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"New Scientist" - Cover Story on MDMA Explains Flaws in Neurotoxcity Studies


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Scientific evidence that ecstasy damages the brain is fundamentally flawed and has misled politicians and the public, according to New Scientist magazine. Long, but EXCELLENT article.

Pubdate: April 20, 2002
Source: New Scientist (UK)
Page: 3 (editorial) 26-33 (article)
Copyright: New Scientist, RBI Limited 2001
Contact: letters@newscientist.com
Website: http://www.newscientist.com/
Author: David Concar and Claire Ainsworth



[Brainscan image accompanies editorial]

E is for evidence
Basing drugs policy on flawed science helps no one

THERE are no ironclad certainties in science. All theories and observations have their critics. And just because a finding appears in a peer-reviewed journal doesn't make it the last word: journals exist as much to enliven debate as to get it right. So on one level, our inquiry into the quality of the scientific evidence suggesting ecstasy harms brain cells is perhaps unsurprising (see p 26).

What we found is that certain high-profile studies claiming ecstasy causes lasting damage are based on flawed brain scans. But so what? Other teams will eventually repeat the experiments with better techniques. The truth will out. And in the meantime, does it matter if the evidence is shaky as long as it sends a suitably grim warning to people taking the drug?

In this case it matters a lot. These scans are not minor bits of academic science. They can be selectively presented to make it look as though ecstasy users have blotchy holes in their brains (see left). It's a potent visual message that's been seized on by drugs education campaigns and continues to guide those who set drugs penalties. That might just be defensible if the findings were simply disputed or uncertain. But our investigation suggests the experiments are so irretrievably flawed that the scientific community risks haemorrhaging credibility if it continues to let them inform public policy.

Parents, teachers and teenagers are increasingly clamouring for reliable evidence on the harm drugs do, not moralising or hyped pseudo-science. And once created, myths about illicit drugs are hard to slay. In the 1970s, scientists published papers purporting to show that cannabis damages brain cells in monkeys. The experiments were refuted, but anti-drugs campaigners made sure the earlier message stuck. Even today, some drugs education programmes in the US wrongly claim that science has proved marijuana can destroy brain cells.

We are not saying that ecstasy is harmless to brain cells. It might not be. But the jury is still out. Which means scientists must resist the temptation to turn their always complex-and sometimes flawed-findings into simple scare stories in pursuit of grants and headlines. The scientific community must also do more to persuade people that it really is impartial and not following a political agenda. Scores of published papers examine the neurotoxic potential of ecstasy. Very few do the same for Prozac-style antidepressants, even though these drugs act on the same serotonin synapses in the brain as ecstasy and are swallowed daily by millions. Where are the colourful scans proving that these legal substances don't cause lasting biochemical changes?

When it comes to illicit drugs, too many critics already accuse scientists of being in the pocket of government paymasters eager for scary evidence of harm. Scientists must not hand them ammunition on a plate. They must rise above the politics of the drugs war by ensuring the same high level of scrutiny for prescription pills-and by clearing up the mess about brain scans.


Some say it will kill you or poison your brain, others that it's a safe enough high if you take precautions. Despite official campaigns highlighting ecstasy's dangers, the drug has never been more popular with clubbers. Are they recklessly risking brain damage or worse, or sensibly ignoring anti-drug propaganda. David Concar looks for the facts behind the hype

IN A SMALL clinic in Charleston, South Carolina, preparations are under way for a landmark medical experiment. As New Scientist went to press, the researchers were still waiting for final approval from an ethics panel. But if all goes to plan, a dozen or so traumatised victims of violent crime will soon be given a mind-altering substance in a bid to release them from their terrible fears.

The trial is funded by the Multidisciplinary Association for Psychedelic Studies, a maverick body founded by an enthusiast with a drugs policy PhD called Rick Doblin. And if it seems a little hippy-trippy, appearances are deceiving. Double-blinded and placebo-controlled, the trial is, on paper at least, as rigorous as anything a pharmaceuticals company might carry out. What's more, every detail has been approved by stern-faced government regulators at the US Food and Drug Administration.

Their colleagues over at the Drug Enforcement Agency are furious, and it's not hard to see why. The pill in question is ecstasy, otherwise known as MDMA. And in normal circumstances of course, government authorities do not see swallowing it as a remedy for the psychological effects of crime. They regard it as a crime itself, not to mention a threat to people's health. Especially in the US, where the drug's rising popularity has been rattling law enforcers.

Indeed, fearing a crack-style epidemic, the US government has in the past couple of years stiffened legal penalties and stepped up efforts to publicise the dangers. Dose for dose, ecstasy offences are now punished more harshly in the US than those involving heroin. Radio ads and posters in malls warn of memory loss. The hugely influential National Institute on Drug Abuse near Washington DC has even been distributing postcards picturing brain scans. The cards set a normal brain, looking bright and radiant, alongside a "brain after ecstasy" -- a lump with dark blotches that look like holes.

