March 1, 2008
Dear Human Brain,
How are you today? Here’s hoping my letter finds you well. I just have to say that you really are a remarkable entity and I admire you greatly. You’re very beautiful with your busy neurons and hard-working glial cells, and all those intricately placed connections… Oh, you’re probably wondering who I am! Please, allow me to introduce myself. My full name is 3,4-Methylenedioxymethamphetamine. I know, I know… a bit of a mouthful. But you can call me MDMA for short. I’ll also respond to the name Ecstasy, and maybe once we’re better friends, just ‘E’ or ‘X’ (to tell you the truth, I’m a bit partial to ‘X’… makes me feel all mysterious). I have a lot of other nicknames as well; don’t be confused if I also respond to other names you’ve never heard. I love having nicknames, makes me feel all warm and fuzzy. Oh sorry, there I go again, getting all caught up in the moment, I tend to do that. I’m just in such a good mood today, and I’m so eager to make you my new friend! Anyway, I am writing this letter to tell you about myself. If you like what you read, please write back and let me know if you’d like to get together. I know we could have a lot of fun, and I really love to party!
Let me tell you a bit about my history.
I’ve been around for a while, since 1912, when G. Mannish and W. Jacobsohn, two chemists at Merck Pharmaceuticals, created me by accident (1). Yes, I was unplanned. I was a by-product of an attempted synthesis of hydrastinin, a vasoconstrictive and styptic medicine. And by styptic, I’m referring to a drug having the ability to contract tissues or blood vessels, and to check bleeding. I was patented in Germany two years later, in 1914, because of my anorectic properties (1). However, my ability to suppress appetite was never of much commercial interest because of my other side effects, and I was then forgotten (2). That was definitely a bit of a rough period in my history, but everyone has to deal with those, right? Between you and me, I think it is those lonely times that have made me the loving, attentive chemical I am today. Oh, would you like to see a picture of me? I have a few!
Here’s me, just my basic structure.
Here’s me again, this time my molecular structure. Personally I think I look better in this one… more colorful at least!
Oh dear, there I go again, getting carried away. But I just love pictures! Anyway, back to my story. I was ‘re-discovered’ in a sense, in the 1970s. My good friend, Dr. Alexander Shulgin, a psychadelic chemist at San Francisco State University, took an interest in me (2). I was re-created, and taste-tested by Dr. Shulgin himself in the late 70s. Dr. Shulgin recorded his experience with me, writing the following in his lab notes from September 1976 (2).
“I feel absolutely clean inside, and there is nothing but pure euphoria. I have never felt so great or believed this to be possible. The cleanliness, clarity, and marvelous feeling of solid inner strength continued throughout the rest of the day and evening. I am overcome by the profundity of the experience…”
Dr. Shulgin and I developed a close relationship, and he spoke very highly of my effects. By the early 1980s, I had gone from being a lonely, forgotten ‘accident’ to the new “yuppie psychadelic” drug (from the San Francisco Chronicle, 10 June 1984). I had become an important new part of psychotherapy because of my ability to create feelings of comfort, empathy and closeness with others. As a result of my growing popularity, and despite my loving nature, I was quickly banned. However, my popularity on the street as a recreational drug continued to grow, and I became “Ecstasy, the Party Drug.” As you’ve probably heard, my modern-day use is most closely tied to the underground rave and dance club scenes throughout the world.
What can I do for you pharmacologically?
Well, dear Brain, in a nutshell, I like to release serotonin. But I know how you human brains like to categorize and classify things, so I’ll give you a run-down of my various pharmacological classifications. I am pretty unique, in that my effects are not observed in strict hallucinogens or in stimulants (3). In 1983, I was classified as an “empathogen” because of my ability to induce feelings of empathy. However, chemistry professor David Nichols felt that the term empathogen was too limiting and didn’t cover all my therapeutic uses as a drug, so he later coined the term “entactogen,” which literally means “touching within” (2). I am also what they call a ‘psychadelic amphetamine.’ Psychadelic refers to creation of an altered state of awareness, and my chemical structure is related to those compounds in the amphetamine family. Hey, I even have a picture of my family. I’m in the lower right!
