MDMA - Ecstasy: A Current Overview Introduction - Ce4less
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MDMA - Ecstasy: A Current Overview
Introduction
MDMA (3,4-methylenedioxy-methamphetamine) is a synthetic stimulant that
alters a person’s perception and mood. A person using MDMA will have an
altered awareness of surrounding objects and conditions. The drug is similar
chemically to hallucinogens and stimulants. It can produce feelings of
increased pleasure, energy, emotional warmth, and a distorted perception of
time. Although MDMA has psychedelic effects that cause a sense of euphoria
and increased energy, over the long-term the drug may lead to fatigue and
depression. MDMA is often combined with other drugs, which increases its
potentially harmful effects on the user. Because of these harmful effects,
MDMA was made illegal and listed as a Schedule I drug. Nevertheless,
experimental use of MDMA has increased for psychiatric disorders, for
example, posttraumatic stress disorder (PTSD), in an attempt to treat
symptoms.5
The History And Evolving Use Of MDMA
Anton Kollisch discovered MDMA in Germany in 1912. Kollisch was a chemist
working for the German pharmaceutical company Merck. The research
interest in the drug was to synthesize methylhydrastinine as a possible
treatment for uterine bleeding.6 Ecstasy was patented in 1914 by Merck and
was used in therapy. Major tests for MDMA took place in the 1950s at the
University of Michigan for the U.S. Army to study its toxicity in animals.
In the mid 1970s the substance came to the attention of Alexander Shulgin.
Shulgin was a former chemist with Dow Chemical Company and he is known
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ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comas the godfather of Ecstasy. MDMA came to his attention when he was
researching another psychoactive compound called MDA. Shulgin worked
with David Nichols from Perdue University and in 1978 they published a
report about the effects of MDMA in humans. They compared the drug to
mushrooms and marijuana.The report by Shulgin and Nichols caught the
attention of psychotherapists interested in the disinhibiting effects of MDMA.
They saw the drug as a possible tool to overcome fear in patients. The drug
was thought to increase patients’ insight into their emotions. Eventually,
MDMA became the drug of choice within the rave culture, house parties,
clubs, and festivals, and goes by the popular name Ecstasy or Molly.1-6
After MDMA was introduced into psychotherapy, people began using MDMA
recreationally. MDMA became attractive recreationally because it has the
effects of both a hallucinogenic drug and a stimulant. The name Ecstasy was
coined because it described the drug’s effect on people. Production of the
drug in the 1980s could not keep up with its use. Safrole and sassafras oil
was used to manufacture MDMA. Initially popular at nightclubs and all-night
dance parties known as raves, MDMA spread through networks including
young, urban professionals (yuppies), users of psychedelics, psychiatrists,
and psychotherapists. A psychedelic drug closely related to MDMA,
methylenedioxyemphetamine (MDA), nicknamed Sally, spread to U.S.
college campuses. Recreational users and psychotherapists were hopeful
that MDMA and MDA would remain legal in the United States.1-6
MDMA: Schedule I Substance
Because of the perceived, serious dangers of MDMA, in 1985 the United
States Drug Enforcement Agency (DEA) issued an emergency notice
declaring MDMA a Schedule I substance and the DEA also issued an alert to
2
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comindividuals and businesses that it was illegal in the U.S. to use safrole and
sassafras oil to manufacture MDMA.7
Some psychiatrists and psychotherapists objected to the DEA classifying
MDMA as it did. They cited anecdotal use of its benefits in their practices.
These objections failed and in 1988 MDMA and similar psychedelic drugs
were classified as Schedule I substances. The Schedule I classification is
according to the federal Controlled Substances Act, which is part of the
Comprehensive Drug Abuse Prevention and Control Act of 1970. Other
examples of Schedule I drugs include heroin, LSD, peyote, and marijuana
(cannabis).8
Under federal law, substances are categorized under schedules listed from
Schedule I to Schedule V. Schedule I drugs are considered to be the most
dangerous drugs. The schedule is assigned based on a drug’s 1) potential for
abuse, 2) safety, 3) addictive potential, and 4) whether there is a legitimate
medical application for the drug.
The potential for severe psychological or physical addiction exists with
Schedule I drugs and there is no legitimate medical application.8-10 No
clinical studies have established the safety and efficacy of Ecstasy in a
psychotherapy setting, which could make MDMA become a Schedule II drug,
so the classification as a Schedule I drug remains.
Statistics On MDMA Use
Use of MDMA is reported at age 12 and older. There are indications that the
peak age for use is between ages 18 to 25. There is less use above the age
of 26 and under the age of 17. Statistics show that the use among adults
3
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.commay be decreasing overall but this may not be true of adolescents.2,3 This
could be because younger users may think that MDMA provides a high that
is safe; however, it is not safe.
Table 1
Use of MDMA (%): Grade 8, 10, and 12 (2016)
Drug Time period Grade 8 Grade 10 Grade 12
MDMA Lifetime 1.70 2.80 4.90
Past year 1.00 1.80 2.70
Past month 0.30 0.50 0.90
Table 2
MDMA % Use: Ages 12 and older, 12 - 17, 18 - 25, and 26 or older (2015)
Time Period 12 and older 12 to 17 18 to 25 26 and older
Lifetime 6.80 1.40 13.10 6.5
Past year 1.00 0.80 4.10 0.50
Past month 0.20 0.10 0.90 0.10
MDMA shares toxicities with amphetamines. It is also associated with specific
adverse effects that can be serious or even lead to death. Deaths associated
with the use of MDMA have increased since 2013.4 In other countries around
the same time, such as Germany, the highest percent of MDMA reached
increased for people aged 25 to 29. In Europe, in 2012 the estimate was
that 37 percent of club goers ages 14 to 35 used MDMA.1-4
The cost of Ecstasy varies across the globe. Prices tend to be higher in North
American than in Europe. A tablet of MDMA/Ecstasy in the United States can
be as high as $50 for 50-150 mg of the drug. The lower prices can be $10 to
4
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com$25 per tablet. Production of Ecstasy is mainly in Canada but it is also
imported from China.