In other words, while bona fide doctors supported by one US government agency get ready to dole out E as a medicine, other agencies are doing their utmost to warn teenagers off the drug. It's all very confusing. And you'll find equally mixed messages elsewhere. Take Britain. Last year the government introduced a tough new law making it a crime for club owners to permit the use of ecstasy on their premises. This year it issued a booklet telling the same club owners to lay on chill-out rooms, treatment areas and plentiful supplies of water. If not a green light to ecstasy use, then surely a sign of greater tolerance... or maybe not. For in Britain, the law puts ecstasy on a par with heroin and crack cocaine. And while some senior British police officers think that's wrong, the government insists it will not be downgrading a substance that the evidence to date shows is so dangerous.

But just how dangerous is it? In recent years the US government has spent tens of millions of dollars, way more than anyone else, trying to pinpoint the harm. And according to its most senior scientific officials there's no longer any doubt: even if it doesn't kill you, ecstasy is a recipe for lasting, possibly permanent, damage to the serotonin neurons in the brain that are involved in everything from memory and mood to sleep, sex and appetite. In a hearing before the Senate last July, NIDA's then director Alan Leshner stated: "There is across-the-board agreement that brain damage does occur." Research, he added, has "unequivocally shown that MDMA literally damages brain cells".

New Scientist went behind the scenes to talk to a wide range of researchers. We found that no such agreement exists. Nobody claims ecstasy is benign. It isn't, and never could be-no drug is. Yet few of the experts we contacted believe that research has yet proved ecstasy causes lasting damage to human brain cells or memory. Far from it, according to some, the highest-profile evidence to date simply cannot be trusted.

Blotchy brain scans of ecstasy users have become the ace card in public information campaigns. In the US, they also strongly influenced the move to tougher sentences. Yet impartial experts told us that the scans, though published in a respected journal, are based on experiments so fundamentally flawed they risk undermining the credibility of attempts to educate people about the risks of drugs. "The brain scans do not prove ecstasy damages serotonergic neurons," said one researcher, who asked for anonymity. "Whether to use the evidence is therefore a matter of politics rather than science."

Our enquiry doesn't prove ecstasy is harmless to brain cells. But it does raise questions key to the future of drugs policies the world over. When the evidence about the safety of an illicit drug is complex and disputed, who gets to decide which findings are sound enough to influence policy? How active should government policy makers be in screening out unreliable findings? And how open should they be about scientific dissent?

Some things about ecstasy are reasonably certain. Like many legal drugs, it affects the way brain cells handle the neurotransmitter serotonin. The cells in question are rooted near the brain's base but have long nerve fibres that fan out into higher regions. Here the fibres meet and communicate with other nerve cells, "messaging" them by squirting serotonin into the tiny joints, or synapses, that connect all nerve cells in the brain.

Alex D. from TRIBE on Utility Room


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MDMA turns these squirts into surges. It makes cells shoot virtually their entire load of serotonin and reabsorb it unusually slowly. And the drug does this by latching onto certain proteins dotting the surfaces of the nerve cells, called serotonin transporters. The normal job of these proteins is to absorb serotonin back into cells. MDMA makes the proteins work in reverse and pump the stuff out. It's not all the drug does to brain chemistry, but most scientists think it's the key to E's loved-up sensations.

And the key, too, to the drug's less desirable effects. Some short-term problems are no longer in serious dispute. In recent years it's become clear that ecstasy can make it dangerously difficult for some people to pass water, and help to bring on sudden and sometimes fatal heatstroke, especially in hot dance clubs (see "Life and death on the dance floor", p 31). Most experts also agree that by temporarily depleting the brain of serotonin, MDMA can leave users vulnerable to the mid-week blues. Yet neither of these risks, say experts, has created a serious public health problem. The mood swings are comparatively mild, and, despite the drug's massive popularity, ecstasy deaths remain extremely rare: downhill skiing kills more people. Even Britain's leading ecstasy expert, John Henry of St Mary's Hospital Medical School in London, thinks the risk of sudden death has been "overemphasised".

What most worries scientists like Henry is the possibility that hundreds of thousands of ecstasy users could be storing up mental health problems for the future. Are they? George Ricaurte and Una McCann, a husband-and-wife team at Johns Hopkins University in Baltimore, Maryland, have led the way in trying to pinpoint the drug's longterm impact on the brain. And after nearly 15 years of research, they are convinced the drug can damage serotonin synapses and nerve fibres. Indeed, they say, really persistent users even risk succumbing to "pruning", in which the longer, thicker serotonin nerve fibres in the brain wither and are replaced by a denser growth of spidery, shorter ones. In short, swallow E week in week out and the fine structure of your brain may never be the same again.

Hardly a basis for pressing for lower legal penalties. But how good is the evidence? For years it came exclusively from animal experiments. Typically, researchers give rats or monkeys high doses of ecstasy, leave them a few weeks, months or even years, and slice open their brains. It's not easy to scrutinise entire nerve fibres and synapses directly, but scientists can take a snapshot of the serotonin transporters dotted around the brain to see if any are missing or out of place. Many studies have found such changes, but some haven't, and the experiments continue to this day. So does the debate about what they really mean (see "Brain drain?").

