA can cause major, lasting damage to the serotonergic system and thus the entire organism. The cause of this damage is that MDMA prohibits the reuptake of the serotonin, which allows for so many receptors to be filled and created, but inversely the reuptake transporters are left vacant, and are not functioning as they should be to help actively diffuse serotonin back into the cell.

As was indicated before, there are also other neurotransmitters in the synapse being released at all times. The most important of these for this discussion is dopamine. Dopamine relies on a more sturdy recovery and release system than serotonin, and is therefore called a robust system (Sferios). The neurotoxic effect most prevalent in the study of MDMA is the process of axon degeneration. The cause of which is dopamine.

When the receptor sites have absorbed all the serotonin, the dopamine is in high concentration in the synapse, and the inside of the serotonin axons is in a very low concentration. Because there is nothing to inhibit its entrance at the reuptake transporters, dopamine is transferred into the serotonin cells. This is extremely damaging to the cell. To begin, studies have proven that dopamine itself could be extremely toxic to the cells. However, the real problem occurs when dopamine encounters the MAO. The MAO oxidizes the dopamine and forms hydrogen peroxide.

This substance is deadly to the nerves so that when it is released that part of the axon will die. The proof comes from many former studies in the field that led them to postulate this theory of deterioration. In 1988, studies done by a team of scientists led by Stone found that treating mice with a-methyl-p-tyrosine prevents the normally observed axon terminal degeneration. This substance is proven to prevent the release of dopamine, so they hypothesized that with the lack of dopamine, the MDMA would not have its normal effects of neurotoxicity. Other studies suggest the same thing. One such, performed by Schmidt et al.

, was conducted so that they destroyed the dopamine terminals in the rats' brains, receiving the same effects and also attributing the effect to the lack of dopamine. Also in 1990, two researchers, Nash and Nichols, proved that if you add the substance L-DOPA, the damage sustained is much greater, presumably because L-DOPA is a stimulant to the dopamine receptors, which works a great deal like MDMA. However, since dopamine is considered a robust system, the brain's reserves cannot be used up as quickly as those of serotonin (Sferios). Dopamine's effect is also extended as a side effect of MDMA itself. MDMA's serotonin release also affects a serotonin receptor, called receptor 2 A, which by itself is a precursor to the release of dopamine (Sferios). It has been proven that axon terminals can regenerate themselves, however poorly, and in bad condition.

Some studies suggest that even the appearance of axons affected by MDMA is swollen and heavily distorted (Ricaurte). The serotonin nerve cells, when deteriorated in this way, are prone to reform further down the axon (Cloud). This space is now an increased synapse that takes messages of serotonin longer to diffuse across, thus slowing the organism's responses of happiness and other effects of serotonin. This can also be a cause of depression in the users of MDMA. In studies performed on monkeys and rats, the axon regeneration observed after the use of MDMA was shown to be extremely abnormal.

After the dopamine destroys the terminals, the axonal sprouting has trouble reaching areas of the brain away from the raphe nuclei such as the dorsal neocortex and the frontal cortex. The areas close to the nuclei, "such as the hippocampus and amygdala were re innervated or hyper innervated" ("Effects... ." ). In most cases, the regeneration could be more harmful than the actual degeneration.

When the serotonin cannot reach the dorsal neocortex, there can be severe reduction of motor and cognitive skills ("Effects... ." ). The hyper innervation of the hippocampus and hypothalamus regions cause severe changes in personality ranging from loss of sexual drive and motivation due to the altered connections of the cells. It has been proven that Alzheimer's disease can be induced by abnormalities in areas surrounding the raphe nucleus. Therefore, the regeneration of the axons in this area can be a cause of the early onset of the disease or general dementia.

The biggest flaw of the data collected in all the studies mentioned above is that their merits were relative. The exact reason why MDMA releases so much serotonin is unknown. The acute systemic effects are primarily based on personal accounts. Also, most of the primary biological observations were done on monkeys and rats, making all identification with humans speculative at best.

However, the research does present some major points and can definitely conclude that Ecstasy is not a safe drug. With the depletion of serotonin, the destruction of important brain cells, even the severe effects of hyperthermia, all these make this one of the most dangerous illicit drugs to ever be studied. The risk factor is raised exponentially because when MDMA is used in pill form, it is sometimes used as a "garbage pill" which could mean that the addition of many other drugs with their own side effects have to be worried about. Aertes, Leon van, PhD. "Toxicity of Ecstasy." Ecstasy.

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