High Risk Drugs And Substance Use Disorder
Before beginning an in depth discussion of MDMA, Ecstasy/Molly, a review of
the drugs known to have high risk to develop into a substance use disorder
and addiction are raised here. It is important for clinicians to be aware of
other substances known to commonly have a high risk of addiction as they
are often combined with MDMA use and are co-occurring disorders that need
to be diagnosed as multiple or poly-substance use disorders, which
complicate the medical management and treatment plan for recovery.
When determining drug of use, the medical guidelines for testing can vary
between regions, however, the clinician diagnosing a problem of MDMA or
co-occurring will need to review a laboratory drug screen. Five drugs
considered most important in a routine drug screen have evolved over time,
such as new variants of amphetamines, synthetic marijuana/cannabinoids,
opioids, and PCP not detectable with a routine drug test. PCP has been
reported to be relatively obscure and used with lower frequency than
numerous other street drugs, and amphetamine use is relatively infrequent
compared now with methamphetamine and amphetamine derivatives, such
as MDMA (Ecstasy), MDPV (bath salts), and numerous other drugs in this
class. It is important that clinicians stay abreast of the drugs reported as
frequently used, as the popular notion of drug use evolves based on media
report, supply, demand and cost.47
In the United States, currently only amphetamine, cocaine, marijuana,
opioids, and PCP should be expected on drug screen test, unless otherwise
5
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comspecified or requested. Certain drugs and substances have strong potential
for a substance use disorder while others do not. Drugs such as cocaine and
heroin and substances such as alcohol are intensely psychoactive, and the
user will prefer them for a more powerful feeling of being high. This is
certainly one of the known reasons for why they are the agents of choice for
people who develop a substance use disorder. However, the pleasures of
being intoxicated or high cannot fully explain a substance use disorder, and
research has shown that continued and excessive use of these harmful
agents causes changes in the central nervous system. These changes both
cause and reinforce substance use. Of course, there are many people who
take illicit or prescription drugs and/or drink alcohol that do not develop a
substance use disorder, and these individual responses to commonly used
drugs and substances further complicate the efforts at understanding the
development of a substance use disorder.
The mechanism of action and medical consequences of long-term use of
alcohol, amphetamines/stimulants, cocaine, opioids, and sedative-hypnotics
are important considerations when starting and continuing a patient
treatment plan. The mechanisms of action by which alcohol and specific high
risk drugs cause a substance use disorder, and the withdrawal syndromes
associated with each one, is highlighted below.46
Alcohol
Aside from tobacco, alcohol is the most commonly used psychoactive drug in
our society. There are many types of alcohol, for example, ethylene glycol,
isopropyl, but the one that is most often consumed for its intoxicating effects
is ethanol.
6
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comThe exact mechanisms by which ethanol alters consciousness and causes
tolerance and withdrawal are not completely understood. But it is thought
that these effects are due to ethanol changing the activity of two
neurotransmitters and their receptors: a major inhibitory neurotransmitter
called gamma aminobutyric acid (GABA) and a sub-type of the major
excitatory neurotransmitter glutamate called N-methyl-d-aspartate (NDMA).
Gamma aminobuytric acid acts as an inhibitory neurotransmitter by
increasing intracellular chloride concentration and decreasing intracellular
potassium concentration. This hyperpolarizes the cells and makes them less
able to respond. N-methyl-d-aspartate increases the movement of calcium
and sodium across cell membranes, and this increases the cells’ ability to
respond to a stimulus and depolarize.
Ethanol binds to receptors that are associated with GABA and NDMA
receptors on cell membranes in the CNS. This binding increases the affinity
of GABA for GABA receptors and it decreases the affinity of NDMA for DMA
receptors. The result is increased inhibition and decreased excitation.
However, when large amounts of alcohol are used chronically the body
responds by decreasing the number, sensitivity, and function of GABA
receptors and increases the number, sensitivity, and function of NDMA
receptors.
This effect explains alcohol intoxication as well as tolerance to alcohol, for
example, the need for larger amounts of alcohol to produce the same effect;
and, it explains withdrawal, the clinical state that is produced when alcohol
intake is stopped. Intoxication is caused by increased inhibition and
decreased excitation in the central nervous system. Tolerance occurs
because of the effect of chronic alcohol intake on the neurotransmitter
receptors. Furthermore, when the intake of alcohol is stopped, withdrawal is
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ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comcaused because there are large numbers of highly active NDMA receptors
that can respond to NDMA and a greatly decreased number of GABA
receptors that can respond to GABA.
Alcohol intoxication is characterized primarily by CNS depression and
impairment. Someone who has ingested an excess amount of ethanol will be
drowsy, may be ataxic (incoordination of movement), have impaired
judgment, decreased impulse control, and slurred speech. Extreme
intoxication can cause coma, hypoglycemia, hypotension, respiratory
depression, and death. Long-term use is associated with liver disease, heart
failure, brain atrophy, gastritis and ulcers, anemia, and various cancers; it is
particularly dangerous to the unborn child.
Amphetamines and Stimulants
Amphetamines and stimulants act by directly stimulating the adrenergic
nerve endings. This causes a release into the synapses of norepinephrine
and dopamine, neurotransmitters that stimulate the peripheral α receptors
and β receptors. Acute intoxication causes anxiety, diaphoresis,
hypertension, mydriasis, and tachycardia. More serious effects such as
dysrhythmias, hallucinations, hyperthermia, myocardial ischemia,
myocardial infarction, psychosis, seizures, stroke, and rhabdomyolysis are
possible, as well.
Long-term effects of amphetamine and stimulant use include aortic and
mitral valve regurgitation, cardiomyopathy vasculitis, cardiomyopathy,
pulmonary hypertension, and permanent damage to the dopaminergic and
serotonergic neurons. Amphetamines and stimulants can be taken as
tablets, injected, smoked, or insufflated (snorted). Probably the most
commonly abused amphetamine is methamphetamine.
