MDMA reaches maximal concentrations in
the blood between 1.5 and 3 hours after
ingestion. It is then slowly metabolized
and excreted, with levels decreasing to
half their peak concentration over
approximately 8 hrs. Metabolites of MDMA
that have been identified in humans
include 3,4-methylenedioxyamphetamine (MDA),
4-hydroxy-3-methoxy-methamphetamine (HMMA),
4-hydroxy-3-methoxyamphetamine (HMA),
3,4-dihydroxyamphetamine (DHA, also
called alpha-methyldopamine),
3,4-methylenedioxyphenylacetone (MDP2P),
and
N-hydroxy-3,4-methylenedioxyamphetamine
(MDOH). The contributions of these
metabolites to the psychoactive and
toxic effects of MDMA are an area of
active research.
MDMA is known to be metabolized via
three pathways. One such pathway
proceeds via N-demethylation; byproducts
of which include several active
metabolites, including MDA. The
metabolism may be primarily by the
cytochrome P450 enzymes CYP2D6 (in
humans, but CYP2D1 in mice), and CYP3A4.
Complex, nonlinear pharmacokinetics
arise via autoinhibition of CYP2D6 and
CYP2D8, resulting in zeroth order
kinetics at higher doses. It is thought
that this can result in sustained and
higher drug concentrations if the user
takes consecutive doses of the drug. 65%
of MDMA is excreted unchanged in the
urine (additionally 7% is metabolised
into MDA) during 24 hours after usage.
MDMA is a chiral compound and has been
almost exclusively administered as a
racemate. However, an early uncontrolled
report suggests that the S-enantiomer is
significantly more potent in humans than
the R-enantiomer (Anderson et al. 1978).
Studies in humans indicate that the
disposition of MDMA is stereoselective,
with the S-enantiomer having a shorter
elimination half-life and greater
excretion than the R-enantiomer. For
example, Fallon et al. (1999) reported
that the area under the plasma
concentration versus time curve (AUC)
was two to four times higher for the R-enantiomer
than the S-enantiomer after a 40 mg oral
dose in human volunteers. Similarly, the
plasma half-life of (R)-MDMA was
significantly longer than that of the S-enantiomer
((5.8 ± 2.2 hours) vs 3.6 ± 0.9 hours).
However, because MDMA has dose dependent
kinetics, it is likely that these half
lives would be higher at more typical
doses (100 mg is sometimes considered a
typical dose). Given as the racemate,
MDMA has a half-life of around 8 hours.
[edit] Short-term neurochemical effects
Serotonin is a neurotransmitter believed
to play a role in the regulation of mood
and pleasure. MDMA causes serotonin
vesicles in the neurons to release
quantities of serotonin into the
synapses. Although popular press
accounts focus on the role of serotonin
release, the mechanism by which MDMA
causes its unusual psychoactivity is
largely unknown. In vitro and nonhuman
animal studies have established that
MDMA also induces dopamine,
norepinephrine, and acetylcholine
release and can act directly on a number
of receptors, including a2-adrenergic
(adrenaline) and 5HT2A(serotonin)
receptors. MDMA promotes the release of
several hormones including prolactin and
the antidiuretic hormone vasopressin,
which may be important in its occasional
production of water intoxication or
hyponatremia.
Subjective effects
Effects desired by users include:
increased positive emotion and decreased
negative emotion
increased sense of well-being
increased sociability and feelings of
closeness or connection with other
people
reduced defensiveness and fear of
emotional injury
a sense of increased insightfulness and
introspective ability
MDMA, particularly with larger doses, is
sometimes reported to cause visual
distortions. In a review of studies in
which 1.5 to 1.7 mg/kg oral MDMA was
administered in their laboratory to 74
people, Vollenweider et al. reported
that scenic hallucinations were reported
only once, while simple patterns,
distorted objects, and flashes of light
were commonly reported.
Other short-term effects
Acute physiological effects include:
Pupil dilation with attendant
photosensitivity and color perception
Impaired vision
Nystagmus, rapid involuntary rhythmic
eye movement, with the eyes moving
quickly in one direction (quick phase),
and then slowly in the other (slow
phase).
General restlessness
Loss of appetite
Increased heart rate and blood pressure
Loss of sleep/ inability to sleep
Dehydration
Depression after the effects have worn
off, the depression can last anywhere
from a few hours to several weeks.
