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From: an13187@anon.penet.fi (H-Man)
Subject:  MDMA article #1
Message-ID: <1993Jul3.005303.4695@fuug.fi>
Date: Wed, 30 Jun 1993 02:03:49 GMT

[some bs deleted - cak]

                          JAMA(R) 1987; 257: 1615-1617
 
                                 March 27, 1987
 
SECTION: ORIGINAL CONTRIBUTIONS
 
LENGTH: 2656 words
 
TITLE: 'Eve' and ' Ecstasy' ;
A Report of Five Deaths Associated With the Use of MDEA and  MDMA
 
AUTHOR: Graeme P. Dowling, MD; Edward T. McDonough III, MD; Robert O. Bost, PhD
 
ABSTRACT: 3,4-Methylenedioxymethamphetamine ( MDMA, "Ecstasy" ), a synthetic
analogue of 3,4-methylenedioxyamphetamine, has been the center of recent debate
over its potential for abuse vs its use as a psychotherapeutic agent.
Following its emergency classification in Schedule 1 by the Drug Enforcement
Administration in 1985, 3,4-methylenedioxyethamphetamine (MDEA, "Eve") has
appeared as  MDMA's  legal replacement.   MDMA  is thought to be safe by
recreational users and by psychotherapists who support its use.  The details of
five deaths associated with the use of  MDMA  and MDEA are reported.  In three
patients,  MDMA  or MDEA may have contributed to death by the induction of
arrhythmias in individuals with underlying natural disease.  In another
patient, use of MDMA preceded an episode of bizarre and risky behavior that
resulted in accidental death.  In another patient, MDMA was thought to be
the immediate cause of death.  Death as a consequence of the use of these
drugs appears to be rare, but it does occur; this outcome may be more common
in individuals with underlying cardiac disease.
 
TEXT:
    MDMA (3,4-methylenedioxymethamphetamine, " Ecstasy" ), a synthetic
analogue of 3,4-methylenedioxyamphetamine (MDA), was first developed as an
appetite suppressant in 1914 but was never marketed.  In the early 1970s, a
small number of psychiatrists began using it as an adjunct to psychotherapy,
noting that it appeared to facilitate therapeutic communication, increase
patient self-esteem, and limit the use of other drugs (G. Greer, MD,
unpublished data, 1983; Greer and Strassman [n1]; and Shafer [n2]). 
 
   Since 1983,  MDMA  has become a popular recreational drug, especially among
college students.  It is also known as "XTC," "Adam," and "MDM" and is sold as
gelatin capsules or loose powder for $10 to $40 per 100-mg dose (Newsweek,
April 15, 1985, p 96).  Users report that the drug is a pleasant way to get
in touch with oneself and that it does not produce hallucinations (Newsweek,
April 15, 1985, p 96; Life, August 1985, pp 88-94; and Baum [n3]). 
 
   Until July 1, 1985,  MDMA  was not a controlled substance and was legally
available for use.  At that time, the Drug Enforcement Administration placed
MDMA  in Schedule 1 on an emergency basis, as a drug with high potential for
abuse and without accepted medical use.  It was claimed that the abuse
potential of MDMA was proved by its widespread use.  In addition, because of
the structural similarity to MDA, which had been shown to selectively damage 
serotonin nerve terminals in rat brains, [n4] dangerous side effects were felt
to be possible.

   It was only later that Drug Enforcement Administration officials learned of
the therapeutic use of MDMA in psychiatry.  While MDMA is still available on
the illicit drug market, a related drug, 3,4-methylenedioxyethamphetamine
(MDEA, "Eve"), has appeared as a non-scheduled substitute for MDMA, with
milder but similar effects.
 
    MDMA  is reported to be safe by psychotherapists and users (Newsweek, April
15, 1985, p 96; Baum [n3]; and Gehlert et al [n5]), but the medical literature
contains few articles on  MDMA  or MDEA, and no controlled trials to document
and investigate their clinical effects have been completed. [n2] One death
related to the use of  MDMA  has been reported in the popular media (Life,
August 1985, pp 88-94).  This article describes five patients, seen over a
period of nine months (June 1985 to March 1986) in Dallas County, in which
MDMA  or MDEA were thought to have caused or contributed to death.
 
