ECSTASY ON THE BRAIN
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.
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. Ricaurte'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 50 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, lead 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.
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 cannabis, a 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 pre~ maturely 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. " 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."