MDMA (Ecstasy)
While this is not late-breaking news, it is going to be a focus of this lesson on
MDMA, or ecstasy. The story is a report from National Public Radio, recorded
in 2004, and is found at http://www.youtube.com/watch?v=4lU1dYI5o7A
This lesson extends the previous on amphetamines. In fact, MDMA, better known as Ecstasy,
stands for methylene dioxy methamphetamine, thus is legitimately categorized as an
amphetamine. However, several of its properties, including the subjective reports about the
type of mood alteration experienced by MDMA users, are quite distinct from amphetamines.
Therefore MDMA must be considered on its own.
This lesson doesn't consider just the science of MDMA but the PROCESS of science as can be
revealed by analyzing some reports related to MDMA toxicity.
Objectives
After successfully completing this lesson you will be able to:
to understand what MDMA is, and how is related (and not) to amphetamines
to understand how MDMA works at the level of the molecule, the neuron, the brain, and
behavior
to be able to weigh risks and benefits of this drug in a knowledgeable way that assists in wise
decision making.
to learn about contaminants, when to expect them, what they contribute.
to learn about accountability in science publication.
Before you begin!
Your ideas
Ecstasy resembles a class of drugs you have already studied. Which class?
How long has Ecstasy been available?
What are the primary effects one experiences while using Ecstasy? From this, which
neurotransmitter do you think is impacted?
What are the primary worries related to using Ecstasy and how do people deal with
them?
Previously learned material
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MDMA (Ecstasy)
Ecstasy causes recycling transporters to work in reverse. What other drug gives this
effect?
Based on your answer to the previous question, what will an Ecstasy user experience the
day following drug use?
Ecstasy is neurotoxic. What does this mean and based on previous drugs, what are some
of the ways neurotoxicity can be detected?
Ecstasy has a strong impact on neurons of the hypothalamus. Based on what you know
about this structure, what types of side effects would you predict for ecstasy use?
Lesson 19: MDMA (Ecstasy)
Guiding Questions
1. What is the result of blocking neurotransmitter recycling to a neuron and to the brain and
behavior?
2. How are serotonin and dopamine similar? How are they different?
3. What are some ways of detecting damage to the brain?
4. What areas of the brain are impacted by MDMA and what symptoms can result from its use?
5. How do scientists deal with conflicting results and behave honorably when incorrect
experimental outcomes are published?
Key Terms




Methylenedioxy-methamphetamine
Serotonin syndrome
Sympathomimetic
Retract
Activity One: Web Site Review
Please review the Web sites below: guiding questions precede each URL.
1) Find the MDMA mouse at "Mouse Party"
Guiding questions:
What molecule(s) does MDMA impact in a neuron?
How does the story of MDMA's impact sound familiar to / different from the story
this web site tells about methamphetamine?
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MDMA (Ecstasy)
Where are the serotonin pathways located in the brain?
How does serotonin interact with dopamine pathways?
Is MDMA addictive?
http://learn.genetics.utah.edu/content/addiction/mouse/
2) Next see what the NIDA has to say about MDMA
Guiding questions:
Serotonin is implicated in what types of brain functions?
What is an indicator that MDMA can be addictive?
What are some minor and major side effects of MDMA use?
What are MDA and PMA and how do they relate to MDMA toxicity?
What happens when a scientist discovers that her work was in error after
publication?
http://drugabuse.gov/infofacts/ecstasy.html
History Side Bar
Activity Two: What is MDMA? Why do we use MDMA?
Methylene dioxy methamphetamine (MDMA) is generally thought of as a party drug. People use
MDMA to enhance social interactions and sensory perceptions and reduce inhibitions. People who use
MDMA report that the drug acts like a:
Euphoriant - it stimulates a heightened sense of pleasure and euphoria
Sympathomimetic - it energizes users
Empathogen - it makes people feel very in touch with and sensitive to other people
Entactogen - it makes people reflective and introspective about themselves and their place in the
world
Sexual aide - MDMA makes a person more likely to engage in sex (it lowers inhibitions) and
enhances sensory aspects of that encounter.
But it is short-sighted to just think about MDMA as we have come to know it in its association with
partying. MDMA was previously used to assist people undergoing psychotherapy and since 2004 is
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MDMA (Ecstasy)
back in clinical trials to measure its effectiveness as a psychotherapeutic aide. Thus, like almost any of
the substances we investigate, there are benefits and costs associated with MDMA use.
