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MDMA At Work (and Play)

     This simple animation demonstrates how MDMA actually causes serotonin to be released. Read the text, then push the 'play' button to see the accompanying animation for that slide. If you want to see the animation again, right-click on the screen and select 'rewind' from the menu.



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     Exactly how MDMA acts on the SERT still isn't known.  It should be noted that the SERT isn't really a spinning disc; its actual shape is more like this: 

     Serotonin actually passes through the center of the SERT while the SERT stays in place.  But, that would be a lot harder to animate in Flash, so I stuck with the 'general concept' approach. (Yay, laziness!)  For biochemistry students: The red (alpha-helix) sections are the trans-membrane domain; the part of the SERT that crosses through the cell membrane.



Neuroadaptation (or, Where E-tards (usually) Come From)

     Your brain doesn't just take getting kicked around by drugs sitting down:

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     This system of neuroadaptation is the basis of physical addiction and drug tolerance; when your brain is frequently exposed to a drug it adapts to compensate for the presence of the drug. As a result, if the drug is taken away, it leaves your brain 'overcompensating' and off balance in a new way. If you frequently use a drug that suppresses anxiety, then go off it suddenly, you are likely to experience 'rebound' anxiety. If you take a lot of pain killers, then go off them, you are likely to experience 'rebound' pain, even if nothing is wrong with you.

     Neuroadaptation isn't 'strange' or abnormal; it's something that is always going on, with or without drugs. It's the reason we develop a tolerance to caffeine...and why that tolerance goes away if we give up caffeine for an extended period.

     Neuroadaptation isn't limited to changing the existing receptors. Neurons can also adapt by producing more or less of enzymes that break down neurotransmitters or drugs, or by producing more or fewer new receptors over time. (Proteins like receptors are constantly wearing out and being replaced; thus, if the neuron produces fewer new receptors, the number of receptors will go down over time.)

     In the case of drugs like MDMA, use temporarily alters your brain's sensitivity to serotonin. If you use heavily, these changes start to add up as your brain continues to work to counteract the drug effect. As a result, periods of heavy MDMA use can leave your serotonin system hardly knowing if it's coming or going; it doesn't quite work as it should when you're high, and it doesn't quite work as it should when you're sober. The result is often anxiety, depression, memory problems, lack of motivation, and feelings of emptiness. This is the real reason you shouldn't use MDMA frequently; the aftermath of the more impressive binges can be quite disruptive to your life and sometimes lasts for months.

      This graph shows the effect of a very large dose of MDMA (up to 20 mg/kg twice a day for four days) on the number of available serotonin receptors in the brains of a group of rats: [5]

     After the last dose of MDMA was given to the rats, their neurons had deactivated most of their serotonin receptors; over the next 3-4 weeks, the process slowly reversed itself, and the receptor density returned to normal. In the meanwhile, these rats might have felt a little strange.

     Now, let's imagine what this effect might look like in a human MDMA user's brain as they go from infrequent to frequent use:


      Given enough time, the brain's sensitivities return to normal (human research suggests this takes about 3-4 weeks after a single moderate dose.) However, if additional doses are taken before this recovery occurs, the changes can be made greater, increasing the symptoms it might cause and taking even longer to recover from. People seem to vary in their sensitivity to frequent use; some rare people claim that once-a-week use for prolonged periods hasn't had a major negative impact on them, while others have felt a little irritable and 'off' even with just once-a-month use. Pay attention to your mental state; if you start to feel a little irritable or otherwise emotionally unstable the week after use, cut back on your usage.

     The only cure for such neuroadaptation is time, although treatments that support the serotonin system may help with symptoms (SSRIs, 5-HTP.)

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The Neurotoxic Question

      Of course, recovery depends on not having done any real damage in the first place. MDMA is well known for it's potential neurotoxicity (ability to damage neurons.) If neurotoxicity occurs, then the slow reversal of neuroadaptation isn't enough to truly restore your brain to its pre-use state. Repeated or large doses of MDMA may cause permanent harm, not just transient neuroadaptation. MDMA's neurotoxic potential (and it's implications for human users) is a complex subject, but is covered in detail on this site's Neurotoxicity page.

      The short version is that the more you take, the greater the risk. I advise against taking more than a single oral dose in an evening, and never mix with amphetamines. MDMA neurotoxicity is not an all-or-nothing issue; just because you're taking some MDMA does not mean you have nothing more to lose by upping the dose; if anything, the second dose in an evening may be more dangerous to you in terms of neurotoxic potential than the first dose.



For further reading on transporter mediated exchange and MDMA, see:

[1] Rudnick G, Wall SC "The molecular mechanism of "ecstasy"; Serotonin transporters are targets for MDMA-induced serotonin release" Procedings of the National Acad Sci (USA), 1992; 89:1817-1821. Abstract

[2] Gu XF, Azmitia EC "Integrative transporter-mediated release from cytoplasmic and vesicular stores in cultured neurons" Eur J Pharmacol, 1993; 235(1):51-7. Abstract.

[3] Wichems CH, Hollingsworth CK, Bennett BA, "Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release" Brain Res. 1995; 695(1):10-8. Abstract.

[4] Crespi D, Mennini T, Gobbi M, "Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine" Brain J. Pharmacology, 1997; 121(8):1735-1743. Abstract.

[5] Scheffel U, Lever JR, Stathis M, Ricaurte GA "Repeated administration of MDMA causes transient down-regulation of serotonin 5-HT2 receptors" Neuropharmacology, 1992; 31(9):881-93. Abstract.

[6] Ravma AW. Sylte I, Dahl SG "Molecular model of the neural dopamine transporter" J Comput Aided Mol Des., 2003 May-Jun;17(5-6):367-82. Abstract.