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Does 3, 4 – Methylenedioxymethamphetamine (MDMA, Ecstasy) decrease the level
of serotonin in the brain?
A Positional Argument for the Scientific Community
Regina Conde
Fall 2005
There is much controversy surrounding the question of whether or not to use
3, 4 – Methylenedioxymethamphetamine (MDMA, ecstasy) as a pharmaceutical drug.
The reason for this is that the full effects of MDMA are not yet known. Determining the
full effects of MDMA is significant, for the reasons that it could have profound effects
on medicine. If the alleged risks are found to be false or minimal we can use it
pharmaceutically.
Ecstasy is a phenylethylamine that is similar in chemical structure to both
amphetamine and mescaline. It was synthesized in 1912 and patented by the Merck
Company in Germany in 1914. Alexander Shulgin then rediscovered MDMA in 1960.
He reported that MDMA “produced an easily controlled altered state of consciousness
with emotional overtones and suggested it might be useful as an adjunct in insight
oriented psychotherapy” (Vollenweider et al. 1998). However, in the 1980s the drug
became increasingly abused and there were reports of its possible neurotoxicity, which
caused it to be classified a schedule 1 drug in 1985 (Gill et al. 2002). There are still
ongoing trials to determine its full psychotherapeutic effect. It is possible that it could
have tremendous healing effects on trauma victims. It has been suggested that the drug
allows the victims to become more open with their experiences so that they may
overcome the trauma inflicted upon them.
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Researchers have come to the conclusion that MDMA affects “mood
improvement, closeness, sensual and perceptual enhancement, gained insight and general
activation hence influencing their emotions and behavior,” (Gerra et al. 2000). For these
reasons MDMA is thought to have a psychotherapeutic treatment effect. This type of
reaction would enable a psychiatrist to have a more productive session, because the
patients would be able to address subjects of trauma that they normally could not tolerate
to speak of otherwise.
In Vollenweider et al. (1998) study the type of reactions subjects elicited when
treated with MDMA are outlined. These types of reactions would be useful in
psychotherapeutic environments. Vollenweider et al. measured the psychological states
of their subjects using the Altered States of Consciousness (APZ-OAV) rating scale and
Adjecting mood rating scale (EWL). In this double blind placebo – controlled the
subjects were tested at monthly intervals and given 1.7mg/kg doses of MDMA. The
mood of the subjects was evaluated using EWL and APZ-OAV upon their arrival, which
established a baseline. Then there reactions were evaluated 75 minutes after placebo or
MDMA intake. The patients also fasted prior to this experiment.
The EWL has six scales; efficiency, inactivation, extroversion-introversion,
feelings of well-being, emotional excitability and anxiety. In this study all of these
factors were increased in the MDMA experimental group. However, the anxiety variable
had two factors. The state anxiety increased as a result of increased thoughtfulnesscontemplativeness scale. The apprehension-anxiety and dejection subscales were not
significantly changed. The APZ-OAV measures shifts in mood, thought disorder and
change in the experience of the self/ego and of the environment in drug and non-drug
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altered states of consciousness (ASC). These variables were also found to be
significantly altered from the effects of MDMA. The change in mood had the most
profound effect. They found that the level of depersonalization and derealization were
altered in relation to mood. These effects caused the subjects to have a general positive
nature with increased responsiveness to emotion, a heightened openness and sense of
closeness to other people. Because of the effects observed in this experiment, MDMA
psychological medical advances are thought to be possible in the psychotherapeutic field.
If subjects are able to feel more open and confident then they can overcome issues that
impact their mental wellness negatively.
This review is based on eight studies and three reviews that have evaluated the
effects of MDMA on the serotonin neurons of the brain. The body of research is current,
conducted over the past eight years. The research question of these articles focuses on
whether or not there are degradation effects on the serotonin neurons specifically
decreases in brain serotonin, 5-hydroxyindoleacetic acid (5-HT), and the density of the
serotonin transporters, as a result of MDMA use. There are a variety of research designs
that have been conducted. The few studies evaluated in this review used either previous
users or current users of MDMA as subjects for their experimental group. For their
control group they used ex-users or subjects who had never been exposed to MDMA.