In 1998, however, the case against ecstasy took a dramatic new turn. Ricaurle's team published a paper in The Lancet reporting what looked to be lasting brain damage in people who use ecstasy. This time the evidence was from a PET brain scanning study and seemed clear-cut. Where scans of control subjects were alive with colour, those of ecstasy users looked dull and dark. Ecstasy "injures brain for life", declared one of many startling newspaper headlines.

The study involved injecting 14 people who'd used ecstasy on average more than 100 times with chemical probes designed to stick to the serotonin transporter proteins that ecstasy targets. Wherever the probes end up they give off a detectable but safe radioactive glow. If ecstasy destroys serotonin synapses and fibres, the reasoning went, there ought to be fewer transporters for the probe to find in these damaged brains, and they ought to glow less. Sure enough, the brains of the ecstasy users did on average glow less than those of control subjects.

At the time, not every expert was convinced this deficiency was evidence of longterm damage by ecstasy. The drug users used lots of substances and the researchers reported no urine or saliva tests to prove they were drug-free at the time of the scan. Some critics even suggested the subjects could have been naturally deficient in serotonin synapses. But as it was impossible to prove these alternative explanations, the bleaker view of the brain scans took hold.

Soon the scans were at the centre of the US government's campaign on the dangers of club drugs and featuring in TV documentaries. The scans also featured prominently in the official report by the US Sentencing Commission that last year led to longer prison sentences for ecstasy offences. The brains scans, it claimed, showed "that users had a significantly reduced number of serotonin transporters throughout the brain".

And soon too other brain-imaging teams were attempting to build on the 1998 finding. A year later, researchers from the Royal Edinburgh Hospital in Scotland also published a paper claiming that regular ecstasy users have fewer serotonin transporters in the brain-further evidence, they concluded, of the drug's "neurotoxicity".

More recently, a team led by Liesbeth Reneman and Gerard den Heeten of the Academic Medical Centre in Amsterdam wanted to find out if heavier users of ecstasy lose more serotonin synapses than lighter users. To this end, they scanned the brains of four groups: moderate users of ecstasy who claimed to have taken no more than SO tablets in their lifetime; heavy users who claimed to have taken hundreds; heavy users who claimed to have abstained for at least a year; and a control group. "Our results," the team concluded in a paper published last year in The Lancet, "indicate that women could be more susceptible than men to the neurotoxic effects of MDMA".

It was another worrying finding that on the face of it seemed to back up the crucial 1998 study. Except that on close inspection, there were discrepancies and contradictions. This time, the male ecstasy brains in the study lit up just as much as the control brains, and it was only after analysing the female brains separately from the male brains that the researchers found anything different about some of the women. The brains of the heavy female users, it turned out, did light up less than those of the moderate female users and female controls. Yet even these "damaged" female brains performed no worse than the brains of the supposedly healthy male non-users.

It's a confusing picture, so New Scientist asked some leading independent scientists to look at the evidence afresh. What we learned was that the probes used in the scanning studies have serious deficiencies and that despite the poster depiction of "your brain on ecstasy", there never was-and never has been -- a typical scan showing the typical brain of a long-term ecstasy user.

"There are no holes in the brains of ecstasy users," says Stephen Kish, a neuropathologist at the Center for Addiction and Health in Toronto. "And if anyone wants a straightforward answer to whether ecstasy causes any brain damage, it's impossible to get one from these papers." Marc Laruelle, a Columbia University expert on brain scanning probes, agrees: "All the papers have very significant scientific limitations that make me uneasy."

According to both experts, the key flaw in the 1998 study is the sheer variability of the measurements. Some control brains performed up to 40 times better than others, and even some of the ecstasy brains outshone control brains by factors of 10 or more -- a level of scatter that both experts say is unprecedented in this type of study. According to Kish, the huge variations seen even in the healthy controls are a sure sign that the probe failed to give precise and reliable measurements. It's taken years for the problem to surface, says Kish, because the full range of the scatter is obscured in the original paper by the unusual way the researchers analysed their findings, converting the raw brain scan measurements into logarithms before plotting them out.

So why the unreliability? Laruelle says the probes used in all the ecstasy brain scan studies don't always stick just to serotonin transporters and should therefore only be used in certain brain areas. In recent years, his team has established that only the midbrain, thalamus and striatum have enough serotonin transporters to give reliable readings. None of the ecstasy studies focused exclusively on these structures. The Edinburgh team looked only at the cerebral cortex.

Ricaurte rejects the criticism. "Variability in the data would lessen our ability to detect differences between groups and, potentially, lea to an underestimation of differences between MDMA users and controls," he told New Scientist. "The fact that significant differences were found speaks for itself."

When it comes down to it, what brains look like in a scanner shouldn't matter as much as whether ecstasy has any noticeable long-term effect on the way people think, feel and act. So does it? There's certainly been a rash of papers in psychology journals suggesting ecstasy users have poorer memories and mental reflexes than nonusers. And some of the conclusions make disturbing reading. In one typical study, ecstasy users "showed significantly poorer verbal fluency and immediate and delayed recall". In another, they were "worse on a sustained attention task requiring arithmetic calculations, a task requiring short-term memory and a task of semantic recognition and verbal reasoning". Last year one British team even equated such symptoms with those seen early on in Alzheimer's disease.



