**********************************03319********************************** PAGE 1
DATE: JANUARY 13, 1993

CLIENT: .
LIBRARY: MEDEX
FILE: DRUGDX

YOUR SEARCH REQUEST IS:
MDMA OR ECSTASY OR ECSTACY

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MICROMEDEX data is provided for reference only. Health professionals are
responsible for therapy decisions. Entire documents should be reviewed.

MDMA - FDA REPORT, 1985

RESPONSE:

The Food and Drug Administration has received inquiries about
the drug MDMA (3,4-METHYLENEDIOXYMETHAMPHETAMINE) referred
to in news media stories as an unregulated "DESIGNER DRUG."

The following may be used to answer inquiries.

MDMA is a psychotropic drug, street named "ADAM" and
" ECSTASY, " popular among a small number of therapists and
psychiatrists, although it has never been approved by FDA. The
therapists claim that MDMA increases perceptions of self-insight
and empathy. Recreational users claim that the drug relaxes
inhibitions and enhances communications and sex. However, no
INDs have been filed with FDA.

Chemically, MDMA is related to both the amphetamines and
mescaline and especially to a potent stimulant known as MDA.
Although it was developed in the 1970's, there was no
enforcement activity involving MDMA manufacture or possession
prior to last July. At that time, after a strong upsurge of
MDMA street use, the Drug Enforcement Administration (DEA)
proposed listing it as a "Schedule 1 Controlled Substance" --
the category for drugs with no medical use and a high abuse
potential. In the Schedule 1 category (which includes heroin,
LSD and MDA), clandestine production or sale of MDMA would be
punishable by up to 15 years in prison and a $125,000 fine.

The DEA proposal was protested by some nurses, physicians and
professors of pharmacology who wrote letters demanding a
hearing. They challenged the proposed scheduling on the grounds
that the drug has only a low or moderate abuse potential and has
great therapeutic usefulness.

DEA announced May 31, 1985 it will not wait for hearings before
acting because recent data indicate that the drug is being
abused in 28 states. DEA is using a 1984 change in the
Controlled Substances Act which allows emergency scheduling of
drugs for one year. DEA's emergency ban will become effective
July 1.

The emergency action is an interim measure to curb MDMA abuse
until the longer administrative process can be completed. DEA
has scheduled hearings June 10 and 11 in Los Angeles and July 10
and 11 in Kansas City. A third hearing will be scheduled later
in Washington, DC. FDA will participate in the hearings to PAGE 3
(c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed.

testify on the pharmacological aspects of the drug. PAGE 4
3RD DOCUMENT of Level 1 printed in FULL format.

MICROMEDEX data is provided for reference only. Health professionals are
responsible for therapy decisions. Entire documents should be reviewed.

MPTP-CONTAMINATED DESIGNER DRUGS - TREATMENT

PATIENT DATA:

Please review the presentation and treatment of patients who
have used MPTP-contaminated designer drugs.

RESPONSE:

DESIGNER DRUGS are analogs of known pharmacological agents,
synthesized by underground chemists, for sale on the street.

The concept of designer drugs is to manipulate the chemical
structure of a narcotic, for example, and create a totally new
compound. The "underground" chemist has two goals. First, is
the belief that the nature and duration of the "high"

experienced can be changed through chemical manipulations.
Although the science of medicinal chemistry involves predictions
of structure-activity relationships regarding psychodynamic
effects, associated toxicities are frequently unexpected.

Second, since there are no laws against newly formulated
compounds, legal ramifications are bypassed. Fortunately,
emergency laws have been implemented against such agents and new
regulations are being processed (Baum, 1985). This consult
includes a brief overview of designer drugs and a discussion of
DESIGNER MEPERIDINE, proposed mechanisms of its toxicities and
some treatment possibilities.

There are at least three popular types of designer drugs:
MDMA (3,4-METHYLENEDIOXYMETHAMPHETAMINE), FENTANYL
ANALOGS, and MEPERIDINE ANALOGS. MDMA is not a true designer
drug, as this agent is a schedule I agent that was once used in
psychiatry. Street names for MDMA include: MDA, ADAM,
ECSTASY and XTC. MDMA interacts with serotonergic neurons.
MDMA produces effects that are similar to those of LSD without
hallucinatory properties. These include increased
self-awareness and decreased communication barriers. Side
effects consist of increased heart rate and blood pressure,
irregular heart beat, panic attacks, anxiety, sleep disorders,
drug craving, paranoia, and rebound depression.

Fentanyl analogs include the following:
alpha-methyl-p-fluoro-3-methyl and alpha-methyl-acetylfentanyl.
In 1979 the alpha-methyl analog was found in users of "CHINA
WHITE". The effects of these compounds are similar to heroin
in terms of the nature of the "high" and its duration of action. PAGE 5
(c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed.

However, these analogs can be up to 40 times more potent than
heroin. This potency makes overdose a serious risk. The
drug-induced respiratory depression can be fatal (Baum, 1985).
Adverse Drug Reactions of Designer Meperidine
Designer meperidine is sold as SYNTHETIC HEROIN. The primary
street analog of meperidine is MPPP
(1-methyl-4-phenyl-4-propionpiperidine). Very specific chemical
reaction conditions are required to produce MPPP. In the event
of sloppy synthesis, where the pH is too low or the temperature
is too high, a contaminant, MPTP
(1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) is formed. MPTP
is a known industrial toxin which affects the dopaminergic
neurons of the substantia nigra. Cases of PARKINSON'S DISEASE
caused by MPTP have been reported (Baum, 1985).

The proposed biochemical mechanism of action of MPTP involves
the rapid oxidation of MPTP to MPP+ after systemic
administration. This conversion takes place in all tissues
studied (brain and systemic), except for the eye, and is
necessary for MPTP to exert its toxic effects (Irwin & Langston,
1985). Monoamine oxidase catalyzes this reaction. Highly
reactive intermediates may also be formed in the conversion.
MPP+ is then taken up by neurons in the substantia nigra where
it destroys dopaminergic neurons in this area. Although the
formation of MPP+ occurs in many parts of the brain, it remains
unclear as to why it selectively accumulates in the substantia
nigra and not in other dopaminergic areas of the brain such as
the striatum (Langston, 1985). These biochemical mechanisms are
undergoing further studies.

MPTP exposure is suspected if the patient answers "yes" to the
following questions on initial presentation: 1. Did the pure
form of the drug resemble brown sugar? 2. Was there a burning
sensation on intravenous injection at the injection site and up
through the vein? 3. Was the "high" more "spacey and giddy"
than that of heroin? These questions can help identify MPTP
exposures (Latimer, 1985). Other symptoms of MPTP toxicity are
discussed below.

Three phases of MPTP toxicity have been identified (Langston,
1985a). The first is an acute phase which occurs on initial
exposure to MPTP. Symptoms include disorientation,
hallucinations, blurred vision, "nodding off" (a slow downward
drifting of the head, and drooping and closure of the eyelids),
difficulties in speech and swallowing, intermittent jerking of
the limbs, slow movement, and tremor at rest. The second phase
is a subacute event which occurs after exposure to the drug.

Two to three days post-exposure there are reports of increased
bradykinesia and rigidity of extremities, abrupt onset of
"freezing up" and inability to move. Up to three weeks after
exposure, awkward posture, progressive slowness of movement and
"freezing up" have been reported. Finally, if there is no
recovery from the above two phases, a chronic syndrome results. PAGE 6
(c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed.

A permanent Parkinsonian syndrome evolves consisting of
classical Parkinsonian symptoms such as bradykinesia, rigidity,
resting tremor, fixed stare, and loss of postural reflexes.
Recovery from the acute or subacute phase may occur, but it is
unlikely once the chronic phase has been reached.

Several mechanisms have been proposed to explain the
manifestations of each of the three phases. Possible mechanisms
regarding the acute phase include an opiate receptor interaction
with MPTP, serotonergic effects of the substance, and a slight
dopaminergic deficiency caused by MPTP. Because MPTP is a
meperidine analog, an opiate receptor interaction is probably
responsible for the "nodding off" which takes place. This
phenomenon is typical of exposure to heroin and is due to the
same type of opiate receptor interaction. An initial
suppression of serotonin in the central nervous system by MPTP
is the suggested cause for the hallucinations and retropulsions
which occur (Ballard et al, 1985). Motor symptoms are
attributed to MPTP's effect on the dopaminergic neurons in the
substantia nigra, but the dopamine deficiency is not yet
substantial.

The subacute phase is thought to occur once MPTP accumulation
reaches a critical threshold before killing cells in the
substantia nigra. This theory thus offers an explanation for
the delayed onset of symptoms and for the continuation of
symptoms after exposure. Metabolic damage, such as impaired
dopamine synthesis, is also suggested as a cause of dopamine
depletion. Further study of this delayed phase is in progress.
The likely cause of the chronic phase is actual nigral cell
death. This, in turn, leads to a permanent hypodopaminergic
state, and thus permanent Parkinsonism.

Recovery from the acute and subacute phases has two possible
explanations. A critical toxic threshold of MPTP may not be
reached intracellularly in the substantia nigra, thus the cells
can return to normal once exposure is stopped. Or, perhaps less
than a critical number of dopaminergic neurons are lost and the
remaining cells are able to compensate by overproduction of
dopamine, therefore resolving the clinical symptoms.

Typical Parkinsonian treatment modalities are employed in
patients who present with MPTP toxicity. Anticholinergic agents
only help to reduce the tremor, and thus are of little benefit.
CARBIDOPA and LEVODOPA therapy, with or without dopamine
agonists, such as BROMOCRIPTINE, are helpful, but
complications typical of this therapy have resulted. These
problems include dyskinesias, end of dose deterioration, and
on-off swings between choreathetosis and Parkinson's symptoms.
Studies with monoamine oxidase type B inhibitors, such as
PARGYLINE and SELEGILINE, suggest a possible alternative
treatment (Tetrud & Langston, 1989; Langston et al, 1984; Fuller
& Hemrick-Lueck, 1985). If monoamine oxidase (MAO) is
inhibited, the conversion of MPTP to MPP+ is prevented. Thus,
MAO inhibitor drugs may provide a protecting effect if given PAGE 7
(c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed.

prior to MPTP and may be effective in retarding the progression
of symptoms if given after MPTP. Further research is underway
concerning drug therapy for MPTP toxicities.

CONCLUSION:

Several significant points can be noted regarding MPTP
contamination. First, the risks of designer drugs are great due
to the lack of purification after synthesis, the lack of
knowledge about what is actually being created, and the presence
of possible adulterants. Secondly, MPTP is a very specific
neurotoxin which can induce irreversible Parkinson's symptoms at
any age. Finally, MPTP administration to laboratory animals,
provides scientists an opportunity to study the function of
dopamine on the nervous system, the effects of chronic dopamine
deficiency, and the effects of chronic dopamine agonist therapy,
and other areas of interest. It is hopeful that understanding
the mechanisms of MPTP will provide further understanding of
Parkinsonism and offer new insights to the understanding and
management of this disease.

