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A Review of a Recent
Claim Of Parkinson's from "Recreational" MDMA Use
by Earth Erowid
Sep 27, 2002
EROWID NOTE: After we published thd review below questioning the research findings, the lab retracted their article after it was discovered that they administered Methamphetamine instead of MDMA in this experiment. This caused huge damage to the credibility of the lab.


Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy"),
by Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann UD.
Science Sept 27, 2002. 2260-2263

View This Article's Index Page

In the September 27th, 2002, issue of Science, George Ricaurte published a scientifically controversial paper that claimed to show MDMA (ecstasy) causes yet another type of brain damage.

Ricaurte's team injected 5 squirrel monkeys and 5 baboons with 2 mg per kilogram of MDMA (subcutaneously and intramuscularly, respectively) with the intended regimen consisting of 3 separate doses each spread 3 hours apart. While MDMA is well known for its serotonin neurotoxicity at high doses in laboratory settings, this paper reports "severe" and "profound" damage to the dopamine system. The research found dramatically lower striatal concentrations of dopamine (often written as 'DA') and DOPAC, a dopamine metabolite, in the dissected brains of the monkeys. These are novel findings for MDMA, which is one of the best studied recreational psychoactives.

Few media descriptions of this research mention that the results reported in this paper are inconsistent with previous research. Other research has failed to find dopamine-system damage when neurotoxic doses of MDMA were given to rats and non-human primates. Similarly, researchers scanning the brains of human ecstasy users (Reneman 2002, Semple 1999) and conducting the only direct examination of a brain of a deceased heavy ecstasy user (Kish 2000) found no dopamine-related damange.

Ricaurte's team suggests not only that extreme doses of MDMA can cause dopamine "damage", but that the doses they used were equivalent to "common" recreational doses. They suggest that this damage could lead to Parkinson's disease for users later in life. As the first research to document severe dopamine reductions resulting from MDMA toxicity, Ricaurte's paper is interesting, but its conclusions have been sensationalized by some news outlets and the importance of the findings exaggerated. Moreover, its claims of a future Parkinson's epidemic are not supported by the evidence.

The primary--and fundamentally invalidating--problem with the paper is that the authors claim that their choice of doses (injected 2 mg/kg of MDMA, 3 times in 6 hours) is representative of normal, oral, recreational doses used by humans.

The question of how to scale and compare dosages across animals is extremely complicated. Different animals have different metabolisms, different enzymes, and can simply react differently to the equivalent amount of a given drug. While animal research can often yield valid results for humans, when research animals react very differently than humans it should be cause for questioning how valid the assumptions are. For more information about interspecies scaling, see Baggott 2001 and Vollenweider 2001.

Of the 10 non-human primates the researchers report giving this regimen to, 2 died immediately, and 2 others exhibited symptoms of such extreme physical distress that the researchers stopped the experiment in the middle and chose not to give these two monkeys the third injection.

This result (20% fatalities and 20% severe physical distress) should be a very clear indicator that these doses were not equivalent to normal recreational human doses. The researchers' inter-species dose extrapolation is clearly flawed. In the United States, Baggott et al. estimated that the number of Emegency Department (ED) visits by Ecstasy-users is currently between 2.9 to 3.6 per 10,000 ecstasy-use sessions (Baggott 2001). These are 3 in 10,000 emergency-room visits, not deaths. An Australian study estimated that there were around 11 ED visits per 10,000 use sessions. According to Baggott, "Deaths relating to ecstasy use are poorly documented in the US. Gore (1999) estimated that 0.21 ecstasy-related deaths per 10,000 illicit users occurred annually in England from 1995-96 and 0.87 ecstasy-related deaths per 10,000 illicit users occurred annually in Scotland from 1995-97."

Because recent surveys in the US indicate that over 10% of the adult population under 25 has tried ecstasy, to suggest that 1 in 5 "single recreational dose regimens" could be fatal goes well beyond absurd. It is improper and raises the question of the authors' motives. If the researcher's dose-scaling was correct, it would suggest that millions of people are dying each year at parties. Yet Ricaurte's article fails even to mention this discrepancy nor does it offer any indication why this assumption should be taken seriously.

"The sheer number of ecstasy users indicates that there would be millions of these patients presenting for treatment," said Jon Cole, a cognitive neuroscientist at the University of Liverpool, in the summary of Ricaurte's paper from the same issue of Science (Holden 2002). Even if the researchers killed only 1 out of 100 monkeys they tested with a given regimen, it would indicate their dose scaling was flawed.