METHODS
 
   All cases were examined by the Chief Medical Examiner's Office of Dallas
County.  Body fluid and tissue samples were screened for the presence of
alkaline drugs, including MDMA and MDEA, by the method of Foerster et al.
[n6] Gas chromatography was used with fused methylsilicone and fused 5%
phenylmethylsilicone columns connected to flame ionization detectors.
Identification was based on retention times on the two columns and confirmation
was by gas chromatography-mass spectrometry.   MDMA  or MDEA levels were
quantitated by gas chromatographic comparison with known standards of these
drugs.  Body fluids were also screened for the presence of acid and neutral
drugs, narcotics, and alcohol.
 
REPORT OF CASES
 
   CASE 1. -- The body of a 22-year-old man was found at the base of an
electrical utility tower.  He was reportedly last seen alive the previous
evening when he ingested an unknown quantity of  MDMA.   Examination at the
scene suggests that he drove his automobile to the utility tower and climbed it
to a height of 13 m.  At 1:23 AM, he came too close to one of the 138 000-V
power lines, was electrocuted, and fell to the ground.
 
   At autopsy, widespread burning of the clothing and the skin of the face,
thorax, abdomen, and both arms was noted, consistent with his having received a
high-voltage electrical shock.  Other injuries, presumably sustained in the
fall, included a complete atlantooccipital dislocation, rib fractures,
pulmonary contusions, and lacerations of the liver.
 
   Postmortem toxicology showed  MDMA  in the blood, but unfortunately, the
amount could not be quantitated.  No alcohol or other drugs were present.
 
   CASE 2. -- A 25-year-old man was seen by his family physician complaining of
pleuritic chest pain on inspiration.  Physical examination results and chest
roentgenogram were unremarkable, and a follow-up appointment was arranged for
the next day.  While he was driving home, his truck jumped a curb and struck a
telephone pole.  His only apparent injury was a small laceration of the
forehead, but he required cardiopulmonary resuscitation at the scene and en
route to the hospital.  He was pronounced dead one-half hour after the
accident.

   At autopsy, the only injury was a 4-cm laceration on the right side of the
forehead.  The proximal left anterior descending and left circumflex coronary
arteries were narrowed to less than 75% of their original area by
atherosclerotic plaques, and the lumen of the right coronary artery was
narrowed to a pinpoint 5 cm from its origin.  The heart was not enlarged
(280 g), and there was no evidence of recent or old myocardial infarction.
The other organs were unremarkable.
 
   Although the cause of death was listed as atherosclerotic cardiovascular
disease, postmortem toxicology revealed 0.95 mg/L (4.6 mu mol/L) of MDEA and
0.8 mg/L (3.6 mu mol/L) of butalbital in the blood.  No alcohol was detected.
 
   CASE 3. -- A 32-year-old man with a history of asthma was found dead beside
his car.  A 0.5% epinephrine inhaler was in his hand.  He had been drinking
alcohol with friends until two hours prior to the discovery of his body.
 
   Postmortem examination showed gross and histologic features of acute and
chronic bronchial asthma, including hyperinflation of the lungs, mucus
plugging, peribronchial muscular hyperplasia, submucosal eosinophilic
infiltrates, and thickening of bronchial basement membranes.  The remaining
organs were congested but were otherwise unremarkable.
 
   The cause of death was attributed to asthma; however, postmortem toxicology
showed 1.1 mg/L (5.7 mu mol/L) of  MDMA  in the blood.  No alcohol or
theophylline were detected.
 
   CASE 4. -- A healthy 18-year-old woman ingested 1 1/2 "hits" of  Ecstasy
(approximately 150 mg) and an unknown amount of alcohol within a 60- to
90-minute period.  Shortly thereafter, she collapsed, and on arrival of the
paramedics, she was found to be in ventricular fibrillation.  She was
pronounced dead after resuscitation attempts were unsuccessful.
 