REFERENCES:

1. Ballard PA, Tetrud JW & Langston JW: Permanent human
Parkinsonism due to
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven
cases. Neurology 1985; 35:949-956.
2. Baum RM: New variety of street drugs poses growing problem.
Chem Eng 1985; 9:7-16.
3. Fuller RW & Hemrick-Lueck SK: Influence of selective
reversible inhibitors of monoamine oxidase on the prolonged
depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,
6-tetrahydropyridine in mice. Life Sci 1985; 37:1089-1095.
4. Irwin I & Langston JW: Selective accumulation of MPP+ in
the substantia nigra: a key to neurotoxicity? Life Sci
1985; 36:207-212.
5. Langston JW: MPTP and Parkinson's disease. Trends in
Neurosciences 1985; 8:79-83.
6. Langston JW: MPTP neurotoxicity: an overview and
characterization of phases of toxicity. Life Sci 1985a;
36:201-206.
7. Langston JW, Irwin I & Langston EB: Pargyline prevents MPTP
induced Parkinsonism in primates. Science 1984;
225(4669):1480-1482.
8. Latimer D: MPTP "brain damage dope" floods west coast
suburbs. High Times 1985; 122:19-27.
9. Tetrud JW & Langston JW: The effect of deprenyl
(selegiline) on the natural history of Parkinson's disease.
Science 1989; 245:519-522.
PAGE 8
DATE: JANUARY 13, 1993

CLIENT: .
LIBRARY: GENMED
FILE: PINK

YOUR SEARCH REQUEST IS:
MDMA OR ECSTASY OR ECSTACY

NUMBER OF ARTICLES FOUND WITH YOUR REQUEST THROUGH:
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1ST ARTICLE of Level 1 printed in FULL format.

The Pink Sheet 1992; 54(29): T&G-11-T&G-12

July 20, 1992

SECTION: TRADE & GOVT. MEMOS

LENGTH: 483 words

TEXT:
HALLUCINOGENS POSE NO GREATER RISK THAN OTHER INVESTIGATIONAL DRUGS, FDA's
Drug Abuse Advisory Committee agreed at its July 15 meeting. Summarizing the
committee's discussion, FDA Pilot Drug Staff Medical Officer Curtis Wright, MD,
said: "I have not heard . . . any discussion of risks involving these compounds
that we do not routinely face with every new drug we put through the IND
process."

The committee was asked to assess problems that might be associated with
allowing research to be conducted with hallucinogenic drugs. Wright said FDA,
in the last few years, automatically has put IND applications for hallucinogenic
drugs on hold, taking from months to years to respond to investigators regarding
their protocols.

Wright told the group: "We are coming to the committee because we are going
to have to deal with the issue of hallucinogens . . . because drugs of this
class are likely to be explored as potential therapies or modifiers of the
effects of a variety of agents, including cocaine." FDA's reluctance to approve
IND requests for hallucinogens stems from several concerns, Wright explained,
including the potential for diversion of controlled substances by researchers
and patients, and animal data indicating that selective serotonin agonists, such
as substituted amphetamines, can permanently alter the serotonin pathways.

While committee members and consultants agreed that the potential
long-lasting neurologic changes caused by these drugs are of concern, they
concurred with Wright's comments that the harm caused by these agents "is
outweighed in most cases by the knowledge to be obtained or by the therapeutic
benefit to the patient." Wright said that all neurologic or psychological risks
"need to be addressed in evaluation of the protocol."

Synthesizing the comments of the committee and consultants, Wright said: "I
have heard great concerns by almost every speaker that the usual standards of
research must be followed: that there must be meticulous attention to questions
of patient selection, informed consent, [and] monitoring." He remarked: "I
haven't heard anything that leads me to believe that this is a qualitatively
different kind of research than the rest of the research we do with other
agents."

In closed session, the committee considered an IND protocol submitted by
University of California at Irvine researcher Charles Grog, MD, for the
selective serotonin agonist methylenedeoxymethamphetamine ( MDMA, commonly
known as " Ecstasy" ) for use in psychotherapy and pain relief of terminally-ill
pancreatic cancer patients. PAGE 10
(c) 1992 F-D-C Reports, Inc., The Pink Sheet, July 20, 1992

Patients in the proposed protocol would receive 1.5-2 mg/kg MDMA every two
to four weeks. MDMA, synthesized and purified at Purdue University, is one of
the hallucinogenic drugs that has been found to be associated with neurotoxicity
(alteration of the serotonin-producing neurons) in rodents and primates.
PAGE 11
DATE: JANUARY 13, 1993

CLIENT: .
LIBRARY: GENMED
FILE: JNLS

YOUR SEARCH REQUEST IS:
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JAMA(R) 1992; 268: 1505-1506

September 23, 1992 / September 30, 1992

SECTION: MEDICAL NEWS & PERSPECTIVES

LENGTH: 1565 words

TITLE: Ecstasy -Fueled 'Rave' Parties Become Dances of Death for English Youths

AUTHOR: Teri Randall

TEXT:
THE ILLEGAL designer drug ecstasy -- promoted by some as a safe, nontoxic
means to "warm, loving relaxation" -- has killed at least 15 young people in
England in the last 2 years and caused severe toxicity in numerous patients,
experts report from that country's National Poisons Unit. In almost every case,
a recreational dose of the drug had been taken at a dance club or party where
crowds danced vigorously in popular, all-night dance sessions called "raves."

In most of the serious cases reported, the users had collapsed unconscious or
started to convulse while dancing. By the time they were noticed and taken to
emergency departments, their body temperatures had soared as high as 110 degrees
F (43.3 degrees C), their pulses were racing, and their blood pressures were
plummeting. These patients with severe toxicity usually developed disseminated
intravascular coagulation, rhabdomyolysis, and acute renal failure. Despite
treatment, death sometimes ensued from 2 to 60 hours after admission, usually
due to severe hyperthermia accompanied by disseminated intravascular
coagulation.

Severe or fatal reactions of this type are virtually undocumented in the US
drug abuse literature concerning ecstasy (also known as MDMA for its
chemical name, 3,4-methylenedioxymethamphetamine). But this pattern of illness
has recently become all too familiar in British medical journals (J R Soc Med.
1991; 84:371; J R Soc Med. 1992;85:61; BMJ. 1992;305:5,6,29; BMJ.
1992;305:309-310; and Lancet. 1992;339:677-678).

The most recent report, published 6 weeks ago, describes seven fatalities,
all associated with rave dances (Lancet. 1992;340:384-387). The report also
describes seven cases of unexplained hepatotoxicity (including one death)
attributed to a history of ecstasy use.

According to the authors, the pattern of illness and the amounts of MDMA
ingested rule out the possibility of an overdose. In most cases the user had
taken only a few tablets or capsules. By comparison, one analytically
documented MDMA overdose -- allegedly 42 tablets taken at home -- was
accompanied by no symptoms other than a "hangover" with tachycardia and
hypertension. The patient's plasma MDMA level was 7.72 mg/L, which is six to
70 times greater than the plasma levels measured in the fatal cases.

John Henry, MD, consulting physician for the National Poisons Unit at Guy's
Hospital, London, England, and lead author of the most recent Lancet report,
says that prolonged, vigorous dancing (which may itself be an effect of PAGE 13
Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992

MDMA) may compound the pharmacologic effects of the drug. The
amphetamine-derived MDMA has been shown to increase body temperature in rats,
presumably by interfering with serotonin metabolism in the brain.

Higher ambient temperatures seem to intensify this effect, and the hot,
poorly ventilated environments of some nightclubs, together with inadequate
fluid replacement, may be sufficient to elevate body temperature to lethal
levels in susceptible individuals, Henry suggests.

The finding has relevance for the international medical community because the
rave culture is now being exported to the United States and other countries (see
accompanying article). Henry urges physicians to be aware of the drug's
pharmacologic effects when it is combined with this type of dancing. Cases of
severe hyperthermia or unexplained jaundice or hepatomegaly should suggest
possible MDMA toxicity, he says.

For the patient who is taken acutely ill, medical treatment is urgent and
includes control of convulsions, measurement of core temperature, rapid
rehydration, active cooling measures, and possibly use of the antispasmodic drug
dantrolene (Anaesthesia. 1991; 47:686-687).

A 'Cultural Reformulation'

Of great interest to Henry is how the drug has been adopted by, and has
perhaps even catalyzed, the new rave culture in England -- similar, he says, to
the Acid Test parties of the 1960s and the use of LSD (lysergic acid
diethylamide) and amphetamines. The drug's association with the rave scene has
led to its enormous popularity in England. An estimated half-million people in
that country have taken MDMA, he says, most of them young people.

MDMA use had been widespread in both the United States and England
throughout the 1980s, but in a much different context, and with different
outcomes. Users usually took it while they were alone or with a small group of
people. Ninety percent of users in one US study said the drug made them feel
euphoric, more verbal, and closer to other individuals. Some called it the
"love drug."

In a study done at Stanford (Calif) University School of Medicine in 1987 --
at the peak of the drug's popularity in the United States -- 39% of the
undergraduates reported they had used MDMA at least once (N Engl J Med.
1987;317:1542-1543).

In the late 1980s, the drug was "'reformulated,'" Henry says, "not in the
pharmacologic sense, but in the cultural sense." The rave scene in England
provided a "new 'formula,' a new package, a new culture." And it is this new
cultural context that has, unfortunately, provided a real-life showcase for
ecstasy's previously unknown lethal potential.

Before this "reformulation," the handful of reported fatalities were mostly
cardiac arrhythmias in individuals with underlying natural disease (JAMA. 1987;
257:1615-1617).

Many users did experience adverse effects, however. In a 1986 study, 29
volunteers were given 75 mg to 150 mg (a "recreational dose") of pure MDMA by
psychotherapists (J Psychoactive Drugs. 1986;18:319-327). All 29 experienced PAGE 14
Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992

undesirable physical symptoms: 28 lost their appetite, 22 had trismus or
bruxism, nine had nausea, eight had muscle aches or stiffness, and three had
ataxia. Sweating was common, and tachycardia and hypertension were recorded.
Afterward, 23 people noted fatigue for hours or days, and 11 had insomnia.

The mechanism by which MDMA elevates body temperature is still a matter of
speculation, although experts suspect it involves the drug's interference with
serotonin metabolism in the brain. In experimental animals, MDMA stimulates
the release of this neurotransmitter from serotonergic neurons, particularly
from those in the dorsal raphe. Under normal conditions, released serotonin is
taken up into the terminal endings of the cells that released it. But in the
presence of MDMA, this reuptake process is altered, leaving the nerve cells
depleted of serotonin.

The waters are muddied, however, when one looks at clinical experience. Some
experts have argued that there is no clinical evidence that people who use
MDMA develop such typical symptoms of serotonin depletion as disorders of
sleep, mood, and sexual function (Arch Gen Psychiatry. 1990;47:288-289).

Lewis Seiden, PhD, professor of pharmacology at the University of Chicago,
Ill, conducted extensive research on the neurotoxicity of MDMA in the
mid-1980s. When he heard of the recent reports of fatalities associated with
the use of the drug in English nightclubs, he was reminded, he says, of a
well-established phenomenon in amphetamine research called "aggregation
toxicology": One solitary rat or mouse given an injection of amphetamine will
survive. But several animals, confined in a small cage and given the identical
dose of amphetamine, will die.

Over the years, one of several proposed explanations for this phenomenon has
been amphetamine-induced hyperthermia, Seiden says.