The authors claim that subcutaneous (s.c.) and intramuscular injection (i.m.) are equivalent to human oral use. Ricaurte writes "It is possible that humans are at a decreased risk for neurotoxic injury because of differences in the route of administration. However, in the case of MDMA, oral administration offers little or no significant neuroprotection." This statement seems to contradict the research Ricaurte cites to support this view, including one of his own papers which states: "Orally administered MDMA was approximately one-half as effective as subcutaneously administered drug." (Ricaurte 1988)

Another question is why most previous research, including that done by Dr Ricaurte, has failed to detect dopamine damage.

In earlier studies that have looked at dopamine metabolite levels, no differences were found between heavy ecstasy users and the comparison group (McCann 1994, Semple 1999, Ali 1993, Insel 1989, Ricaurte 1988). McCann's 1994 paper found lower levels of dopamine metabolite levels in women who used ecstasy, but not in men. As a combined group, there was no statistical correlation between dopamine metabolite levels in the spinal fluid and ecstasy use, despite an average of nearly 100 uses each. Also, there is a paper by Commins from 1986 where they detected dopaminergic changes in rats injected with 80 mg per kilogram of bodyweight twice per day for two days. Generally these findings have not been considered important and in an article published in 2001, Taffe writes: "In all studies, markers for both dopaminergic and noradrenergic systems remain unchanged following MDMA exposure, indicating that the effect is specific to 5-HT neurons."

Steven Kish published a paper in 2000 which discussed the examination of the brain of a deceased ecstasy user. This person had reportedly used ecstasy at very high levels: over 10 years of recurring use with a maximum use of 4-5 times per week, 6-8 pills per session. Kish confirmed the MDMA use post mortem with blood and hair tests. In the same (caudate) region of the brain found to be damaged in Ricaurte's monkeys, this user did not show signs of dopamine depletion or toxicity. However, the expected serotonin depletions were found.

Earlier in 2002, Reneman published a paper that looked at the influence of amphetamine in possible dopamine toxicity in ecstasy users. The researchers found that, as expected, ecstasy users who also used amphetamines had slightly lower binding levels of a particular dopamine-related detection chemical. (Reneman 2002) Although the results of this type of scientific study are complex, the authors write: "In the present study we did not observe evidence indicating loss of DA neurones in sole ecstasy users, whereas in the group of combined ecstasy and amphetamine users [123I]B-CIT binding ratios were only approximately 12% lower when compared to ecstasy users." (Reneman 2002)

In addition, research by Ricaurte in the late 1980s failed to show this type of dopamine damage in rats given high doses of MDE, a related compound with similar effects, (Ricaurte 1987). Nor did the study detect dopamine changes in the spinal fluid of regular ecstasy users who were found to have lower levels of the serotonin metabolite 5HIAA. It is unclear how to reconcile these and other findings with Ricaurte's current claim that "a single recreational dose regimen" would cause "severe" injury.

The Ricaurte paper also brings up the specter of MDMA as a potential cause of Parkinson's disease, a debilitating neurological disorder characteristically resulting in a loss of muscular control. Since there is no evidence of long-term movement disorders associated with MDMA use, Ricaurte raises the fear that people's natural dopamine decline could lead to future Parkinson's cases.

There is a single published case of young-onset Parkinson's where doctors speculated that the condition could have been caused by ecstasy use, but this speculation has been widely discredited. In discussing the results of their research into ecstasy and amphetamine-related dopamine toxicity, Reneman points out that since their research shows only 12% lower dopamine levels in those who use both amphetamine + ecstasy. Reneman writes: "It is well known that parkinsonian signs do not occur before more than 50% of DA terminals are degenerated (Fearnley and Lees 1991)... [Therefore] we can now say that the parkinsonian signs were most probably not caused by use of ecstasy or the combined use of ecstasy with amphetamine or methamphetamine." (Reneman 2002)

Strong evidence against Ricaurte's claim that ecstasy use could lead to Parkinson's is found in the fact that amphetamine and methamphetamine are documented to be much stronger dopamine toxins than MDMA, but they have been prescribed for decades without causing a documented increase in Parkinson's disease.

Essentially, the claim is that, despite there being no current signs that ecstasy use causes serious, widespread health problems, many users could deteriorate in the future. This claim seems to be predicated on the idea that ecstasy is something new and only young people have tried it. MDMA has been in wide use for over 20 years now and there are thousands (if not tens of thousands) of people in their 60s, 70s, and 80s who have taken MDMA numerous times. If Ricaurte's claim that age-weakening of the dopamine system would bring about many cases of Parkinson's were correct, then we would already see many cases of Parkinson's and Parkinson's-like symptoms in the older generation of ecstasy users. No such problems have been documented.