The effects on the serotonin neuroreceptors were evaluated by injecting the subjects with
radioglandins and then measuring the affinity with which they bound to a specific portion
of the serotonin neuron, the seretonin transporter (SERT). The researchers used either
positron emission tomography (PET) or single – photon – emission computed
tomography (SPECT) to measure the efficiency with which the radioglandins bound to
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the serotonin receptors of the neuron. All the experiments found that MDMA does
decrease the serotonin levels of the brain. However, there are severe methodology flaws
within their experiments, which make their findings unreliable. For this reasons, I
believe that we cannot determine that ecstasy does cause a decrease in the serotonin
levels of neurons in the brain. Therefore, the unresolved issue is whether or not MDMA
causes a decrease in the levels of 5-HTof serotonin neurons of the brain. As of today the
data is inconclusive and problematic, hence I conclude that MDMA does not decrease the
neuron serotonin levels of the brain.
An ideal study to test the effects of MDMA would be a double-blind study
conducted on subjects who had never used any drug. Both the control and experimental
group would consist of non-drug users. Each subject would have an in depth psychiatric
evaluation to determine his or her level of mental wellness and anyone questionable
would be disqualified. There would also be extensive hair samples taken, enough so that
we could determine their entire life drug histories. In addition to these measures, a
reliable way to measure the effect of serotonin would be used. It may be necessary to
create an entirely new radioglandin, which is specific to only serotonin receptors.
MDMA is recognized as a hazardous drug; however, the studies conducted thus
far are methodologically questionable in several aspects (see Chart 1). Currently
researchers use radioglandins that bind to SERT (the site on serotonin neurons which
takes released serotonin back into the neuron), then they measure the affinity with which
the radioglandin binds using either PET or SPECT. There are two radioglandins that
have been used 123iodine-2β-carbomethoxy-3β-(4-iodophenyl) tropane ([123I] β-CIT) and
carbon – 11- labeled McN - 5652 ([11C] McN-5652). However, the reliability of both of
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these radioglandins is considerably problematic (See Chart 2). In addition to the
questionable reliability of radioglandins used, there are also problems regarding the
populations evaluated in these studies. Poly-drug users were the subjects used in the
experimental group of all of these studies and because of so it is questionable whether or
not the observed effects of MDMA are due to MDMA, or due to the prior usage of other
drugs. It is also debatable whether or not pre-existing depression, that is not detected, is
affecting the results. Depression can lower the serotonin in the brain; therefore,
decreases in 5-HT within the neurons could be due to this factor and not to MDMA use.
In the studies conducted by Reneman et al. and Sempler et al. there were several
problematic methodologies that make their studies questionable. The neuroimaging
technique used was single-photon-emission computed tomography (SPECT) and the
radioglandin employed was [123I] β-CIT. There is much controversy surrounding the use
of the radioglandin [123I] β-CIT, used in these studies (see chart 2). First of all, it is
undetermined as of yet whether or not the radioglandin is measuring the serotonin level
within the brain. [123I] β-CIT binds to the serotonin and dopamine receptors with high
affinity. Because of this, it is questionable whether or not the serotonin level is being
measured. The serotonin receptor must compete with the dopamine receptor for the
radioglandin. In addition, [123I] β-CIT binding ratios are reduced in drug – free patients
with depression. Serotonin affects several biological processes such as mood. It plays a
key factor in mental wellness. Therefore, it cannot be ruled out that the decrease in the
uptake of the radioglandin may be related to disease.
Another factor in relation to this radioglandin is that changes in [123I] β-CIT could
be due to other drugs. Both of these studies used ex-users as their experimental group.
