Ecstasy or MDMA (3,4 methylenedioxymethamphetamine) is an increasingly
popular drug with teenagers and college age adults. It has an unfounded
reputation for being a "safe" drug. However there is mounting evidence
that MDMA posses a risk of great harm and even death. Additionally
there is increasing evidence of a permanent injury to the serotonergic
neurons with potential for long term learning deficits and other sequelae.
This educational offering will review the history of the drug, the clinical
picture it presents and offer recommendations for management of these cases.
3,4 Methylendioxymethamphetamine (MDMA) is commonly known as "Ecstasy" but may be known as XTC, Adam, E, X, Xphoria, the Love drug, The Love Dove, Cloud 9, Disco, Biscuit and Dennis the Menace.
Case
Scenario
On exam the patient is an adolescent male, approximately 5'10" tall, muscular and about 10 pounds overweight. His shirt is sweat soaked. His vital signs are: HR 160 bpm, fast and thready, BP 170/88, respirations 20/min and regular, temperature 103.4O F.. Pupils are 7-8mm, equal and slow to react. Retinas are normal, no bulging disks, and no nystagmus. The patient appears awake but is confused and unable to answer questions. A peripheral IV line is started with D5 0.45% saline. Blood is drawn for blood chemistries and a CBC. When you look for the "friend" who came with the patient to question him about possible drugs or substances that the patient may have ingested, you find the "friend" has left the hospital. When you return, as you prepare the patient for a spinal tap, he begins to have a violent tonic-clonic seizure.
History
of MDMA
In 1985 the Drug Enforcement Agency in the United States placed MDMA on Schedule 1 of controlled substances,citing increasing recreational use and concern over potential neurological damage. (Lawn) In 1986 it was banned from Great Britain as having no accepted medical purpose and a high potential for abuse. At the time there was evidence from rodent studies suggesting damage to and depletion of serotenergic nerves. Additionally there had been a number of reports of fatalities from overdose
Physical
properties of MDMA
3,4 Methylenedioxymethamphetamine (MDMA) is a ring substituted amphetamine
derivative that is structurally related to the hallucinogens and the stimulants.
Pure MDMA is a white crystalline solid. It is chemically stable and does not decompose
in air, light or heat. It is soluble in water. MDMA has a distinct, strong and bitter, taste.
There are at least six possible methods that may be used to produce MDMA. Information on the chemical
process and supplies necessary to manufacture MDMA are widely available, including sources in scientific
journals, text books and Web Sites (http://www.hyperreal.org/~lamont/pharm/faq/FAQ-MDMA-Synth.html)
(Dal Cason). It is not the purpose of this article to instruct people on the manufacture of MDMA.
However, it should be known that it is relatively easy to manufacture and it has been postulated
that people with as little as 2 years of college chemistry may be able to successfully synthesize MDMA.
In fact one reference site claimed to have interviewed two workers at a clandestine drug manufacturing
operation and found they had no previous chemistry experience prior to beginning manufacture. They
claimed to have learned the entire operation from several text books. (http://www.ecstasy.org/books/e4x/e4x.ch.12.html).
There are NO legal producers of MDMA. One of the problems with the clandestine manufacture of MDMA
is poor quality assurance and the risk of contaminants and unwanted derivatives. The risk of such
contaminants is unknown, but may be equal to or worse than MDMA itself.
Additionally there may be intentional substitutions of other drugs by the seller.
Some of the drugs found in tablets that had been sold as "Ecstasy" were MDA (methylenedioxyamphetamine),
MDEA (methylenedioxyehtyleneamphetamine), amphetamine and caffeine, psuedoepphedrine, LSD and GHB. (Milroy)
In fact it has been speculated that MDA is often sold/substituted as MDMA because it is easier to produce.
MDA is easier to make since it is a halfway stage in one method of manufacturing MDMA, and requires fewer
controlled precursors than MDMA.
Structures of Methamphetamine and MDMA
Pharmacokinetics
of MDMA
Absorption
· Well absorbed orally.
· Onset of clinical effect is 15 to 30 minutes.
· Peak serum concentration occurs at 2 hours.
