When Science Goes Wrong: Twelve Tales From the Dark Side of Discovery - Simon LeVay (2008)
NEUROSCIENCE: The Ecstasy and the Agony
IN 2002, WHEN a neurologist at Johns Hopkins School of Medicine in Baltimore, Maryland, published a study on the toxic effects of the drug Ecstasy, his findings bolstered a political campaign against recreational use of the drug. Only much later did it turn out that the findings were the consequence of an almost laughable laboratory blunder.
The year 2002 was a high-profile one for Ecstasy. On June 18, Joseph Biden, then the senior Democratic senator from Delaware and now the US Vice President, introduced the Reducing Americans’ Vulnerability to Ecstasy Act into the US Senate. As its acronym suggested, the RAVE Act was directed against the scenes where the use of Ecstasy and other ‘club drugs’ was most in evidence: the all-night music and dance parties known as raves. (Ecstasy use has since expanded to other venues, such as college campuses.)
Although Biden is best known as a foreign-policy expert, he also has a long history of involvement in drug-control legislation, including the laws that created the Office of National Drug Control Policy (the ‘Drug Czar’). The RAVE Act was actually an amendment to a section of the existing Controlled Substances Act – the so-called crack-house statute – which allowed prosecutors to seek the destruction of premises used for drug sales or drug use. Biden’s bill allowed for $250,000 fines against persons who promoted or provided space for raves if they knowingly permitted the use of illegal drugs such as Ecstasy at these events.
In the preamble of the bill, Biden depicted rave organisers as deliberately fostering a drug culture under the hypocritical guise of concern for partygoers’ welfare. ‘Because rave promoters know that Ecstasy causes the body temperature in a user to rise and as a result causes the user to become very thirsty,’ Biden wrote, ‘many rave promoters facilitate and profit from flagrant drug use at rave parties or events by selling overpriced bottles of water and charging entrance fees to ‘chill-rooms’ where users can cool down.’ Seemingly well-meaning security measures were fraught with malevolent intent. ‘Some [rave promoters] even go so far as to hire off-duty, uniformed police officers to patrol outside of the venue to give parents the impression that the event is safe,’ according to Biden’s bill.
The RAVE Act represented a certain change of emphasis in the war against drugs. With the traditional targets – people who used or dealt in hard drugs like heroin and crack cocaine – there was little social controversy about the value of drug-control measures. With those drugs, the public perception was of random acts of violence committed by addicts in a desperate quest to finance their next fix, or by warring gang lords in disputes over their drug fiefdoms. With club drugs like Ecstasy, on the other hand, a threat to public order was much less apparent. For most users, Ecstasy is not an addictive drug – not in the traditional sense of generating an all-consuming physical dependency, at least. Because Ecstasy is generally used on an occasional basis, it doesn’t usually threaten its users with financial ruin. Nor, in most cases, does it threaten their jobs, studies, or relationships. Ecstasy use, in other words, is largely compatible with a conventional middle-class lifestyle.
Lacking a public-order platform, the advocates of strict measures against Ecstasy concentrated on the dangers that the drug might pose to its users’ health. These dangers certainly exist. Most well-recognised is the risk of acute hyperthermia – heatstroke – while under the influence of the drug. Every year, a few Ecstasy users die of hyperthermia or of hyponatraemia (overdilution of the blood caused by drinking excessive amounts of water to keep cool). Ecstasy users sometimes die in traffic accidents while under the influence of the drug, or from other drugs that are taken along with Ecstasy or that are present as adulterants in Ecstasy tablets.
Still, Ecstasy causes only a handful of acute deaths in the United States per year, and relatively few acute health problems of any kind. In the year before Senator Biden introduced the RAVE Act, fewer than two persons in 100,000 visited an emergency room with an Ecstasy-related problem, compared with 76 per 100,000 with a cocaine-related problem, according to the Drug Abuse Warning Network.
Although the acute risks are not especially great, there are some indications of long-term health hazards associated with Ecstasy use. For some users, the initial positive feelings engendered by the drug – euphoria, energy, intensified sensations, and a deep sense of intimacy with others – fade with repeated use, to be replaced by depression, memory difficulties, sleep disorders, and cognitive problems. The prevalence of these ill-effects is a topic of debate: many of the people who experience them had taken a variety of drugs, making the specific role of Ecstasy difficult to tease out. And conceivably, cause and effect are at least partly the other way around – a disposition to these mental problems might promote drug use, rather than drug use triggering the problems.
Given the nebulous nature of some of Ecstasy’s reported ill-effects, educating young people to avoid the drug has always been a challenge. One strategy has been to replace the reported psychological hazards with a very concrete physical effect – damage to the brain.