8
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comMethamphetamine is commercially produced, and it has labeled uses for the
treatment of patients who have exogenous obesity or attention deficit
disorder with hyperactivity disorder. Methamphetamine is lipid-soluble and
crosses the blood-brain barrier more easily than the parent compound
amphetamine, making it a more powerful drug. The great majority of the
methamphetamine involved in substance use is illicitly produced, and this
form of the drug is commonly called Crank or Speed.
Cocaine
Cocaine causes the release and blocks the re-uptake of the
neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin.
These actions produce a hyper-adrenergic state, and the common signs and
symptoms of cocaine intoxication are agitation, anxiety, chest pain,
diaphoresis, hypertension, hyperthermia, mydriasis, tachycardia, and
tachypnea. Cocaine also acts to stabilize the cardiac membrane by an effect
on the sodium channels in the myocardium, and it bocks the movement of
potassium through cardiac membrane ion channels.
Blockade of the sodium channels produces cardiac membrane stabilization,
typically called the quinidine-like effect. This can cause a prolonged QRS in
the heart conduction pattern, and cardiac dysrhythmias. Blockade of the
potassium ion channels can cause QTc prolongation and cardiac
dysrhythmias, as well.
Cocaine use has also been associated with serious medical problems
affecting essentially every organ system; such as, acute angle-closure
glaucoma, aortic dissection, coronary artery vasospasm, dystonic reactions,
intestinal infarction, myocardial infarction, pneumothorax, pulmonary
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ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.cominfarction, rhabdomyolysis, seizures, stroke, and transient ischemic attack.
Long-term effects of cocaine abuse include atherosclerosis, cardiomyopathy,
endocarditis, malnutrition, and behavior that can be characterized as
virtually identical to personality disturbances, paranoia, and schizophrenic
syndromes.
Cocaine can be ingested, applied to mucous membranes, insufflated,
smoked, or injected. As mentioned previously, there are many well-
documented cases of dangerous contaminants and adulterants being added
to cocaine, and these can cause significant harm.
Opioids
The opioids are a class of drugs that are derived from chemical modification
of an opiate, an opiate being one of several alkaloids that are derived
directly from the opium poppy. In common practice the term opioid is the
one used for all drugs that have similar structure and clinical effects
including, but not limited to, buprenorphine, codeine, dextromethorphan,
fentanyl, heroin, hydrocodone, methadone, morphine, oxycodone, and
propoxyphene. In the United States all of these drugs except for heroin are
commercially produced and are commonly prescribed.
In the United States, heroin is classified as a Schedule 1 drug with a high
potential for substance use and addiction. Heroin has no currently accepted
medical use, and there is a lack of accepted safety for use of the drug while
under medical supervision. Heroin is commercially available in other
countries and is used for treating people who have severe, intractable pain.
The opioids act by binding to and stimulating opioid receptors in the brain,
spinal cord, and peripheral sites. Opioid receptor stimulation causes the cells
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ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comto become hyperpolarized and thus less active and less able to respond to
stimuli. As with alcohol and other drugs discussed in this module, chronic
use of opioids affects the function and activity of neurotransmitters and their
receptors, and this causes tolerance and the potential for a withdrawal
syndrome. The therapeutic effects of the opioids are analgesia and an anti-
tussive effect. Constipation, drowsiness, nausea, and vomiting are common
side effects of the opioids.
Opioid intoxication is characterized by ataxia, central nervous system
depression, euphoria, hypotension, miosis, respiratory depression, and
slurred speech. With profound intoxication coma, hypoxic seizures, hypoxic
brain injury, pulmonary edema, and respiratory arrest are possible.
Propoxyphene intoxication can cause myocardium sodium channel blockade
and arrhythmias. Long-term effects of opioid use include heart valve
infections, infectious diseases such as hepatitis B and C and human
immunodeficiency virus (HIV) that occur with intravenous use, arthritis,
collapsed and sclerotic veins, malnutrition, and a depressed immune system.
Opioids can be taken as tablets, injected, smoked, or insufflated. As
mentioned previously, there are many well-documented cases of dangerous
contaminants and adulterants being added to illicit opioids (typically
injectable heroin) and these can cause significant harm.
Sedative-hypnotics
The sedative-hypnotics are a group of drugs that are used to treat anxiety
and/or agitation (sedatives) or to induce sleep (hypnotics). There are many
drugs that are classified as sedatives or hypnotics, but the sedative-
hypnotics that are most often involved in substance abuse disorders are the
benzodiazepines and the barbiturates.
11
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comThe commonly available sedative-hypnotics are shown in the Table 1 below.
Flunitrazepam is not commercially available in the United States but it is
included here because of its highly publicized status as the date rape drug,
also known as roofies. Midazolam is an injectable benzodiazepine that is
used for pre-operative sedation. It is seldom a drug of choice for use but it is
included here because it is well known and often used. The non-
benzodiazepine hypnotics shown in Table 2 have a similar mechanism of
action as the benzodiazepines.
The barbiturates, listed in Table 3, were at one time the drugs of choice for
treating anxiety/agitation or for inducing sleep, but the benzodiazepines
have been shown to have similar effectiveness for those purposes and a
superior safety profile. The barbiturates are now used to help induce pre-
operative sedation or for the treatment of seizure disorders. The short-acting
barbiturate butalbital is available in prescription analgesics, compounded in
various combinations with acetaminophen, aspirin, caffeine, and codeine.
These drugs are almost always used and used in tablet or capsule from, but
injectable preparations are available.