On the other hand, one "can't make the assumption the MDMA is just a fancy
form of amphetamine," points out Steven Karch, MD, research director of the
Trauma Center at the University Medical Center of Southern Nevada, Las Vegas.
"The molecules are very close structurally [figure]. But then again, all
stimulants look roughly the same."

Seiden also speculates that because MDMA is such a potent
serotonin-releasing agent in the brain, it might also effect serotonin-releasing
cells elsewhere in the body. Ninety percent of the serotonin in the body is
located outside the brain, much of it in the gut and mast cells, he says.

The Long Road to Rave

MDMA has a long, controversial history that spans nearly a century, says
Karch, who is also editor of the Forensic Drug Abuse Advisor.

The patent for MDMA was initially granted in 1914 to E. Merck in Darmstadt,
Germany, as an appetite suppressant. The compound's toxicology wasn't
systematically studied until the early 1950s, under a US Army contract with a
group at the University of Michigan, Ann Arbor. The results of these studies
were eventually declassified and published in 1973, when it was revealed that
MDMA is somewhat less toxic than MDA (another amphetamine derivative), but
more toxic than the hallucinogen mescaline (Toxicol Appl Pharmacol.
1973;25:299-309). PAGE 15
Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992

No pharmaceutical company has ever made MDMA, nor has the Food and Drug
Administration approved it. A small number of psychiatrists have advocated its
use in therapy, based on the belief that it lowers patients' defenses and
promotes trust and confidence.

In 1985, after several studies showed neurotoxicity in animals, the Drug
Enforcement Agency classified MDMA as a Schedule I compound. Schedule I
compounds, such as heroin and LSD, are believed by the agency to have a high
potential for abuse and no currently accepted medical use.

GRAPHIC: Figure, Structural formulas of amphetamine, methamphetamine, and MDMA
("Ecstasy" ). PAGE 16
3RD ARTICLE of Level 1 printed in FULL format.

JAMA(R) 1992; 268: 1506

September 23, 1992 / September 30, 1992

SECTION: MEDICAL NEWS & PERSPECTIVES

LENGTH: 493 words

TITLE: 'Rave' Scene, Ecstasy Use, Leap Atlantic

AUTHOR: Teri Randall

TEXT:
THE BRITISH rave counterculture, and its liberal use of ecstasy (MDMA) , has
become a hot export to the United States, wrapped in a high-tech music and video
package and supported by low-tech laboratories that illicitly produce the drug
stateside.

An August 19, 1992, article by United Press International says that a
clamp-down on rave parties by British authorities has inspired several English
rave promoters to move their business to the United States. Staged in empty
warehouses or open fields outside San Francisco or Los Angeles, their parties
are drawing thousands of young Californians on designated weekend nights.

Partygoers -- attired in Cat in the Hat-hats and psychedelic jumpsuits -- pay
$ 20 at the door to dance all night to heavily mixed, electronically generated
sound, surrounded by computer-generated video and laser light shows. They pay
another $ 3 to $ 5 for "smart drinks" -- amino acid-laced beverages that
reputedly enhance energy and alertness. And for another $ 20, those so inclined
can purchase an ecstasy tablet (see accompanying article).

Many observers can't help but draw comparisons to the LSD-laced "human
be-ins" of a quarter-century ago. The scene has come full circle, they add,
noting that several Los Angeles raves have been hosted by Timothy Leary's son.
The elder Leary, a former Harvard professor who advocated the use of LSD
(lysergic acid diethylamide) three decades ago, has made several appearances at
his son's raves, calling them "high-tech Acid Tests."

Large raves also have been staged in New York, NY, and other urban centers in
the United States. Their popularity is increasing in parts of India, Indonesia,
Belgium, and New Zealand, and a promoter is working to popularize the scene in
Sweden, United Press International reports.

So far, there appear to be no published reports of death or severe toxicity
caused by MDMA use.

Most of the MDMA available in England is supplied by clandestine
laboratories in the Netherlands. In the United States, the drug is made
predominantly on the West Coast by small-scale operators, says Joseph Bono,
supervisory chemist, special testing, Drug Enforcement Agency.

The synthesis of MDMA requires minimal knowledge of chemistry. Illicit
laboratories are often set up in kitchens, mobile trailers, or garages with PAGE 17
Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992

little concern for cleanliness. Reactions may be set up in cookie jars. Solid
products may be removed with coffee filters; and the coffee filter may be thrown
back into the reaction vessel for a second synthesis step (J Forensic Sci.
1988;33:576-587). Bono detects a lot of contaminants and by-products in the
samples that reach his laboratory for analysis.

"We're not dealing with Smith, Kline, and French here. We're dealing with
people who are just interested in turning out a product," Bono says. "If it
assays at 50% as opposed to 100% or 95%, they don't really care. And what is
that other 50%? Who knows?" PAGE 18
9TH ARTICLE of Level 1 printed in FULL format.

Arch Gen Psychiatry 1990; 47: 288-289

March, 1990

SECTION: LETTERS TO THE EDITOR

LENGTH: 1278 words

TITLE: Second Thoughts on 3,4-Methylenedioxymethamphetamine ( MDMA)
Neurotoxicity

AUTHOR: CHARLES GROB, MD, GARY BRAVO, MD, ROGER WALSH, MD, PHD, University of
California, Irvine Medical Center, Department of Psychiatry and Human Behavior,
101 City Dr S Rte 88, Orange, CA 92668

TEXT:
To the Editor. -- Recent attention has been drawn to the purported neurotoxic
dangers associated with 3,4-methylenedioxymethamphetamine ( MDMA) . Price et al
[n1] have attempted to assess possible serotonergic neurotransmitter damage by
contrasting serum prolactin response to the challenge with intravenous
L-tryptophan in subjects with a history of MDMA use vs control subjects.
Their primary finding was a blunted rise in the expected serum prolactin level
in MDMA users, but not to a statistically significant degree. The importance
of this finding appears to be questionable and perhaps misleading. Even if the
data had yielded a statistically significant result, would such a correlation
necessarily imply causation?

A methodological limitation to the study would appear to be that subjects
were not adequately screened on selection to exclude those who were using other
psychotropic drugs. There is no mention that toxicology screens were ever
performed. In fact, three subjects (33%) admitted to marijuana use during the
3-week supposed drug-free interval prior to the testing. As marijuana is known
to affect dopaminergic function (and, consequently, prolactin secretion), [n2]
the implications for MDMA effect on serotonergic function are further
questioned. One additional point regarding this study is that even if one could
demonstrate that MDMA users had diminished serotonergic function compared with
control subjects, what does this imply? Without data as to baseline
serotonergic functioning prior to the first ingestion of MDMA, such findings
are of limited significance.

Numerous animal studies have been performed over the past several years that
were designed to evaluate the neurotoxic potential of MDMA. Until recently,
most have examined short-term degeneration of serotonin neurons in animal brain
following repeated systemic administration of MDMA. Battaglia et al [n3] have
examined the brains of rats treated with massive subcutaneous dosages of MDMA
(cumulatively up to 100 times the usual human oral dose) over time, and have
noted complete regeneration 1 year after administration of the drug. This,
together with the fact that there have yet to be documented clinical cases of
MDMA -induced serotonergic neurotoxicity (ie, there have been no reports of
sleep, mood, appetite, aggressive, or sexual dysregulation), may indicate that
concerns over long-term neuropsychiatric damage have been overstated. PAGE 19
Copyright 1990 Amer. Medical Assn., Arch Gen Psychiatry, March, 1990

The related controversy over fenfluramine hydrochloride has some relevance
here. During the last 25 years, approximately 50 million people have been
clinically treated with fenfluramine. [n4] Fenfluramine has been utilized
primarily as a weight-reducing agent and has also been used in clinical trials
for the treatment of infantile autism and childhood attention-deficit disorder
with hyperactivity. However, animal studies have demonstrated that fenfluramine
has a serotonergic neurotoxic capability three times that of MDMA. [n5] Yet
despite such findings, fenfluramine has accepted clinical indications, has a
history of widespread use, and is without the known induction of neurological
side effects.

Claims have been made that MDMA enhances the processes of psychotherapy by
facilitating empathy, heightening introspection, and lowering defensive anxiety.
[n6] Because of concerns of possible neurotoxicity, however, rigorous clinical
trials designed to validate these claims have not been performed. The data
reviewed suggest that fears of MDMA neurotoxicity may have been exaggerated
and it may well be significantly less toxic than a very widely used medication,
fenfluramine. In view of its purported unique psychoactive properties, it may
be appropriate to pursue clinical trials of MDMA. Alternatively, the search
for a nontoxic analogue should be encouraged.

REFERENCES:
[n1.] Price LH, Ricaurte GA, Krystal JH, Henninger GR. Neuroendocrine and mood
responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine
( MDMA) users. Arch Gen Psychiatry. 1989;46:20-22.

[n2.] Markianos M, Stefonis C. Effects of acute cannabis use and short-term
deprivation on plasma prolactin and dopamine-beta-hydroxylase in long-term
users. Drug Alcohol Depend. 1982;9:251-255.

[n3.] Battaglia G, Yeh SY, DeSouza EB. MDMA -induced neurotoxicity: parameters
of degeneration and recovery of brain serotonin neurons. Pharmacol Biochem
Behav. 1987;29:269-274.

[n4.] Derome-Tremblay M, Nathan C. Fenfluramine studies. Science. 1989;243:991.

[n5.] Barnes DM. Neurotoxicity creates regulatory dilemma. Science.
1989;243:29-30.

[n6.] Grinspoon L, Bakalar JB. Can drugs be used to enhance the
psychotherapeutic process? Am J Psychother. 1986;40:393-404.

In Reply. -- Grob et al raise some valid points regarding the methodological
limitations of our findings, which we ourselves had attempted to acknowledge,
both in the "Comment" section and in our characterization of our results as
"preliminary observations." There are, however, several other issues raised by
Grob et al on which we offer the following comments:

1. Urine toxicology by enzyme immunoassay (EMIT) was obtained on all
subjects on the morning of the intravenous L-tryptophan test, immediately prior
to beginning the test. Although inadvertently omitted from the final draft of
the article, these screens revealed no evidence of recent use of psychoactive
drugs. However, most of our subjects did have a past history of use of illicit
psychoactive drugs; as Grob et al imply, we cannot state with certainty that use
of these other drugs did not account for or contribute to the altered PAGE 20
Copyright 1990 Amer. Medical Assn., Arch Gen Psychiatry, March, 1990

responses to L-tryptophan. The fact is, however, that extensive preclinical
evidence demonstrates considerable effects of MDMA on serotonergic function,
and our subjects were primarily heavy users of MDMA. We disagree with the
assertion that the demonstration of altered serotonergic function in MDMA
users would be of limited significance "Without data as to baseline serotonergic
functioning prior to the first ingestion of MDMA. " Altered serotonergic
function in MDMA users would suggest, but not confirm, effects of MDMA on
serotonergic functioning in such individuals. Even though inconclusive, we
believe such a suggestion would be of very real significance. As Grob et al
well know, the classification of MDMA as a schedule I drug currently makes it
virtually impossible to conduct the kind of study that we and they agree would
be "conclusive."