Already in 1987, the US government’s National Youth Anti-Drug Media Campaign tried this approach with a series of TV commercials that featured a chicken egg (‘This is your brain’) and the same egg frying in a pan (‘This is your brain on drugs’). For some reason, the commercials were extraordinarily memorable, even iconic – they spawned endless spin-offs, imitations and parodies. Whether they achieved their goal of reducing drug use was less clear. ‘When I saw people that were on the high school honour roll smoking pot, I realised that the commercial’s message was false,’ one young woman told CNN. ‘I remember thinking, “When are their brains going to fry?”’ By 2003, more than one billion federal dollars had been spent on this and related media campaigns, but they had no significant effect on drug use among young people, according to a US government study.
In the case of Ecstasy, the main evidence for brain damage was provided by George Ricaurte, M.D., Ph.D., a neurologist at the Johns Hopkins University School of Medicine. Ricaurte (pronounced ri-CART-ey) had made a name for himself by investigating the damaging effects of several illegal drugs on the brain, and he lost no opportunity to stress the significance of his findings to potential drug users. As such, he was a darling of the National Institute on Drug Abuse (NIDA). Along with psychiatrist Una McCann, who is his wife and collaborator, Ricaurte received nearly $16 million in funding from NIDA and other government agencies between 1989 and 2003.
In 1998 Ricaurte, McCann, and three junior colleagues had published a study that purported to show brain damage resulting from recreational use of Ecstasy. Ecstasy is a chemical derivative of amphetamine: its scientific name is 3,4 methylenedioxy-methamphetamine, or MDMA. It causes a surgelike release of the ‘feel-good’ neurotransmitter serotonin, as well as a more modest release of another transmitter, dopamine. In the 1998 study, Ricaurte’s group used a radioactive tracer, combined with positron-emission tomography (PET) scanning, to visualise the distribution of a serotonin-related molecule in the brains of persons who had used Ecstasy in the past, as well as in control subjects who had not. The resulting images showed less of the serotonin tracer in the Ecstasy users than in the controls, and some patches of brain seemed to be devoid of the tracer altogether.
Ricaurte described these results as evidence of ‘structural’ changes in the brain induced by Ecstasy use – a bit of a semantic stretch, perhaps, when referring to the distribution of a molecule. His paper did include some cautionary statements, such as an admission that the changes might not be permanent. And in fact, a German research group, who used similar techniques to study Ecstasy users at various lengths of time after their last use of the drug, has recently reported that the effects of Ecstasy ingestion on the brain’s serotonin system do at least partially reverse themselves with time.
NIDA administrators decided that they could illustrate Ricaurte’s message without harming any eggs: they printed up and distributed thousands of postcards and posters carrying images taken directly from Ricaurte’s paper. These images (which can still easily be found on the internet) juxtaposed a PET scan of the left side of the brain of a control subject with the right side of the brain of an Ecstasy user. Absurdly, most of the front of the drug user’s brain appeared to be missing, and the rest of it was riddled with large holes. By presenting PET scans as if they were actual pictures of brains, the poster heightened the paradox raised by CNN’s interviewee. Forget about honour rolls – how could a person even live and breathe with such a horrendous injury?
When I interviewed Ricaurte in 2006, I was struck by the contrast with Robert Iacono, the maverick neurosurgeon I interviewed for chapter one. Whereas Iacono was by turns humorous, pithy, and abrasive – in other words, an interviewer’s dream – Ricaurte was drily circumspect, rarely failing to discuss every possible side of a question in his desire for accuracy and fairness. When I asked him whether he thought the poster campaign was misleading, for example, he said, ‘An investigator does not play any active part in coming up with these things – the campaigns that are taken on. I don’t even know if it’s appropriate to label it a campaign. I certainly would endorse the research that generates findings that are relevant to the community or public health. I think it would be irresponsible to not make those results available to the public that pays for the research. If we’re doing research in the lab, the people who pay for that research should be privy to the results of that work. As you know, communicating results of scientific studies to the lay public is an art in itself; it’s not always easy to speak in laymen’s terms. Having said that, I think it becomes exceedingly important to make sure that the data that are being presented communicate the message in as accurate and responsible a way as possible. So the images you refer to, if what they are conveying is the impression that MDMA produces holes in people’s brains, somebody should have caught that and said, wait a minute, that is not what MDMA is doing; we think based on this research that it’s damaging serotonin neurons. And how to convey that notion appropriately with the appropriate recognitions of animal data and dosages and how much of the animal data generalises to humans – there are a number of limitations that should be recognised. If you go to the article where those images come from, we try to explain very clearly what the images are showing.’