Although Parkinson's is quite rare in young people, ecstasy use is widespread. Given that 5-10% of the young population has tried ecstasy, it is hardly a surprise that some individuals who have gotten such a rare disease would also have used ecstasy.

In addition, Parkinson's disease is associated with cell death, not simply reductions in the dopamine system and this study did not find dopamine cells dying. Parkinson's researcher Sanchez-Ramos Ph.D., points out that even with the 'severe' damage to the dopamine system that Ricaurte found, there was still no cell death. "He showed us very nicely that MDMA will kill an animal before it will kill a neuron," a press release states.

A recent Associated Press report on the Science article noted that Ricaurte's research was funded by a grant from NIDA when NIDA was under the direction of Alan Leshner. Leshner has since become the CEO of the AAAS, the organization responsible for publishing and promoting this article. This is the first time Ricaurte has appeared as first author on a paper published in one of the "top tier" scientific journals. Some speculate that ongoing conflicts of interest may play a role in influencing choices over who and what gets published and how its publicized.

The issue of potential dopamine-system toxicity associated with high, repeated dose MDMA use is certainly interesting and deserves more careful follow-up studies. But given previous findings and the obvious and inherent difficulties with Ricaurte's dosage scaling, his findings are better suited for a curious footnote than placement on the front page of CNN and other major world news publications. On the website for Science, the journal in which the article was published, the link to the text is titled "The perils of 'Ecstasy'", CNN asked "Ecstasy Now, Parkinson's Later?", and the journal article itself was titled "Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (Ecstasy)", the words seemingly chosen to capture sensational media attention.

Thanks to this combination of science spin and uninformed reporting, a significant percentage of the population--including science editors, doctors, law makers, and news sources--will now misunderstand the (very small) importance of this finding and will most likely be unable to put it in proper perspective. Ricaurte has made his career in the last 10 years publishing worst-case-scenario research that is publicized as if such scenarios describe most ecstasy use.

Should ecstasy users be concerned about the health of their brains? Of course. Should this come as yet another reason for people to limit their exposure to MDMA and keep their doses and frequencies low? Absolutely. Does this research pave the way for some interesting new studies where heavy ecstasy users and non-fatal overdoses are checked for dopamine-system problems? Yes.

Should we be worried about 10% of the population getting Parkinson's disease because Johns Hopkin's researchers were able to kill 2 monkeys, almost kill another 2, and damage the brains of 6 monkeys? Certainly not until further and more careful research, by other labs, confirms these findings.

An interesting side note about the MDMA & Parkinson's disease is that it was reported in February 2001 that a man who had been diagnosed with Parkinson's in his mid 30's and had subsequently taken ecstasy, discovered that for around 6-8 hours, he regained muscular control and felt many of the Parkinson's symptoms recede. "I was suddenly looking down at my body aware that the twitching had gone, and I had this incredible fluidity. I was completely normal." February 19, 2001 Vol. 157 No. 7. BBC also published an interview with this man. (URL??) New Scientist Article about possible benefits to Parkinson's patients.

In 1999, a case report was published in the New England Journal of Medicine of a young man who had been diagnosed with Parkinson's disease. The man had previously taken ecstasy 10 times in the past and the authors of this paper suggested a causal link between the two. Because they lacked any data connecting the two, their case report was criticized and it has been mostly dismissed. This case report and the responses to it can be viewed in the references area.

One of the reasons that Parkinson's is associated in people's minds with "designer drugs" is that in the mid 1980s, a toxic contaminant in a batch of a synthetic analog of Demerol caused massive dopamine-system damage to the users unfortunate enough to try it. Many users started having Parkinson's symptoms and the US Congress rushed to pass the Analogue Drug Laws partially as a result of the media frenzy surrounding this tragedy. The contaminant is called MPTP and more information about this can be found in the MPTP Vault.

Although there is no documented connection between amphetamines and Parkinson's disease, a small number of those who use ecstasy or methamphetamine regularly do report experiencing some tremors and ticks. These symptoms generally recede within a few weeks or months of cessation of use, they have not been well characterized, and their cause is unknown. It is not known whether these have anything to do with short or long term dopamine depletion, whether they are simply stress related, or if they have some other cause.