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Yet take a closer look and, as with the brain scans, the evidence is not as clear-cut as it sounds. For a start, in the majority of tests of mental agility, ecstasy users perform just as well as non-users. Their reaction times, visual memories and ability to concentrate all come out looking normalsometimes better than normal.

In one study, psychologist Andrew Parrott of the University of East London and his team found ecstasy users outperforming non-users in tests requiring them to rotate complex shapes in their mind's eye. Ecstasy users also had the edge on non-users when it came to searching a series of virtual rooms on a computer screen to find a small red toy car. Afterwards, says Parrott, the ecstasy users were better at answering questions about the shapes of the rooms and the positions of their doors.

Where ecstasy users do seem to perform worse is in learning new verbal information. In tests where people are given lists of words and then asked to recall them later, a group of non-users might score an average of, say, 10 out of 15, while a group of ecstasy users of the same age and social background might get 8. According to Parrott, who published the first finding of this type in 1998, ecstasy users are also slower on average to improve when the test is repeated. But their performance still lies well within the spectrum of what counts as normal.

In other words, whatever ecstasy's cognitive effects may be, they are subtle. So subtle that some experts think it's jumping the gun to blame ecstasy when most users of the drug take many other substances. A team at Imperial College Medical School in London recently tested three different groups for recall, word fluency and speed of thought. One used no drugs, another just cannabis, and the third both ecstasy and cannabis. On average, the "no drugs" group performed the best. But the "just cannabis" people scored no better than those who used ecstasy and cannabis. So is cannabisa drug people often smoke to "come down" from an ecstasy high-the real problem?

Or are scientists worrying about a cognitive impairment that just isn't there? It's an open secret that some teams have failed to find deficits in ecstasy users and had trouble publishing the findings. "The journals are very conservative," says Parrott. "It's a source of bias." Parrott himself has had two papers of this sort turned down.

But is any of this a reason to dilute the ecstasy health warnings ? Surely if there are any suspicions at all, governments and scientists should make the strongest possible statements about risk. Perhaps. But some in the field feel this approach carries a risk of its own. If people think the health warnings are exaggerated or at odds with their own experience of the drug, the authorities risk losing credibility, and with it their chance to educate anyone about drugs.

Kish says many of the ecstasy users he interacts with already consider the brain scans to be "simply unbelievable". Harry Sumnall, who studies ecstasy users at the University of Liverpool, fears that by prematurely highlighting the drug as especially dangerous, psychologists and the media risk giving out the false message that "as long as you stay away from E, you'll be fine".

The situation isn't helped by the impression that double standards are at work, with one set of rules for prescription drugs and much stricter rules for drugs used illicitly.

While scores of studies have looked for evidence of biochemical changes in the brains of animals and people exposed to ecstasy, only a handful have looked for anything similar in brains exposed to antidepressants and other prescribed agents that act on the serotonin transporter. And when scientists do scrutinise such drugs, officials don't jump so readily to alarming conclusions.

In the 1980s, for instance, Ricaurte's team began publishing papers suggesting a diet pill, taken daily by millions, called fenfluramine could damage brain cells. The evidence was strikingly similar to that seen in animals given ecstasy. But while ecstasy's "neurotoxicity" triggered government action, fenfluramine's was brushed aside.

Of course, many people feel more comfortable about prescribed medicines carrying risks, because they provide benefits too. That's why Rick Doblin's efforts to turn MDMA into a prescription pill could be so crucial to reversing the drug's demonisation. Anecdotal evidence already suggests ecstasy could ease the pain and fears of patients with cancer or post-traumatic stress disorder, and perhaps even help Parkinson's sufferers. But Doblin knows only evidence from the most rigorous of rigorous trials will do. There's no evidence, he says, that the low doses the patients will be getting could damage serotonin nerve fibres. Yet nor will the pills be instant miracle cures: each patient in the Charleston trial will have 16 hours of psychiatric counselling as well.

And the hundreds of thousands of recreational users? Nobody can yet put their hands on their heart and say that none of them will ever have serious mental health problems, especially the heavy users, but this drug is not new, says Doblin. "I first tried it in 1982, and many of the early users are now in their 50s and 60s. We are not flooding into treatment centres."

SIDEBAR1 Brain Drain?

Does MDMA harm brain cells? High doses of the drug can certainly cause subtle longlasting biochemical changes in the brains of lab animals, especially when injected. But should these be interpreted as evidence of damage? And are they likely in people popping "human doses" of the drug? The jury is still out.

To date, George Ricaurte and his team at Johns Hopkins University in Maryland have carried out the most influential research. In the early 1990s, they began a long-term experiment with squirrel monkeys. Twice a day for four days, they gave one group of monkeys ecstasy, another salt water. So that their brains could be examined, the animals were then killed in batches at varying time intervals.