Biotransformation
· 65% of the drug in cleared in the urine as the parent drug. MDMA is metabolized via N-demethylation to MDA. There have been at least four other known metabolites identified, which are cleared as conjugates.
Elimination
· In the abuse setting ("Raves") patients frequently may take a second "booster dose" after about 3 to 4 hours, as some of the hallucinogenic effects beginning to "wear off".
· Elimination half-life is reported to be 3 to 7 hours.
· MDMA itself is taken up into the cell via the serotonin uptake channel and/or
through diffusion across the membrane. Once within the cell MDMA is known to deplete
stores of tryptophan hydroxylase (TPH) via acute oxidative inactivation. The loss
of this enzyme occurs primarily in the cell terminal (as opposed to the cell body
with its greater size and metabolic reserves) (Schmidt) The loss of this enzyme
leaves the cell terminal open to damage from oxidative stress. This is most likely
the reason for serotonergic cell terminal damage seen with MDMA abuse and the most
likely explanation for the long-term seroternergic damage. (Schmidt)
· Pre-treatment with a serotonin reuptake inhibitor, such as paroxetine (Paxil ®),
fluoxetine (Prozac ®) or sertraline (Zoloft ®), blocks the effects of MDMA. (Liechti, Stein,
Schmidt) This is probably a competitive event at the serotonin reuptake transporter
binding site. Additionally, treatment within one hour of MDMA ingestion with a selective
serotonin reuptake inhibitor blocks the loss of tryptophan hydroxylase (TPH), and
potentially reduces the nerve terminal damage. (Schmidt)
· The ability of MDMA to stimulate both the sympathetic and central nervous systems
ultimately results from its structural similarity to the endogenous catecholamines:
epinephrine, norepinephrine, and dopamine. This is the basis for their amphetamine-like
effects. The methylenedioxylation of the catechol ring is responsible for their
hallucinogenic activity. This is based on their potent effects on serotonin release.
· A biphasic effect on serotonergic neurons has been observed with MDMA. Acutely
serotonin levels fall 3 to 6 hours after drug administration, but return to near
normal by 24 hours. Levels then decrease again by 1 week. The acute depletion is
secondary to serotonin secretion from the neurons, while the long-term depletion
occurs because of toxic degeneration of the serotonergic nerve terminals.
· The exact mechanism responsible for the hyperthermia has not been elucidated
but is probably related to the serotenergic control of thermo-regulation in the
hypothalmus. MDMA causes a loss of self thermo-regulation (Malberg, Drafters).
Elevated ambient temperature (room/environment temperature) after MDMA ingestion
has been shown to cause an increase in core body temperature, loss of thermo-regulation
and an increase the damage seen in serotenergic neurons. (Malberg, Drafters) This
is a potentially significant risk factor to those who use MDMA at "rave" parties
where the ambient temperature is elevated from the large active crowds and inadequate
ventilation facilities.
· Acute toxicity from a single ingestion (whether large or small) does NOT appear
to be dose related. (Waldo, Rugenthal, Mueller, Henry, Ramcharan). Serum levels
have been recorded in acute overdoses as high as 7.72 mg/L and 4.3 mg/L with minimal
toxicity (Henry, Regenthal, Barret) These are 20 to 30 times expected serum levels
from recreational use. Conversely, fatalities that have been published with histories
of small ingestions (one of two tablets) and have had serum levels that supported the
history (range 0.1 to 0.4 mg/L) (Henry). Other factors such as environment (ambient
temperature), over exertion with inadequate rehydration and perhaps an indiosycratic
event appear to play an important role in the majority of severe acute cases.
· Long term damage to Serotonergic neurons from MDMA DOES appear to be a
dose-related event. However the therapeutic index (the difference between
a therapeutic dose and a toxic dose) is very narrow.Mechanism
of Action
· The primary mechanism of action of MDMA is a potent release of brain serotonin
as well as inhibition of serotonin reuptake. MDMA does NOT cause release of serotonin
via exocitosis of serotonin containing secretory vesicles. Rather, MDMA uses a
unique mechanism that causes a reverse in the direction of the normal inward bound
serotonin reuptake channel. (Rudnick) So that the high concentrations of serotonin
within the cell flood OUT through the transporter channel. This causes a sudden
increase in serotonin in the synapse and at the same time blocks reuptake. This
causes a rapid and profound acute depletion of serotonin within 3 to 6 hours.