   Autopsy findings included pulmonary congestion and edema, associated with
congestion of other viscera.  Postmortem toxicology revealed 1.0 mg/L (5.2 mu
mol/L) of  MDMA  and 40 mg/dL (8.7 mmol/L) of ethanol in the blood.
 
   CASE 5. -- A 21-year-old man was found unconscious after ingesting three
Ecstasy capsules (approximately 300 mg), one propoxyphene capsule (65 mg),
and several drinks over a period of ten to 11 hours.  Attempts at
resuscitation were unsuccessful. 
 
   Significant autopsy findings were confined to the heart, which was enlarged
(420 g) due to concentric left ventricular hypertrophy and slight dilatation.
The coronary arteries contained scattered, nonocclusive, atheromatous plaques,
and the valves were unremarkable.  Histologically, some myocytes showed
enlarged, hyperchromatic nuclei, but there was no evidence of the bizarre cells
found in hypertrophic cardiomyopathy.
 
   Given the absence of coronary atherosclerosis and valvular abnormalities and
the lack of history of hypertension, the cause of death was attributed to
idiopathic cardiomyopathy.  Postmortem toxicology showed the following drug
levels in the blood: MDEA, 2.0 mg/L (9.7 mu mol/L); propoxyphene, 0.26 mg/L
(0.8 mu mol/L); and norpropoxyphene, 1.0 mg/L (3.1 mu mol/L).  MDEA levels
in other body fluids and tissues are shown in the Table.  No MDMA (the drug
the decedent thought he was taking) or alcohol was present.
 
Clinical, Autopsy, and Toxicology Findings in Five Deaths Associated With  MDMA
and MDEA Use
 
   [SEE ORIGINAL SOURCE]
 
COMMENT
 
    MDMA and MDEA are structurally related to MDA, as shown in the Figure.
All three drugs share structural similarities to methamphetamine, which has
sympathomimetic properties, and to mescaline, a hallucinogen.  MDA was a
popular drug of abuse during the 1960s, and although several deaths related
to MDA overdose were reported, [n7-n11] these appeared to be rare occurrences.
 
    MDMA  and MDEA apparently cause euphoria and enhanced sociability as MDA
does, [n7] but they are not thought to be hallucinogenic. [n3] Both have a
rapid onset of action of approximately one-half hour. [n12] MDMA users
describe three phases of action: an initial period of disorientation,
followed by a rush during which the user experiences tingling and may
exhibit spasmodic jerking motions, and finally a period of "happy
sociability" (Life, August 1985, pp 88-94).  Generally, MDMA's effects wear
off in four to six hours [n1]; however, confusion, depression, and anxiety
have been reported by some users for several weeks after a single dose. [n2]
 
   To date, there have been no reports of  MDMA - or MDEA-related deaths in the
medical literature, but one death has been described in the popular press
(Life, August 1985, pp 88-94).  The five cases reported herein and
associated with MDMA and MDEA use were seen in Dallas and surrounding
counties within a period of nine months (June 1985 to March 1986).  In four
patients, MDMA or MDEA appears to have played only a contributory role in
causing death, while in the fifth,  MDMA  was the immediate cause of death.
 
   Although MDMA has not been described as causing bizarre behavior
(Newsweek, April 15, 1985, p 96; Life, August 1985, pp 88-94; Shafer [n2];
and Baum [n3]), case 1 illustrates that such behavior is possible.  Although
it is not possible to rule out suicidal intent, information available from
relatives and friends indicates that this individual's behavior was
motivated solely by his use of MDMA.
 
   The role of  MDMA  and MDEA in patients 2 and 5 is more difficult to
delineate, particulary in the presence of low concentrations of other drugs
(butalbital in patient 2, propoxyphene in patient 5).  Both individuals
suffered from underlying cardiac diseases, which could have been responsible
for death without MDMA or MDEA use.  However, MDMA is known to have
sympathomimetic actions, including mydriasis and hyperhidrosis (Life, August
1985, pp 88-94; Greer and Strassman [n1]; Shafer [n2]; and Riedlinger
[n13]).  Although their cardiovascular effects are unknown, MDMA and MDEA
may well have actions similar to their parent amphetamines, including
increased cardiac output, hypertension, and induction of arrhythmias. [n14]
Arrhythmias are a recognized mechanism in amphetamine-related deaths, [n15]
and are thought to be the mechanism of death in both patients 2 and 5. 
 
