by Simon Levay
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, e
ven 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.’