Although Ricaurte has generally been well-regarded within the academic community, he has had his critics, especially among researchers who thought that Ecstasy might have therapeutic applications. One such person was Charles Grob, director of child and adolescent psychiatry at Harbor-UCLA Medical Center in Southern California. As he told me in a 2006 interview, Grob believes that Ecstasy, given in a carefully controlled clinical psychotherapeutic setting, might have value in the treatment of post-traumatic stress disorder, but he doesn’t support legalisation of Ecstasy for general, recreational use. A year before Senator Biden introduced the RAVE Act, Grob testified before the US Sentencing Commission. His remarks included the following:
‘Carefully examining the record of human research with MDMA, particularly the NIDA-funded studies of George Ricaurte, one observes a persistent pattern of poorly controlled studies, often with deliberate exclusion of vital data sets from published reports as well as unreported pre-selection biases in criteria used to recruit research subjects, which have led to grossly exaggerated and misleading claims in the scientific literature and in the media.’
Unperturbed by such criticism, Ricaurte pushed his Ecstasy research in a new direction. Earlier reports in the scientific literature, based on experiments in rodents, suggested that Ecstasy might also have damaging effects on neurons that used dopamine – the other transmitter whose release is triggered by Ecstasy. The doses needed to produce the toxic dopamine effects were rather high, and the damage didn’t appear to be as great as the damage suffered by the serotonin system. In 2000, however, Ricaurte set out to establish whether Ecstasy, even when given in a dose comparable to what a person might consume in the course of a single rave, could damage dopamine neurons in the brains of monkeys. Ricaurte gave pure MDMA (Ecstasy) to five squirrel monkeys and five baboons. Most of the animals received three doses of the drug, spaced at three-hour intervals. The total dose was six milligrams per kilogram of body weight. This would correspond to a person taking three pure Ecstasy tablets of about 150 mg each in the course of a single night’s partying – an amount that is within the range of what some rave attendees might consume, though probably higher than the typical user’s consumption. Because dosing monkeys orally is inconvenient – monkeys often reject food that has been spiked with drugs – Ricaurte gave the animals their MDMA doses by subcutaneous injection.
Two of the animals – one squirrel monkey and one baboon – developed uncontrollable hyperthermia soon after their final dose, and they died within hours. Another two monkeys – again, one of each species – fell ill after their second doses, and were therefore not given their final dose. The four surviving animals of each species were allowed to live for two to eight weeks, and then killed so that their brains could be studied, along with those of several control animals who had received injections of saltwater.
The results were striking: the monkeys that had received MDMA, even those who only received two of the planned three injections, showed signs of profound damage to the dopamine systems in the brain. Contrary to what might have been expected on the basis of previous studies, the damage to the dopamine system was even more severe than the damage to the serotonin system. And it wasn’t just a reduction in the levels of dopamine-related molecules, though that had certainly happened. In addition, Ricaurte found that the nerve endings of the dopamine neurons were physically degenerating. The cell bodies may have survived, but their terminals – the all-important sites of transmitter release – were shrivelling and dying like autumn leaves. And in response to the destruction, a special set of inflammatory cells were enlarging and multiplying in the affected areas of the brain. It seemed like the kind of thing that could give an Ecstasy abusing partygoer the morning after from hell.
As has already been discussed in the first chapter of this book, the loss of brain dopamine function is a central feature of Parkinson’s disease, the movement disorder that strikes between 8,000 and 10,000 Britons every year and that ends up killing many of them. So the finding of severe damage to the dopamine system in his monkeys’ brains immediately provoked an alarming thought in Ricaurte’s mind: could people who indulged in a single night’s use of Ecstasy be setting themselves up for a lifetime of Parkinson’s disease?
There was a precedent. In 1976 a Maryland college student by the name of Barry Kidston cooked up a novel designer drug, mainlined it and went into a state of permanently suspended animation – he simply couldn’t move or speak. His condition resembled the most advanced stage of untreated Parkinson’s disease. Kidston eventually responded to treatment with L-dopa, the standard therapy for Parkinson’s disease, but he later died of a cocaine overdose on the campus of the National Institutes of Health. When NIH researchers examined his brain they found that most of the dopamine neurons in his substantia nigra had died. A few years later, six drug abusers in California were found to be similarly affected.