My amphetamine family has structures similar to those of some of the lovely neurotransmitters made by your own neurons. Specifically, our structures resemble those of the monoamines, including dopamine (DA), norepinephrine and serotonin (also known as 5-hydroxytryptamine, or 5-HT). My relatives, amphetamine and methamphetamine, affectionately known as ‘Speed’ and ‘Crystal Meth’ respectively, specifically affect dopaminergic pathways, however, I am known to have most of my effects via the serotonergic system. Of all your beautiful brain cells, my favorite is the serotonergic nerve cells, and specifically my good friend the presynaptic serotonin transporter, nicknamed SERT (3,4). SERT provides me with a way to enter the presynpatic nerve terminals. As I enter the terminals, this causes a reversal of the action of SERT and induces the release of intracellular serotonin into the synapse. I also deplete intracellular vesicle stores of their 5-HT, which then leaks out of the cell or is released by the terminals; either way, this 5-HT also ends up in the synapse (3). So to summarize, my pharmacological action on serotonergic neurons basically causes a massive and rapid efflux of 5-HT into the synaptic spaces. Though I have my most potent effects on serotonin, I do also have an effect on dopamine. After a flood of 5-HT in the synapse, an increase in dopamine release is also seen (1,2). Notably, release of both 5-HT and DA are observed to be especially increased in the reward centres of the striatum and in the nucleus accumbens (2). These brain regions are associated with rewarding properties and euphoria induced by drugs of abuse.
Anyway, enough of that… I want to show you another picture! I am most commonly found in tablet form, so here are a few of many different appearances.
After being taken orally, I am rapidly absorbed, and can be detected in the bloodstream after about 30 minutes (3). I have a half-life of about 6-8 hours (3), and my effects peak 60-90 minutes after tablet ingestion. My rapid 5-HT efflux effect accounts for the fairly short duration of my psychoactive effects, which usually last about 2-4 hours (3,5). The duration of effects, of course, ultimately depends on dose. Word on the street is that people typically take 50-150 mg of me as a recreational dose (1), but this amount can be as much as 250-300 mg. One important thing to keep in mind is that I am often not the only psychoactive substance found in tablets claiming to be ‘Ecstasy.’ Other substances that may be found in ‘Ecstasy’ tablets are substituted amphetamines, caffeine, or dangerous ‘dissociative anesthetics’ like dextromethorphan, PCP and ketamine (4,6). So here I must warn you, because these other drugs obviously contribute to the overall effect and can sometimes cause unexpected/negative effects.
Speaking of effects…
I like to think of myself as a “gateway to the soul.” I can “open up your heart.” I am magical, mystical, sublime… Right, where was I going with this? Basically, I can do a lot for you! Now that we’ve been through the basics from the pharmacological side of things, I’ll tell you about my physiological and psychological effects. As you’ve probably gathered by now, I’m a “mood elevator” and I am most popularly known for feelings of love and empathy. I induce feelings of comfort, belonging and closeness to others, as well as acceptance, talkativeness and sensuousness, or the urge for touch (1,7). Yup, I’m a “hugdrug” (2) and I’m okay with it! Other reported effects are euphoria, a carefree state, dissolution of fear, acceptance, happiness and even profound spiritual experiences (1,7)! Most of these effects are attributed to my ability to release serotonin from neurons. Don’t I sound just wonderful? However, I have to be honest with you dear Brain, I do have some less pleasant effects as well. These negative effects increase with higher doses and in frequent users. Psychologically, I can induce insomnia, difficulty concentrating, short-term memory loss, confusion, and depression and fatigue for up to a week following my use (1,7). I am a potent activator of the sympathetic nervous system, resulting in increased heart rate and blood pressure, and an elevated body temperature. You’ve probably heard about the risks of hyperthermia and dancing all night at a rave or club, which can lead to severe dehydration… I really hate to say so many negative things about myself, I really prefer a more positive light… but I know you appreciate my honesty, so I’ll continue, I suppose. I can also cause visual distortion, nystagmus (rapid involuntary eye-jiggling), jaw clenching and teeth grinding, nausea and vomiting (7). In very rare cases, my abuse has been linked to reports of severe intoxication and even death. I’m nice though, really, I am! I’m not physically addictive, but experience with me can cause a strong desire to use me again to re-create my effects, known as a psychological addiction.