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This is a questionable aspect of their study because the extent of subjects’ drug usage,
along with their histories is unclear. Some subjects were not only ex-users of ecstasy, but
also of a variety of additional drugs, such as cocaine and marijuana. This makes their
studies problematic. They required their subjects to refrain from using three weeks prior
to beginning the study, and to ensure this the subjects had to submit a urine sample to be
screened. Sempler et al. also employed a hair test that measured the subjects’ use of
drugs up to a month prior to the date the test was administered. In these research designs
the subjects were questioned on their previous drug use through questionnaires.
However, the way in which data was gathered causes this aspect of the studies to be open
to discussion, for the reason that subjects could have withheld information. Urine test
only allow the researcher to assess their subjects prior use for a limited time frame, hence
not making them a reliable source for evaluating drug histories. Their entire drug
histories may not be known and factored in. Therefore, it is difficult to come to the
conclusion that the decrease in 5-HT is solely due to the effects of MDMA, if at all.
In the study performed by McCann et al. the neuroimaging technique used was
positron emission tomography (PET ) and the radioglandin employed was [11C] McN5652. As stated above this radioglandin is also considered problematic (see Chart 2). The
radioglandin [11C] McN-5652 has questionable attributes. It measures the rate of
serotonin synthesis and by implication the serotonal neuronal integrity of the brain (Kish
2002). However, [11C] McN-5652 is recognized as being a problematic measurement for
SERT, because of its nonspecific binding and suboptimal pharmacokinetic profile (Kish
2002). It may be able to measure SERT in regions of the brain that contain high density
of the transporter (midbrain, thalamus and striatum), if the nonspecific binding uses the
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cerebellum as a reference region. However, McCann et al. procedure of administration is
controversial because they used the non – specific binding radioglandin in an area of the
brain, which may have yielded an overestimate of specific binding especially in cortical
regions (Kish 2002). It is also debatable whether or not the results of this radioglandin
reflect the level of serotonin synthesis or simple typtophan uptake. Another drawback of
this study is that the evidence in relation to the individual subject binding values revealed
a wide range of [11C] McN-5652 binding values. The points were very scattered and
needed to be logarithmically transformed in order to show significant effects. They also
did not present any test-retest data, which would help justify the scattered data.
Another limitation of the McCann et al. study is that they relied on the
participants’ reports to evaluate their subjects’ drug histories. Although, they took
several measures in order to gather accurate drug histories of their patients, their evidence
is still problematic. They questioned their subjects on prior drug usage but they could
have withheld information. This may influence the interpretation of their results. Like in
the studies conducted by Reneman et al. and Sempler et al., McCann also cannot
determine whether the effects of MDMA are being measured when evaluating the level
of serotonin of the brain. Other drugs used could influence the results.
A further limiting factor that affects both radioglandins, ([123I] β-CIT and [11C]
McN-5652 is that subjects may be have pre-existing differences between controls and
MDMA users in relation to the underlying differences in serotonin neuron transporter
densities. This means that regardless of the drug therapy elicited the results are
incomparable because the subjects cannot be compared due to individual differences.
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Hence, it is possible that the effects of MDMA will have to be evaluated on subjects with
similar drug backgrounds or no drug exposure what so ever.
Reneman et al., Sempler et al. and McCann et al. conclude, even with the
limitation of their methodologies, that MDMA lowers the levels of serotonin in the brain.
Reneman et al. and Sempler et al. state that the limitations are minimal in their
counterargument. They state that although [123I] β-CIT has a high affinity to both
serotonin and dopamine the displacement studies conducted on animals previously have
shown that β-CIT is predominantly associated with the serotonin receptors of the brain.