1. A dose of 2.5 and 5 mg/kg produced 44 and 90% depletion of serotonin,
respectively. (Ricuarte) Neither dopamine nor norepinephrine were depleted,
showing MDMA's selective impact on serotonin stores. Structural changes
and axonal damage to serotonin nerve fibers in the cerebral cortex was
demonstrated by pathological examination at 5 mg/kg (Ricaurte).
2. Single doses of MDMA have been shown to produce long-lasting
serotonin depletion (30% of neurons for up to 2 weeks) when administered
orally to monkeys at near usual human doses (5 mg/kg) (usual doses in
humans are 1 to 4 mg/kg) (Ricaurte).
3. MDMA appears to produce damage to and depletion of serotonergic nerve
terminals. Cell body damage of serotonergic neurons in monkeys was shown
by Ricaurte, etal. It is unknown at this time if there is axonal
regeneration from the damaged cell bodies or if the damage is permanent.
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Clinical
effects
The clinical effects of MDMA will be separated into acute effects and
long term effects for purposes of this paper. However, it should be
noted that even casual users of this drug are at potential risk for
significant long-term sequelae.
Acute
Clinical effects
The acute clinical effects appear to generally fall into three separate
"syndromes" 1) "serotonin syndrome " usually associated with hyperthermia
mental status changes and cardiovascular instability; 2) severe hyponatremia
induced cerebral and pulmonary edema and 3) idiosyncratic hepatotoxicity.
There is also a direct "amphetamine-like" effect on the cardiovascular system.
The hyperthermia may be related to the key role serotonin plays in the
hypothalamus in thermo-regulation. (Mueller)
Syndrome #1
. The true number of patients is probably very under reported (Barret, Walubo)
MDMA induced Serotonin Syndrome
. Neurologic effects in this syndrome include mydryasis, confusion agitation,
hallucinations, seizures and coma. (Ramcharan, Mueller, Brown, Walubo, Roberts)
The seizures may increase the risk of hyperthermia, rhabodomyolysis and
acidosis. Respiratory depression may occur.
. A key finding in these cases has been hyperthermia.
Pathological findings in fatalities has shown evidence consistent with heat-stroke
induced multi-organ damage. (Milroy, Henry) Additionally, published reports
of severe cases and fatalities have consistently shown a hyperthermia
associated with multi-organ damage, DIC and/or rhabdomyolysis. (Walubo, Brown, Mueller, Henry, Singarajah, Screaton, Logan, Dar)
The exact mechanism for the progression to severe hyperthermia is unclear.
However, in the presence of MDMA, increased ambient temperature (similar
to a situation like that of the "Rave House") has been shown to increase
core temperature and loss of thermoregulation in rats. (Malberg, Drafters)
Essentially there may be a direct effect of the drug on the thermo-regulatory
system in the hypothalamus that is potentiated by sustained physical activity,
a high ambient temperature and inadequate fluid replacement.
. Cardiovascular effects in this syndrome
include hypotension, transient hypertension tachycardia, SVT, ventricular
arrhythmias and asystole (Brown, Mueller, Walubo, Dar)
. Disseminated intravascular coagulopathy
(DIC) has been reported and is believed secondary to hyperthermia (Walubo, Henry,
Milroy, Logan, Dar)
. Renal failure secondary to rhabdomyolysis. These patients
are frequently acidotic, which increased the risk of renal damage during rhabdomyolysis.
. Metabolic acidosis and hyperkalemia, secondary to hyperthermia
and seizures. The acidosis may increase the risk of ventricular arrhythmia.
Syndrome #2
. Severe Hyponatremia with serum sodium as
low as 101 mmol/L have been reported. (O'Connor, Holmes, Maxwell, Holden)
This may be due to the MDMA-induced increased vasopressin release. (Henry)
A low dose (40 mg) of MDMA increased vasopressin level on an order of
4 to 5 times normal in adult volunteers. (Henry)
Severe hyponatremia induced cerebral and pulmonary edema
. Also reported are decreased Serum Osmolality
as low as 248 mOsmol/kg and hyperkalemia. (Ajaelo, Holden, Mueller, Brown)
. Coma, Cerebral Edema and Seizures. (O'Connor,
Holmes, Ajaelo, Holden, Maxwell) In some cases the cerebral edema has
been severe with herniation and fatal outcomes.