Table 1: Benzodiazepines
• Alprazolam (Xanax®)
• Chlordiazepoxide (Librium®)
• Clonazepam (Klonopin®)
• Diazepam (Valium®)
• Flunitrazepam (Rohypnol®)
• Flurazepam (Dalmane®)
• Lorazepam (Ativan®)
• Midazolam (Versed®)
• Oxazepam (Serax®)
• Temazepam (Restoril®)
• Triazolam (Halcion®)
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ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comTable 2: Non-Benzodiazepine Hypnotics
• Eszopiclone (Lunesta®)
• Zaleplon (Sonata®)
• Zolpidem (Ambien®)
Table 3: Barbiturates
1. Amobarbital (Amytal®)
2. Butalbital
3. Pentobarbital (Nembutal®)
4. Phenobarbital (Luminal®)
5. Primidone (Mysoline®)
6. Secobarbital (Seconal®)
7. Thiopental (Pentothal®)
The mechanism of action differs slightly for the three different categories,
but essentially all these drugs act by binding to specific receptors that are
part of the GABA receptor complex. This binding increases the affinity of
GABA for GABA receptors and, as explained previously, this increases the
inhibitory effect of GABA in the central nervous system.
Intoxication with a sedative-hypnotic causes ataxia, central nervous system
depression of varying degrees, from mild drowsiness to coma, hypotension,
slurred speech, and respiratory depression. Death is caused by respiratory
13
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comdepression. The barbiturates, compared to the benzodiazepines and the non-
benzodiazepine hypnotics, will produce more severe effects: if very large
amounts are ingested coma and respiratory depression may last for days.
Compared to alcohol, cocaine, amphetamine/stimulants, and opioids, the
long-term medical consequences of sedative-hypnotic abuse are relatively
mild. Perhaps the biggest risks are the potential for dependency and
development of a substance use disorder. And although acute intoxication
and the long-term medical consequences of alcohol, cocaine,
amphetamines/stimulants, and opioids are much more severe, the sedative-
hypnotic withdrawal from the benzodiazepines and the barbiturates is
comparatively more severe and can be life threatening.
MDMA Effect On Neurotransmitters
MDMA is known as a serotonin-norepinephrine-dopamine releasing agent
(SNDRA), which is also known as a triple-releasing agent (TRA). Examples of
SNDRAs include specific amphetamines such as MDMA and MDA. Other
examples are mephedrone and methylone. These drugs produce a euphoria
and psychostimulant effect. Some SNDRAs were once used as
pharmaceutical drugs, specifically as antidepressants. With time these were
withdrawn in the 1960s due to issues with toxicity and problems perceived
with recreational use.9,10 The effect of MDMA on neurotransmitters and
potential for substance use and addiction will be introduced in this section,
and discussed more in depth later on in subsequent sections of the course.
MDMA is a drug that induces the release of serotonin, norepinephrine or
epinephrine, and dopamine in the body and brain. Specifically, MDMA is
reported to have ten times more affinity for uptake at serotonin transporters
compared to dopamine and norepinephrine transporters. Within the brain,
14
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comMDMA increases the activity of at least three neurotransmitters - serotonin,
dopamine, and norepinephrine. These neurotransmitters are the chemical
messengers of brain cells.
Factors to consider include that MDMA causes neurotransmitters to be
released from storage sites in neurons. This is like other amphetamines, and
results in increased neurotransmitter activity. Additionally, MDMA causes
greater serotonin release and less dopamine release than a potent stimulant
such as methamphetamine. MDMA is a monoamine transporter substrate. It
enters monoamine neurons via neuronal membrane transport proteins; and
acts as a monoamine transporter substrate and produces competitive
reuptake inhibition at the neuronal membrane transporters. MDMA inhibits
vesicular monoamine transporters with one of these two being highly
expressed within monoamine neurons at vesicular membranes. MDMA also
increases quantities of cortisol, prolactin, and oxytocin in serum. A study
that was placebo controlled with 15 human volunteers found 100 mg of
MDMA increased blood levels of oxytocin. The amount of oxytocin increase
correlates with a subjective, prosocial effect of MDMA, which likely motivates
the drug’s recreational use.9,10
Physical And Cognitive Effects Of MDMA Use
The physical effects of MDMA are hard to predict because of adulterants
added in the manufacture of the drug. There are no safety protocols. MDMA
may be synthesized in a subpar lab. It can also be cut with volatile
adulterants that increase health risks.
Serotonin is an important neurotransmitter. It plays a role in regulating
sleep, mood, pain, appetite, and other factors. The release of serotonin
when using MDMA likely causes the elevated mood reported by MDMA users.
15
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comWhen a large amount of serotonin is released, MDMA causes the brain to get
depleted of this neurotransmitter. This contributes to the low or negative
after effects users can experience for days after taking MDMA.
Measuring serotonin damage in humans can be difficult but studies of heavy
MDMA users show that these users can experience confusion, depression,
and problems with working memory and attention process that is long-
lasting. A memory impairment of this type is associated with decreased
serotonin metabolites as well as other markers of serotonin function. Studies
in animals showed that MDMA can damage serotonin-containing neurons.
Some studies even showed that these effects can be long-lasting. Such
damage could also occur in humans, and many clinicians carry the belief that
there is long-lasting damage from MDMA as well as other hallucinogen drug
use.18-21
When imaging studies were conducted on MDMA users, changes in brain
activity were seen. This involved the regions relating to cognition, emotion,
and motor function. Multiple drug use, which is common with Ecstasy, could
contribute additionally to behavioral effects from use. The drugabuse.gov
site cautions that more research is needed in this area to confirm these
findings and to determine exactly what effect MDMA has on the human
brain. One hindrance to these studies involving human subjects is that they
do not consider behavioral measures before users began taking drugs. This
makes it difficult to rule out pre-existing conditions. Other factors that
should be considered when studying humans with cognitive deficits resulting
from MDMA use include gender, dosage, genetic factors, environmental
factors, frequency and intensity of use, use of other drugs, and age at which
use began.22-27
16
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comMDMA users may be young. A young female user could be pregnant when
taking MDMA, and may believe that MDMA is a safe drug or not be aware
that she is pregnant when taking MDMA. There is also great concern of the
effects of MDMA on a developing fetus. Studies done with animals found
adverse effects on tests of memory and learning from exposure to MDMA
during a developmental period similar to the third trimester in humans. The
effects on a fetus from MDMA on animals earlier in development are not
clear. More research is needed to see the effect of MDMA on the
development of the human nervous system.