After two weeks, the ecstasy monkeys had less serotonin in their brain fluids compared with the control monkeys, and fewer of the serotonin transporter proteins that are the main targets of ecstasy in the brain. Ecstasy, the team concluded, had "pruned" these monkeys' serotonin synapses and nerve fibres. After 18 months, the ecstasy monkeys still had fewer serotonin transporters, except that there was now evidence of new serotonin nerve fibres growing up from the base of the brain. After seven years, the new fibres were still there but had grown only as far as the midbrain, leaving them short of their usual summit in the cortex.

Perhaps even more worrying for clubbers is evidence suggesting that MDMA's impact on serotonin transporters increases as animals get hotter. But not everyone thinks losing these transporters is a sign of nerve damage: the nerve fibres themselves may remain intact. One such dissident is James O'Callaghan, a neurotoxicologist at the US Centers for Disease Control and Prevention. O'Callaghan has long maintained that MDMA does not provoke the crucial inflammatory response expected from a chemical that injures nerve cells-the build up of star-shaped cells known as glia.

And some animal studies have failed to find any lasting biochemical changes. A team at the US National Center for Toxicological Research in Arkansas gave a range of ecstasy doses to rhesus monkeys but found no significant effects nearly two years later. What's more, few studies to date have reported long-lasting behavioural problems in animals exposed to ecstasy.

Weeks after the Arkansas team administered high doses of the drug, their animals performed just as well as control animals in tests of short-term memory and motivation. A team at the Scripps Research Institute in La Jolla, California, trained monkeys to carry out tests of memory, reaction time and coordination and then gave them high doses. Afterwards the animals performed the tests just as well as before.

SIDEBAR2 Life and Death on the Dance Floor

When British student Lorna Spinks died after taking ecstasy, her grieving parents decided to publish a picture taken minutes after her death. They hoped Lorna's swollen, bleeding face would make others think twice before taking ecstasy.

It didn't. Nearly two years and a couple of dozen ecstasy-related deaths later, British youngsters are still thought to be popping anything between half a million and 2 million tablets every weekend. The inescapable truth seems to be that taking ecstasy is fun, and that, despite the tabloid horror stories, clubbers think the chances of dying are vanishingly remote and can be reduced by taking sensible precautions. But just how true is this?

In the mid-1990s, when there were thought to be around 420,000 ecstasy users in England, the drug was listed on the death certificates of an average of nine young people a year. So the chance of a typical ecstasy user dying at some point in the year after taking the drug was about I in 50,000, or about five times less likely than dying in a traffic accident. Ecstasy can come out of such calculations looking riskier than traffic, but only if it's assumed that all the recorded ecstasy deaths in any one year involved people experimenting with the drug for the first time -- A possible but extremely unlikely scenario.

The annual figure for ecstasy-related deaths in Britain has crept up. The latest, for the year 2000, is 27, the highest so far. But the fact is glue sniffing and over-the-counter painkillers still kill more people, while cocaine is responsible for double that number and heroin 20 times as many. And of the 27 British deaths, 19 victims had other drugs in their system, raising questions about which substance really killed them.



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Clearly, though, ecstasy cannot be completely absolved. Why do a tiny number of people who swallow the pills die? Genetic make-up is a likely part of the answer. Lorna Spinks had taken ecstasy many times. The night she died she took two pills that were just a little stronger than she was used to and couldn't handle it. She suffered a poorly understood and unpredictable reaction called serotonin syndrome that plunged her body into a shivering state of rigidity and hyperthermia, leading to organ failure and internal bleeding.

Fortunately, such marked reactions to MDMA are incredibly rare. Contrary to popular belief, MDMA is incapable of directly triggering heatstroke in all but a handful of unusually sensitive people. In the vast majority of cases the direct cause of the hyperthermia is in fact the dance floor. The drug makes users fail to notice they are overheating and dehydrating, so they carry on dancing when they should be cooling off, says John Henry, a toxicologist and MDMA expert at St Mary's Hospital in London. "This explains why one tab can kill." And why studies on volunteers taking MDMA in a calm setting fail to find any evidence of heatstroke.

Another of ecstasy's side effects is to impair the body's ability to handle water. In experiments on volunteers, Henry has discovered that MDMA makes the brain's hypothalamus secrete a substance known as antidiuretic hormone, which stops the kidneys producing urine and makes it hard for MDMA users to pass water even if they are drinking pints of it. If they do drink excessively, disaster can ensue. In rare cases, the blood thins and the brain swells, creating a pressure that in extreme cases pushes the brainstem down the spine where it can no longer support breathing.

The condition is called hyponatraemia and is what killed Leah Betts, a young British ecstasy victim, in 1995. Unlike the highly unpredictable serotonin syndrome reaction that killed Lorna Spinks, however, it is easy enough to avoid. Experts reckon ecstasy users can protect themselves by drinking no more than half a litre of water per hour if they are dancing and sweating it off, and nothing at all if they are not. What's more, although the details are unclear, it seems young women should take extra care since their sensitivity to antidiuretic hormone could vary over the course of the menstrual cycle.