   These two cases are not unlike an  MDMA -related death, reported in the
popular press (Life, August 1985, pp 88-94), wherein an individual with known
cardiac disease died suddenly, shortly after taking a large dose of  MDMA.
Therefore, it is possible that these drugs can induce or augment potentially
fatal arrhythmias in those individuals with predisposing cardiac diseases.
Clearly, this is an area that needs further study.
 
   In patient 3, MDEA use was associated with the sudden death of an individual
who had asthma.  The absence of theophylline in postmortem blood samples and
his use of an over-the-counter epinephrine inhaler indicate that the
individual was not likely receiving adequate medical therapy.  Inadequate
treatment is a major finding reported in those dying suddenly of asthma,
[n16] so it is possible that this individual would have suffered his fatal
attack even if he had not taken MDEA.  Amphetamines, in general, relax
bronchial smooth muscle, which would tend to argue against MDEA's playing a
contributory role in initiating the acute attack. [n14] However, based on
the previous discussion, one cannot rule out the possibility that MDEA
potentiated a cardiac arrhythmia in this individual whose cardiopulmonary
function was already impaired as a result of asphyxia induced by his asthma
attack. 
 
   Use of  MDMA  was thought to be the immediate cause of death in patient 4.
This 18-year-old woman was healthy prior to her death.  Autopsy revealed that
she had no underlying natural disease that would predispose her to sudden
death. If the witnesses to the event are reliable, she did not taken an
extraordinarily large amount of MDMA (approximately 150 mg).  The mechanism
of death was clearly a cardiac arrhythmia, as she was determined to be in
ventricular fibrillation on the arrival of paramedics.  The low dose of MDMA
ingested resulting in sudden death may be an example of an idiosyncratic
reaction, or may suggest that the toxic-to-therapeutic ratio of  MDMA  is low.
 
   To our knowledge, levels of  MDMA  and MDEA in human blood and tissues have
not previously been reported, so it is difficult to interpret the significance
of the drug concentrations found.  It is interesting to note that the blood
MDMA  level of 1.0 mg/L (5.2 mu mol/L) in patient 4, where the cause of death
was attributed to  MDMA  intoxication, is slightly lower than that in patient 3
of 1.1 mg/L (5.7 mu mol/L), where an anatomic cause of death (ie, asthma) was
found.  At the present time, it is not known whether these represent unusually
high or just "therapeutic" levels of MDMA.  The tissue distribution of MDEA
in patient 5 shows the highest concentrations of this drug in liver and
lung. Amphetamines are metabolized in the liver and are also excreted in the
urine in varying proportions, depending on urine pH. [n14] Metabolism of
MDEA in the liver may account for the relatively high levels found in this
organ; however, the significance of the high lung and lower kidney
concentrations is unknown. 
 
   Unfortunately, these five cases do little to resolve the present controversy
as to the abuse potential and dangers of  MDMA  and MDEA vs the possible
therapeutic usefulness of  MDMA  in psychotherapy.  Deaths directly and
indirectly related to the use of  MDMA  and MDEA do occur; however, they appear
to be rare at this time.  Their rarity is confirmed by the recently published
statistics of the Drug Abuse Warning Network for 1985.  Neither  MDMA  nor MDEA
was included in the list of drugs found most frequently by 73 medical examiner
facilities across the United States (drugs reported less than ten times were
excluded from this list). [n17] It would appear that preexisting cardiac
disease may be one factor that predisposes individuals to sudden death while
using these drugs.  It is hoped that the reporting of these cases will
inaugurate a search for more objective information about MDMA and MDEA.
 