Trisma (jaw-clenching) and bruxia
(grinding of the teeth)
Stimulated senses. (hear, touch, smell,
etc)
Acute toxic/dangerous effects
MDMA has been involved in some death
cases, and very rarely with only MDMA
involved in the case. Figures in the
United States show that fewer than 10
people per year die with just MDMA in
their system, and fewer than 100 per
year dying with both MDMA and other
drugs present. This is compared with CDC
reports that show over 440,000 US deaths
from tobacco annually and over 81,000
per year due to alcohol. They report
over 1,000 infant deaths per year
resulting from tobacco use in mothers,
and over 3,000 deaths per year from
second hand smoke to non-smokers. In
fact, more people die each year in
America from common food allergies (e.g.
shellfish or peanuts) than from MDMA.
However, this does not mean that
irresponsible abuses of MDMA will not
have dangerous or even lethal effects.
Care should be taken not to overheat
(the biggest acute threat from MDMA) or
to drink too little water or else
excessively large amounts of water. It
may be beneficial to eat sweets while
under the effects of the drug (MDMA,
like most amphetamines, severely
depletes the body's glycogen reserves,
which can induce hypoglycemic seizures).
Apart from the dangers from impurities,
the primary acute risks of taking MDMA
resemble those of other stimulant
amphetamines. The majority of fatalities
and cases requiring emergency care
involve hyperthermic syndromes. MDMA
appears to decrease heat loss in the
body by causing constriction of blood
vessels near the skin. In addition, it
may sometimes increase heat production
by muscles and the brain. These effects
may be amplified in people who become
dehydrated and are therefore unable to
cool by sweating. On top of this, MDMA
can mask the body's normal thirst and
exhaustion responses, particularly if a
user is dancing or is otherwise
physically active for long periods of
time without hydration. Because of these
effects, MDMA can temporarily reduce the
body's ability to regulate its core
temperature, and in high-temperature
surroundings (e.g. clubs) combined with
physical exertion this may lead to
hyperpyrexia if precautions are not
taken to remain cool. Sustained
hyperpyrexia may lead to rhabdomyolysis
(skeletal muscle breakdown), which in
turn can cause renal failure and death.
It has been argued that "the seriousness
of the effects can be dependent on
environmental factors other than the
drug concentration", as blood
concentrations of the drug spanned a
large range in cases of death in MDMA
users. This notwithstanding, "most of
the cases of serious toxicity or
fatality have involved blood levels...
up to 40 times higher than the usual
recreational range." (Kalant H., 2001)
While dehydration is undesirable, there
also have been a number of users
suffering from water intoxication and
associated hyponatremia (dilution of the
blood that can cause swelling of the
brain). Although many cases of this
clearly involved individuals drinking
large amounts of water, there are cases
where there is no evidence of excessive
water consumption. Their cases may be
caused by MDMA inducing release of the
antiduretic hormone vasopressin by the
pituitary gland. This causes one to
retain water to a greater extent. The
death of British teen Leah Betts may be
the most widely publicised MDMA-related
fatality, and resulted from her
consuming too much water due to concerns
over dehydration. Signs of hyponatremia
include confusion, nausea, headache, and
loss of consciousness. Hyponatremia in
MDMA users is a medical emergency and
requires prompt treatment. In general,
females are at greater risk of
developing symptoms and dying from
hyponatremia than males.
MDMA users have also been recorded to
demonstrate bruxism (teeth grinding) and
trisma (jaw clenching) as a short-term
effect from the drug . Many users of
MDMA alleviate this by using chewing
gum, however this can result in
temporary mouth ulcers through
inadvertent biting of the mouth lining.
Temporary jaw ache often results from
jaw clenching or excessive chewing. Some
users consume supplemental magnesium
tablets to relax the jaw muscles and
relieve clenching.
While users sometimes report increased
sexual desire, there are many reports of
difficulty achieving orgasm and erection
while on the drug. "[MDMA] is a love
drug but not a sex drug for most
people." (Beck & Rosenbaum, 1994). This
is the rationale behind the use of
sextasy (combining MDMA with Viagra).
There are reported allergic reactions,
which are extremely rare. Liver damage,
which may have an immunological cause,
has been seen in a small number of
users. Animal studies suggest risk and
extent of liver damage is increased by
high body temperature.
A UK parliamentary committee
commissioned report found the use of
"Ecstasy" to be less dangerous than
tobacco and alcohol in social harms,
physical harm and addiction.
While most MDMA is taken orally, some
users resort to drug injection to
achieve a faster, more intense effect.
This entails the risks associated with
injection of many illicit drugs,
including the transmission of
blood-borne viruses, bacterial
infections, vein damage, and increased
chance of overdose. |
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