MDMA’s Addictive Properties
A significant consideration for clinicians during treatment and education of
patients is that MDMA impacts many of the same neurotransmitter systems
in the brain as do other addictive drugs. In fact, an experiment showed that
animals will self-administer MDMA. This is an indicator that the drug has a
dependency potential. The degree of self-administration is less than other
drugs such as cocaine.
Few studies have tried to determine MDMA use and addiction among the
general population. The few studies done show widely varying results. This
could be because of different population samples. It could be because of
different types of measures also. Some MDMA users report continued use of
MDMA while knowing of the physical and psychological harm. They also
report tolerance with diminished response and withdrawal effects such as
depressed feelings, trouble concentrating, loss of appetite, and fatigue.
When considering what is known about preventing MDMA use, it should be
realized that the social context and networks are an important factor. What
could help might be peer led advocacy and drug prevention programs aimed
17
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comat lowering MDMA use among teenagers and young adults. A high school or
college could be a venue for delivering messages about the possible harm
done by using MDMA. Providing accurate information is important through
education aims at prevention of MDMA use and addiction.10-12
MDMA Use: Short-Term Effects
This section discusses the short-term effects of MDMA use including
euphoria, increased energy, distorted perception, nausea, muscle cramps,
involuntary teeth clenching, blurred vision, chills, and sweating. Among the
most serious, short-term risks to physical health when using MDMA are
dehydration and hyperthermia. What can happen is a life-threatening or fatal
hyponatremia. This can develop when a MDMA user tries to prevent
dehydration by consuming a large quantity of water without replenishing
electrolytes.
Some of the immediate adverse effects of MDMA use can include not only
dehydration and hyperthermia but also bruxism (the grinding and clenching
of teeth). Other effects are increased wakefulness, insomnia, increased
perspiration or sweating, increased heart rate and blood pressure, loss of
appetite, nausea and vomiting, diarrhea, erectile dysfunction, visual and
auditory hallucinations, and increased psychomotor activity. Dilation of the
pupil has also been reported. The negative effects can last up to a week
after cessation of moderate MDMA use. These effects can be physiological
and include loss of appetite, insomnia, tiredness, lethargy, and lockjaw. The
effects can also be psychological and include impulsiveness, irritability,
depression, memory impairment, anxiety, paranoia, and restlessness.18-21
While use of MDMA has been linked to reduced feelings of fatigue, increased
psychomotor activity, suppressed appetite, blood pressure increase, impact
on heart rate and body temperature, dilation of the pupils of the eye and
18
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comgrinding of the teeth, rarely are visual or auditory hallucinations
encountered. Complications that are severe include psychotic crises,
hypertensive bleeding, dehydration, and hyperthermia. With high dosages
and when taken with antidepressants such as MAO inhibitors and serotonin
reuptake inhibitors, MDMA users can develop severe serotonin syndrome.
Subjective experiences of those who use MDMA depend on the dose, the
situation, and the mental and physical state of the user.18-21,33
MDMA Use: Long-Term Effects
The long-term effects of MDMA use involves both physical and mental health
concerns. It can cause irritability, impulsiveness, aggression, depression,
sleep problems, anxiety, memory problems, attention problems, decreased
appetite, decreased sexual interest and pleasure, and increased body
temperature. Reports have shown that the long-term effects of MDMA on
human brain structure and function have not yet been fully determined.
Chronic MDMA use results in serotonergic toxicity. This alters the regional
cerebral blood flow that can be studied using functional magnetic resonance
imaging (fMRI).17-19
The effects of chronic MDMA use have been analyzed in various
neurocognitive domains. This includes working memory, episodic memory,
semantic memory, visual stimulation, motor function and impulsivity.
Neuroimaging in MDMA users shows a reduction in brain 5-HT transporter
and 5-HT2A receptor levels. This is shown when using positron emission
tomography (PET) or single photon emission computed tomography (SPECT)
and reduced grey matter density in various brain regions using the voxel
based morphometry method. Using proton magnetic resonance
spectroscopy, chemical neuroimaging and assaying the levels of important
19
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.combiochemical markers and metabolites in the brains of MDMA users revealed
no consistent results.18
Functional magnetic resonance imaging studies have shown task evoked
differences in regional brain activation. This is measured as blood oxygen
level dependent signal intensity and/or spatial extent of activation. This is in
MDMA users and controls.18 Also, neurocognitive studies in MDMA users
revealed memory and learning problems. Serotonergic innervation regulates
cerebral microvasculature, and, as mentioned, chronic MDMA users have
serotonin toxicity. MDMA users are expected to have altered regional blood
flow, detectable in a functional MRI study.
Data from animal studies suggests that MDMA is more toxic to the axons
more distal to the brainstem cell bodies; that is, those present mainly in the
occipital cortex. In addition, PET and SPECT studies in humans show
reductions in serotonin transporter binding, most evident in the occipital
cortex. The hyperthermia induced by MDMA is a pro-oxidant neurotoxic
condition. Hyperthermia is known to accentuate the neurotoxic potential of
MDMA same as with methamphetamine. It should also be noted that
interventions to lower the core body temperature was shown to have a
neuroprotective effect.18-21
With a high, lifetime exposure to MDMA there is consistent evidence that
MDMA users have structural and functional deficits. With moderate lifetime
usage (less than 50 doses used and less than 100 tablets consumed), there
is no such structural or functional changes. At high doses MDMA use can
produce brain lesions, a form of brain damage in the serotonergic neural
pathways of humans and animals. It is not clear if a typical user of MDMA
develops neurotoxic brain lesions. With long-term exposure to MDMA in
20
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comhumans, marked neurodegeneration in hippocampal, striatal, prefrontal, and
occipital serotonergic axon terminals is found. Neurotoxic damage can
persist for more than two years in serotonergic axon terminals.18-21
MDMA-induced Neurotoxicity
MDMA elevation in brain temperature correlates with MDMA induced
neurotoxicity. Low doses of MDMA cause adverse neuroplastic changes to
brain microvasculature and white matter in humans. MDMA users have also
been found to have reduced gray matter density in certain brain
structures.22,23 For long term users, global reductions in gray matter volume,
decreased hippocampal activity, and thinning of the parietal and
orbitofrontal cortices has been found. With recreational use of Ecstasy, there
is a range of moderate to large effects for SERT reduction.24
For regular users of MDMA, impairments in several aspects of cognition
include memory, learning, attention, visual processing, and sleep. The
magnitude of the impairment related to lifetime MDMA use can be reversed
in part with abstinence. With MDMA use there is an association with
increased impulsivity and depression. Serotonin depletion can cause
depression following several days of using MDMA. In certain cases,
symptoms of depression persist longer. There are studies where even after
quitting repeat recreational use of the drug there are increased rates of
anxiety and depression. A major reason to stop using the drug is
depression.23-25
With a high dose of MDMA a neuro-immune response that increases the
permeability of the blood brain barrier through several mechanisms is seen.