2. As Grob et al note, the clinical implications of serotonergic
neurotoxicity are controversial and currently undefined. Their reference to the
current debate surrounding fenfluramine is entirely appropriate. However, their
citation of the Barnes [n1] report is somewhat disingenuous. In that article,
it is noted that "Fenfluramine has demonstrated clinical usefulness, whereas
MDMA does not. MDMA is also classified as a substance that people abuse,
but fenfluramine is not." We would further point out that the general tone of
the Barnes article is not exculpatory, but cautionary; although fenfluramine has
not been known frequently to cause clinically significant neurotoxic effects,
the possibility that it may do so is now under intensive scrutiny.

3. Claims that MDMA may be a useful pharmacological adjunct to
psychotherapy are of great theoretical and practical interest. Of course, such
claims have been made for numerous other compounds over the years, and none have
borne fruit. We agree that rigorous clinical trials are necessary to validate
such claims, but we do not feel that "concerns of possible neurotoxicity" are
irrelevant to the initiation or conduct of such trials. It may be that Grob et
al are correct in suggesting that fears of MDMA neurotoxicity have been
exaggerated; we trust that further research can and will clarify this point.
Until such clarification is made, we believe it would be premature to pursue
clinical trials of MDMA in conditions that are not life-threatening.

LAWRENCE H. PRICE, MD
JOHN H. KRYSTAL, MD
GEORGE R. HENINGER, MD
Department of Psychiatry
Yale University School of Medicine and the Connecticut Mental Health Center
Clinical Neuroscience Research Unit
Ribicoff Research Facilities
34 Park St
New Haven, CT 06508
GEORGE A. RICAURTE, MD, PHD
Department of Neurology
The Johns Hopkins University School of Medicine
4940 Eastern Ave
Baltimore, MD 21224

[n1.] Barnes DM. Neurotoxicity creates regulatory dilemma. Science.
1989;243:29-30. PAGE 21
13TH ARTICLE of Level 1 printed in FULL format.

Arch Gen Psychiatry 1989; 46: 191

February, 1989

SECTION: LETTERS TO THE EDITOR

LENGTH: 623 words

TITLE: ' Ecstasy' : A Human Neurotoxin?

AUTHOR: STEPHEN J. PEROUTKA, MD, PHD, Department of Neurology, C-338, Stanford
University Medical Center, Stanford, CA 94305

TEXT:
To the Editor. -- 3,4-Methylenedioxymethamphetamine ( MDMA; "ecstasy" ) is a
ring-substituted amphetamine derivative that is chemically related to both
hallucinogens and stimulants. The drug appears to have unique psychoactive
properties and has been advocated by certain therapists as an adjunct to
psychotherapy. [n1] However, due to findings in laboratory animals [n2] of
neurotoxicity caused by MDMA and related compounds, the drug was placed on
Schedule I by the Food and Drug Administration in July 1985. Significant
controversy exists concerning the legal status of MDMA, its potential clinical
efficacy, and, most importantly, the possibility that it may cause irreversible
neurotoxicity in human users. [n3]

In addition, undocumented reports have suggested that the recreational use of
MDMA has been increasing at university campuses in the United States during
the past few years. Although no formal epidemiological studies have been
performed, a recent informal survey found that a significant number of students
on an undergraduate campus reported taking at least one recreational dose of
MDMA. [n4] The median amount of MDMA usage was four doses, while the mean
number of doses taken was 5.4. The amount of drug taken in a single dose ranged
from 60 to 250 mg (approximately 1 to 4 mg/kg). Similar dosage patterns have
been reported to be neurotoxic in primates, [n3] and at least five deaths in
humans have been attributed to recreational use of MDMA and related compounds.
[n5]

Presently, there are no data to indicate that recreational doses of MDMA
permanently damage the human brain. However, it should also be stressed that no
scientific studies have addressed this problem. Nonetheless, based on informal
discussions with approximately 100 recreational users of MDMA, a number of
personal observations suggest that MDMA is much different from other
recreational drugs, as described below.

1. Recreational users of MDMA frequently state that they usually wait at
least two to three weeks between doses of the drug. The reason given for this
unusual pattern of recreational drug use is that the "good" effects of the drug
appear to diminish while the "negative" side effects of the drug appear to
increase if the drug is taken too frequently. For example, taking a double dose
of MDMA does not double the supposed good effects of the drug but simply
increases the negative effects of the drug. PAGE 22
Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, February, 1989

2. The majority of people who have taken more than five individual doses of
MDMA state that the good effects of the drug change with successive doses. As
stated by one college student, "Freshmen love it; sophomores like it; juniors
are ambivalent, and seniors are afraid of it." These observations are of
concern, since no other drugs are known that, when taken at very infrequent
intervals (ie, every month or so), cause different effects with successive
doses.

3. MDMA is not "addictive." It is extremely rare to find individuals who
have taken large quantities of this drug. Again, this is quite different from
many recreational drugs, which tend to be either psychologically or physically
addictive. To my knowledge, there are simply no reports of individuals who take
frequent and large amounts of MDMA for an extended period.

In summary, these completely informal anecdotal observations are consistent
with the belief that there is a long-term, and potentially irreversible, effect
of MDMA on the human brain. Obviously, a definitive assessment of the human
neurotoxic potential of MDMA must await the completion of formal clinical [n6]
and epidemiological studies. However, a reasonable and informed conclusion
would be that recreational use of MDMA should be avoided.

REFERENCES:
[n1.] Greer G, Tolbert R: Subjective reports of the effects of MDMA in a
clinical setting. J Psychoactive Drugs 1986;18:319-328.

[n2.] Schmidt CJ: Neurotoxicity of the psychedelic amphetamine, MDMA. J
Pharmacol Exp Ther 1987;240:1-7.

[n3.] Barnes DM: New data intensify the agony over ecstasy. Science
1988;239:864-866.

[n4.] Peroutka SJ: Incidence of recreational use of
3,4-methylenedioxymethamphetamine ( MDMA, 'Ecstasy' ) on an undergraduate
campus. N Engl J Med 1987;317:1542-1543.

[n5.] 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.

[n6.] Price LH, Ricaurte GA, Krystal JH, Heninger GR: Neuroendocrine and mood
responses to intravenous L-tryptophanin 3,4-methylenedioxymethamphetamine
( MDMA) users: Preliminary observations. Arch Gen Psychiatry 1989;46:20-22. PAGE 23
14TH ARTICLE of Level 1 printed in FULL format.

Arch Gen Psychiatry 1989; 46: 20-22

January, 1989

SECTION: ORIGINAL ARTICLE

LENGTH: 2051 words

TITLE: Neuroendocrine and Mood Responses to Intravenous L-Tryptophan in
3,4-Methylenedioxymethamphetamine ( MDMA) Users;
Preliminary Observations

AUTHOR: Lawrence H. Price, MD; George A. Ricaurte, MD, PhD; John H. Krystal, MD;
George R. Heninger, MD

ABSTRACT:3,4-Methylenedioxymethamphetamine ( MDMA; "ecstasy" ) is a selective
serotonin (5-HT) neurotoxin in laboratory animals. To assess its effects on
5-HT function in humans, serum prolactin (PRL) and mood responses to intravenous
L-tryptophan were measured in nine recreational users of MDMA and compared
with findings from nine matched healthy controls. L-Tryptophan induced a rise
in the PRL concentration in controls, but not in MDMA users. Peak change and
the area under the curve of the PRL response appeared to be blunted in MDMA
users, but the difference from controls did not reach statistical significance.
This study provides suggestive evidence of altered 5-HT function in MDMA
users, but more definitive studies clearly are needed.

TEXT:
Aring-substituted amphetamine derivative, 3,4-methylenedioxymethamphetamine (
MDMA; "ecstasy" ) has serotonin ic effects in the vrains of (5-HT)-selective
neurotoxic effects in the brains of rats [n1-n5] and nonhman primates. [n6,n7]
Although classified on Schedule I by the Drug Enforcement Agency since July
1985, MDMA has become popular in some settings as a recreational drug. In an
informal survey, up to 40% of undergraduates at a major university reported
having used it at least once. [n8] Some clinicans have claimed therapeutic
utility for MDMA as an adjunct to psychotherapy, stating that it facilitates
interpersonal communication, enhances insight, and increases selfesteem. [n9]

We are aware of only one published report on the effects of MDMA on 5-HT
function in humans. Peroutka et al [n10] measured cerebrospinal fluid levels of
the 5-HT metabolite 5-hydroxyindoleacetic acid in five recreational MDMA
users. They found no significant difference from mean levels in historical
control subjects. It is possible, of course, that this sample was too small to
detect a difference, or that lumbar cerebrospinal fluid does not sensitively
reflect MDMA -induced changes in central 5-HT function in humans.

The neuroendocrine challenge strategy offers a more dynamic means of
assessing central 5-HT function. Intravenous infusion of the 5-HT precursor
L-tryptophan increases the serum prolactin (PRL) concentration, probably via
enhanced synthesis and release of 5-HT from hypothalamic 5-HT neurons. [n11] The
PRL response to L-tryptophan is blunted in depressed patients compared with
healthy controls, [n12] consistent with other evidence of abnormal 5-HT function
in depression. [n13] May antidepressant drugs, particularly those with
demonstrable effects on 5-HT function, enhance the PRL response. [n14] PAGE 24
Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989

Depletion of dietary L-tryptophan also enhances the PRL response, perhaps by a
mechanism analogous to denervation supersensitivity. [n15] In a pilot study, we
compared neuroendocrine and behavioral responses to L-tryptophan in nine heavy
users of MDMA with those of matched healthy controls.

SUBJECTS AND METHODS

Nine subjects (seven male, two female; mean [+/- SD] age, 34 +/- 7 years; age
range, 22 to 47 years) with a current or recent history of substantial MDMA
use volunteered to participate. They had been using what they believed to be
MDMA for a mean of 5.1 +/- 2.3 years (range, two to seven years) at a rate of
1.9 +/- 1.7 times per month (range, 0.33 to 5.0 times per month). The average
"usual" dose used was 135 +/- 44 mg (range, 50 to 200 mg), corresponding to a
mean dose of 1.8 +/- 0.4 mg/kg (range, 1.1 to 2.3 mg/kg). Many subjects
reported the occasional use of much higher doses (up to 500 mg, or 6 mg/kg).
The mean cumulative total dose of MDMA was estimated at 13.3 +/- 13.4g (range,
2.5 to 44.2g). Nine healthy controls (seven male, two female; mean age, 33 +/8
years; age range, 22 to 48 years), matched to the MDMA -using subjects for sex
and age, were selected from a larger sample of normal volunteers who had
undergone testing. Controls were screened for mental disorder and substance
abuse by a research psychiatrist using a structured review.

All subjects gave voluntary informed consent and were found to be free of
serious medical illness after physical, neurologic, and laboratory evaluations.
Among MDMA -using subjects, the last reported use of MDMA was a mean of
66+/-50 days before testing (range, 20 to 180 days). Both control and
MDMA -using subjects were instructed to remain free of psychoactive drugs for
at least three weeks before testing, although three MDMA -using subjects
admitted to infrequent marijuana use during that time. Testing was conducted on
an outpatient basis at the Clinical Neuroscience Research Unit, New Haven, Conn.
Control subjects were recruited locally, but MDMA -using subjects flew to New
Haven from their previous residences the day before testing.

