(David Concar of the New Scientist published two articles on the topic of MDMA and Parkinson's, the first was a shorter version for the New Scientist website and the second was a longer version for the magazine itself. Both articles are posted below.)

People using Ecstasy for as little as one night are putting themselves at risk of developing Parkinson's disease, warns a new investigation of the drug's effects on animal brains.

The study uncovers evidence of a type of nerve damage never previously seen in monkeys or rats exposed to Ecstasy, or MDMA, and will stoke an increasingly acrimonious debate about whether it is toxic to human nerve cells.

George Ricaurte and his team at Johns Hopkins University in Baltimore, Maryland, gave up to three consecutive doses of the drug to squirrel monkeys and baboons. The doses were administered two hours apart in a bid to mimic the way some all-night clubbers use the drug.

Weeks later, the researchers examined the animals' brains and found evidence of what they call "profound and severe" damage to dopamine-producing neurons. These are the nerve cells lost in Parkinson's disease and their healthy function is important for movement, speech and cognition.

The animals' brains had abnormally low levels of both dopamine and certain "transporter" proteins that handle this neurotransmitter. The researchers also detected signs of inflammatory damage.

"The damaging effect of MDMA, together with the decline in dopaminergic function known to occur with age, may put individuals at increased risk of developing Parkinsonism and other neuropsychiatric diseases either as young adults or later in life," the researchers write in the journal Science.

The paper also claims some people already diagnosed with early-onset Parkinson's disease may unknowingly be victims of MDMA.

Nerve network

The link with dopamine overturns a 15-year assumption about the way MDMA interacts with the brain. Previous studies in monkeys and rats claimed the drug's toxicity was strictly limited to serotonin-producing cells, a quite different nerve network. But in the new research these serotonin effects were mild compared with those seen with dopamine cells.

The researchers suggest the discrepancy reflects the way the drug was administered to animals in the latest study, in multiple doses given in quick succession.

But opinion is sharply divided on the relevance to human Ecstasy users. Robert Meadowcroft, policy director of the UK's Parkinson's Disease Society, told New Scientist that there is no evidence early-onset Parkinson's disease is on the increase or that former MDMA users are turning up at clinics with Parkinson's symptoms. This is despite the fact that the drug has been widely used since the early 1980s.

"If the drug, used in large quantities, were responsible for the young-onset of Parkinson's disease we might have expected to see some early evidence of this," says Adrian Williams, a neurologist at the University of Birmingham in the UK. Another recreational drug from the 1980s, called MTMP, did cause Parkinsonism and was detected very quickly when users presented with severe symptoms.

Equivalent doses

The difficulty of comparing species makes it is impossible to know if the MDMA doses used in the experiment are equivalent to human doses, says Stephen Kish, a neuroanatomist at the Center for Addiction and Mental Health in Toronto.

And there are signs that they were not, say experts. The MDMA was injected rather than given orally and two of the 10 animals got so sick with hyperthermia that they died during the experiment. Overheating can strike down human users of the drug but at this frequency.

"The money would have been better spent investigating the dopamine effects in humans," says Kish.

Journal reference: Science (vol 297, p 2260)

It's that drug again
If a few monkeys get brain damage from ecstasy, does it mean clubbers will get Parkinson's disease?
David Concar
New Scientist
September 26, 2002

THERE can be no doubt that the prospect of hundreds of thousands of young people deliberately laying themselves open to Parkinson's disease is truly frightening. So when a leading journal publishes evidence linking the illness to one of the most commonly used recreational drugs of our time, as Science did last week with ecstasy -- it makes sense to sit up and take note.

Doubly so, when the study states that just a single night's dabbling with the drug may be all it takes to trigger the type of brain damage that could in time give you Parkinson's.

Triply so, when it bases that conclusion on the fact that monkeys and baboons exposed to "human-like" doses suffered "profound and severe brain injury". As news of the research sped round the globe journalists had little need to hype it up to sell it to their editors. For once the typical headline -- One night of ecstasy may bring on Parkinson's -- was an almost verbatim summary of the study's own top line.

Even so, the evidence behind the Parkinson's link is complicated and, being based on lab animals, indirect. It also hails from a lab, led by George Ricaurte at the Johns Hopkins University in Baltimore, whose previous findings have been the focus of an increasingly acrimonious debate about how science interprets ecstasy research for public consumption.

Put crudely, one school of thought says experts should paint the worst possible scenario to scare youngsters off the drug. The other camp says experts should scrupulously avoid raising false fears, since these could give youngsters an excuse to write-off everything they're told about the drug as scaremongering. The latest animal findings are certainly the most alarming to date. But how relevant are they to human users of the drug? That's the big question.

First the basic facts. The scientists gave up to three consecutive doses of MDMA to five squirrel monkeys and, in a follow-up experiment, five baboons. They gave the doses at three-hour intervals in a bid to mimic the way some all-night clubbers use the drug. Weeks later, the researchers examined the animals and found evidence of damage to dopamine-producing neurons in the brain's striatum. These are the nerve cells lost in Parkinson's disease -- hence the alarm.

And the surprise, for the dopamine link overturns a 15-year assumption about the way MDMA interacts with the brain. Previous studies in monkeys and rats claimed the drug's toxicity was strictly limited to serotonin-producing cells, a quite different nerve network.

But let's be clear what the new study means by "brain damage". The animals' brains had abnormally low levels of both dopamine and certain "transporter" proteins that handle this neurotransmitter. There were also signs of inflammation. All of which suggests damage to the tips of the animals' dopamine nerve fibres. Not good -- but, just as you can prune a rose bush without killing it, you can damage nerve cell tips without destroying the cells, and there's no evidence any nerve cells actually died. This distinction is important because dopamine cells certainly do die off in Parkinson's.

Nevertheless, it's not unreasonable to speculate that losing dopamine nerve endings as a youngster might put you at greater risk of developing Parkinson's later in life -- so it's vital to ask whether similar dopamine effects are likely to afflict human users.

Here we run into two big problems. Surveys suggest that only about 50 per cent of pills sold as ecstasy actually contain MDMA. So many users of E may have never been exposed to the substance. The second problem is whether the MDMA doses in the study are equivalent to human doses.

You'd think this could readily be agreed upon from the animals' sizes. Not so. Quirks in the way livers and body metabolisms function in different species could easily make an apparently low dose behave like a very high one. Ricaurte and his team claim their doses are equivalent to human ones, but other scientists doubt their calculation. The MDMA was injected rather than given orally and two of the 10 animals overheated so much that they died during the experiment. Overheating can strike down human users of the drug but not at this frequency.

And if the doses are comparable, where are the human victims of this dopamine effect? Some people already diagnosed with Parkinson's disease may in fact be victims of MDMA, suggest the researchers -- and their ranks may swell as users age. That view is backed by one or two doctors citing anecdotal cases. But with so many millions having used the drug, these could be just a coincidence. Britain's Parkinson's Disease Society, for one, is sceptical. It says there is no evidence that Parkinson's disease is on the increase among people in their 30s, 40s and 50s. This despite the fact that the drug has been used on a massive scale since the early 1980s.

So far, scientists have also drawn a blank looking for dopamine damage in the brains of users without Parkinson's. Two imaging studies that looked for such damage failed to find any. And two years ago Stephen Kish, at the Center for Addiction and Mental Health in Toronto, analysed the brain of a chronic ecstasy user after death. He remains the only neuroscientist to have published such a study. He found no evidence of dopamine depletion.

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