Review and commentary; Ilsa Jerome, November 2003

Kish (2003) wrote an editorial to accompany the publication of a case report of Parkinson’s disease in an individual who used Ecstasy (O’Suilleahbain and Giller 2003) appearing in the same journal. The editorial examines relevant research on MDMA neurotoxicity, considers previous case reports, and offers a prescription for future treatment of this topic. The editorial concludes that research in humans and non-human primates fails to support a causal link between MDMA and Parkinsonian symptoms, and that previous case studies do not provide enough information to for drawing any firm conclusions about the relationship between Ecstasy use and etiology of Parkinsonian symptoms. Because case reports of adverse events after recreational drug use can shape drug policy decisions, Kish argues that such reports need to present information in a balanced manner, with scientifically justifiable conclusions. He also argues for the application of rigorous peer review when considering whether to publish accounts of adverse events after drug use, and not holding these accounts to lower standards than are applied to other areas of medical case reporting.

The case report the editorial was written to accompany concerns the development of Parkinsonian symptoms, including rigidity, slow gait, and tremor in a 38-year old man with no family history of Parkinson’s disease. A succession of treatments was tried, including pramipexole (not well tolerated), L-DOPA/carbidopa, selegiline, (L-Deprenyl), and subthalamic stimulation. Each treatment produced moderate improvement followed by decline in improvement. Though initially denying any illicit drug use, a positive cocaine screen led the patient to admit cocaine use. On learning of other cases of PD reported in Ecstasy users, the patient acknowledged prior Ecstasy use, including a one-month period of daily use of 2 to 4 tablets of MDMA/Ecstasy, at an estimated 200-400 mg per session, given estimated tablet contents for that time period (Siegel 1986). He claimed he also continued to use Ecstasy for the next ten years, and he reported cocaine use throughout his 20s and 30s. In their report, the authors stress that the association between MDMA and development of PD could have been coincidental.

After briefly summarizing the three case reports of Parkinsonian symptoms in former Ecstasy users, Kish asks whether fears of middle aged Parkinson’s disease arising in Ecstasy users are well-founded and how information from the case reports should be presented to the medical community. Kish notes that while research in non-human animals has demonstrated that MDMA can be neurotoxic to serotonin axons, "it is not possible to derive any clear conclusion or consensus" from imaging investigations of serotonin transporter (SERT) in humans because "of the uncertainty in most, and perhaps all of the cases, that SERT was ever measured reliably" (p. 1219). Kish recounts discrepancies and flaws in measurement in prior imaging studies, suggesting that to date, studies in humans do not offer definitive evidence for Ecstasy-induced serotonin toxicity. For instance, the degree of apparent reduction in serotonin transporter (SERT) sites reported in two comparisons of Ecstasy users and non-Ecstasy using controls that used the same radioactively labeled drug (or "ligand") are wildly different (McCann et al. 1998 versus Buchert et al. 2003). Furthermore, Kish concludes that evidence supporting MDMA toxicity to human dopamine neurons is entirely lacking. After cautioning the reader that it may "never be possible to establish whether low striatal levels of dopamine terminal markers in humans indicates actual physical loss of dopamine nerve terminals," Kish describes findings from imaging studies of dopamine transporter sites in humans. These studies failed to find evidence of reduced dopamine transporter (Reneman et al. 2002; Semple et al. 1999). As well, a post-mortem study conducted by the author and his colleagues also failed to see any signs of dopamine toxicity in a heavy Ecstasy user, even though evidence of serotonin toxicity was present (Kish et al. 2000). Lastly, the only study to have reported MDMA-induced dopamine toxicity in non-human primates (Ricaurte et al. 2002) has since been retracted after it was discovered that the animals had received the psychostimulant methamphetamine, and not MDMA. Since Parkinson’s disease results from damage to dopamine neurons, and since research has so far failed to find any indications of dopamine toxicity after MDMA, the preponderance of the scientific evidence fails to support a link between Ecstasy use and Parkinson’s disease, regardless of the strength of evidence for MDMA’s toxicity to serotonin neurons.

Kish then considers other sources of evidence for a link between Ecstasy use and Parkinsonian symptoms, including the three published case reports of Parkinsonian symptoms in people who have used Ecstasy. First, Kish questions the significance of findings of self-reported twitches and tremors in regular Ecstasy users (Parrott et al. 2002). He notes that diagnosis was not formal, and Ecstasy use was not forensically determined, as through analysis of blood, urine or hair. When considering the case reports, Kish notes that one of three case reports does not provide sufficient information for establishing a diagnosis of Parkinson’s disease (Kuniyoshi and Jankovic 2003), and another case study was of Parkinson’s disease that was unresponsive to L-DOPA (Mintzer et al. 1999), a condition that may differ from PD that is responsive to treatment with L-DOPA. Furthermore, the editorial notes that two of three case studies do not acknowledge the widespread use of Ecstasy in the general population, thus failing to address issues of expected co-occurrence of PD in people reporting Ecstasy use. Given that research so far fails to support MDMA dopamine toxicity in humans, and given the large numbers of people who have used Ecstasy, Kish considers coincidental occurrence to be the most likely explanation for Parkinsonian symptoms in Ecstasy users. In other words, the two events are independent of each other.