Subjects fasted overnight and throughout the three-hour L-tryptophan test,
which began at 9 AM. The test dose consisted of 7 g of L-trypophan diluted in
500 mL of 0.45% saline solution that was infused through an antecubital vein
catheter over 20 minutes. Subjects were awake and supine with the head elevated
during the test. Blood for PRL measurement was obtained through the indwelling
catheter, which was kept patent by the slow infusion of saline solution.
Starting at least 60 minutes after catheter insertion, samples were obtained at
15 and 0.5 minutes before, and at 30, 40, 50, 60, 70, and 90 minutes after the
start of the L-tryptophan infusion. Visual analog scales (0 indicates "not at
all"; 100 indicates "most ever") and 11 different mood states (happy, sad,
drowsy, nervous, calm, depressed, anxious, energetic, fearful, mellow, high)
were scored by subjects at these times.

The L-tryptophan infusions were prepared by dissolving 8.4 g of L-tryptophan
in 600 mL of a 0.45% saline solution, with 50% sodium hydroxide added to bring
the solution to a pH of 7.4. Each 600-mL aliquot was sterilized by passage
through a 0.22-mm filter and tested for pyrogenicity and sterility before use.
Serum was assayed for PRL in control subjects using a radioimmunoassay (RIA) kit
(Serono Diagnostics Inc, Randolph, Mass) with intra-assay and interassay
coefficients of variation of 3% and 7%, respectively. Because manufacture of
this kit was discontinued, all serum from MDMA -using subjects was assayed for
PRL with a radioimmunoassay kit (Clinical Assays, Cambridge, Mass), with PAGE 25
Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989

intra-assay and interassay coefficients of variation of 6% and 11%,
respectively. Values obtained with the Serono assay were converted to values
comparable with those obtained with the Clinical Assay kit using a formula
(y=1.99x+14.343; r= .93) that we derived from the testing of 59 specimens with
both kits.

Data from the -15-minute and -0.5-minute time points were averaged to obtain
a single baseline value for each variable. The peak change in the PRL level was
determined by subtracting the baseline from the highest PRL value after
L-tryptophan infusion. The area under the curve (AUC) was calculated for PRL
responses using the trapezoidal rule. Because of nonnormal distributions,
comparisons of PRL data within and between subjects used the Wilcoxon
signed-rank and Wilcoxon rank-sum tests, respectively. Mood ratings were
subjected to analysis of variance (ANOVA) with repeated measures. Correlations
were determined using Spearman's p. All tests were two-tailed, with
significance set at P< .05.

RESULTS

The mean (+/-SD) baseline PRL concentration did not differ between
MDMA -using subjects (9.8+/-5.4 mu g/L) and controls (10.8+/-4.8 mu g/L).
After L-tryptophan infusion the peak increase in the PRL level over baseline was
robustly significant in the controls (11.0+/-13.1 mu g/L; P< .008), but failed
to reach statistical significance in the MDMA users (5.9+/-8.5 mu g/L; P<
.07). However, the difference in peak change in the PRL concentration between
the two groups was not statistically significant. There was no correlation
between the baseline PRL concentration and peak change in the PRL concentration
in the MDMA group (p=-0.12; not significant), whereas these variables were
significantly correlated in the controls (p=0.72; P< .03). The AUC PRL response
was also significantly greater than baseline in the controls (568.8+/-762.5 mu
g-min/L; P< .02), without reaching statistical significance in the MDMA users
(224.8+/-491.9 mu g-min/L; P< .09) (Figure). Again, the difference between
groups was not significant. Within the MDMA group, baseline PRL and peak PRL
concentrations and the AUC PRL did not correlate with total duration of MDMA
use, frequency of monthly use, "usual" dose, or estimated cumulative dose.

As in previous studies, L-tryptophan caused significant decreases in ratings
of energy (F=4.7; df=5,80; P< .001) and happiness (F=3.2; df=5,80; P< .02), and
increases in ratings of drowsiness (F=5.2; df=5,80; P< .0005). However, there
were no significant differences between diagnostic groups nor were there
differences in group responses to L-tryptophan.

COMMENT

Results of this exploratory study have suggested some intriguing differences
between MDMA users and healthy controls. The peak change in the PRL
concentration after L-tryptophan administration was 46% lower and the AUC in the
PRL response was 60% lower in MDMA -using subjects than in controls. Although
neither of these differences between groups was statistically significant, PRL
response measures within the control group were significantly greater than
baseline, while those within the MDMA group were not. Most subjects in both
groups had relatively modest increases in their PRL concentration after
administration of L-tryptophan, as would be expected in samples composed
primarily of men. [n12] However, the MDMA users seemed less likely to manifest
the very marked PRL responses demonstrated by some healthy subjects, PAGE 26
Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989

suggesting a degree of blunting in the responsivity of those subjects ordinarily
most sensitive to the effects of L-tryptophan.

This evidence suggesting altered 5-HT function in MDMA users is consistent
with preclinical studies in laboratory animals that have found MDMA to have
highly toxic effects on 5-HT neurons. Such studies have reported MDMA to
cause decreased brain levels of 5-HT and 5-hydroxyindoleacetic acid, [n1-n7]
decreased tryptophan hydroxylase activity, [n1] loss of 5-HT uptake sites,
[n2,n5] and degeneration of 5-HT axons and cell bodies. [n3,n6] While large
doses of MDMA (10 to 20 mg/kg) have been required to demonstrate these effects
in rodents, neurotoxicity in monkeys has been observed at doses comparable with
those used by our subjects (2.5 to 5.0 mg/kg). [n6,n7]

The present findings obviously must be interpreted cautiously. The suggested
attenuation in the PRL response to L-tryptophan in MDMA users must be
considered in light of the multiple factors known to affect PRL secretion. [n16]
It is also possible that our findings could reflect the nonspecific stress
experienced by MDMA subjects in flying to New Haven on the day before testing,
although our extensive experience with PRL in neuropsychiatric assessment does
not support this hypothesis.

Our failure to demonstrate more statistically significant effects of MDMA
probably reflects the small sample size of this study. Even assuming a large
effect of MDMA (standardized difference between group means=0.8), ruling out a
type II error (alpha=0.05; 1-beta=0.80) would require 26 subjects in each group.
In addition to larger samples and more rigorous methodology, other approaches to
assessing 5-HT function in humans might prove more sensitive to MDMA effects.
Such approaches include modification of the standard L-tryptophan test (eg, use
of lower or higher doses of L-tryptophan to determine if the "threshold" for an
increase in PRL is altered), use of tryptophan depletion techniques, and use of
direct 5-HT agonists (eg, m-chlorophenylpiperazine). At present, the nature of
MDMA's effects on 5-HT function in humans is unknown and the alteration in
function suggested by the results of this study cannot be considered
established. The potential for 5-HT neurotoxicity in humans is a pressing
concern, however, and the development of sensitive and reliable tests for
assessing this remains a challenge.

SUPPLEMENTARY INFORMATION: Accepted for publication Oct 19, 1988.

From the Department of Psychiatry, Yale University School of Medicine, and
the Connecticut Mental Health Center, Clinical Neuroscience Research Unit,
Ribicoff Research Facilities, New Haven, Conn (Drs Price, Krystal, and
Heninger); and the Department of Neurology, The Johns Hopkins University School
of Medicine, Baltimore (Dr Ricaurte).

Reprint requests to Department of Psychiatry, Yale University School of
Medicine, and the Connecticut Mental Health Center, Clinical Neuroscience
Research Unit, Ribicoff Research Facilities, 34 Park St, New Haven, CN 06508 (Dr
Price).

This study was supported in part by grants MH-00579, MH-36229, MH25642, and
DA-04060 from the US Public Health Service, Washington, DC; by the
Multidisciplinary Association for Psychedelic Studies, Sarasota, Fla; and by the
state of Connecticut. PAGE 27
Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989

Daniel X. Freedman, MD, was instrumental in facilitating the collaboration.
The laboratory, clinical, and research staffs of the Abraham Ribicoff Research
Facilities, New Haven, Conn, provided assistance. Huan Gao, MA, assisted in the
data analysis and Evelyn Testa typed the manuscript.

REFERENCES:
[n1.] Stone DM, Stahl DC, Hanson GR, Gibb JW: The effects of
3,4-methylenedioxymethamphetamine ( MDMA) and 3,4-methylenedioxyamphetamine
(MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol
1986;128:41-48.

[n2.] Battaglia G, Yeh SY, O'Hearn, Molliver ME, Kuhar MJ, DeSouza EB:
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy
serotonin terminals in rat brain: Quantification of neurodegeneration by
measurement of [<3>H] paroxetine-labeled serotonin uptake sites. J Pharmacol
Exp Ther 1987;242:911-916.

[n3.] Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS:
Biochemical and histological evidence that methylenedioxymethylamphetamine
( MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther
1987;241:338-345.

[n4.] Mokler DJ, Robinson SE, Rosecrans JA: (+/-)
3,4-Methylenedioxymethamphetamine ( MDMA) produces long-term reductions in
brain 5-hydroxytryptamine in rats. Eur J Pharmacol 1987;138:265-268.

[n5.] Schmidt CJ: Neurotoxicity of the psychedelic amphetamine,
methylenedioxymethamphetamine. J Pharmacol Exp Ther 1987;240:1-7.

[n6.] Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME,
Langston JW: (+/-) 3,4-Methylenedioxymethamphetamine selectively damages central
serotonergic neurons in nonhuman primates. JAMA 1988;260:51-55

[n7.] Ricaurte GA, DeLanney LE, Irwin I, Langston JW: Toxic effects of MDMA on
central serotonergic neurons in the primate: Importance of route and frequency
of drug administration. Brain Res 1988;446:165-168.

[n8.] Peroutka SJ: Incidence of recreational use of
3,4-methylenedioxymethamphetamine ( MDMA, 'ecstasy' ) on an undergraduate
campus. N Engl J Med 1987;317:1542-1543.

[n9.] Greer G, Tolbert R: Subjective reports on the effects of MDMA in a
clinical setting. J Psychoactive Drugs 1986;18:319-327.

[n10.] Peroutka SJ, Pascoe N, Faull KF: Monoamine metabolites in the
cerebrospinal fluid of recreational users of 3,4-methylenedioxymethamphetamine (
MDMA; 'ecstasy' ). Res Commun Drug Abuse 1987;8:125-138.

[n11.] Charney DS, Heninger GR, Reinhard JF Jr, Sternberg DE, Hafstead KM: The
effect of IV L-tryptophan on prolactin, growth hormone, and mood in healthy
subjects. Psychopharmacology 1982;78:38-43.

[n12.] Heninger GR, Charney DS, Sternberg DE: Serotonergic function in
depression: Prolactin response to intravenous tryptophan in depressed patients
and healthy subjects. Arch Gen Psychiatry 1984;41:398-402. PAGE 28
Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989

[n13.] Meltzer HY, Lowy MT: The serotonin hypothesis of depression, in Meltzer
HY (ed): Psychopharmacology: The Third Generation of Progress. New York, Raven
Press, 1987, pp 513-526.

[n14.] Price LH, Charney DS, Delgado PL, Heninger GR: Lithium treatment and
serotonergic function: Neuroendocrine and behavioral responses to intravenous
L-tryptophan in affective disorder patients. Arch Gen Psychiatry 1989;46:13-19.

