Long-term effects are still unknown and
heavily debated among scientists. There
are several reports of Hallucinogen
Persisting Perception Disorder being
induced by MDMA. In some cases, the
disorder appears to be permanent. The
disorder seems to occur in only a small
fraction of a percentage of users, and
its mechanism of causation is unknown.
Some experiments indicate that use at
very high doses may lead to the Synaptic
Terminals of serotonin neurons being
damaged. The precise mechanism of this
action is unknown, but recent evidence
(Jones 2004; Miller 1997; Monks et al.
2004) suggests that the metabolic
breakdown of MDMA includes the formation
of reactive oxygen species (ROS),
chemicals known to cause oxidative cell
damage when taken up into the releasing
synapse.
This effect has been demonstrated
experimentally in the brains of rats,
where the serotonin terminals of animals
who are given extremely high doses of
MDMA over a prolonged period of time
(usually ten to one hundred times
greater than a typical human dose)
become withered and useless, although
this isn't certain. This hypothesis is
supported by the fact that the
administration of selective serotonin
reuptake inhibitors ("SSRIs", which bind
to the serotonin cell's reuptake
transporters and thus block ROS from
entering the serotonin cells) along with
or immediately following MDMA seems to
block neuron damage in rats given MDMA.
The mechanism proposed as a large part
of this neurotoxicity and its functional
consequences appear to involve the
induction of oxidative stress. This
stress results from an increase in free
radicals and a decrease in antioxidants
in the brain. (Shankaran, 2001)
Oxidation is part of the normal
metabolic processes of the body. As the
cell goes about its life, by-products
called oxidative radicals are formed,
also called free radicals. These
molecules have an unpaired electron that
makes them highly reactive. They pull
strongly on the electrons of neighboring
molecules and destabilize the electrical
balance of those molecules, sometimes
causing those molecules to fall apart.
This can become a chain reaction.
In normal functioning, there are
antioxidants in the system that act as
free radical scavengers. These are
molecules with an extra electron that
they are willing to give up to the free
radicals, making both the free radical
and the antioxidant more stable. MDMA
rapidly increases the levels of
free-radicals in the system and
overwhelms the reserves of scavengers.
The radicals then damage cell walls,
reduce the flexibility of blood vessels,
destroy enzymes, and cause other
molecular damage in the neurological
pathways. (Erowid, 2001) It has been
shown that MDMA-neurotoxic effects are
increased by a hyperthermic environment
and decreased by a hypothermic one. (Yeh,
1997)
Studies have suggested that the
neurotoxic molecules are not hydroxyl
free radicals, but superoxide free
radicals. When rats are injected with
salicylate, a molecule that scavenges
hydroxyl free radicals, the neurotoxic
effects of MDMA are not attenuated, but
actually potentiated. Further evidence
of this superoxide theory comes from the
observation that CuZn-superoxide
dismutase transgenic mice (mice with
excess human antioxidant enzyme)
demonstrate neuroprotective mechanisms
that protect the mice from MDMA-induced
depletion of 5-HT (serotonin) and 5-HIAA
and lethal effects. (Baggott, 2001 and
Yeh, 1997)
Studies giving animal species injections
have shown that ascorbic acid, alpha
lipoic acid, l-cysteine, and some other
radical scavengers are effective in
reducing oxidative stress caused by MDMA.
(Erowid, 2001) A combination of
antioxidants, including Vitamin A, C,
and E are recommended; taking
multivitamins including selenium,
riboflavin, zinc, carotenoids, etc.
should help reduce oxidative damage.
Many of these vitamins, though, are
water soluble, and are quickly excreted
from the body. The typical MDMA user is
psychoactive for 4-6 hours and may not
have an appetite from the time of taking
until the following sleep cycle or many
hours later. These vitamins flush
through the system in 3-4 hours[citation
needed]. Damage occurs in the absence of
these antioxidants.
There are some fallacies in applying
these animal studies to human use.
Firstly, it is difficult to equate rat
doses to human doses, rats metabolise
MDMA twice as fast as humans and often
larger doses or multiple doses are
administered to simulate human plasma
levels. The doses given in experiments
are far greater than typical human use
of 100-300 mg in order to notice the
problems caused so that we may say that
if this happens at large doses, then a
lesser form should happen at low doses.
There could be a threshold of nothing
happening or a threshold of the worst
problems at low doses.
Secondly, the effective doses of
antioxidants given to these animals are
much higher than humans would ever take
both in its method of administration
(injected vs. oral) [citation needed]
and in its dosage. Essentially both the
neurotoxic and neuroprotective effects
are exaggerated, but it is not possible
to say if this scales down the same way.
Some MDMA users administer an SSRI
while, or shortly after taking MDMA, in
an attempt to prevent possible
neurotoxicity. These SSRIs are typically
antidepressants such as fluoxetine or
sertraline. This is done to prevent
dopamine from entering through the
serotonin reuptake mechanism, where it
is theorized that monoamine oxidase
enzymes then break it down into harmful
chemicals. However, administration of
SSRIs before using MDMA is known to
block the euphoric high from the drug,
due to the regulation of serotonin. This
blocking effect can last several weeks,
depending on the half-life of the SSRI.
The same effects are seen with recent
cocaine use, which itself is an DARI
(Dopamine reuptake inhibitor).
However, MDMA use in conjunction with a
different class of antidepressants,
namely Monoamine oxidase inhibitors, is
strongly contra-indicated due to danger
of serotonin syndrome and the
possibility of life-threatening
hypertension. The safety of this
practice has not been systematically
evaluated.
Many users also attempt to replenish the
deficit of serotonin which follows the
use of MDMA by administering 5-HTP, in
an attempt to alleviate to a degree the
depression and overall mental
unsettlement in the days following MDMA
usage (including the immediate
"come-down" and what is known as
"suicide Tuesday" or "mid-week blues").
The serotonin precursor 5-HTP, which is
commercially available as a dietary
supplement, reportedly supplies the user
with more of the raw materials to
synthesize the neurotransmitter,
reducing the negative psychological
effects of depleted serotonin.
Pre-loading with 5-HTP has not been
shown to increase the subjective effects
of MDMA. Anecdotal reports seem to
indicate this is largely placebo with
some users reporting a moderate muting
of the MDMA effect when 5-HTP is
consumed within 24 hours prior to MDMA
use.
Because the neurotoxicity of MDMA is
believed by some to be highly dependent
on its metabolic disposition (Jones
2004; de la Torre & Farré 2004), it is
unclear how to generalize to humans from
experiments in rats and monkeys.
Considerable research has been done into
possible cognitive-behavioral deficits
among ecstasy users but data have been
largely inconclusive. At least two
meta-analyses of these studies have been
completed (Morgan 2000; Sumnall & Cole
2005). Morgan's analysis of 17 studies
showed that ecstasy users had a slight
tendency to be more impulsive and
depressed than controls. Sumnall and
Cole's analysis showed a slight increase
in the prevalence of depressive symptoms
in ecstasy users over controls. Of
course, in retrospective studies like
these we are always faced with a
chicken-or-egg question: did these
impulsive and depressed people use
ecstasy to self-medicate or did
otherwise normal people become depressed
and impulsive after using ecstasy? This
question has not been answered.
Although some experimental evidence
exists indicating that long-term ecstasy
users experience memory difficulties
[citation needed], a large study in 2002
(Strote et al.) showed that ecstasy
users in 4-year colleges have GPAs which
do not differ significantly from those
of non-users. |
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