SUPPLEMENTARY INFORMATION: From the Department of Pathology, University of
Texas Health Science Center, Dallas, and the Southwestern Institute of
Forensic Sciences, Dallas.  Dr Dowling is now with the Departments of
Pathology at the Universities of Calgary and Alberta, and is the Assistant
Deputy Chief Medical Examiner in Alberta.  Dr McDonough is now the Associate
Medical Examiner in Connecticut. 
 
   Reprints not available.
 
   The authors are grateful to the Office of the Chief Medical Examiner of
Dallas County for granting permission to publish these cases.  We also wish to
thank the toxicology technologists of the Institute of Forensic Sciences for
their technical assistance, Elizabeth Todd, PhD, Thomas Kurt, MD, and Graham
Jones, PhD, for their helpful suggestions, and Sylvia Plehwe for typing the
manuscript.
 
   Standards for  MDMA  and MDEA levels were provided by the Drug Enforcement
Administration South Central Regional Laboratory, Dallas.
 
REFERENCES:
[n1.] Greer G, Strassman RJ: Information on " Ecstasy. " Am J Psychiatry
1985;142:1391.
 
[n2.] Shafer J:  MDMA:  Psychedelic drug faces regulation.  Psychol Today
1985;19(5):68-69.
 
[n3.] Baum RM: New variety of street drugs poses growing problem.  Chem Eng
News 1985;63(36):7-16.
 
[n4.] Ricaurte G, Bryan G, Strauss L, et al: Hallucinogenic amphetamine
selectively destroys brain serotonin nerve terminals.  Science
1985;229:986-988. 
 
[n5.] Gehlert DR, Schmidt CJ, Wu L, et al: Evidence for specific
methylenedioxymethamphetamine ( Ecstasy) binding sites in the rat brain.
Eur J Pharmacol 1985;119:135-136.
 
[n6.] Foerster EH, Hatchett D, Garriott JC: A rapid comprehensive screening
procedure for basic drugs in blood or tissues by gas chromatography.  J Anal
Toxicol 1978;2:50-55.
 
[n7.] Poklis A, Mackell MA, Drake WK: Fatal intoxication from
3,4-methylenedioxyamphetamine.  J Forensic Sci 1979;24:70-75.
 
[n8.] Reed D, Cravey RH, Sedgwick PR: A fatal case involving
methylenedioxyamphetamine.  Clin Toxicol 1972;5:3-6.
 
[n9.] Cimbura G: 3,4-Methylenedioxyamphetamine (MDA): Analytical and forensic
aspects of fatal poisoning.  J Forensic Sci 1972;17:329-333.
 
[n10.] Lukaszewski T: 3,4-Methylenedioxyamphetamine overdose.  Clin Toxicol
1979;15:405-409.
 
[n11.] Simpson DL, Rumack BH; Methylenedioxyamphetamine: Clinical
description of overdose, death, and review of pharmacology.  Arch Intern Med
1981;141:1507-1509.
 
[n12.] Shulgin AT: Psychotomimetic drugs: Structure-activity relationships, in
Iversen LL, Eversen SD, Snyder SH (eds): Handbook of Psychopharmacology.  New
York, Plenum Publishing Corp, 1978, vol 11, pp 243-333.
 
[n13.] Riedlinger JE: The scheduling of  MDMA:  A pharmacist's perspective.  J
Psychoactive Drugs 1985;17:167-171.
 
[n14.] Weiner N: Norepinephrine, epinephrine, and the sympathomimetic
amines, in Gilman AG, Goodman LS, Gilman A (eds): The Pharmacological Basis
of Therapeutics.  New York, MacMillan Publishing Co Inc, 1980, pp 138-175.
 
[n15.] Benowitz NL, Rosenberg J, Becker CE: Cardiopulmonary catastrophes in
drug-overdosed patients.  Med Clin North Am 1979;63:267-296.
 
[n16.] Benatar SR: Fatal asthma.  N Engl J Med 1986;314:423-429.
 
[n17.] Data From the Drug Abuse Warning Network.  Series 1, No. 5.  Rockville,
Md, National Institute on Drug Abuse, 1985, p 53.
 
GRAPHIC: Figure, Structural formulas of  MDMA,  MDEA, and related compounds.
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