[n15.] Gelgado PL, Charney DS, Price LH, Anderson G, Landis H, Heninger GR:
Dietary tryptophan restriction produces an upregulation of the neuroendocrine
response to infused tryptophan in healthy subjects. Soc Neurosci Abstr
1987;13:227.

[n16.] McCann SM: Lumpkin MD, Mizunuma H, Khorram O, Ottlecz A, Samson WK:
Peptidergic and dopaminergic control of prolactin release. Trends Neurosci
1984;5:127-131.

GRAPHIC: Figure, Mean (+/-SEM) prolactin response over time to intravenous
L-tryptophan in nine 3,4-methylenedioxymethamphetamine users and nine healthy
controls. PAGE 29
17TH ARTICLE of Level 1 printed in FULL format.

JAMA(R) 1988; 260: 1791

September 23, 1988 / September 30, 1988

SECTION: BOOKS

LENGTH: 500 words

TITLE: Designer Drugs, By M. M. Kirsch, 176 pp. $ 7.95, Minneapolis, CompCare
Publications, 1986.

AUTHOR: Peter L. Putnam, MD, MPH, Washington, DC

ED/SECT: Edited by Harriet S. Meyer, MD, Contributing Editor; adviser for
software, Robert Hogan, MD, San Diego.

TEXT:
Designer drugs, like designer clothes, are produced to sell. They are
created and marketed to a clientele of growing size that is looking for an ever
more varied or specific experience in a recreational drug. The designer drug is
usually a variation on a previously controlled substance.

These drugs, which are manufactured by altering the chemical structure of
narcotics, stimulants, or other recreational drugs, produce similar effects.
Often, as in the case of " Ecstasy, " the effect is preferred to that of the
original drug.

Crack has been successfully marketed because its use replaces free-basing in
convenient form. It is easily produced from cocaine with little equipment.
Similarly, phencyclidine (PCP) can be produced in almost any home or garage
laboratory by anyone who is willing and able to follow a simple cookbook.

Synthetic narcotics many times as potent as natural narcotics can be produced
by a chemist who has a little skill and ingenuity. This book, in fact,
describes one such chemist who apparently grew tired of working for the salary
he received from a large chemical company.

It is clear that the drugs described, such as "Ectasy," "crack," "dust,"
"china white," and MPTP (methylphenyltetrahydropyridine), represent a serious
health menace -- some because of the unknown potency and ease of overdose (such
as the fentanyl derivatives), some because of the inherent quality of the drug
itself (such as PCP), and others because of poor manufacturing techniques (such
as the fenantyl derivatives) that produce toxic analogues.

The book uses generous excerpts from a variety of sources, including the
producers, distributors, users, and law enforcement officers. Even though there
are vivid descriptions of the risks involved in the use of such drugs, it will
come as no surprise to the reader that there is convincing evidence in this book
that the manufacture, distribution, and sales of these drugs are a
well-established business worth billions of dollars.

This business has grown despite all attempts at federal and local
interdiction. It is not surprising, therefore, that the authors have PAGE 30
Copyright 1988 Amer. Medical Assn., JAMA, September 23, 1988

concluded that the way to stop the drug trade is not by increased police and
military action to halt manufacture and distribution but by means that will
reduce the demand. The book goes so far as to suggest that the most important
thing that prohibition has done has been to increase the price and profit in the
drug trade. The focus of intervention would be on increasing a sense of
individual responsibility and public awareness of the risks involved in drug
use.

This is not a clinical handbook and is of little value in the recognition and
treatment of chemical dependence. It is of significance in that it might
promote a rational debate about the issues. Certainly on these issues, as
physicians, we should be part of an informed electorate. It is quite clear that
the rhetoric of our representatives is often more emotional than rational. PAGE 31
18TH ARTICLE of Level 1 printed in FULL format.

JAMA(R) 1988; 260: 51-55

July 1, 1988

SECTION: CLINICAL INVESTIGATION

LENGTH: 3242 words

TITLE: (+/-) 3, 4-Methylenedioxymethamphetamine Selectively Damages Central
Serotonergic Neurons in Nonhuman Primates

AUTHOR: George A. Ricaurte, MD, PhD; Lysia S. Forno, MD; Mary A. Wilson; Louis
E. DeLanney, PhD; Ian Irwin; Mark E. Molliver, MD; J. William Langston, MD

ED/SECT: Thomas P. Stossel, MD, Section Editor

ABSTRACT: (+/-) 3, 4-Methylenedioxymethamphetamine ( MDMA) is a popular
recreational drug that has been proposed to be useful as an adjunct to
psychotherapy. This study assessed the neurotoxic potential of MDMA in
nonhuman primates. Monkeys were repeatedly administered doses (2.50, 3.75, and
5.00 mg/kg) of MDMA subcutaneously and analyzed for regional brain content of
serotonin and 5-hydroxyindoleacetic acid two weeks later. In all regions of the
monkey brain examined, MDMA produced a selective dose-related depletion of
serotonin and 5-hydroxyindoleacetic acid. These neurochemical deficits were
associated with evidence of structural damage to serotonergic nerve fibers. In
addition, MDMA produced pathological changes in nerve cell bodies in the
dorsal, but not median, raphe nucleus. These results indicate that MDMA is a
selective serotonergic neurotoxin in nonhuman primates and that humans using
this drug may be at risk for incurring central serotonergic neuronal damage.

TEXT:
RECREATIONAL abuse of controlled substance analogues ("designer drugs")
potentially poses a major health problem. [n1-n3] (+/-) 3,
4-Methylenedioxymethamphetamine ( MDMA) , variously known on the street as
" Ecstasy, " "Adam," or "XTC," [n4] is an analogue of the controlled substance
(+/-) 3, 4-methylenedioxyamphetamine (MDA). Presently, MDMA is one of the
more popular recreational drugs in the United States. [n5] It has been estimated
that 30 000 capsules of the drug are sold each month (R. K. Siegel, PhD,
unpublished data, 1985). It has also been proposed that MDMA may be useful as
an adjunct to insight-oriented psychotherapy. [n6, n7] This suggestion is based
largely on subjective reports that MDMA improves interpersonal communication
and enhances emotional awareness.

In 1985, the Drug Enforcement Agency placed MDMA on Schedule I of
controlled substances, citing increasing recreational use of this drug and
expressing concern that MDMA might cause neurological damage. [n8] This
concern arose largely because of evidence that MDA (the N-desmethyl derivative
of MDMA) destroys central serotonergic nerve terminals in rats. [n9] Recent
studies indicate that MDMA, like MDA, is toxic to serotonergic nerve terminals
in the rodent brain. [n10-n15] However, findings in rats appear to have done
little to deter recreational use of MDMA. At least in part, this may be
because studies in rodents do not always accurately predict drug toxicity in
humans For example, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is PAGE 32
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

relatively inactive in rats [n16, n17] but profoundly toxic in primates. [n18,
n19] Conversely, 1, 2, 3, 6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine,
an analogue of MPTP, is very toxic in rodents [n20] but inactive orally in
primates. [n21] In addition, differences in the way rodents and primates
metabolize amphetamines [n22] may alter the neurotoxic effects of these drugs.
For these reasons, we thought it critical to assess the neurotoxic activity of
MDMA in nonhuman primates.

METHODS

Subjects

Seventeen monkeys were used in this study. Eleven female squirrel monkeys
(Saimiri sciureus) 6 to 8 years of age and weighing 0.6 to 0.7 kg were used for
neurochemical studies and for anatomic studies of the raphe nuclei. Three
female rhesus monkeys (Macaca mulatta) 1.5 to 4.0 years of age and weighing 2.5
to 3.5 kg and two female and one male cynomolgus monkeys (Macaca fascicularis)
weighing 2.0 to 4.5 kg were used for immunohistochemical studies. No
differences in response to MDMA were noted among the three species.

Drug Treatment

The hydrochloride salt of MDMA was administered subcutaneously twice daily
at 0800 and 1700 hours for four consecutive days. This dosing regimen was used
to permit comparison of the present results with those previously obtained in
rodents. [n12, n14] For neurochemical studies, eight of 11 squirrel monkeys were
administered the following doses of MDMA according to the above-mentioned
schedule of drug administration: 2.50 mg/kg (n = 2), 3.75 mg/kg (n = 3), and
5.00 mg/kg (n = 3). The three remaining squirrel monkeys served as untreated
controls. For immunohistochemical studies, three of six macaque monkeys were
given the high-dose (5.00 mg/kg) regimen of MDMA; the other three untreated
monkeys served as controls.

Neurochemistry

Two weeks after drug treatment, the monkeys were killed under deep ether
anesthesia. The brain was removed from the skull, and the brainstem was
dissected away and placed in 10% formol saline for later anatomical study. The
forebrain was dissected over ice, and the various brain regions were isolated
for analysis of monoamine content. Concentrations of serotonin,
5-hydroxyindoleacetic acid, dopamine, and norepinephrine were measured by
reverse-phase high-performance liquid chromatography coupled with
electro-chemical detection, using the method of Kotake et al [n23] with minor
modification. [n24]

Histology

For routine histological studies of the raphe nuclei, the brainstems of three
monkeys that had received the 5-mg/kg regimen of MDMA two weeks previously
were immersion-fixed in 10% formol saline for one week prior to paraffin
embedding and staining. Sections were stained with hematoxylin-eosin, Luxol
fast blue (LFB)-cresyl violet, LFB-periodic acid-Schiff (PAS), or
LFB-Bielschowsky. For immunohistochemical studies of serotonergic nerve fibers
in the forebrain, three monkeys that had received the 5-mg/kg regimen of MDMA
two weeks previously and three controls were administered the monoamine PAGE 33
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

oxidase inhibitor trans-2-phenylcyclopropylamine (10 mg/kg intraperitoneally)
one hour prior to being killed by intracardiac perfusion under deep sodium
pentobarbital anesthesia. After the vascular tree was cleared with ice-cold
phosphate-buffered saline, perfusion was continued with 4% paraformaldehyde, pH
6.5, followed by 4% paraformaldehyde and 0.12% glutaraldehyde (pH 9.5). Tissue
blocks were placed in buffered 4% paraformaldehyde for seven hours and then in
10% dimethyl sulfoxide in phosphate-buffered saline overnight. Frozen sections
(30 mum) were incubated in an antiserotonin antisera (R8) diluted 1:5000 (or in
anti-tyrosine hydroxylase antisera diluted 1 U:48 mL) in phosphate-buffered
saline with 0.2% octyl phenoxy polyethoxyethanol (Triton X-100) and 1% normal
goat serum at 4 degrees C for three days. The antibody was visualized with a
peroxidase-labeled avidin-biotin complex (Vector Laboratories Inc, Burlingame,
Calif), and staining was enhanced with the osmiophilic reaction sequence of
Gerfen. [n25]

Statistics

After a simple one-way analysis of variance showed an F value of P<.05,
individual values were compared with the control using a two-tailed Student's t
test. Thereafter, regression analysis was performed and the 3df between groups
were partitioned into a regression component (1 df) and a deviation from
regression component (2df).