The evidence that Ecstasy use might cause a Parkinson-like condition alarmed Ricaurte, but it was also an opportunity for public education. In September 2002, Ricaurte and his colleagues published their results in Science, under the title ‘Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (‘Ecstasy’).’ After presenting their data, Ricaurte’s group concluded as follows:
‘These findings suggest that humans who use repeated doses of MDMA over several hours are at high risk for incurring severe brain dopaminergic neural injury (along with significant serotonergic neurotoxicity). This injury, together with the decline in dopaminergic function known to occur with age, may put these individuals at increased risk for developing Parkinsonism and other neuropsychiatric diseases involving brain dopamine/serotonin deficiency, either as young adults or later in life.’
There was only one problem with this line of thought: there were no reports of anyone having put themselves into a ‘frozen’ state by using Ecstasy, whether for one night or over a lifetime. In fact, there wasn’t any documented relationship between Ecstasy use and Parkinson’s disease or other disorders of movement.
According to Ricaurte, however, this could simply be the result of a failure to look for a connection. When young people fell ill with Parkinson’s disease, he wrote, doctors didn’t usually inquire about their past use of recreational drugs, so the causative role of Ecstasy might have been missed. Furthermore, it was known that a large fraction of a person’s dopamine neurons – about 80 percent of them – have to die before the symptoms’ of Parkinson’s disease become apparent. Maybe, Ricaurte suggested, Ecstasy users didn’t destroy a large enough portion of their dopamine system to cause symptoms immediately, but they would nevertheless develop the disorder years or decades later, as natural attrition finished off the job that drug abuse had begun.
Ricaurte’s study was a shot in the arm for the RAVE Act. Joe Biden’s bill had faltered since its introduction three months earlier. It had sparked numerous demonstrations and protests, as well as thousands of letters, from people who saw the bill as threatening an innocent and popular pastime – raves. What sane person would organise a rave or allow their premises to be used for one, it was asked, if they risked a quarter-million-dollar fine every time a participant popped a pill? Organised opposition to the bill also came from the electronic music industry. In response to the protests, two of the bill’s cosponsors withdrew their sponsorship.
When Ricaurte’s study was published, public statements from Ricaurte, Johns Hopkins Medical School, NIDA, Science, and other authoritative sources painted Ecstasy as a proven threat to human health. Within weeks, Ricaurte’s study was being cited in Congress. In October of 2002 Asa Hutchinson, director of America’s Drug Enforcement Agency (DEA), told a House Judiciary Subcommittee that ‘[Ricaurte’s] study discovered evidence that severe brain damage occurs to the nerve cells which produce the neurotransmitter dopamine in the area of the brain controlling movement. The study concluded that neurological damage could stay hidden for years and increase the risk of Parkinson’s disease and associated movement-related disorders.’ According to Charles Grob, Ricaurte’s work ‘created an atmosphere of hysteria’ that fostered this and other legislation related to Ecstasy.
The RAVE Act didn’t pass in 2002, but early in 2003 Biden reintroduced it under a new name – the Illicit Drug Anti-Proliferation Act. Biden added it as an amendment to the Amber Alert Act, whose purpose was to facilitate the rescue of abducted children. Riding on those popular coattails, the Act cruised through both Houses without resistance or even discussion, and on April 30, 2003, it was signed into law by President George W Bush.
Ricaurte’s paper naturally incurred the scorn of the rave and drug-liberalisation communities. Within academe it was mostly well received, but it did have some detractors – mostly the people, such as Charles Grob, who wanted to legalise Ecstasy as a therapeutic drug. Grob told me that he was ‘incredulous’ when he read the paper. Another critic in this group was Rick Doblin, Ph.D., a public-health specialist and founder of the Multidisciplinary Association for Psychedelic Studies (MAPS). Doblin had long sought to sponsor a trial of Ecstasy, in conjunction with psychotherapy, for the treatment of post-traumatic stress disorder. Doblin is a more radical figure than Grob in that, as he told me quite frankly in 2006, he sees legalising Ecstasy for therapeutic purposes to be an initial step toward a long-term goal of a general decriminalisation of the drug.
Doblin had teamed up with Michael Mithoefer, a South Carolina psychiatrist, who would conduct the actual study. After many setbacks over a period of years, it seemed in 2002 that their project was about to be approved by the Food and Drug Administration. But, according to Doblin, Ricaurte’s wife and collaborator, Una McCann, wrote to the Institutional Review Board (IRB) that was considering the application and spelled out what she considered to be the neurotoxic effects of MDMA, including its newly discovered damaging effects on the dopamine system.
In a 2007 email, McCann gave me a different account of the interaction. She said that it took the form of a brief telephone conversation initiated by one of the IRB members. In the conversation, according to McCann, she emphasised the potential for damage to the serotonin system rather than to the dopamine system, and she said that she would have no problem with the proposed study so long as the subjects were made aware of the serotonin toxicity and the study was conducted in a safe environment.