Activity Three: How is MDMA Administered? How Much is Used?
MDMA is taken as a pill. It is a synthetic drug although some non-synthetic sources have measureable
amounts of MDMA in them (sassafras tree oil and nutmeg). Stamps on MDMA pills can sometimes be
used to identify a synthetic lot or batch of the drug. This can be important because any synthetic, and
illegal substance CAN be adulterated. Adding non-drug ingredients to a batch of an illegal drug is one
way to increase profit margins. And with no FDA oversight (testing by FDA pertains only to sanctioned
drugs), these adulterated products can easily get into the market place. A company called "DanceSafe"
capitalized on this problem by creating test kits it markets to the more careful among the MDMA users.
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A typical MDMA tablet is 125 mg. Typical use is one tablet, but people do sometimes take two. An
estimate of the lethal dose of MDMA is 20 mg per kilogram body mass (and an “average” person 60-70
kg2).
TEST OF CONTENT
Compute the therapeutic index for Ecstasy and propose an explanation for
why there are very few toxic overdoses.
Activity Four: Bioavailability of MDMA
Once in the body, MDMA is metabolized by CYP1A2, CP3A4, and CYP2D6. It is inefficiently
metabolized despite the large number of metabolic enzymes. Approximately 65% of it leave the body
intact within 24 hours of use. It's half life is approximately 7 hours.
One of MDMA's metabolites (MDA - methylene dioxy amphetamine) is also psychoactive. This
effectively extends the duration of the drug experience.
TEST OF CONTENT
Predict whether or not Ecstasy shows cross tolerance with other drugs and
justify that position.
Activity Five: Where Does MDMA bind? Then What?
MDMA does appear to bind to the serotonin recycling transporters. As suggested by the Mouse Party,
MDMA, at least partially, resembles serotonin and fools the transporters into admitting it (MDMA) into
1
2
http://dancesafe.org/
Erowid.org
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MDMA (Ecstasy)
the neuron and in turn working in reverse to let serotonin out. Thus levels of serotonin in the synapse
are elevated. This enhancement of serotonin release does NOT adapt, but is sustained at a high level
despite frequent use.3
Serotonin has taken a back seat to dopamine so far in this course. And while dopamine is certainly
important for euphoria (and other behaviors like voluntary motor control), serotonin is equally
important in mood. Unlike dopamine's intensity of arousal, serotonin increase make a person have a
heightened sense of sensuality and sense of well-being. In fact, as you'll learn in the next lesson, most
anti-depressant drugs primarily impact serotonin.
Because the brain has a VAST network of serotonin-regulated neurons, the impacts of a drug which
influences serotonin are equally broad. Sertonin-releasing neurons project to virtually ALL areas of the
cerebral cortex as well as subcortical regions involved in mood, homeostasis, sexual appetite and sleep.
Thus, MDMA has impacts on perception (cerebral cortex), body temperature regulation (hypothalamus),
sleep cycles, sexual inhibition (or lack thereof), and impulse control (frontal cortex).
And recall that one neuron talks to another which talks to another. Our brains are complex networks of
interconnected neurons. Serotonin stimulation leads to dopamine release as a secondary impact, so yes,
MDMA causes users to feel euphoric.
While less is known about the impact of MDMA directly on dopamine neurons, one study showed that
cells pretreated with dopamine antagonists results in a reduction of MDMA's impact on these cells.4
TEST OF CONTENT
Another drug you've learned about impacts monoamines more
generally than others. Formulate a hypothesis for how MDMA might
elevate dopamine release DIRECTLY based on what you learned about this
other drug
TEST OF CONTENT
Drugs that block reuptake transporters generally stimulate neurotransmitter
release. Why might these effects be paired (what might be the underlying
mechanism suggested by the Mouse Party)?
Activity Six: Why Is MDMA Addictive?
Many would argue that MDMA is NOT addictive. Indeed, there are many casual users who opt to use
only occasionally or to stop using with ease. But keep in mind that addiction is not a YES or NO
3
PMID: 20484864
PMID: 1988133
4
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MDMA (Ecstasy)
situation: what is addictive to one may not be addictive to another and some things may have moderate
ability to be addictive. A study of adolescent male MDMA users showed evidence that 43% of them had
signs of dependence. 5 Dependence was determined by an inability to stop using despite knowledge of
self harm. The primary effect of a body withdrawing from MDMA is 1) let down - a user coming off
MDMA's effects feels a worsening of mood in comparison with the elevation just experienced, and 2)
craving to reuse the drug and regain the sense of well-being.
