Ecstasy or MDMA
Above, I mentioned that ecstasy damages serotonergic neurons. What the heck are those? Serotonin is a neurotransmitter, a chemical that nerve cells (neurons) use to communicate with other. Neurons that use serotonin to communicate are called serotonergic neurons. People who are depressed don't seem to make enough serotonin, and drugs like Prozac and Paxil increase the amount of it in the brain. The amino acids tryptophan and 5-hydroxytryptophan are converted into serotonin and when taken orally tend to be somewhat antidepressant and make people sleepy. Hallucinogenic drugs work by tricking some neurons into thinking they're seeing serotonin, and blocking serotonin messages to other neurons. Serotonergic neurons send messages all over the brain, including to the areas involving thinking and memory (the amygdala, cortex, and hippocampus).
Another neurotransmitter that ecstasy affects is dopamine. Dopamine is involved in many brain functions, including movement, psychosis, and pleasure. Parkinson's disease is caused by too little dopamine in a specific brain area, the striatum, and psychosis by too much dopamine. Cocaine is addictive and pleasurable because it increases dopamine levels in the brain's "pleasure center". Amphetamine, ecstasy's close cousin, also works partly by increasing brain levels of dopamine. Too much ecstasy, cocaine, or amphetamine, and abusers can become psychotic and paranoid.
Finally, like amphetamine, ecstasy is sympathomimetic. That means that it mimics your body's fight or flight response. Taking too much ecstasy can cause sweating, dry mouth, dizziness, restlessness, pounding heart, and high blood pressure. Eighty-seven people have died so far from strokes and heart problems caused by these side effects, and they didn't even overdose.
Ecstasy makes people high by causing a large release of both serotonin and dopamine from neurons out into the brain. The dopamine release causes ecstasy's amphetamine-like qualities - pleasurable and stimulating in moderate doses, and just plain speedy in large doses. The serotonin release and action on serotonin receptors cause the empathogenic and "trippy" effects of ecstasy. For you scientist types, ecstasy is mildly active at the serotonin 5-HT2 receptor, the receptor where LSD, peyote and psilocybin mushrooms also work. That's probably why some people get closed-eye visuals.
Unfortunately, it appears that the way ecstasy causes neurons to release dopamine and serotonin stresses them and kills the cells. Dead neurons are a huge problem because, for the most part, they don't grow back. Now, here's where I'm going to part paths with many other writers on ecstasy. Lots of articles out there, including some on Erowid and the Lycaeum offer platitudes like "toxicity has only been seen in animals" or "Prozac helps prevent the toxicity" or even "the animal studies are invalid because of the dosing regimens." Folks, my past training is a Masters degree in Neuroscience from Johns Hopkins and I am currently a Ph.D. candidate in bioinformatics. I am as qualified to evaluate the literature as any other writer on this topic and I disagree. Ecstasy is neurotoxic. It's a subtle, insidious poison, and the more you use it, the more damage you do.
You see, while I was in school, I reproduced some of the rodent studies in Dr. Molliver's lab that are so frequently shot down. Most of the people writing about ecstasy out there on the web have simply read articles but I have hands-on experience in a real lab. I've dosed rats and looked at their brains after ecstasy treatment. After a single high dose, the serotonergic neurons in rats can be as much as 90% GONE. Blown away. Vanished. Poof. If you could see the slides I made under a microscope you wouldn't even think of doing ecstasy. And no, for those familiar with the studies, it isn't just that the serotonin is gone - it's the axons themselves. That's been clearly demonstrated in follow-up publications (Axt et al. 1991, 1992).
Dr. Molliver's lab also did the first, often cited primate study of ecstasy toxicity. I've seen those slides too. Much like in the rats, the serotonergic neurons are gone at the higher doses and clearly damaged at the lower ones. The studies are often discounted because Dr. Molliver chose to use repeated, fairly high doses. You want to know why he did it that way? Most researchers really dislike working with primates. They're expensive, require a lot of space, and working on such close cousins disturbs many more scientists than you might expect. So, when primate protocols are designed, the object is to show a really clear effect in as few experiments as possible. These studies were designed based on a dosing regimen that was very reliable in rodents. Sure enough, it worked. Also, many critics overlook the fact that the the lowest dose in the study, 2.5 mg/kg, is actually not too far from a high rave dose. In a 50 kg (110 lb.) person, the monkey dose would be 125 mg. Ecstasy tablets are usually 80-150 mg, so for a small person who goes to a few raves over spring break and takes one tablet each time, the monkey study is right in the ballpark.
Even more disturbing, the effects are long-term and could be permanent. Serotonergic neurons grow back but they seem to do so abnormally, and some serotonin based responses do not recover (for example, serotonin mediated prolactin release). Monkeys treated with ecstasy and allowed to recover for seven years have abnormal patterns of serotonergic innervation from incomplete regrowth. (Hatzidimitriou et al., 1999).
Below is Figure 1 from the 1999 Hatzdimitrou et al. paper. It's a microscopic picture of the brain damage caused by ecstasy in monkeys. The white lines are serotonergic neurons running through the cortex, the part of the brain responsible for higher thinking. Pictures A, D, and G are healthy monkey brain. There are lots of white-colored serotonergic neurons running through the brain tissue. Pictures B, E, and H are of the brain of a monkey two weeks after twice-daily doses of ecstasy. The serotonergic neurons are almost gone! Pictures C, F, and I were taken from an animal treated with ecstasy 7 years previously, and the serotonergic neurons have still not recovered.