Whether McCann had any role in the matter or not, the IRB dropped its support of the application, leaving Doblin and Mithoefer high and dry.
Shortly after Ricaurte’s paper was published, Doblin and Mithoefer wrote a critical letter to Science. According to the letter, which wasn’t published until the following June, there were four main reasons for believing that Ricaurte’s findings were incorrect or at least irrelevant to the human use of Ecstasy: first, the fact that two of his ten monkeys died, and two fell acutely ill, suggested that the dose of MDMA they were given didn’t correspond to a typical human dose, given that the vast majority of Ecstasy users suffered no acute ill-effects. In fact, Ricaurte himself in an earlier study had reported that MDMA given by injection was twice as potent as when given by mouth, suggesting that he had effectively overdosed his monkeys. Second, the letter pointed out that several previous primate and human studies, including some by Ricaurte himself, failed to find damage to the dopamine system from Ecstasy use. Thirdly – in a comment that later turned out to be uncannily perspicacious – it pointed out that the pattern of damage described in Ricaurte’s paper resembled the damage that was known to be produced by administration of high doses of methamphetamine (speed), yet that drug did not produce Parkinson-like symptoms in humans. Finally, it reminded readers that there was no reported association between Ecstasy use and Parkinson’s disease.
Ricaurte responded to the letter in a somewhat awkward fashion. Only one monkey had died, he said – contradicting what he had written in the published paper. (When Science requested clarification on this, Ricaurte explained that he had been talking about the squirrel monkeys – as if he had temporarily forgotten that baboons are monkeys too.) As to his earlier study that reported a difference between oral and injected dosages, Ricaurte responded by citing other studies that contradicted his own. The reason other studies didn’t find effects of MDMA on the dopamine system, Ricaurte suggested, was that they didn’t employ the three-in-a-row dosage regime that was designed to mimic a one-night Ecstasy binge. And as for the effects of methamphetamine, Ricaurte cited studies that did find some indication of Parkinson-like effects. Ricaurte wrapped up his response with a none-too-subtle dig at the motive behind Doblin and Mithoefer’s letter: he argued that clinical trials of Ecstasy should not be permitted because of the possible health risks that his research had demonstrated.
Although Ricaurte seemed unruffled by Doblin’s attacks, they did in fact motivate him to undertake new experiments. Specifically, he decided to repeat the published experiments, but administering the MDMA by mouth rather than by injection. In this way he would circumvent the comparable-dosage issue and would approximate more closely the actual drug experience of an Ecstasy-using partygoer. Starting just a month after his Science paper was published, Ricaurte treated a series of monkeys with the same three-dose regime of MDMA, but he gave the drug by mouth and varied the total dose to levels both higher and lower than those that he had given in the published paper. Although the animals did show signs of damage to their serotonin system, Ricaurte was surprised to find that none of them exhibited damage to their dopamine system. In order to be able directly to compare the oral and injection routes, Ricaurte treated another group of monkeys with Ecstasy by injection: in other words, he repeated his published study. None of these monkeys showed any impairment of their dopamine system either.
One can only imagine Ricaurte’s state of mind at this point. Not being able to reproduce one’s own published (and much publicised) findings has to be a scientist’s worst nightmare. To his credit, he reacted just as he should have done. Rather than stonewalling, ignoring the new findings, or fleeing the country, he set out very systematically to identify the source of the discrepancy between the results of the two studies.
Ricaurte first thought that the failure to replicate his earlier results might have to do with the temperature at which the monkeys were housed during the experiment. This was because high temperatures were known to worsen the effects of Ecstasy. So, in March and April of 2003, he injected another group of squirrel monkeys with MDMA and housed some of them at the normal animal-house temperature and some at a higher temperature. Again, neither group of monkeys suffered any damage to their dopamine neurons. Next he tried varying the humidity, with equally negative results. Then he tested the hypothesis that male and female monkeys were affected differently, but this also turned out not to be the case.
It was beginning to look as if some fundamental error had been made in the published study. Had the drugs been wrongly prepared, such that the monkeys received more than the intended total dose of six milligrams per kilogram? To test this idea, Ricaurte undertook yet another set of experiments, in which the monkeys were given 12 milligrams per kilogram – double the previous dose. Yet even these monkeys suffered no damage to their dopamine systems. Finally, Ricaurte repeated the original published study with baboons, but these animals, just like the squirrel monkeys, experienced no dopamine injury.
