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MAPS: MDMA and Parkinson's
To All:
If we wait long enough, MDMA will be linked to chromosome damage. A report
suggesting a possible link between MDMA and Parkinson's appeared in the New
England Journal of Medicine. Parkinson's is caused by substantially
decreased dopamine levels. There must be about 90% decreases before
Parkinson's appears. MDMA does not decrease dopamine levels in humans. This
has been confirmed in numerous studies including those by Dr. George
Ricaurte, the principal proponent of the idea of MDMA neurotoxicity. MDMA may
decrease serononin levels in human users but whether this does really happen
or, if it does, whether it has any functional or behavioral consequences, is
still controversial. Decreased serotonin levels have no relationship
whatsoever to Parkinson's.
Dr. Charles Grob, Matt Baggot, myself, and Dr. Adam Darnell (who is working
on the MAPS-supported effort to obtain permission in Israel to study MDMA in
the treatment of PTSD) all attended a recent conference on the neurotoxicity
of amphetamines, sponsored by the American Society for Pharmacology and
Experimental Therapeutics (ASPET). Dr. Ricaurte was there and presented his
latest data. There is absolutely no evidence that MDMA causes persisting
reductions in dopamine in humans. The most that can be said about MDMA and
serotonin is that a small group of people who have taken massive amounts of
MDMA have within the normal range of serotonin transporter reuptake sites but
had, on average, about 25% lower levels than a group of controls matched on
some parameters (but not personality types, which can be related to serotonin
levels). Whether MDMA causes persisting reductions in serotonin and
serotonin transporter reuptake sites can only be determined conclusively by
studying people before and after they are administered MDMA, not by comparing
people to supposedly matched control groups. The MDMA group did not show any
symptoms of Parkinson's, or depression. No evidence at the conference
remotely suggested or hinted that MDMA caused Parkinson's. Parkinson's was
discussed at the conference as being a separate issue not linked to MDMA.
Now to the report in the New England Journal of Medicine:
Dan Perrine posted the following message to another e-mail list:
In this weeks issue of the New England Journal of Medicine there is a
correspondance from the University of Michigan regarding a man who seems to
have developed Parkinsonism, possibly from taking MDMA or from some
contaminant in the MDMA.... Or from something else, this all being somewhat
hypothetical. Nonetheless.....
The letter reads as follows:
To the Editor:
Recreational use of 3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy"),
a hallucinogen, has increased both in Europe and the United States. (1) This
substance is manufactured in illicit laboratories from a variety of organic
ketone precursors. MDMA, which is structurally related both to the stimulant
amphetamine and to the hallucinogen mescaline, promotes the release of both
serotonin and dopamine from synaptic terminals. (2) We report a case of
parkinsonism after repeated use of this drug.
A 29-year-old man had slight clumsiness of his upper and lower extremities
in August 1998. During the following four weeks he began to have difficulty
walking and lost the ability to write and to drive. He was unable to
continue his work in retail merchandising and then could not live
independently. The results of magnetic resonance imaging,
electroencephalography, lumbar puncture, and positron-emission tomography
with [18F]fluorodeoxyglucose were normal. Tests for antibodies to the human
immunodeficiency virus were negative on two occasions. Eleven weeks after
the onset of symptoms, examination revealed a disturbance in gait and
impairment of fine coordination. The patient's condition continued to
worsen, and eight weeks later examination revealed bradykinesia of the face
and limbs, absence of blinking, hypokinesia in relation to speech, postural
instability, and a markedly parkinsonian gait. Cognitive function was
normal, and there was no tremor.
The patient had ingested MDMA nine times in 1997 and once more in May 1998.
He denied having used any other illicit substances except cannabis.
Treatment with the maximal tolerated doses of levodopa and pramipexole did
not improve his symptoms.
Parkinsonism has not previously been associated with the use of MDMA.
Although we have no firm evidence of a causal relation between this
patient's drug use and his parkinsonism, there are no other tenable
explanations. Idiopathic Parkinson's disease rarely develops in this age
group and is responsive to medication, and neither it nor parkinsonism of
any other neurodegenerative cause progresses this rapidly. Our patient's
condition most closely resembled the parkinsonism produced by
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a byproduct of the illicit
manufacture of meperidine, which is highly toxic to neurons of the
substantia nigra. Positron-emission tomographic studies have shown that even
subclinical exposure to this substance produces progressive nigrostriatal
damage, making the subject vulnerable to subsequent parkinsonism. (3)
We hypothesize that our patient may have had parkinsonism as a result of a
delayed neurotoxic effect of MDMA on the substantia nigra and striatum.
There is evidence for such dopaminergic neurotoxicity in animals, (4,5) and
delayed neurotoxicity in humans could occur as a result of neuronal damage
induced by free radicals. (5) Recent research regarding the neurotoxic
effects of this substance has focused on serotonergic neurotoxicity and
impairment of memory. (6) This patient's case suggests that the effects of
MDMA on dopaminergic systems should be studied further to characterize more
fully the dangers of its use.
Scott Mintzer, M.D.
Susan Hickenbottom, M.D.
Sid Gilman, M.D.
University of Michigan
Ann Arbor, MI 48109
References
1. Johnston LD, O'Malley PM, Bachman JG. National survey results on drug use
from the Monitoring the Future Study, 1975-1995. Vol. 2. College students
and young adults. Rockville, Md.: National Institutes on Drug Abuse, 1997.
Return to Text
2. Steele TD, McCann UD, Ricaurte GA. 3,4-Methylenedioxymethamphetamine
(MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans.
Addiction 1994;89:539-51.
Return to Text
3. Vingerhoets FJ, Snow BJ, Tetrud JW, Langston JW, Schulzer M, Calne DB.
Positron emission tomographic evidence for progression of human MPTP-induced
dopaminergic lesions. Ann Neurol 1994;36:765-70.
Return to Text
4. Obradovic T, Imel KM, White SR. Repeated exposure to
methylenedioxymethamphetamine (MDMA) alters nucleus accumbens neuronal
responses to dopamine and serotonin. Brain Res 1998;785:1-9.
Return to Text
5. Seiden LS, Sabol KE. Methamphetamine and methylenedioxymethamphetamine
neurotoxicity: possible mechanisms of cell destruction. In: Majewska MD, ed.
Neurotoxicity and neuropathology associated with cocaine abuse. NIDA
research monograph 163. Washington, D.C.: Government Printing Office, 1996.
(DHHS publication no. (ADM) 96-4019.)
The WWW site for the letter with links to the references is:
http://www.nejm.org/content/1999/0340/0018/1443a.asp
Daniel M. Perrine, Ph.D.
Loyola College in Maryland
Chemistry Department, KH 468
4501 North Charles St.
Baltimore, MD 21210-2699
voice: 410-617-2717
fax: 410-617-2803
email: dmp@xxxxxxxxxx
Now here is a message on the topic from Nicholas Cozzi:
*Very* hypothetical. It seems the authors are really grasping here. Why
not do a PET scan with a dopamine transporter ligand rather than
[18]F-deoxyglucose? FDG is nonspecific. Was the MDMA even authentic?
Despite millions of MDMA users and over 15 years of publications, I have
never read or heard any reports about any motor impairment ala Parkinson's
disease associated with MDMA. To their credit, the authors call for more
research; I'm all for that.
Nicholas V. Cozzi, Ph.D.
Department of Pharmacology
East Carolina University School of Medicine
Greenville, NC 27858
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