One of the explanations for dependence is that the brain-on-drugs compensates for the drug's presence
by producing FEWER molecules to which the drug can bind. Indeed, studies using a radioactive label
(11C-DASB) for serotonin transporters (SERT) reveal that users of MDMA showed lower levels of SERT in
some cerebral cortical regions, particularly the insula, an area already discussed (nicotine lesson)
involved in craving. In the graph above, MDMA users are represented by gray dots while non-user
controls are black dots.
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Activity Seven: Does MDMA do ANY Good?
MDMA had some limited use in the 1970s as an aid in psychotherapy. Patients having
difficulties processing difficult and disturbing realities in therapy were more open to do so
under MDMA's influence. After 30 years of prohibition on MDMA research, several clinical
trials are underway to reexamine (or more objectively examine) the therapeutic potential of
MDMA for psychotherapy. In 2011, Time Magazine featured some of the news on clinical trials examining
potential benefits of therapeutic MDMA. Examine the article with these guiding questions in mind.

Why was it thought that MDMA impacts cognition? Now what do we think?
5
Cottler LB, Womack SB, Compton WM, Ben-Abdallah A. Ecstasy abuse and dependence among adolescents and young adults: Applicability and reliability of DSM-IV
criteria. Human Psychopharmacol 16:599–606, 2001.
6
PMID: 20483717
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MDMA (Ecstasy)

Why was it thought that MDMA use leads to Parkinson's like symptoms? Now what do we think about
MDMA use and neurodegeneration?

Time article found here http://healthland.time.com/2011/02/18/ecstasy-as-therapy-have-some-of-itsnegative-effects-been-overblown/
Bear in mind, whether or not a drug has potential benefit does not make using the drug right for you and it certainly
does not make an illegal drug less "illegal". Also bear in mind that long-term studies on MDMA are decades away.
TEST OF CONTENT
Which property of MDMA probably underlies its potential ability to help people
undergoing psychotherapy?
It is a euphoriant
It is an entactogen
It is an empathogen
It is a sympathomimetic
MDMA (or more likely, an MDMA derivative) may also be of benefit for conditions in which dopamine
neurons are under attack, such as Parkinson's disease. A 2006study showed that fetal exposure to
MDMA in rats increased the survival of dopamine neurons in regions of the brain necessary for
voluntary movement.7
Activity Eight: What are MDMA's Harmful Side Effects?
Because the story of MDMA's risks is intertwined intimately with a lesson on the process
of reporting science, please follow the link below to view a presentation about MDMA's
harmful side effects (and how the process of science has helped us understand them).
Doc Linda’s Presentation:
http://uweoconnect.extn.washington.edu/public_mdmasideeffects/
Activity Nine: Individual Experience May Vary
Add to all the reasons why one person's MDMA experience would not be the same as another's
(previous drug use, expectation, mental health, and more), add to that story one more. The fact that
MDMA is an illegal, synthetic drug, leads to elevated risk that the tablets one buys that are called
MDMA are actually something else or at very least contaminated with something else. Thus users of
7
http://www.sciencedaily.com/releases/2006/10/061018150856.htm
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MDMA (Ecstasy)
street-ecstasy will have very different experiences because each pill runs the risk of being very different
in composition.
There has been very little research on MDMA at all. Most of it relates to studies whose mission is to
uncover harmful side effects. Very little has been geared toward understanding particular genes and the
alleles of those genes that might cause a person's MDMA-experience to be unique.
TEST OF CONTENT
While genes involved in determining your experience when using Ecstasy have
not been studied, name TWO proteins (or the genes that encode them) that you
would PREDICT might influence drug experience.
Activity Ten: Reading
Required Reading
Liska
Liska - section 12.6.4 and questions 6, 7, and 21
Web sites
http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html
http://www.drugabuse.gov/infofacts/ecstasy.html
http://www.erowid.org/chemicals/mdma/mdma_research2.shtml
Audio story
http://www.youtube.com/watch?v=4lU1dYI5o7A
Supplemental Reading
Internet
http://www.mdma.net/toxicity/retracted.html - full text of Ricaurte's team's retraction of MDMA
paper.
http://www.maps.org/research/mdma/studyresponse.html Timeline of Infamous MDMA
research retraction
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