. Respiratory arrest, Pulmonary Edema. (O'Connor, Holmes, Ramcharan)
. It is common for users of MDMA to drink
large amount of water, following instructions in an attempt to avoid dehydration
and hyperthermia. However this large fluid intake puts the patient at risk
for MDMA-induced hyponatremia which results from a pharmacologic effect of the
drug compounded by excessive fluid ingestion.
Syndrome #3
Hepatotoxicity and Liver failure
. Elevated Liver Transaminases and Fulminant
Hepatic Failure has been reported in a number of cases (Andreu, Ellis, Dykhuizen, Brauer, O'Conner, Brown, Milroy, Henry)
. This appears to be an idiosyncratic event.
A number of cases of fulminant hepatic failure and of acute hepatitis have
been described after a single dose (Henry, Ellis, Dykhuizen,, O'Connor)
However in other cases hepatotoxicity occurred after chronic abuse. (Andreu)
. The onset of hepatic injury is delayed
in most cases by 2 to 3 days after the ingestion of MDMA ("ecstasy").
However in some cases it was up to 15 days (Andreu)
. The mechanism for injury has not been clearly
elucidated but several possible explanations have been offered. 1) It may
be an idiosyncratic event (in several cases eosinophils in the portal track
have been documented, but fever and erythmatous rash were not seen), 2)
In some cases the hepatic damage may be due to ischemic shock secondary
to heat stroke (as a number of the patients presented with MDMA-induced
hyperthermia and shock) 3) it may be related to contaminants of the drugs
ingested (quality control in the clandestine manufacture of MDMA is non-existent).
However Andreu, et al argue for a direct toxic injury as opposed to an
anoxic injury based on their findings.
Scenario #4
Massive Overdose without Hyperthermia
Two cases of massive ingestion with documented elevated serum MDMA levels have been reported.
Both experienced minimal toxicity, including somnolence, confusion, hallucinations and tachycardia. (Regenthal, Barret) In the absence of malignant hyperthermia or hyponatermia these cases may present similar to a moderate amphetamine overdose.
Long
Term effects of MDMA
There is growing evidence of a permanent neurologic injury related to
MDMA use. The long-term effects of MDMA are related to damage to/depletion
of the serotonergic nerve terminals themselves. To date the deficits appear
to be related to memory function.
· Impaired memory function has been found in MDMA users (Klugman, Krystal Morgan Parrot, Bolla, McCann) The impairment noted has been in: immediate and delayed word recall, delayed visual recall, recognition memory for faces, learning a repeatedly administered word list and a sequence of digits. Tests on executive function (frontal lobe), measured by verbal fluency and verbal and non-verbal working memory, were not impaired. (Klugman) These results do NOT represent a global impairment of cognitive function. Instead they suggest a discrete deficit in verbal and non-verbal memory and learning, while other cognitive functions remain intact. These deficits may be long lasting or permanent as a number of the studies used subjects who had been abstinent from MDMA use for weeks to months prior to testing.
· Persistent psychiatric symptoms have been associated with MDMA use. (McGuire) These include psychosis, panic attacks, depersonalization, depression, flashbacks and obsessive-compulsive symptoms. However it is difficult to determine whether MDMA use is directly responsible for these events or triggers symptoms in subjects predisposed to mental illness or is incidental.
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Management
of MDMA exposures
Prompt attention to airway, breathing and circulation is the primary initial concern.
Decontamination:
Except in the case of a recent large ingestion GI decontamination may NOT have a role.
· Most cases of serotonin syndrome, hyponatremia and hepatotoxicity involve ingestion of small amounts of MDMA hours before presentation. It is unlikely that GI decontamination (lavage, activated charcoal, etc) would provide any benefit to the patient and generally is not recommended.
· In the case of a recent large ingestion a single dose of activated charcoal is recommended - 1 gm/kg in small children, 50 to 100 gm in adolescents and adults.