Having exhausted other hypotheses, Ricaurte now began to suspect that there was something wrong with the MDMA – either the MDMA he had used in the original study, which had gravely impaired the monkeys’ dopamine system, or the MDMA that he had used in his more recent experiments, which had not. Ricaurte had obtained all his MDMA from the Research Triangle Institute (RTI), a non-profit corporation based in North Carolina that produces special-purpose drugs under contract with the US government. Like most scientists, Ricaurte, relied on his suppliers to verify the purity of their drugs and didn’t check them himself.
The MDMA that Ricaurte used for his published study came from a 10g bottle that he received from RTI on April 27, 2000. That bottle had long since been used up and discarded, so its contents couldn’t be tested. But RTI did still have some of the same batch in storage. That sample, as well as a sample of the batch that Ricaurte had used in the newer studies, tested correctly for authentic MDMA.
In perplexity, Ricaurte ordered authentic MDMA from yet another, newer batch, and tested it on a baboon: it too failed to damage the animal’s dopamine neurons.
It then occurred to Ricaurte that, although the original bottle of MDMA had been discarded, he did still have the brains of two monkeys who had received injections from that bottle. These were the two monkeys (one squirrel monkey and one baboon) who had died shortly after receiving their third injections; Ricaurte had frozen their brains and put them in storage. Because these two animals had died so quickly, some of the MDMA should still have been present in the frozen brains. Ricaurte therefore tested for the presence of MDMA in these two brains as well as in the brains of other animals that he was certain had received authentic MDMA. He detected MDMA in those other animals readily enough, but there was no sign of MDMA in the two animals that had died after receiving the three injections from the suspect bottle. So Ricaurte concluded that the bottle, though labelled ‘MDMA’, had not in fact contained that drug.
But something had to have been in the bottle, and that something had to have been a drug capable of severely damaging the monkeys’ dopamine systems, as well as inflicting lesser damage on their serotonin systems. Ricaurte was very familiar with a likely candidate, if for no other reason than that Rick Doblin had forcefully reminded him of it in his letter to Science just a few weeks earlier. That drug was methamphetamine – speed. If Ricaurte had given his monkeys methamphetamine rather than MDMA, that would not only explain the damage to their dopamine system; it might also explain why two animals had died and two had fallen sick. That’s because methamphetamine is a more potent drug than MDMA: when users take pure speed (often referred to as ‘crystal meth’ or ‘ice’) they typically take no more than 100mg, but Ricaurte had given his monkeys an amount that would correspond to a human dose of 150mg, and he had given the animals this dose three times in a row in the course of just a few hours.
So Ricaurte wanted to test the frozen monkey brains for the presence of methamphetamine. But he wasn’t very familiar with the testing protocol, so he started by taking some pure methamphetamine from a bottle also supplied by RTI and testing it. To his puzzlement, the test didn’t seem to come out right – the results were more suggestive of MDMA than methamphetamine. Ricaurte therefore sent out a sample for testing by a much more sensitive procedure – mass spectrometry. The results were unambiguous: the substance was not methamphetamine but MDMA.
It was now beginning to seem that RTI had provided Ricaurte with incorrectly labelled drugs, and not just once but twice. And, even more remarkably, the two suspect bottles had been received from RTI on the same day, April 27, 2000, as part of the same order and in the same package. Was it possible that a technician at RTI had accidentally switched the labels between the two bottles so that the MDMA ended up being labelled as methamphetamine and vice versa?
By this time it was July of 2003, and Ricaurte’s annual progress report to NIDA was due. But Ricaurte had no progress to report: he had shelved all the experiments that he had planned to do in that year in order to get to the root of the MDMA mystery. So he wrote a report that described his failure to replicate his own study and the various attempts he had made to understand the reason.
Having sent off the report, Ricaurte did the clincher experiment: he took samples from the brains of the two monkeys who had died after their ‘MDMA’ injections and sent them for analysis by mass spectrometry. The results were unambiguous: the brains contained methamphetamine, but no trace of MDMA. Clearly, the dopamine injury sustained by these and the other monkeys had been caused by an overdose of speed, not by Ecstasy. Ricaurte’s 2002 Science paper was utterly and completely wrong, though apparently through no fault of his own.
At this point only a very few people – chiefly Ricaurte’s research group, NIDA staff and a few other colleagues – knew what had transpired. But Ricaurte now had to do what scientists dread ever having to do, which was to write a letter of retraction to his publisher, Science. The letter was not simply a retraction but a recounting of the entire investigation that had led him to conclude that RTI had provided him with mislabelled drugs. Interestingly, Ricaurte did not completely recant the conclusions of the retracted study; that is, he did not state that recreational doses of Ecstasy were harmless to dopamine neurons, even though his results indicated that they were. On the contrary, he cited other papers that suggested that Ecstasy was toxic to the dopamine system and hinted that future experiments would document the fact. It was an odd way to sign off on a letter of retraction – a kind of dogged ‘I’ll be back and I’ll prove I was right.’