Materials

Dopamine hydrochloride, norepinephrine hydrochloride, and serotonin
creatinine sulfate were purchased from the Sigma Chemical Company, St Louis;
MDMA hydrochloride was provided by David Nichols, PhD, Department of Medicinal
Chemistry, Purdue University, Lafayette, Ind, and the National Institute of Drug
Abuse. Tranylcypromine (tranyl-2-phenylcyclopropylamine) was purchased from
Regis Chemical Company, Morton Grove, Ill. The rabbit antiserotonin was
generated by H. Lidov against serotonin conjugated to bovine serum albumin with
formaldehyde. Rabbit anti-tyrosine hydroxylase antisera was purchased from
Eugene Tech International Inc, Allendale, NJ.

RESULTS

Chemistry

Dose Response. -- Measurement of serotonin two weeks after drug treatment
showed that multiple subcutaneous doses of MDMA 92.50, 3.75, and 5.00 mg/kg)
produced a dose-related depletion of serotonin in the somatosensory cortex of
the monkey, with the lowest dose (2.50 mg/kg) producing a 44% depletion and the
highest dose (5.00 mg/kg) producing a 90% depletion (Table 1). Statistical
analysis (simple analysis of variance followed linear regression with
partitioning of the degrees of freedom into a regression component [1 df] and a
deviation from regression component [2 df] revealed that linearity explained
virtually all of the variability between doses (r = .97). The deviation from
regression component was not statistically significant (F [2, 8] = 2.28; P>.05).

Table 1. -- Dose-Related Decrease in Serotonin Concentration in the
Somatosensory Cortex of the Monkey Two Weeks After Administration of MDMA

[SEE ORIGINAL SOURCE] PAGE 34
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

Regional Effects. -- Multiple doses of MDMA also produced large depletions
of serotonin in the caudate nucleus, putamen, hippocampus, hypothalamus, and
thalamus of the monkey (Table 2). One of the most severely affected areas was
the cerebral cortex (Table 2), where the lowest dose (2.5 mg/kg) of MDMA
produced a 44% depletion of serotonin (Table 1).

Table 2. -- Regional Concentrations of Serotonin in the Monkey Brain Two Weeks
After Administration of MDMA (5 mg/kg)

[SEE ORIGINAL SOURCE]

Other Markers. -- Measurement of 5-hydroxyindoleacetic acid, another chemical
marker for serotonergic nerve fibers, showed that multiple doses of MDMA also
markedly reduced the concentration of this compound (Table 3). Concentrations
of 5-hydroxyindoleacetic acid were reduced by 84% in the neocortex, 76% in the
caudate nucleus, 75% in the hippocampus, and 40% in the hypothalamus.

Table 3. -- Decreased Concentration of 5HIAA in the Monkey Brain Two Weeks After
Administration of MDMA (5 mg/kg)

[SEE ORIGINAL SOURCE]

Selectivity. -- Measurement of dopamine and norepinephrine concentrations in
monkeys receiving the highest dose (5 mg/kg) showed that MDMA produced no
depletion of dopamine or norepinephrine (Table 4).

Table 4. -- Unchanged Concentrations of Dopamine and Norepinephrine in the
Monkey Brain Two Weeks After Administration of MDMA (5 mg/kg)

[SEE ORIGINAL SOURCE]

Morphology

Nerve Fibers. -- Immunohistochemical studies performed to assess the
structural integrity of serotonergic nerve fiber projections to the forebrain
demonstrated a marked reduction in the number and density of
serotoninimmunoreactive axons throughout the cerebral cortex of three of three
monkeys receiving the 5-mg/kg dose of MDMA (Fig 1). In addition, at higher
power, some serotonergic axons appeared swollen and misshapen. Staining with an
antibody to tyrosine hydrosylase revealed no evidence of damage to
catecholamine-containing nerve fibers in the cerebral cortex.

Cell Bodies. -- Examination of nerve cell bodies in the raphe nuclei of the
monkeys receiving the highest dose of MDMA (5 mg/kg) showed that while MDMA
produced no obvious cell loss in either the dorsal or median raphe nuclei, the
drug induced striking cytopathological changes in nerve cells of the dorsal
raphe nucleus. In three of three of these animals, hematoxylineosin-stained
paraffin sections of the dorsal raphe nucleus showed numerous, somewhat shrunken
nerve cells that contained brownish-red spherical cytoplasmic inclusions that
displaced the nucleus to the periphery of the cell (Fig 2, top left). In
LFB-PAS-stained sections, the inclusions appeared granular and were vividly PAS
positive (Fig 2, bottom right). This staining reaction suggests the presence of
an increased amount of ceroid or lipofuscin, possibly due to lipid peroxidation
of cell components and subsequent phagolysosomal activity. The presence of
lipofuscin within the inclusions was confirmed by a number of staining PAGE 35
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

procedures. Specifically, the granules were autofluorescent in ultraviolet
light, acid fast in Ziehl-Nielsen stain for lipofuscin, and positive with
Schmorl's reaction and Sudan Black B stain. Glycogen did not account for the
staining, as demonstrated in PAS stain with and without diastase.

No abnormal inclusion-bearing cells were found in the median raphe nucleus,
in other raphe nuclei, or in nonserotonergic nuclei such as the substantia nigra
or locus ceruleus. No similar inclusions were found in ten control monkeys of
varying ages (including three 15- to 20year-old monkeys), although some
increased lipofuscin pigment was occasionally found in the older animals.
(Seven of these ten animals were not formally part of the present study but had
served as controls in other experiments. The brains of these seven animals were
fixed by immersion in 10% formol saline.)

COMMENT

The major finding of this study is that central serotonergic neurons in
nonhuman primates are highly vulnerable to toxic effects of MDMA. Compared
with the rodent, [n10-n15] the primate has been found to be approximately four
to eight times more sensitive. In the monkey, a dose of 2.5 mg/kg produces a
44% depletion of serotonin in the cerebral cortex (Table 1). By contrast, in
the rat a 10- to 20-mg/kg dose is required to produce a comparable effect. [n14]
Also of note is the fact that in the primate small increments in dose from 2.50
mg/kg to 3.75 and 5.00 mg/kg produced 78% and 90% depletions of serotonin,
respectively (Table 1). This indicates that the dose-response curve of MDMA
in the monkey is steep, suggesting that the margin of safety of MDMA in humans
may be narrow.

The striking loss of serotonin-immunoreactive nerve fibers in the cerebral
cortex of the MDMA -treated primate (Fig 1) suggests that MDMA produces a
long-term depletion of serotonin by actually damaging serotonergic nerve fibers.
Axonal damage is further suggested by the swollen and distorted appearance of
some of the remaining fibers. Morphological evidence of nerve fiber damage is
important because it suggests that the prolonged depletion of serotonin induced
by MDMA is not merely due to a pharmacologic action of the drug, but rather
represents a neurotoxic effect. Anatomical studies in rats have led to a
similar conclusion. [n12, n14]

It is not yet known whether the effects of MDMA on serotonergic neurons in
the primate are permanent or reversible. Under some circumstances, regeneration
of serotonergic nerve fibers in the central nervous system can take place. [n26]
However, for axon regrowth to occur, the cell body must be preserved. It
remains to be determined if serotonin-containing cell bodies in the dorsal raphe
nucleus of the MDMA -treated primate survive beyond two weeks. If they do, and
if regeneration of nerve fibers takes place, it is still not certain that the
new fibers would establish normal connections. For functional integrity to be
maintained, normal connections would need to be reestablished. It will be
important to determine if this occurs in MDMA -treated animals.

This study provides the first direct evidence that serotonergic cell bodies,
as well as nerve fibers, are affected by MDMA. As shown in Fig 2, the
pathological change in cell bodies involves formation of intracytoplasmic
inclusions. These inclusions resemble the more eosinophilic but usually
PAS-negative inclusions recently described in monkeys given MPTP, [n27] a
compound that destroys nigral cell bodies. [n18, n19] Whether the inclusions PAGE 36
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

in the MDMA -treated primate herald nerve cell death or reflect a metabolic
response of the cell body to anoxal injury is not yet known but needs to be
ascertained because, if cell-body death occurs, the possibility of axonal
regeneration would be precluded.

The fact that abnormal inclusions were found in nerve cells of the dorsal,
but not median, raphe nucleus is noteworthy because it suggests that MDMA
selectively damages a particular subset of serotonergic neurons in the brain
(ie, the B7 group of Dahlstrom and Fuxe). That this is the case is also
suggested by the recent finding in the rat that serotonergic nerve fibers
arising from the dorsal, but not median, raphe nucleus are damaged by MDMA.
[n12, n28] Taken together, these findings indicate that MDMA is likely to be a
valuable new tool for further defining the functional anatomy of different
serotonergic cell groups in the mammalian brain.

The mechanism by which MDMA exerts its toxic effects on central
serotonergic neurons is at present not well understood. Like a number of other
ring-substituted amphetamines (eg, p-chloroamphetamine, fenfluramine
hydrochloride, MDA), MDMA appears to release serotonin. [n29-n31] Commins and
colleagues [n32] have proposed that MDMA and related compounds destroy
serotonergic neurons by releasing large amounts of serotonin and inducing
endogenous formation of 5, 6-dihydroxytryptamine, a well-known serotonergic
neurotoxin. [n33] However, other investigators [n34] maintain that the
degenerative effects of ring-substituted amphetamines may be mediated by a toxic
metabolite. It remains to be determined which, if either, of these
possibilities proves correct.

The results of this study raise concern that humans presently using MDMA
may be incurring serotonergic neuronal damage. The fact that monkeys are
considerably more sensitive than rats to the toxic effects of MDMA suggests
that humans may be even more sensitive. Before extrapolating the present
results to humans, however, it should be noted that monkeys were given multiple
rather than single doses of MDMA and that the drug was given subcutaneously
rather than orally. Humans generally take MDMA via the oral route and use
single 1.7- to 2.7-mg/kg doses of the drug, usually weeks apart, although some
individuals have used higher and more frequent doses. [n4] It remains to be
determined if administration of MDMA to monkeys in a pattern identical to that
used by humans produces similar neurotoxicity. In this regard, however, it is
important to bear in mind that the sensitivity of human and nonhuman primates to
the toxic effects of MDMA may not be the same. In fact, humans are generally
regarded as being more sensitive than monkeys to the toxic effects of drugs.
For example, humans are fivefold to tenfold more sensitive than monkeys to the
toxic effects of MPTP (compare references 19 and 35). In view of these
considerations, it would seem prudent for humans to exercise caution in the use
of MDMA. Caution may also be warranted in the use of fenfluramine, a
ring-substituted amphetamine that is closely related to MDMA and is currently
prescribed for obesity [n36] and autism. [n37]

From an experimental standpoint, MDMA appears to hold promise as a
systemically active toxin that can be used to study the functional consequences
of altered serotonergic neurotransmission in higher animals. Clinically, it
will be important to determine if humans who have taken MDMA show biochemical
signs of serotonergic neurotoxicity (eg, decreased 5-hydroxyindoleacetic acid
concentration in their cerebrospinal fluid). If they do, it will be critical to
ascertain if these individuals have any functional impairment. In particular, PAGE 37
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

such individuals will need to be evaluated for possible disorders of sleep,
mood, sexual function, appetite regulation, or pain perception, since central
serotonergic neurons have been implicated in all of these functions. [n38, n39]
These studies could offer the unique opportunity to better delineate the
neurobiology of central serotonergic neurons in the human brain, something that
until now has not been possible.