Specific management
Hyperthermia
· aggressive external cooling
· Dantroline - 1 mg/kg by rapid IV injection. If symptoms persist or reappear, the dose may be repeated, to a cumulative dose of 10 mg/kg.
· Benzodiazepines may be useful. Diazepam: Adult: 5 to 10 mg IV every 5 to 10 minutes as needed, Child: 0.25 mg/kg IV every 5 to 10 minutes.
· Non-depolarizing paralytics may be used in severe cases.
Seizures
· Attempt initial control with a benzodiazepine (diazepam or lorazepam).
If seizures persist or recur administer phenobarbital followed by phenytoin
or fosphenytoin if necessary
· If seizures are refractory to the above measures, consider continuous
infusions of midazolam (loading dose 0.2 mg/kg slow bolus followed by an
infusion of 75 to 10 mcg/kg/min) or Propofol (initial dose 1 to 2 mg/kg,
maintenance dose 2 to 10 mg/kg/hr)
Hypotension
· Administer 10 to 20 ml/kg 0.9% saline bolus
and place patient in Trendelenburg position.
· Control hyperthermia.
· Pressor agents with dopaminergic effects
may theoretically worsen serotonin syndrome and should be used with
caution. - If necesarry may use norepinephrine and/or dopamine.
Metabolic acidosis
· Metabolic acidosis in MDMA cases is most
likely secondary to hyperthermia and/or seizures. Initial therapy should
be addressed at the cause. Acidosis may increase the chance of ventricular
arrhythmias. Acidosis may increase the risk of renal failure in the
presence of rhabdomyolysis.
· Sodium bicarbonate therapy at 1-2 mEq/kg
IV and address the cause of the acidosis
Hyponatermia
· hyponatremia will generally correct with
administration of 0.9% NaCl. If severe or life threatening hyponatremia
develops, slow correction with 3% NaCl may be considered.
Ventricular arrhythmias
· Lidocaine - ADULT: 1 to 1.5 mg/kg IV push;
followed by a maintenance infusion of 1 to 4 mg per minute; CHILD: 1 mg/kg
initial bolus IV; followed by a continuous infusion of 20 to 50 mcg/kg/min.
Rhabdomyolysis
· Initial treatment should be directed towards
controlling acute metabolic disturbances such as hyperthermia, hyperkalemia,
and hypovolemia. Control seizures, agitation, and muscle contractions.
· Early aggressive fluid replacement, with
0.9% saline as necessary, is the mainstay of therapy and may help prevent
renal insufficiency. Strive to maintain a urine output of at least 2 to 3
ml/kg/hr. In severe cases 500 milliliters of fluid per hour may be required
for the first several days.
· Diuretics such as mannitol or furosemide
may be needed to maintain urine output.
Elevated liver enzymes
· Remove drug and supportive care.
Serotonin antagonists (blockers)
There are conflicting results from case reports and animal studies as
to the value of using specific serotonin antagonists. (Martin, Mason)
However the serotonin antagonists chlorpromazine and cyproheptadine
appear to have been effective in mild to moderate cases of serotonin syndrome.
· Cyproheptadine (Controlled human trial documenting its efficacy are lacking.)
· ADULT - 4 to 8 mg orally repeated every 1 to 4 hours until therapeutic response is observed or maximum of 32 mg administered.
· CHILD - 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day
· Chlorpromazine (Controlled human trial documenting its efficacy are lacking.)
· ADULT - 25 to 100 mg IM repeated in one hour if necessary.
· CHILD - 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
Selective Serotonin Reuptake inhibitors (SSRIs)
While there is evidence that PRE-treatment with SSRIs will prevent the
clinical effects of MDMA, there is no evidence that treatment post exposure
will provide any benefit. In one animal study SSRIs lost their protective
effect at 3 hours post ingestion of MDMA. (Schmidt) At this time it does
NOT appear that SSRIs will have any role in treatment of severe MDMA exposures.
There is a chance that SSRIs could worsen a serotonin syndrome from MDMA once
it has already appeared.
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AUTHOR
INFORMATION
Written by: Henry A. Spiller, M.S. D.ABAT 11/2000
revised by : Henry A. Spiller M.S., D.ABAT 10/2004
Reviewed by: George m. Bosse, M.D. 10/2004