So the question is, given the clear damage caused by ecstasy to animals, does it generalize to humans? Recent research is showing that the answer is unequivocally yes. Many clinical studies have shown clear decreases in serotonin metabolites (breakdown products) in ecstasy users that sometimes return to normal and sometimes don't. Newer positron emission tomography (PET) scan studies show decreases in both glucose use and in serotonergic markers in the brains of ecstasy users. PET scanning is a visualization technique that allows researchers to "see" into the living human brain, so the PET results suggest neurotoxic lesions in humans that are similar to those in animals. Using ecstasy and amphetamine together is particularly dangerous as researchers have shown depletion of dopamanergic markers in the area of the brain that is dopamine deficient in Parkinson's disease and movement disorders. These boichemical studies, in combination with the extensive animal data, give convincing evidence of structural damage to serotonergic systems in the brains of ecstasy users.
Now that there is a population of ecstasy users and some are volunteering for studies, scientists are showing dose dependent cognitive deficits and memory problems in ecstasy users, even a year after the last use when biochemical markers have returned to normal. Dose dependent means that the more ecstasy the person reported using, the larger the memory and thinking problems. In agreement with the animal studies, repeated use seems to cause more damage. This is very different from marijuana, the other drug criticized for causing memory loss. Pot smokers who don't use a lot of other drugs recover from their memory deficits, while it looks like ecstasy users don't. As with the monkeys, damaged serotonergic neurons probably don't grow back correctly, causing memory and cognitive impairments. Depression is also often seen in heavy, repeat ecstasy users and is thought to be a direct effect of serotonin depletion.
So, ecstasy causes damage to serotonergic neurons. Repeated use causes more damage. Damage to serotonergic neurons causes memory loss, cognitive deficits, and depression in humans. Or to put it harshly, brain damage. I hope that I've convinced you of the dangers of using ecstasy. Do have fun, go to raves, dance all night - just don't do any ecstasy. If you do, you're risking your mind and your future.
Addendum: Some of the deaths attributed to MDMA have since been determined to be caused a similar but much more dangerous drug, paramethoxyamphetamine or PMA. Rave tablets are sometimes cut with PMA to make them seem stronger. PMA is even more toxic than MDMA and can cause uncontrollable fever and death at typical MDMA dosages. Short of using a lab instrument called a gas chromatograph, there is no easy way to tell whether an MDMA tablet also contains PMA. Yet another reason to go drug-free at raves.
References, in chronologic order
Reneman L, Booij J, Lavalaye J, de Bruin K, Reitsma JB, Gunning B, den Heeten GJ, van Den Brink W. Use of amphetamine by recreational users of ecstasy (MDMA) is associated with reduced striatal dopamine transporter densities: a [(123)I]beta-CIT SPECT study -- preliminary report. Psychopharmacology (Berl) 2002 Jan;159(3):335-340.
Hatzidimitriou G, Tsai EH, McCann UD, Ricaurte GA. Altered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethamphetamine (MDMA) or fenfluramine. Synapse 2002 Apr;44(1):51-57.
Reneman L, Lavalaye J, Schmand B, de Wolff FA, van den Brink W, den Heeten GJ, Booij J. Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"): preliminary findings. Arch Gen Psychiatry. 2001 Oct;58(10):907-8.
Croft RJ, Klugman A, Baldeweg T, Gruzelier JH. Electrophysiological evidence of serotonergic impairment in long-term MDMA ("ecstasy") users. Am J Psychiatry 2001 Oct;158(10):1687-92.
Verkes RJ, Gijsman HJ, Pieters MS, Schoemaker RC, de Visser S, Kuijpers M, Pennings EJ, de Bruin D, Van de Wijngaart G, Van Gerven JM, Cohen AF. Cognitive performance and serotonergic function in users of ecstasy. Psychopharmacology (Berl) 2001 Jan 1;153(2):196-202.
Kalant H. The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ. 2001 Oct 2;165(7):917-28.
Kraner JC, McCoy DJ, Evans MA, et al. Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA). J Anal Toxicol 2001; 24: 645-648.
Morgan MJ. Ecstasy (MDMA): a review of its possible persistent psychological effects. Psychopharmacology (Berl). 2000 Oct;152(3):230-48
Obrocki J, Buchert R, Vaterlein O, et al. Ecstasy— long-term effects on the human central nervous system revealed by positron emission tomography. Br J Psychiatry 1999; 175:186 -188.
McCann DU, Szabo Z, Scheffel U, et al. Positron emission tomographic evidence of toxic effect of MDMA (ecstasy) on brain serotonin neurons in human beings. Lancet 1998; 352:1433-1437.
Fischer C, Hatzidimitriou G, Wlos J, Katz J, Ricaurte
G. Reorganization of ascending 5-HT axon projections in animals previously
exposed to the recreational drug (+/-)3,4-methylenedioxymethamphetamine
(MDMA, "ecstasy"). J Neurosci 1995 Aug;15(8):5476-85
Axt KJ, Mullen CA, Molliver ME. Cytopathologic features indicative of 5-hydroxytryptamine axon degeneration are observed in rat brain after administration of d- and l-methylenedioxyamphetamine. Ann N Y Acad Sci. 1992 May 11;648:244-7.
Axt KJ, Molliver ME. Immunocytochemical evidence for
methamphetamine-induced serotonergic axon loss in the rat brain. Synapse.
1991 Dec 9(4):302-13.
O'Hearn E, Battaglia G, De Souza EB, Kuhar MJ, Molliver
ME. Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine
(MDMA) cause selective ablation of serotonergic axon terminals in forebrain:
immunocytochemical evidence for neurotoxicity. J Neurosci. 1988
Aug;8(8):2788-803.
Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, Langston JW. (+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. JAMA. 1988 Jul 1;260(1):51-5.
Battaglia G, Yeh SY, O'Hearn E, Molliver ME, Kuhar MJ, De Souza EB. 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. J Pharmacol Exp Ther. 1987 Sep; 242(3):911-6.