SUPPLEMENTARY INFORMATION: From the Departments of Neurology and Neuroscience,
The Johns Hopkins University School of Medicine, Baltimore (Drs Ricaurte and
Molliver and Ms Wilson); the Department of Pathology, Veterans Administration
Medical Center, Palo Alto, Calif (Dr Forno); and the institute for Medical
Research, San Jose, Calif (Drs Ricaurte, DeLanney, and Langston and Mr Irwin).

Reprint requests to the Department of Neurology, Francis Scott Key Medical
Center, The Johns Hopkins Health Center, 4940 Eastern Ave, Baltimore, MD 21224
(Dr Ricaurte).
This work was supported in part by the Multidisciplinary Association for
Psychedelic Studies, Sarasota, Fla; the Veterans Administration Medical Research
Program; National Institutes of Health grant NS21011 (M.E.M.); and California
Public Health Foundation Ltd subcontract 091A-701. One of the authors (M.A.W.)
was supported by the L. P. Markey Fund.

We thank Lorrene Davis-Ritchie, ZoAnn McBride, David Rosner, and Patrice Carr
for expert technical assistance.

REFERENCES:
[n1.] Ziporyn T: A growing industry and menace: Makeshift laboratory's designer
drugs. JAMA 1986;256:3061-3061.

[n2.] Baum RM: New variety of street drugs poses growing problem. Chem
Engineering News 1985;63:7-16.

[n3.] Hagerty C: 'Designer Drug' Enforcement Act seeks to attack problem at
source. Am Pharm 1985;NS25(10):10.

[n4.] Seymour RB: MDMA. San Francisco, Haight Ashbury Publications, 1986.

[n5.] Barnes DM: New data intensify the agony over ecstasy. Science
1988;239:864-866.

[n6.] Greer G, Tolbert R: Subjective reports of the effects of MDMA in a
clinical setting. J Psychoactive Drugs 1986;18:319-327.

[n7.] Cotton R: In the matter of MDMA scheduling. Brief including proposed
findings of fact and conclusions of law on behalf of Drs Greer and Grinspoon,
and Professors Bakalar and Roberts. Dewey, Ballantine, Bushby, Palmer and Wood,
1775 Pennsylvania Ave NW, Washington, DC 20006, Jan 15, 1986.

[n8.] Lawn JC: Schedules of controlled substances: Temporary placement of 3,
4-methylenedioxymethamphetamine ( MDMA) into Schedule I. Federal Register
1985;50(July 1):23118-23120.

[n9.] Ricaurte GA, Bryan G, Strauss L, et al: Hallucinogenic amphetamine
selectively destroys brain serotonin nerve terminals. Science PAGE 38
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

1985;222:986-988.

[n10.] Schmidt CJ, Wu L, Lovenberg W: Methylenedioxymethamphetamine: A
potentially neurotoxic amphetamine analogue. Eur J Pharmacol 1985;124:175-178.

[n11.] Stone DM, Stahl DS, Hanson GL, et al: The effects of 3,
4-methylenedioxymethamphetamine ( MDMA) and 3, 4-methylenedioxyamphetamine on
monoaminergic systems in the rat brain. Eur J Pharmacol 1986;128:41-48.

[n12.] O'Hearn EG, Battaglia G, De Souza EB, et al: Methylenedioxyamphetamine
(MDA) and methylenedioxymethamphetamine ( MDMA) cause ablation of serotonergic
axon terminals in forebrain: Immunocytochemical evidence. J Neurosci, in press.

[n13.] Schmidt CJ: Neurotoxicity of the psychedelic amphetamine,
methylenedioxymethamphetamine. J Pharmacol Exp Ther 1987;240:1-7.

[n14.] Commins DL, Vosmer G, Virus R, et al: Biochemical and histological
evidence that methylenedioxymethylamphetamine ( MDMA) is toxic to neurons in
the rat brain. J Pharmacol Exp Ther 1987;241:338-345.

[n15.] Battaglia G, Yeh SY, O'Hearn E, et al: 3, 4-Methylenedioxymethamphetamine
and 3, 4-methylenedioxyamphetamine destroy serotonin terminals in rat brain:
Quantification of neurodegeneration by measurement of [3H] paroxetine-labeled
serotonin uptake sites. J Pharmacol Exp Ther 1988;242:911-916.

[n16.] Chiueh CC, Markey SP, Burns RS, et al: N-methyl-4-phenyl-1, 2, 3,
6-tetrahydropyridine, a parkinsonian syndrome-causing agent in man and monkey,
produces different effects in the guinea pig and rat. Pharmacologist
1983;25:131-138.

[n17.] Boyce S, Kelley E, Reavill C, et al: Repeated administration of
N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine to rats is not toxic to striatal
dopamine neurones. Biochem Pharmacol 1984;33:1747-1752.

[n18.] Burns RS, Chieuh CC, Markey SP, et al: A primate model of parkinsonism:
Selective destruction of dopaminergic neurons in the pars compacta of the
substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc Natl
Acad Sci USA 1983;80:4546-4550.

[n19.] Langston JW, Forno LS, Rebert CS, et al: Selective nigral toxicity after
systemic administration of 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine
(MPTP) in the squirrel monkey. Brain Res 1984;292:390-394.

[n20.] Finnegan KT, Irwin I, DeLanney LE, et al: 1, 2, 3,
6-Tetahydro-1-methyl-4- (methylpyrrol-2-yl) pyridine: Studies on the mechanism
of action of MPTP. J Pharmacol Exp Ther 1988;242:1144-1151.

[n21.] Wilkening D, Vernier VG, Arthaud LE, et al: A parkinson-like neurologic
deficit in primates is caused by a novel 4-substituted piperidine. Brain Res
1986;368:239-246.

[n22.] Caldwell J, Dring LG, Williams RT: Metabolism of [14C] methamphetamine in
man, the guinea pig and the rat. Biochem J 1976;129:11-21.

[n23.] Kotake C, Heffner T, Vosmer G, et al: Determination of dopamine, PAGE 39
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

norepinephrine, serotonin and their major metabolic products in rat brain by
reverse-phase ion-pair high performance liquid chromatography with
electrochemical detection. Pharmacol Biochem Behav 1985;22:85-90.

[n24.] Ricaurte GA, Irwin I, Forno LS, et al: Aging and 1-methyl-4-phenyl-1, 2,
3, 6-tetrahydopyridine-induced degeneration of dopaminergic neurons in the
substantia nigra. Brain Res 1987;403:43-51.

[n25.] Gerfen C: The neostriatal mosaic: I. Compartmental organization of
projections from the striatum to the substantia nigra in the rat. J Comp Neurol
1985;236:454-463.

[n26.] Zhou FC, Azmitia EC: Induced homotypic collateral sprouting of
serotonergic fibers in the hippocampus of rat. Brain Res 1984;308:53-62.

[n27.] Forno LS, Langston JW, DeLanney LE, et al: Locus ceruleus lesions and
eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 1986;20:449-455.

[n28.] Manmounas LA, Molliver ME: Dual serotonergic projections to forebrain
have separate origins in the dorsal and median raphe nuclei: Retrograde
transport after selective axonal ablation by p-chloroamphetamine (PCA). Soc
Neurosci Abstr 1987;13:907.

[n29.] Sanders-Bush E, Sulser F: P-chloroamphetamine: In vivo investigations on
the mechanism of action of the selective depletion of cerebral serotonin. J
Pharmacol Exp Ther 1970;175:419-426.

[30.] Fuller RW, Perry KW, Molloy B: Reversible and irreversible phases of
serotonin depletion by 4-chloroamphetamine. Eur J Pharmacol 1975;33:119-124.

[n31.] Nichols DE, Lloyd DH, Hoffman AJ, et al: Effect of certain hallucinogenic
amphetamine analogs on the release of [3H] serotonin from rat brain
synaptosomes. J Med Chem 1986;25:530-536.

[n32.] Commins D, Axt K, Vosmer G, et al: Endogenously produced 5,
6-dihydroxytryptamine may mediate the neurotoxic effects of
para-chloroamphetamine. Brain Res 1987;403:7-14.

[n33.] Baumgarten HG, Klemm HP, Lachenmayer L, et al: Mode and mechanism of
action of neurotoxic indoleamines: A review and a progress report. Ann NY Acad
Sci 1978;305:3-24.

[n34.] Molliver ME, O'Hearn E, Battaglia G, et al: Direct intracerebral
administration of MDA and MDMA does not produce serotonin neurotoxicity. Soc
Neurosci Abstr 1986;12:1234.

[n35.] Langston JW, Ballard PA, Tetrud JW, et al: Chronic parkinsonism in humans
due to a product of meperidine-analog synthesis. Science 1983;219:979-980.

[n36.] Craighead LW, Stunkard AJ, O'Brien R: Behavior therapy and
pharmacotherapy for obesity. Arch Gen Psychiatry 1981;38:763-768.

[n37.] Ritvo ER, Freeman DJ, Geller E, et al: Effects of fenfluramine on 14
outpatients with the syndrome of autism. J Am Acad Child Psychiatry
1983;22:549-556. PAGE 40
Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988

[n38.] Barchas J, Usdin E (eds): Serotonin and Behavior. New York, Academic
Press Inc, 1973.

[n39.] Messing RB, Pettibone DJ, Kaufman N, et al: Behavioral effects of
serotonin neurotoxin: An overview. Ann NY Acad Sci 1978;305:480-496.

GRAPHIC: Figure 1, Serotonin-immunoreactive fibers in somatosensory cortex (area
3) of cynomolgus monkey. Serotonergic axons form dense terminal plexus in
control animal, in methylenedioxymethamphetamine ( MDMA) -treated animal (5
mg/kg), there is marked decrease in density of serotonergic axons after a
two-week survival period. Changes in somatosensory cortex are representative of
serotonergic denervation caused by MDMA throughout cerebral cortex. Scale bar,
100 mum; Figure 2, Nerve cells in dorsal raphe nucleus of
methylenedioxymethamphetamine ( MDMA) -treated squirrel monkey. Several of
slightly shrunken nerve cells contain intracytoplasmic inclusion
(hematoxylin-eosin, x 550). Nerve cells in dorsal raphe nucleus from untreated
11-year-old squirrel monkey, (hematoxylin-eosin, x 550). Close-up view of one of
abnormal inclusion-bearing cells in dorsal raphe nucleus of the MDMA -treated
squirrel monkey (hematoxylin-eosin, oil immersion, x 1480). Close-up view of
nerve cells in dorsal raphe nucleus to show vividly periodic
acid-Schiff-positive granular inclusions in perikarya of several nerve cells
(Luxol fast blue-periodic acid-Schiff stain, oil immersion, x 1480). PAGE 41
21ST ARTICLE of Level 1 printed in FULL format.

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. PAGE 42
Copyright 1988 Amer. Medical Assn., JAMA, March 18, 1988

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 PAGE 43
Copyright 1988 Amer. Medical Assn., JAMA, March 18, 1988

3,4-methylenedimethoxymethamphetamine ( MDMA, 'Ecstasy' ) on an undergraduate
campus. N Engl J Med 1987;317:1542-1543. PAGE 44
26TH ARTICLE of Level 1 printed in FULL format.

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. PAGE 45
Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987

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. PAGE 46
Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987

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. PAGE 47
Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987

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. PAGE 48
Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987

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. PAGE 49
Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987

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. PAGE 50
Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987

[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.

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