This makes the brain more susceptible to environmental pathogens and
toxins. MDMA in the peripheral nervous system has immunosuppressive
effects and in the central nervous system a pro-inflammatory effect.26-28
21
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comWith the serotonin depletion that is part of the post-ecstatic regeneration
phase can come depressive symptoms during the days following
consumption. This can also happen long after abstinence. This is a major
reason to stop use of MDMA.30-33
Axonal degeneration of serotonergic neurons has been found after exposure
to MDMA in primates, detectable up to seven years later. The degree of
neurotoxicity appears related to the maximum dose and duration of use.
There is still controversy about the neurotoxic effect of MDMA in humans
despite scientific evidence for such long-term effects. MDMA users had lower
levels of serotonin and its metabolite in the cerebral spinal fluid. There was
also lower prolactin and cortisol response to the serotonin indicating a lower
sensitivity to serotonergic stimulation. This could be due to damage of the
serotonergic system and decreased cortical concentration of the serotonin
transporter.
In long-term users, a reduced volume of gray matter plus a thinning of the
parietal and orbitofrontal cortex is found. There is also decreased
hippocampal activity. Concerning the human dopamine system, studies
looked at a toxic influence but none was detected so the question is still
controversial.30-33
Neuropsychological effects due to long-term consumption of MDMA in
humans has been studied. Several dimensions were found to be impaired.
The impairments correlated in most cases to the amount and duration of
consumption of MDMA. The impairments have been found to be reversible
but only to an extent. As mentioned, they can persist for years after
abstinence.
22
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comFunctional Decision-making and Substance Use
Functional decision-making refers to how a person functions in everyday life.
It requires a multidimensional approach and analysis. Executive functions
such as impulse control and action planning are part of the analysis. In
addition to decision-making, investigated domains in the studies included
intelligence, depressive mood, and impulsivity plus executive function and
memory skills.24-26,33
The striatum and orbitofrontal cortex are important neural structures known
to be involved in decision-making. These areas also are associated with the
reward system, and play a role in addictive disorders. A lesion, for example,
of the orbitofrontal cortex leads to greater impulsivity. Damage to
serotonergic and dopaminergic neurons that project into the orbitofrontal
cortex due to lesions or chronic drug use impair functional decision-making
behavior. Dysfunctional decision-making and increased impulsivity are
considered predictors and consequences of a substance use disorder.33 The
assumption is that different conceptual aspects of motivation play a role in
decision-making. They are also related to different neural systems. This can
apply generally and specifically to substance related disorders.34
Decision-making Paradigms and Testing
Regarding decision-making, research studies have used multiple paradigms
or approaches to evaluate outcomes.30-35 the Risky Choice Task. In each
trial, the participant may choose between a control and experimental
gamble. In the outcome phase a green up or red down arrow is displayed
with the amount of credit point to tell the participant if they won or lost the
23
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comgamble. This is followed by feedback on how many credit points the
participant gathered overall, indicating level of risk-taking involved. This test
has been useful when evaluating adolescents and risky behavior.
Other studies used the Iowa Gambling Task. This is a computerized measure
of decision-making. The conditions are high versus low risk with rewards and
losses. Another tool is the Bets 16 task that measures risk-taking.
Two studies also applied imaging data and cognitive tests. Magnetic
resonance imaging used a diffusion tensor image (DTI) and provided
structural information about the brain. Functional MRI measured metabolic
activity of various brain areas during decision-making tasks. Allele length
was identified for the promoter of the serotonin transporter gene to identify
potential effects of this genotype on behavior. Results from imaging or
genetic studies provide further information about the relationship of the
results and brain structure and functional alterations or genetic
predisposition. In addition to decision-making, the studies investigated
intelligence, depressive mood, and impulsivity plus executive function and
memory skills.
With MDMA users, the tasks concerning decision-making showed a variety of
results. One group found lower overall results for points or monetary gain
and a tendency for high-risk gambling in the MDMA group. Four studies
showed the MDMA group with a tendency toward riskier gambling option.
Statistically significant differences with the control group were not
concluded. One group had no group specific differences in the decision-
making test. Another group found specific deficits and higher risk tolerance
in the control groups. Overall, the results were inconsistent. This also
applied to factors such as impulsivity.
24
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comMDMA and Decision-making Using Imaging Methods
A major question is how the use of MDMA could influence decision-making in
humans. Clinical trials addressing the influence of MDMA on human decision-
making has reported whether subjects, investigated in a drug free-interval
and compared to one or more control groups, an impact on human
cognition. Such trials have occurred as early as 2016. Cognitive parameters
and additional use of imaging methods have been included in studies looking
at the acute effects of MDMA.30-35
Using imaging, a study found a reduced, longitudinal diffusivity in the
anterior corpus callosum of MDMA users. This correlated with decision-
making related measures such as scores on an impulsiveness scale, risky
gambling, and lower overall gains. The researchers considered this to mean
possible MDMA associated axonal damage.
When performing a decision-making task and undergoing a functional MRI,
the result is increased signaling of the MDMA heavy users in the parietal
cortex. This relates to anticipating rewards. There is a reduced orbitofrontal
signal during reward feedback and outcome. This means an increased
reward expectation and diminished reward sensitivity in MDMA users.