Research is now under way to discover the underlying factors that make different people react to ecstasy in different ways. The way the body metabolises the drug is likely to be crucial. For example, the liver enzyme CYP2D6 that helps break MDMA down is inactive in up to 1 in 10 people of European descent, which could make them especially sensitive to some of the drug's effects.

Confusingly, it might also protect them from others. The complication is that some of MDMAs effects are caused not by the drug but by its breakdown products. Henry's team has preliminary evidence from rats to suggest that one of these, called HMMA, is better than MDMA at provoking the brain to release antidiuretic hormone. If confirmed, it could mean that people who break down MDMA rapidly are more at risk of hyponatraemia. Claire Ainsworth

[sidebar accompanied by bargraph image]

SIDEBAR3 The Wrong Stuff

You want a good night out, the people running the rave or nightclub don't want you swallowing anything really nasty. So here's the deal. You provide a crumb or two of your ecstasy pills for the checkers to inspect and test. They tell you what they think the pills contain and what the risks of swallowing them might be.

Depending who you talk to, it's either a pragmatic way to curb the harm ecstasy tablets can do or a dubious step toward quality control for illicit drugs that can only create more users. France, Germany, Austria and Spain all unofficially allow drug screening in certain clubs. Even in tough-on-drugs America it happens at certain raves. But the British government says the tests are imprecise, unnecessary and likely to create a false sense of security amongst users. Who's right?

Stories about dangerously contaminated ecstasy pills are certainly exaggerated. Unlike drugs sold in powdered form, such as speed or heroin, it is hard for dealers to "cut" ecstasy tablets with toxic adulterants such as bleach. The problem is that what is sold as ecstasy is often not MDMA at all. Synthesising MDMA can be tricky, especially as the chemicals required are controlled by governments. So some suppliers fake ecstasy by mixing concoctions of other ingredients, some of them a lot more toxic than MDMA.

The most notorious is PMA, or paramethoxyamphetamine. Small doses produce mild hallucinations and euphoria, but take more and it leads to vomiting and hyperthermia. Worse, as the euphoria is milder and slower to appear than with MDMA, some unwitting users take extra pills to get a better high. At least nine deaths in the US and three in Europe have been blamed on PMA.

A foolproof argument for allowing chemical testing in all nightclubs? Not quite. The commonest method, called the "Marquis test", involves scraping some of the pill into a colourless reagent containing sulphuric acid and formaldehyde. MDMA turns the reagent violet/purple and then slowly blue/black. The problem is that some ingredients in fake ecstasy pills trigger the same colour changes. Others, such as PMA, cause no colour change at all, so tablets made of these will pass the test provided they contain a trace of MDMA.

In clubs in Bern and Vienna, experts are now trialling a more accurate technique known as high-performance liquid chromatography. But the machines cost some £35,000 apiece.

The Netherlands has taken a different tack. While stopping ad hoc chemical testing in nightclubs, it runs an official pill testing service at 23 drug prevention and treatment centres. Dutch ecstasy users can take their pills to any of the centres, where trained employees note down the pills' colour, dimensions and logo, and run a Marquis test. They then log on to a database that holds details of all the pills tested more rigorously by an independent lab service in the previous six weeks. If the pill doesn't match any of the known profiles, it can be sent off for rigorous testing and added to the database. Any evidence about potentially dangerous pills is available to clubbers within days.

According to a 1997 survey of Dutch ecstasy users, pill testing neither encourages nor discourages use. But Raymond Niesink, who coordinates the Dutch scheme, believes it has saved lives. "There are no PMA victims in the Netherlands," he says, unlike in Belgium.

In the US, voluntary organisations such as DanceSafe continue to check pills at raves and send samples for analysis. But they operate in a grey area of the law. In Britain, nobody is systematically analysing any of the ecstasy that's out on the street.

THERE. Sorry about the long post, maybe some of you will find this interesting.
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Good read. But I think it can be summed up with:

"We are not saying that ecstasy is harmless to brain cells. It might not be. But the jury is still out. "


"Nobody claims ecstasy is benign. It isn't, and never could be-no drug is. Yet few of the experts we contacted believe that research has yet proved ecstasy causes lasting damage to human brain cells or memory. "


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Usually I can't be arsed to read such a long article, but apparently I was interested enough to trudge through the entire thing. :)

Nonetheless, I've come to generally discard most MDMA studies since the constant litany of "conclusive" evidence of brain damage becomes tiresome after a while. You really only hear about the most "alarming" studies in the media, so you have to immediately be suspicious.


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I couldn't find this info on the New Scientist website, maybe I didn't search enough, but I did find this article:

Forgetting the future

17:47 28 March 01

Memory problems that plague many older people can affect ecstasy users in their mid-twenties, say British psychologists.

They found that ecstasy damages prospective memory - remembering things to be done in the future.

"They were showing the kind of deficits you might expect to find in much older people," Tom Heffernan, at the University of Northumbria, told New Scientist.

"There are problems with asking people with memory problems to fill in these kind of questionnaires," he says. "But, if anything, they would be prone to under-reporting these kind of events."

Why am I here?