Science published Ricaurte’s letter on September 12, 2003, but the news leaked out a few days earlier, and it caused a sensation, sparking articles in all the major American national newspapers and also overseas. The New York Times didn’t just run a news account of the event, it followed that up with an investigative article that alleged all kinds of other scientific misdeeds by Ricaurte. The Times cited experts who claimed that, at one time or another, Ricaurte had used inappropriate statistical procedures or ‘played games with his data.’ A drug user who had been a volunteer in one of Ricaurte’s human studies described what seemed to be a variety of procedural lapses on Ricaurte’s part, such as failing to test for undeclared current drug use. (This particular person had used heroin just five days before participating in the study, but his statement to the contrary was accepted at face value, he told the newspaper.) Richard Wurtman, director of clinical research at the Harvard/MIT health sciences division, told the Times that Ricaurte was ‘running a cottage industry showing that everything under the sun is neurotoxic.’
Most of the scientists who expressed critical views to the Times and other media sources were those who, like Wurtman, had had longstanding disagreements with Ricaurte or who were hoping to use Ecstasy in clinical research. But even scientists who had initially praised Ricaurte’s study expressed very different opinions when his retraction appeared. The British neuroscientist Colin Blakemore, who was head of the Medical Research Council from 2003 to 2007, had expressed himself as follows to the Daily Telegraph when Ricaurte’s study was originally published: ‘This new study provides further evidence that Ecstasy can be toxic to nerve cells... I think people would be well advised to avoid it.’ And he cited unpublished work from his own laboratory as being consistent with Ricaurte’s results. But after the retraction appeared, Blakemore commented (in an unpublished letter to the editor of Science that was quoted by The Scientist) that ‘the study was so obviously flawed that even I (not a pharmacologist) picked up the problems as soon as I saw the paper.’ When I asked him in 2006 about the apparent inconsistency in his comments, Blakemore told me that he had made the earlier, favourable comments on the basis of an inaccurate press release and had not yet actually read Ricaurte’s paper.
Ricaurte’s retraction left a couple of loose ends untied. For one thing, Ricaurte mentioned in the retraction that one of his ‘MDMA’ treated animals – a baboon – received its drug from a different source than the allegedly mislabelled bottle. Presumably that animal received authentic MDMA and not methamphetamine, and it should therefore have been spared any damage to its dopamine system. Yet the published paper implied that all the animals were similarly affected. Grob picked up on this as another problem in Ricaurte’s work. ‘For many years he has had a pattern of being very selective as to the data he discloses and the data he elects not to disclose,’ Grob said.
When I asked Ricaurte himself about this animal, he responded a bit cryptically: ‘In that baboon the level of dopamine was – I don’t recall the exact value, but it was not reduced to the extent that we had seen in the others, and it was difficult to discern from that single value whether it was in the control range or whether it was modestly reduced.’ In other words, that animal was uninformative: it was neither normal enough to raise a red flag about the genuineness of MDMA’s apparent toxicity, nor abnormal enough to undermine the mislabelled-bottle hypothesis as an explanation for the erroneous findings.
Another and more remarkable loose end was this: officials at RTI did not go along with Ricaurte’s explanation for what had happened. After an internal investigation, their spokesman said that there was ‘no evidence’ that the bottles had been mislabelled in the way that Ricaurte had deduced. Of course, there may be no evidence for any number of events that did actually happen. But when I asked an RTI spokesperson in 2006, he denied the company’s responsibility more positively. ‘Although we do not know what might have happened to the materials after they were received by Ricaurte,’ he wrote, ‘we reject with certainty that we mislabelled [them].’
On the face of it, this leaves nothing but conspiracy-style explanations. ‘The only other way that something like that could have happened,’ Ricaurte told me, ‘would be if someone in my lab willingly went in and tried to take all of the contents of the bottle that was supposedly containing methamphetamine and pushed them into the bottle that contained MDMA. And I’ve asked my chemist friends how feasible would that be, without causing some cross-contamination, without disturbing the labelling of the bottles, and without exception chemists who know this business tell me that that would be nearly impossible to do.’
So Ricaurte believes that the error did occur at RTI in spite of the company’s denials. ‘You must recognise,’ he went on, ‘that RTI produces drugs not only for much of the animal research that goes on in the United States and around the world, but the drug supply for many human clinical studies, so in retrospect it was extremely naïve on my part to begin to think that the drug supplier would acknowledge their...’ Ricaurte broke off in mid-accusation and withdrew to safer ground. ‘But in some ways it didn’t matter to me; the question was just identifying the error and making sure that colleagues in the scientific community [were informed], that the scientific record was corrected.’
