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.
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:
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.)
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.
