Correspondence

Parkinsonism after Taking Ecstasy

N Engl J Med 1999; 340:1443May 6, 1999

Article

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. 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

5 References

1. 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.
   

2. 2

   Steele TD, McCann UD, Ricaurte GA. 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy“): pharmacology and toxicology in animals and humans. Addiction 1994;89:539-551
   CrossRef | Web of Science | Medline

3. 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;36:765-770
   CrossRef | Web of Science | Medline

4. 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
   CrossRef | Web of Science | Medline

5. 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.)
   

Citing Articles (16)

Citing Articles

1. 1

   Yen F Tai, Rosa Hoshi, Catherine M Brignell, Lisa Cohen, David J Brooks, H Valerie Curran, Paola Piccini. (2011) Persistent Nigrostriatal Dopaminergic Abnormalities in Ex-Users of MDMA (‘Ecstasy’): An 18F-Dopa PET Study. Neuropsychopharmacology 36:4, 735-743
   CrossRef

2. 2

   Stanley Fahn, Joseph Jankovic, Mark Hallett. 2011. Atypical parkinsonism, parkinsonism-plus syndromes, and secondary parkinsonian disorders. , 197-240.
   CrossRef

3. 3

   John C.M. Brust. (2010) Substance abuse and movement disorders. Movement Disorders 25:13, 2010-2020
   CrossRef

4. 4

   James Allen Wilcox, Aidee Herrera Wilcox. (2009) Movement Disorders and MDMA Abuse. Journal of Psychoactive Drugs 41:2, 203-204
   CrossRef

5. 5

   John C.M. Brust. 2007. Amphétamine et autres psychostimulants. , 129-170.
   CrossRef

6. 6

   Ryan M. Smith, Madalina Tivarus, Heather L. Campbell, Ashleigh Hillier, David Q. Beversdorf. (2006) Apparent Transient Effects of Recent ???Ecstasy??? Use on Cognitive Performance and Extrapyramidal Signs in Human Subjects. Cognitive and Behavioral Neurology 19:3, 157-164
   CrossRef

7. 7

   2006. Methylenedioxymetamfetamine. , 2292-2307.
   CrossRef

8. 8

   Maartje M.L. De Win, Gerry Jager, Hylke K.E. Vervaeke, Thelma Schilt, Liesbeth Reneman, Jan Booij, Frank C. Verhulst, Gerard J. Den Heeten, Nick F. Ramsey, Dirk J. Korf, Wim Van Den Brink. (2005) The Netherlands XTC Toxicity (NeXT) study: objectives and methods of a study investigating causality, course, and clinical relevance. International Journal of Methods in Psychiatric Research 14:4, 167-185
   CrossRef

9. 9

   Lisa Jerome, Rick Doblin, Michael Mithoefer. (2004) Ecstasy use-Parkinson's disease link tenuous. Movement Disorders 19:11, 1386-1386
   CrossRef

10. 10

    M. Isabel Colado, Esther O’Shea, A. Richard Green. (2004) Acute and long-term effects of MDMA on cerebral dopamine biochemistry and function. Psychopharmacology 173:3-4, 249-263
    CrossRef

11. 11

    Padraig O'Suilleabhain, Cole Giller. (2003) Rapidly progressive parkinsonism in a self-reported user of Ecstasy and other drugs. Movement Disorders 18:11, 1378-1381
    CrossRef

12. 12

    Stephen J. Kish. (2003) What is the evidence that Ecstasy (MDMA) can cause Parkinson's disease?. Movement Disorders 18:11, 1219-1223
    CrossRef

13. 13

    Kuniyoshi, Sandra M., Jankovic, Joseph, . (2003) MDMA and Parkinsonism. New England Journal of Medicine 349:1, 96-97
    Full Text

14. 14

    Jina V. Pham, Talia Puzantian. (2001) Ecstasy: Dangers and Controversies. Pharmacotherapy 21:12, 1561-1565
    CrossRef

15. 15

    Ralph Wood, Linda B. Synovitz. (2001) Addressing the Threats of MDMA (Ecstasy): Implications for School Health Professionals, Parents, and Community Members. Journal of School Health 71:1, 38-41
    CrossRef

16. 16

    (1999) More about Parkinsonism after Taking Ecstasy. New England Journal of Medicine 341:18, 1400-1401
    Full Text