Heffernan studied 40 adults in their early or mid-twenties who took ecstasy at least 10 times a month for up to five years. He found significant impairments in everyday measures of three kinds of prospective memory.

The ecstasy users and a group of non-drug users completed questionnaires asking about memory lapses during the previous week and month. The questionnaires probed short-term 'habitual' memory (such as forgetting to switch off an alarm clock in the morning), long-term episodic memory (such as forgetting to pass on messages) and internally-cued memory (such as forgetting what you have come into a room to do).

Even when the team controlled for the use of other drugs known to impair memory, such as marijuana, the regular ecstasy users recorded significantly more memory lapses than the non-drug users.

Cognitive health

Previous studies have found that ecstasy impairs other types of memory, such as short-term retention of a list of words. Researchers suspect that ecstasy may be damaging neurons that make serotonin, a neurotransmitter involved in memory.

"There is a belief that soft drugs - which many consider ecstasy to be - should be legalised when in fact research, including our own, suggests that regular use can have a very damaging effect on your cognitive health," says Heffernan.

Whether the memory impairments are long term is not yet clear, he says.

This research was presented at the British Psychological Society's Centenary Conference in Glasgow, UK.


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It was a very interesting article. I lived in Britain and can relate to the "e" issues over there. I started taking taking "e" 10 years ago in Britain and don't have any "mental" issues (well, at least I don't think I do) and I know plenty of people who haven't taken "e" who are way more unhappy that I am.....so either I have a heck of a lot of seritonin to begin with or I'm just lucky!! And the pills in Britain are a lot better/stronger/purer than over here, so there is less chance of MDMA screwing you over in Canada.

Good reading.



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thanks for the post; read it with avid interest, though i think the public is weary of this topic. generally an excellent site for articles of note.
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I've decided to get a printed subscription.. like 2 dollars an issue, and weekly science news for a nerd like me - gotta love it!


Well-Known TRIBEr
I've said it before, and I'll say it again:

I am truly convinced that most, if not all, problems related to ecstasy use is from screwing up your circadian rhythms.

Here's a test: for one weekend, do NO drugs, but force yourself to stay up until 6am.

Tell me how you feel the next week. My results: it feels like I dosed.

Interesting... the first things to go when the circadian clock is fucked: attention and memory... the very things that are purpotedly fucked by taking mdma.


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I think PosTMOd has a good point. Circaudian rhythm is affects the degree of after/side effects and the possible neurotoxicity. The brain's anti-oxidant activity diminishes after long periods without rest. The aminergic neurotransmitters/receptors are also more exhausted after a day's work as opposed to their robustness right after sleep.

But I still can't attribute the problem with ecstasy use directly to the misalignment in circaudian rhythms. The test Timo is suggesting should be done like a double-placebo study: person rested, person rested + MDMA use, person without sleep, person without sleep + MDMA use. Although the extent of side/after effects would probably mimic the order above, it is rather erroneous to equate side/after effects to neurotoxicity.

For example, after not sleeping, the lack of concentration and the irritability is largely due to the sluggishness of noradrenergic neurons (the CNS "focusing" chemical) and seratonergic neurons (responsible for inhibiting and smoothing out the effects of the other catecholamines and cholines). Because MDMA also depletes seratonin, and somewhat inhibts the adrenergic axis, the effects are augmented. The lack of sleep effect is more profound, and the damage is increased.

Since the sleep deprivation effect and MDMA affect similar systems and shift the neurochemical balance in the same direction, their combined effect is somewhat synergetic. I wouldn't go as far as saying that MDMA has no negative side effects on its own, without sleep deprivation involved. There is simply no way to gauge that at the time.


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PoStMod - Have you taken E during the day and ended up in bed at a normal time? If so, notice any difference??

I've done the sober thing many times and felt quite sketchy the next few days afterwards. However I've never dosed during the day so I have nothing to compare to.
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Memory Tests

I don't think you can dispute the fact that MDMA lowers serotonin levels significantly for at least a few days after dosing. Therefore, if you test someone's memory during a period when their serotonin levels have not yet had a chance to recover, you will certainly notice an impairment.

In this type of study, I would imagine that anyone who doses 10 times per month for 5 years might require a substantial amount of "clean" time before their serotonin levels, and hence their memory, returns to normal.

As the original article pointed out, you cannot extrapolate these test results into conclusive evidence of long-term damage just because Johnny forgot his keys at home on Monday morning.

I'll agree that sleep deprivation is a FACTOR. But as I mentioned, MDMA will significantly deplete serotonin, guaranteed, and how can that NOT have a negative impact on memory (above and beyond the lack of sleep)?


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Originally posted by PosTMOd
I am truly convinced that most, if not all, problems related to ecstasy use is from screwing up your circadian rhythms.

Here's a test: for one weekend, do NO drugs, but force yourself to stay up until 6am.

Tell me how you feel the next week. My results: it feels like I dosed
conversely, i have observed in myself that taking mdma, followed by a restful next day with lots of napping, then getting ten hours sleep the next nights, combined with anti-oxidents and 5-htp virtually eliminates all of the supposed negative after affects.