One more thing…
There is, of course, also the issue of neurotoxicity… a personal issue about which I’m rather sensitive. But I’ll give you the facts straight. Animal research, including research done on non-human primates, has suggested that I may actually cause damage to the 5-HT neurons in the human brain. I don’t do it on purpose though, I assure you! Anyway, if you remember, I stimulate a massive release of 5-HT initially, which leads to all those wonderful, pleasurable feelings. I also inhibit tryptophan hydroxylase, which breaks down 5-HT and its various axonal markers (8). This leads to inhibition of further 5-HT synthesis and after the initial flood of 5-HT from the neurons, a 5-HT deficit occurs in the cells (4). Lower levels of 5-hydroxyindoleacetic acid (5-HIIA), which serves as a marker of 5-HT function in the central nervous system, have also been observed in the cerebrospinal fluid of human MDMA users (1). It is thought that decreased 5-HIIA concentrations in the CSF may be associated with axonal injury and death (8). The evidence here is rather inconclusive, and thus, very controversial. I would like to point out that heavy MDMA users typically have quite different personalities than non-users, and are more likely to be users of other psychoactive drugs as well, such as speed, LSD, cocaine and cannabis (9). Human MDMA studies also rely on self-reported estimates of drug use, a method that is rather unreliable at best. It is therefore almost impossible to point out my specific effects on 5-HT and neurons in human MDMA studies. Much more research is clearly required on this particular aspect, though valid and reliable results are quite tricky to obtain!
Oh dear, I’ve left the worst parts to the end of my letter. Now I’ve gone and made myself look horrible! I hope you will still give careful consideration to everything I have said in this letter. I am very loving, friendly and accepting, and I can promise to make you feel wonderful, should you choose to meet with me.
3, 4-Methylenedioxymethamphetamine (MDMA)
The Chemistry Lab Bench
March 3rd, 2006
Thank you for your letter. You sound quite nice. I definitely got a feel-good sense about you, and your effects really do sound quite enjoyable. Well, the good ones, that is. At this point, I am undecided about meeting with you. I have filed your letter with others I have received from cannabis, LSD, cocaine and amphetamine, to name just a few. Honestly, I would like to see more conclusive evidence on your supposed neurotoxicity issues before making any committed decision regarding a meeting. I apologize for bringing up a sensitive subject, but please remember that the responsibility for ensuring the well-being of billions of neurons rests entirely on my shoulders! As I’m sure you can understand, this responsibility is of paramount importance. But, please feel free to write again if anything else comes to light regarding this issue. Thanks again for writing, and good luck to you.
1. Cami J, Farre M, Mas M, Roset P, Poudevida SP, Mas A, San L, de la Torre R (2000) Human pharmacology of 3,4-Methylenedioxymethamphetamine (“Ecstasy”): Psychomotor performance and subjective effects. J Clin Psychopharm 20(4):455-466
2. BLTC (2006) Utopian Pharmacology: MDMA/Ecstasy. Retrieved Mar 31, 2006, from BLTC Website: http://mdma.net/
3. Dumont GJH, Verkes RJ (2006) A review of acute effects of 3,4-methylenedioxymethamphetamine in healty volunteers. J Psychopharm 20(2):176-187
4. Baumann MH, Wang X, Rothman RB (2006) 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacology [Epub ahead of print]
5. Huxster JK, Pirona A, Morgan MJ (2006) The sub-acute effects of recreational ecstasy (MDMA) use: a controlled study in humans. J Psychopharm 20(2):281-290
6. DanceSafe (2006) What Is Ecstasy? Retrieved Apr 3, 2006, from DanceSafe Website: http://dancesafe.org/documents/druginfo/ecstasy.php
7. Erowid (2006) MDMA (Ecstasy) Vault. Retrieved Mar 31, 2006, from The Vaults of Erowid Website: http://www.erowid.org/chemicals/mdma/mdma.shtml
8. McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998) Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings. The Lancet 352:1433-1437
9. Reed LJ, Winstock A, Cleare AJ, McGuire P (1999) Toxic effect of MDMA on brain serotonin neurons. The Lancet 353:1268