MDMA and Functional Decision-Making
Evaluation of a person’s executive functioning and basic ability to perform
tasks has been a promising approach for studying certain drug and alcohol
addiction and other psychiatric disorders but similar patient evaluations have
not been studied sufficiently with MDMA. What is known is more general.
The serotonergic system is particularly affected by MDMA and plays a role in
25
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comnegative consequences of decision-making; it also plays a role in behavioral
reinforcements such as social rewards.30-35
According to research, alterations in areas of the brain that process
motivation, reward cues, and behavior are possible due to the long-term use
of stimulants such as MDMA. This includes amphetamines and
amphetamine-type stimulants. What also changes are regions of the brain
that affect impulsivity and decision-making in response to these drugs. In
humans and rats, choices involving a greater loss of rewards is associated
with lower serotonergic activity. Subjects with serotonin depletion can prefer
short-term and small rewards compared to long-term high rewards.
With acute consumption of MDMA, researchers observed different effects on
decision-making. Some measured impairments in attention, memory, and
increased impulsivity but no impairment in decision-making. Other
researchers showed increased error rates plus less flexibility in a predictive
decision test.
The potential long-term effects of MDMA on decision-making are important.
This is because dysfunctional choices are a risk factor for initiation and
maintenance of drug use. While the addictive potential of MDMA is small, it
is generally believed that it is a substance that alters human decision-
making and could facilitate development of other addictions.
Decision-Making in Chronic Ecstasy Use
With long-term use of MDMA come different cognitive impairments, as
previously mentioned.30-35 It should be emphasized how important it is to be
aware of how decision-making can potentially become impaired due to
MDMA use, as MDMA use increases impulsivity and altered decision-making
associated with addictive disorders. When assessing the long-term effects of
MDMA, a closer look at the literature on the possible effects of chronic MDMA
26
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comuse on decision-making is helpful, which includes controlled trials that use
specific tasks related to decision-making. The clinical trials involve subjects
that meet specific criteria and this research focuses on findings related to
decision-making disturbances with use of MDMA.
More studies have reported increased risky decisions than those that did not.
Concerning MDMA specific influences on decision-making, studies in general
did show trends of increased impulsivity. In a group of studies, there was
the suggestion of increased impulsivity and dysfunctional decision-making
that was more strongly associated with the general extent of drug use rather
than with the specific use of MDMA. The studies mainly concentrated on the
behavioral and neurocognitive effects of MDMA and polydrug use. It remains
difficult to determine whether observed neurocognitive effects are
specifically attributable to single substances and to what extent distinctive
personality traits and behavioral problems among drug users are predictors
or consequences of drug use.
A minority of studies reported a statistically significant MDMA-specific
alteration of higher order decision-making than those that did not find
MDMA-specific influences. A significant proportion of studies in the literature
reported associations between risky decision-making and impulsivity and the
extent of drug use in general. The current state of research does not
conclude that long-term use of MDMA generally affects decision-making
behavior. While more investigation is needed, risky decision-making has
been observed but needs to be confirmed.
Effects of MDMA on Memory
27
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comThe current state of research regarding MDMA use and neurocognitive
functions as presented in the introduction suggests specific alterations of the
serotonergic system caused by MDMA or Ecstasy use, while the other
transmitter systems seem to be less affected.40-44 Additionally, mild to
moderate impairments of memory functions, attention, and learning as well
as higher levels of impulsivity and depression were found to be associated
with the use of MDMA. As mentioned above, allele length was identified for
the promoter of the serotonin transporter gene to identify potential effects of
this genotype on behavior.
Studies have found that subjects who were homozygous for the low count of
allele-copies had a substantially better performance in a test on working
memory. MDMA users of the genotype underperformed on the test. This
suggests that carriers of specific alleles associated with serotonergic
neurotransmission relative to other alleles are vulnerable to the effects of
Ecstasy on cognitive function.
Study Limitations on MDMA’s Impact on Cognition
Studies on MDMA’s cognitive impact show strengths and weaknesses. A
weakness in all studies is the way participants were recruited. This was
usually through a newspaper ad or direct contact. This could lead to
potential selection bias. Representation from groups was limited in some
studies. One study had gender balance. Another study included only men.
Another used a population with inpatients from a substance use residential
treatment facility. In two studies only students participated. In all the
studies, adults in the age range of 20 to 30 were over represented. This bias
could also reflect the typical age of MDMA users. The highest prevalence of
MDMA consumption is with young adults.40-43
28
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comIt should also be noted that a psychiatric diagnosis either was not included
or did not exclude other addictive disorders than MDMA in the substance use
groups. The disclosure on abstinence and drug use that were submitted by
subjects were verified by a drug test in some but not all studies. Only a
small number of research used hair analysis. The MDMA groups in most
cases showed a higher overall consumption of other drugs than the control
group.
Various difficulties involved in the method and interpretation of studies on
MDMA associated cognitive functioning in humans has been seen. Studies
show that most MDMA users also use other psychotropic substances. This
could be a biasing factor. To control for it some studies use one or more
substance groups with no use of MDMA. It is a challenge to get a clear
distinction between groups. Potential interaction of MDMA with other drugs is
disregarded.
Another issue is that the purity of street Ecstasy and other forms of MDMA
and the use of MDMA among young adults at clubs complicate a clear
understanding of the findings presented. The representative sample can be
called into question.
Compliance from participants is another general challenge. Concerning
identifying substance use and abstinence through user self-disclosure means
information could be distorted by the subject. This could be intentional or
unintentional. This could possibly be minimized by drug screenings. A
combination of urine and blood tests plus hair analysis would be desirable for
validity. This would exclude post-acute influence of substances and when
abstinence is not given.
29
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comCausality is another significant consideration in this field of research. The
question pertains to whether a measured cognitive change follows substance
use or precedes it. This can hardly be clarified by a cross sectional study.