Reneman et al. also stated that their results showed no striatal [123I] β-CIT binding ratios
between MDMA heavy uses and controls, hence they conclude that he findings reflect the
densities of serotonin receptors not the dopamine receptors. Reneman et al. stated they
could not rule out the possibility that disease may be a factor in the decreased level of
serotonin, or that there is a possibility that there may have been pre-existing differences
between the MDMA users and the individuals of the control group in relation to
underlying serotonin transporter densities. However, they simply state that they did not
witness any effects of depression on [123I] β-CIT. They did have two statistical analyses,
one that included the depressed individuals and one that did not. They stated that their
analysis that included the depressed individuals did not affect the overall effect on the
group. They also disregard the theory that the subjects could have lower neuron
serotonin densities as a result of previous poly-drug use. They stated that none of the
other drugs that were reported to have been used have been proven neurotoxin in the
brain; therefore, the differences in the serotonin levels must be attributed to the use of
ecstasy. The present findings are also not believed to have been influenced by current
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drug use for the reason that subjects were instructed to refrain from drug use prior to
beginning the study and were given drug screens (urine tests, blood tests, minimal hair
sampling) to ensure that all subjects were drug free during the duration of the study,
The study conducted by McCann et al. had no justifications discussed about [11C]
McN-5652. They also did not justify their conclusions drawn considering the fact that
the data was scattered.
3, 4 – Methylenedioxymethamphetamine (MDMA or ecstasy) may possibly have
an array of medical uses that may prove to relieve pain and suffering in victims of
trauma. The evidence regarding the issue of whether or not MDMA is responsible for a
decrease in the serotonin levels of the brain thus far is extremely controversial. The
methodologies of the research designs published so far are questionable. The
radioglandins, 123iodine-2β-carbomethoxy-3β-(4-iodophenyl) tropane ([123I] β-CIT and
carbon – 11- labeled McN - 5652 ([11C] McN-5652), that are used to measure the levels
of serotonin in the brain based off of their binding affinities to the receptors, are
problematic. In addition, the drug histories of the subjects used in these studies are
questionable. Researchers are unable to without a doubt claim that the decreased
neuronal serotonin densities in the brain of MDMA users are a direct effect of the
MDMA. There are so many other variables that could influence this measurement such
as depression, and pre – existing differences. Even with the justifications of the authors
these issues have not been resolved. Because of so, we are unable to determine whether
or not MDMA decreases the serotnin levels of the brain. Until future studies that can
resolve these issues are conducted we must conclude that MDMA does not lower the
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level of serotonin in the brain. However, we should approach the use of the drug with
caution until it is proven to be either safe or hazardous.
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Chart 1
Study
Problems within that study
McCann et al.
Use of radioglandin [11C] McN-5652
Unreliable population
- Drug histories unknown
- Extent of usage unknown
Reneman et al.
Other factors such as preexisting
depression not taken into account
- Could cause the uptake of
[123I] β-CIT to be lower
Use of radioglandin [123I] β-CIT
Unreliable population
- Drug histories unknown
- Extent of usage unknown
Other factors such as preexisting
depression not taken into account
- Could cause the uptake of
[123I] β-CIT to be lower
Sempler et al.
Use of radioglandin [123I] β-CIT
Unreliable population
- Drug histories unknown
- Extent of usage unknown
Other factors such as preexisting
depression not taken into account
- Could cause the uptake of
[123I] β-CIT to be lower
Outline of limitations present in studies discussed in this paper
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Chart 2
Limitations of 123iodine-2β-carbomethoxy-
Limitations of carbon – 11- labeled McN -
3β-(4-iodophenyl) tropane ([123I] β-CIT)
5652 ([11C] McN-5652)
1. [123I] β-CIT has an affinity for both
1. Debatable whether of not serotonin
serotonin and dopamine
synthesis or typtophan uptake is
transporters and cannot be
measured by [11C] McN-5652
definitively attributed to serotonin
transporters
2. [123I] β-CIT binding ratios are
reduced in drug-free patients with
depression
2. Is a non-specific binding
radioglandin and needs a baseline
for comparison
3. Changes in [11C] McN-5652 could
be induced by other drugs
3. Changes in [123I] β-CIT could be
due to other drugs besides MDMA
A description of all the limitations of the radioglandins used in the studies presented in
this paper.
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