In conclusion, Kish argues for more rigorous review in publishing further cases of Parkinsonism in Ecstasy users, or any other adverse events arising from recreational drugs. He states, "It is reasonable to publish such single case studies for which the causal link to a toxic substance is suggestive, but only if the information is provided to the reader in a balanced manner and can be justified on scientific grounds." (p. 1221-1222). Providing a balanced and scientific account in a case study is especially important because such case reports can serve as the basis for drug policy decisions. Previous case studies have not been as rigorous or as balanced as would be expected for reports with such significant consequences. In conclusion, Kish argues for employing a rigorous peer review process when publishing future case reports of movement disorders in Ecstasy users.

Not acknowledged in Kish’s critique of evidence of an MDMA-Parkinson’s disease link is the superiority of epidemiological studies over case reports in establishing causality. Comparing rates of diagnosed Parkinson’s disease in appropriately matched groups of Ecstasy users and non-users would seem to be a better way of establishing this link. MDMA exposure in epidemiological studies should be established through a more accurate means than self-report whenever possible, and prospective designs should be favored over retrospective designs. Possible effects of regular use of other drugs, such as amphetamine or methamphetamine, should also be taken into account, since many Ecstasy users are polydrug users. Hence even a finding of higher rates of movement disorders in Ecstasy users cannot be treated as evidence for a direct relationship between the two events, particularly given the lack of supportive evidence for MDMA-associated dopamine toxicity in animals other than mice.

Overall, this editorial highlights the difficulties in drawing conclusions from case reports of Parkinson’s disease in Ecstasy users, particularly when they fail to address relevant research, do not confirm the presence or extent of exposure to MDMA in each case, and fail to give contextual information about rates of Ecstasy use in the general population.

Correction:

Kish reports that Ricaurte and colleagues administered methamphetamine to "all" animals in the retracted study (p. 1220). However, in their retraction, Ricaurte et al. assert that "all but one" animal received methamphetamine.

Further Reading

Some of the issues and arguments presented in this piece are also presented in a critical review of MDMA research also authored by Kish and published in the journal Pharmacology, Biochemistry and Behavior in 2002.

Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M (2003) Long-term effects of "Ecstasy" use on serotonin transporters of the brain investigated by PET. J Nucl Med 44: 375-84.

Kish SJ, Furukawa Y, Ang L, Vorce SP, Kalasinsky KS (2000) Striatal serotonin is depleted in brain of a human MDMA (Ecstasy) user. Neurology 55: 294-296.

Kish SJ (2003) What is the evidence that Ecstasy (MDMA) can cause Parkinson’s disease? [Editorial] Movement Disorders 18; 1217-1223.

Kuniyoshi S.M. and Jankovic J. (2003) MDMA and Parkinsonism. N Engl J Med 349: 96-97.

McCann U, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998) Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain serotonin neurons in human beings. The Lancet, 352, 1433-1437.

Mintzer S. et al. (1999) Parkinsonism after taking ecstasy. N Engl J Med 340: 1443.

O’Suilleahbain P, Giller C (2003) Rapidly progressive Parkinsonsism in a self-reported user of Ecstasy and other drugs. Movement Disorders 18; 1378-1403.

Parrott AC, Buchanan T, Heffernan TM, Scholey A, Ling J, Rodgers J (2003) Parkinson’s disorder, psychomotor problems and dopaminergic toxicity in recreational Ecstasy/MDMA users. Psychopharmacology (Berl). 2003: 167, 449-450.

Parrott AC, Buchanan T, Scholey AB, Heffernan T, Ling J, Rodgers J (2002) Ecstasy/MDMA attributed problems reported by novice, moderate and heavy recreational users. Hum Psychopharmacology 17: 309-312.

Reneman L, Booij J, Lavalaye J, de Bruin K, Reitsma JB, Gunning B, den Heeten GJ, van Den Brink W (2002) Use of amphetamine by recreational users of ecstasy (MDMA) is associated with reduced striatal dopamine transporter densities: a [123I]beta-CIT SPECT study-- preliminary report. Psychopharmacology (Berl) 159: 335-340.

Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann UD (2003B) Retraction. Science 301: 1429.

Semple DM, Ebmeier KP, Glabus MF, O'Carroll RE, Johnstone EC (1999) Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA ('ecstasy') users. Br J Psychiatry 175: 63-69.

Siegel RK (1986) MDMA; Non-medical use and intoxication. J Psychoactive Drugs, 18; 349-354.