Prospective studies are needed to answer this concern, and have been done
only to a small degree. One study that was large and longitudinal was
conducted on the long-term effects of MDMA in the Netherlands. This study
found a negative effect on verbal memory due to chronic MDMA use. Other
cognitive dimensions stayed the same. Another study showed persistently
slower visual associative learning. This was with chronic MDMA users in two
follow up studies. Another group observed a higher probability of starting
MDMA use among people who previously underperformed in a decision-
making task. One group presented the first randomized and double blinded
placebo-controlled study using pure MDMA in a psychotherapeutic setting
with an interest in the use of MDMA for psychiatric treatment. It has been
reported that the benefits of MDMA facilitated treatment in patients with
post-traumatic stress disorder with no relevant cognitive side effects.40-44
Combining MDMA With Other Substances
Current usage of MDMA includes combining it with caffeine, alcohol and
prescription or illicit drugs. Young adults who use Ecstasy and other drugs
have reported using alcohol and cigarettes/nicotine combined with the drug.
Others have reported marijuana, meth, hallucinogen/LSD, powder cocaine
use along with MDMA. Deaths have involved drug cocktails such as MDMA
and cocaine. Another lethal combination is MDMA with cocaine and Viagra.
Clinicians should be alerted to this trend when diagnosing and treating a
drug user.36-39
MDMA Drug Interactions
30
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comMDMA can also interact with prescription drugs that inhibit certain enzymes
like Norvir. Norvir is an antiviral medication that prevents human
immunodeficiency virus (HIV) from multiplying within the body. Use of
MDMA in high dosages with another serotonergic drug can lead to a life-
threatening condition called serotonin syndrome. Severe overdose can result
in death. This was reported by people who took MDMA with a monoamine
oxidase inhibitor such as Nardil, Parnate, or Manerix. Some people mix
MDMA with ketamine (sold under the brand name Ketalar), which is a
medication used in anesthesia or for chronic pain and sedation.36-39
MDMA and Alcohol
Mixing MDMA with alcohol and other drugs is clearly dangerous. It is
commonly known that mixing MDMA with alcohol will lead to greater strain
on the kidneys. Heavy drinking can lead to dehydration and a worse come
down from the drug. Overheating is more likely in such cases.
Most importantly, clinicians should be aware that alcohol is involved in most
MDMA-related deaths. Mixing MDMA with an amphetamine can prolong the
MDMA state. Too much amphetamine places a great strain on the heart and
kidneys. Mixing can also lead to anxiety and paranoia. Some people also mix
antidepressants with MDMA.
MDMA and Cocaine
Cocaine has already been described as a profound nervous system stimulant
that increases energy, alertness, and produces euphoria. Ecstasy, or MDMA,
mimics the effects of both hallucinogens and stimulants and enhances a
sense of emotional closeness, empathy, increased energy, sensory
perception, and euphoria. Mixing the two can severely worsen these effects.
31
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.comSimultaneous use of cocaine and Ecstasy is common in the party or club
culture, especially among teenagers and young adults. Both drugs are life-
threatening when used alone and the risk is compounded when the two are
used together. Among the most dangerous side effects of cocaine use are
heart attack, sudden death even with use for the first time, cardiac
arrhythmias, erratic behavior, paranoia, tremors, strokes, seizures, and
coma. MDMA in the form of Ecstasy when combined with certain activity
such as dancing can be life-threatening. The adverse effect of MDMA include
sweating, nausea, teeth clenching, high blood pressure, panic attacks,
seizures, loss of consciousness, heart failure, dehydration, and
hyperthermia.36-39
While cocaine is not the drug most commonly used in combination with
MDMA in the form of Ecstasy, one study reports 34 percent of participants
used them together. Another study found that Ecstasy users were more
likely to use cocaine as compared to a marijuana user.
Mortality with Ecstasy and Cocaine Use
A seven-year long study showed that the risk of death is four times greater
in a 19 to 49-year-old who uses cocaine regularly, especially for a male.
Research compared 437 sudden cardiovascular deaths to 126 deaths from
other causes. This study excluded acute intoxication and disease. The
suggestion was that the effect of cocaine on the cardiovascular system can
explain the increase in risk of sudden death. The effects include high blood
pressure and contractility of the left ventricle, increased heart rate, potential
for arrhythmia, diminished coronary artery flow, increased clot formation,
and increased risk of sudden death. MDMA is especially dangerous because
the drug is highly variable and often contaminated. Other substances can
32
ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.cominclude cocaine, amphetamines, caffeine, and phencyclidine or PCP/angel
dust. This increases the risk for adverse effects.36-39
MDMA, Cocaine and Alcohol: A Lethal Combination
A majority of MDMA users (in the form of Ecstasy) combine Ecstasy with
alcohol and or cocaine, a trend that has been studied. Research indicates
that concurrent use of cocaine and MDMA could amplify the long-term side
effects. Further, alcohol in combination with cocaine creates a lethal
combination called cocaethylene in the liver. This is a metabolite that
increases the high risk of heart attack, arrhythmias, strokes, and
cardiomyopathy (enlargement and weakening of the heart). Clinicians need
to educate patients that the use of cocaine and alcohol together makes
patients more prone to violent thoughts and behavior among other
aforementioned impairments in cognitive function that can be significant.36-39
MDMA and Caffeine
Millions of people consume caffeine daily with an intake of 50 to 150 mg.
Fatalities related to caffeine overdose are rare. They are associated with oral
doses between 3 and 20 grams. Consumption of caffeine that is habitual is
typically considered safe. Reviews of toxicity of caffeine and presentations of
excess caffeine and overdose includes agitation, nervousness, anxiety, and
insomnia. Caffeine has been found in as many as twenty percent of Ecstasy
tablets analyzed. Caffeinated energy drinks have gained popularity in night
club and rave environments where Ecstasy is consumed. The use of caffeine
with a recreational psychostimulant drug such as MDMA can result in an
acute adverse reaction. Caffeine also has an impact on the discriminative,
stimulatory, and reinforcing effects of a psychostimulant drug. Caffeine
increases the toxicity of psychostimulants because caffeine is an antagonist
33
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