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From: an13187@anon.penet.fi (H-Man)
Subject:  mdma article #8
Message-ID: <1993Jul4.032713.25582@fuug.fi>
Date: Sat, 3 Jul 1993 17:52:10 GMT

                          JAMA(R) 1988; 259: 1649-1650
 
                                 March 18, 1988
 
SECTION: LETTERS
 
LENGTH: 751 words
 
TITLE: The Complications of ' Ecstasy' (MDMA)
 
AUTHOR: Karl Verebey, PhD, New York State Division of Substance Abuse,
Brooklyn; Jamyl Alrazi, Psychiatric Diagnostic Laboratories of America,
South Plainfield, NJ; Jerome H. Jaffe, MD, National Institute on Drug Abuse,
Baltimore 
 
ED/SECT: Edited by Drummond Rennie, MD, Senior Contributing Editor; Sharon
Iverson, Assistant Editor.
 
TEXT:
   To the Editor. -- Drs Brown and Osterloh, [n1] in a recent letter in THE
JOURNAL, reported a nearly fatal toxic reaction to
3,4-methylenedioxymethamphetamine ( MDMA) .  The estimated dose of  MDMA
administered was 100 to 150 mg and the blood levels, measured at one and two
hours after hospital admission, were 6500 and 7000 ng/mL, respectively.
 
   Before  MDMA  became a Schedule 1 drug on July 1, 1985, [n2] it was used in
doses of 100 to 150 mg by some psychiatrists who claimed that it was effective
as a psychotropic catalyst and a sensory disinhibitor; at these doses, no
toxic effects were reported.  (The experiment was performed on March 12,
1985, before the scheduling in MDMA and was carried out by one of us [J.A.]
in partial requirement for the degree of Doctor of Physiology.) At that
time, we carried out a controlled study of MDMA metabolism and disposition
in a single patient. On the basis of that study, we believe that the dose
used in the study by Drs Brown and Osterloh would have had to have been much
higher to produce the reported blood levels of  MDMA  of 6500 to 7000 ng/mL. 
 
   Study. -- A healthy 40-year-old man weighing 74 kg ingested a single 50-mg
dose of  MDMA.  [n3] Blood samples were collected one through 24 hours after
administration of the dose.  Fractional urine samples were collected from zero
to 72 hours.  The samples were analyzed for  MDMA  and
3,4-methylenedioxyamphetamine (MDA) by gas chromatography/mass spectrometry.
3,4-Methylenedioxyamphetamine, the N-demethylated biotransformation product
of MDMA, also was identified in the plasma and urine samples.  Plasma levels
and urinary excretion of MDMA and MDA are presented in the Table.  In
plasma, the MDMA level peaked at 105.6 ng/mL two hours after administration
of the dose and declined monoexponentially to 5.1 ng/mL by 24 hours.
 
Plasma Levels and Urinary Excretion of  MDMA  and MDA in Man After
Administration of a Single 50-mg Oral Dose of  MDMA
 
   [SEE ORIGINAL SOURCE]
 
   Unchanged level of  MDMA  was the major urinary excretion product.  In 72
hours, a total of 36 mg (72%) of the 50-mg dose was recovered from the urine.
The missing 28% of the dose may have been biotransformed into other
metabolites. 
 
   Comment. -- The plasma levels of MDMA of 6500 to 7000 ng/mL reported by
Drs Brown and Osterloh were 60 to 70 times higher than the peak level seen
in our study and indicate that their patient must have taken a much larger
dose than 150 mg, a dose only three times more than that used in our study.
It is more likely that the observed severe toxic effects in the report by
Drs Brown and Osterloh represent an expected toxic reaction to an overdose
rather than a hypersensitivity reaction to the then customary doses of
MDMA.  Since, to our knowledge, ours is the first report on blood levels of
MDMA in man in which the dose is known, the blood level of MDMA found by Drs
Brown and Osterloh cannot be compared with any previously reported MDMA
blood level reference value.
 
   Recently, MDA was identified as a neurotoxic substance that selectively
destroys serotonergic nerve terminals in rat brain. [n3,n4] The finding in our
study that the biotransformation of  MDMA  in man results in the formation of
MDA should be a warning for the future legal or illicit use of  MDMA  by man.
 
REFERENCES:
[n1.] Brown C, Osterloh J: Multiple severe complications from recreational
ingestion of  MDMA ('Ecstasy' ).  JAMA 1987;258:780-781.
 
[n2.] Seymore RB, Wesson DR, Smith DE (eds):  MDMA:  Proceedings of the
conference.  J Psychoactive Drugs 1986;18:278-378.
 
[n3.] Ricaurte C, Bryan G, Strauss L, et al: Hallucinogenic amphetamine
selectively destroys brain serotonin nerve terminals.  Science
1985;229:986-988. 
 
[n4.] Battaglia G, Yeh SY, O'Hearn E, et al: 3,4-Methylenedioxymethamphetamine
and 3,4-methylenedioxyamphetatmine destroy serotonin terminals in rat brain:
Quantification of neurodegeneration by measurement of tritiated peroxylene
labeled serotonin uptake sites.  J Pharmacol Exp Ther 1987;242:911-916.
 
In Reply. -- The data of Verebey et al are useful in interpreting the plasma
concentrations of the  MDMA  measured in the patient we reported.  The dose
reported by the patient was certainly underestimated.  The ratios of MDA/ MDMA
concentrations were never more than 0.02.  This also suggests an overdose when
compared with the ratios in the data of Verebey et al.
 
   The major concern in our letter was to reinforce the warning of Dowling
et al [n1] that severe consequences have resulted from the use of MDMA.
This concern is heightened by (1) a recent report stating that 39% of
students at one college campus had tried MDA [n2] and (2) the neurotoxic
effect of the metabolite MDA cited by Verebey et al.
 
John Osterloh, MD
Christopher Brown, MD
San Francisco General Hospital
University of California, San Francisco
 
[n1.] Dowling GP, McDonough ET, Bost RO: 'Eve' and ' Ecstasy' : A report of
five deaths associated with the use of MDEA and MDMA.  JAMA
1987;257:1615-1617. 
 
[n2.] Peroutka SJ: Incidence of recreational use of
3,4-methylenedimethoxymethamphetamine ( MDMA, 'Ecstasy' ) on an undergraduate
campus.  N Engl J Med 1987;317:1542-1543.