While the retraction of his 2002 paper must have caused Ricaurte a great deal of embarrassment and soul-searching, it does not seem to have affected his career in a major way. He remains an associate professor in good standing at Johns Hopkins University Medical School, and he still receives research funding from NIDA. In fact, his research continues very much in the same vein as before. The large number of experiments that he did in the quest to understand why he couldn’t replicate the 2002 study were not wasted: they were mined for data that went into new papers. In 2005 Ricaurte and his colleagues published an expanded version of his 1998 study of the effects of Ecstasy on the serotonin system; he stuck to the same conclusions as before, although he was more open to the idea that the damage reversed itself over time. And in the same year he published a study reporting that amphetamine – a legal prescription drug used in the treatment of attention deficit/hyperactivity disorder – caused damage to the dopaminergic system in monkeys that was similar in some respects to the damage caused by methamphetamine.
In spite of the continuation of Ricaurte’s research, the retraction of the 2002 paper did seem to weaken the impact of his work in some respects. Most notably, researchers who wanted to test Ecstasy in the treatment of post-traumatic stress disorder, who had previously encountered roadblock after roadblock in the way of their efforts to begin their studies, suddenly found themselves in business. Doblin and Mithoefer’s proposed study got Review Board approval just two weeks after Ricaurte’s retraction was published. Doblin questions any causal connection between the two events, but Charles Grob told me that the approval was ‘clearly attributable to Ricaurte’s work being seriously questioned.’ In any event, the study began in 2004 and, according to Doblin, by two years later it was showing a beneficial effect of the drug.
Ricaurte told me that he wasn’t opposed to the Doblin/ Mithoefer study so long as the subjects were properly informed of the risks. He added: ‘I would have thought that people like Rick Doblin would say, “Gee, maybe we should take what’s coming out of that laboratory more seriously – when they make mistakes, they acknowledge them.” But it’s had completely the opposite effect. Doblin’s a remarkable character in many ways. I think he truly thinks that he can make this a better world if everybody takes Ecstasy. I don’t doubt that he’s trying to be helpful. But if you’re trying to do that, why would you not want people to be aware of any potential risk that your magic pill may have?’ (I don’t know any basis for the suggestion that Doblin does not want people to be aware of Ecstasy’s risks.)
Ricaurte’s retraction did not lead to any rethinking of the Illicit Drug Anti-Proliferation Act by Joe Biden or other Congressional leaders. The Act remains law, although it doesn’t seem to have been enforced in any very energetic way. According to the DEA, the use of Ecstasy by American youth declined significantly from 2002 onward, a change that the DEA attributes to public educational campaigns against the drug. These campaigns include the DEA’s website, which still carries a description of Ricaurte’s study, as presented by the DEA’s director to Congress in 2002, without any mention of the fact that the study has been retracted.
Finally I asked Ricaurte, ‘What would you say to a teenager who said that he or she was thinking of trying Ecstasy?’ I thought I was lobbing him a softball that he could swat out of the ballpark with a terse and quotable comment such as ‘Don’t!’ But he remained true to type. ‘You know it’s really quite remarkable,’ he said. ‘It’s remarkable to me how difficult it is to convey what in many ways I think is a very simple message that emerges from, gosh, almost two decades of research with MDMA and related amphetamine derivatives. What we know, or what I think we know, what I think we’ve learned over the last two decades is (a) MDMA has the potential to damage brain serotonin neurons in most every species that’s been examined except the mouse, where it happens to damage dopamine systems, and we have to recognise that we don’t know what the better animal model is – is it all of the others, just because we live in a democracy, or perhaps the mouse is more representative? I happen to think that the mouse is the outlier, but I don’t know that for a fact, but I think we’ve learned that MDMA is a drug that has the potential to damage monoamine systems, serotonin systems, in most all the animal species tested, and I think the other thing we know, and I think the other thing that should be conveyed, is that you don’t need heroic doses of the drug to produce this selective form of brain injury. What we’ve learned with MDMA is that the difference between the size of the toxic dose and the size of the pharmacologic or effective dose – that that difference seems to be very small. We don’t know exactly what that margin of safety is, but we do know that it appears to be narrow. Where we do know that from? From a number of studies where people have now tested lower doses, single doses, giving the doses orally, in a way that the drug is used by humans, and collectively that data says, you don’t need heroic doses, the margin of safety for this drug may be narrow. And in a nutshell I think those are the two things that people, that any people who are contemplating using MDMA ought to be aware of, just by way of making an informed decision about the drug they’re about to take.’