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Of course they are flawed, were any of those poor monkeys subjected to "wicket Bass Beats" or "strobe lighting" " or given any light shows ? before the sientists Killed them.

I think not !

Bad seintist Bad...

I can see the poor monkey sitting alone tripping out while the others look and think "whats he on"



Well-Known TRIBEr
Originally posted by basic
PoStMod - Have you taken E during the day and ended up in bed at a normal time? If so, notice any difference??

Most certainly... the earlier I have taken mdma and the earlier I have gone to sleep, the better I have felt. Taken during the day for a boat cruise, and the next day, you question whether you even took a drug the day before. Of course, this is with 5-HTP....

For god's sake, if you dose, get 5-HTP to replenish your serotonin (and there is no "a" in serotonin... one pet peeve of mine is to see it written wrong *cough*T_BOY*cough*).

MDMA most definitely depletes serotonin... duh, that's how it works. Your body doesn't quickly replenish it because there is not a lot of the precursor building blocks in the diet. This is where 5-htp comes in... 100 to 150 mg a day for 3 days after dosing...

feisty boy

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Originally posted by PosTMOd

For god's sake, if you dose, get 5-HTP to replenish your serotonin

MDMA most definitely depletes serotonin... duh, that's how it works. Your body doesn't quickly replenish it because there is not a lot of the precursor building blocks in the diet. This is where 5-htp comes in... 100 to 150 mg a day for 3 days after dosing...

i've read some reports which totally question the effectiveness of 5-htp - that it basically cannot be properly absorbed as a supplement, and the premise that ingesting large amounts of the precursor is not in fact aiding in the actual manufacture of serotonin.

or something along those lines...
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Originally posted by feisty boy
i've read some reports which totally question the effectiveness of 5-htp - that it basically cannot be properly absorbed as a supplement, and the premise that ingesting large amounts of the precursor is not in fact aiding in the actual manufacture of serotonin.

I have read dozens of reports that it works. The reports that say it doesn't are usually linked in funding to people with a vested interest in keeping the $18 billion dollars flowing that is wasted every year in the States on the War on Drugs.

Anecdotally, I know it works. I take it, no sketch. I don't, sketch.

Quite simply, if are not taking 5-HTP after dosing, you are a fool.


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Altern Med Rev 1998 Aug;3(4):271-80

5-Hydroxytryptophan: a clinically-effective serotonin precursor.

Birdsall TC.

5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behaviour, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.


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Folia Psychiatr Neurol Jpn 1978;32(2):223-30

Clinical evaluation of 5-hydroxy-L-tryptophan as an antidepressant drug.

Nakajima T, Kudo Y, Kaneko Z.

Effectiveness of 5-hydroxy-L-trytophan as an antidepressant drug was studied with 59 patients with depressive symptoms using Rating Scale for Depression made by Clinico-Psychopharmacology Research Group in Japan for a preparatory step of a double blind clinical study of 5-hydroxy-L-tryptophan treatment of depression. A daily dose of 150--300 mg of 5-hydroxyl-L-tryptophan was administered for three weeks. Favorable responses were observed in 40 patients (67.8%), of whom 13 patients were markedly improved. These effects were noticed in 32 patients (80% of the improved patients) within a week of the treatment. Analysis of General Improvement Rating in the various subtypes of depressive symptoms indicated that endogenous depression and involutional or senile depression were the preferable indication of 5-hydroxy-L-tryptophan loading. The main side effects of 5-hydroxy-L-tryptophan were gastrointestinal disturbances which were minimized by the simultaneous administration of metoclopromide or trihexyphenidyl.


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Depletion of 5-HT disrupts prepulse inhibition in rats: dependence on the magnitude of depletion, and reversal by a 5-HT precursor.

Prinssen EP, Assie MB, Koek W, Kleven MS.

The 5-HT(1A) agonist 8-OH-DPAT has been reported to disrupt prepulse inhibition (PPI) of the acoustic startle reflex after local administration into the raphe nuclei. Because it is likely that 8-OH-DPAT disrupted PPI by activation of somatodendritic inhibitory receptors, and thereby, via a decrease in 5-HT neurotransmission, we tested whether chronic, drug-induced, depletions of 5-HT have similar effects. Rats were drug-treated for three consecutive days and tested in a short PPI paradigm on day 4, and retested 2 h later, after acute saline or drug administration. Repeated treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine methyl ester (PCPA; 160 mg/kg) produced a small, but significant, attenuation of PPI, and a large decrease in extracellular 5-HT levels in the hippocampus, as measured in independent microdialysis experiments. An even larger depletion of 5-HT was obtained by substituting the 3(rd) PCPA administration with the 5-HT releaser d-fenfluramine (10 mg/kg); this combined treatment nearly abolished PPI in the majority of animals. The involvement of 5-HT in the latter effects was confirmed by the finding that low doses of the 5-HT precursor 5-hydroxy-L-tryptophan reinstated PPI during retest. These data, together with recently published studies, provide strong evidence that pharmacologically-induced depletion of 5-HT disrupts PPI.