Deadly combination

New Scientist, vol 155, issue 2090 - 12 July 97, page 20

WHEN Philip Kay collapsed and died after taking ecstasy at a London night club last November, his story did not make the news. But then, Kay was not the sort of casualty that excites newspapers. He was a 32-year-old tax inspector who had taken ecstasy many times before. And - to be blunt about it - his days were numbered anyway because he had AIDS.

The pathologist's report blames his death simply on an overdose of ecstasy (3,4-methylenedioxymethamphetamine or MDMA). But nobody who knew Kay believes the official version. The levels of ecstasy found in his blood that night were staggeringly high - equivalent to most people having swallowed 22 tablets. Yet Kay's friends insist he took only two. They claim the real reason for the high levels of MDMA was that these two pills interacted lethally with a newly approved prescription drug called Ritonavir which Kay was taking to control his HIV infection.

Ritonavir is designed to inhibit HIV's protease enzyme, but it also interferes with a liver enzyme called CYP2D6 that metabolises MDMA. Thus someone who took both drugs could have problems clearing MDMA from their bloodstream.

Jim Lumb, who lived with Kay in London and also takes Ritonavir, says nobody told them that the medicine could form such a cocktail with MDMA. This is hardly surprising. Abbott Laboratories, the Chicago-based drugs company that makes Ritonavir, has never issued a warning, even though its own unpublished calculations indicate that Ritonavir could produce more than a threefold increase in blood levels of MDMA.

Despite Kay's death, Abbott says it has no plans to investigate further the biochemical interaction. Nor, so far, has the company brought it to the attention of health officials who monitor the safety of medicines. Its behaviour is nothing exceptional. Although most prescribed drugs and over-the-counter medicines come with safety notes warning about potentially hazardous interactions with other prescribed drugs, pharmaceuticals companies hardly ever issue warnings about the dangers of mixing their products with illicit substances.

Some toxicologists defend this practice on the grounds that it is difficult to establish the facts in cases like Kay's. Others point to apathy on the part of the regulators: neither Britain's Medicines Control Agency nor the US Food and Drug Administration has a specific policy on how companies should deal with the problem.

But Kay's death exposes a deeper reason for the lack of openness about the dangers of mixing prescribed and illicit drugs. Companies like Abbott argue that to clarify the dangers would be to send out a reckless signal to the public. "We would be seen to be condoning drug abuse," says Gordon Boyd, head of clinical development for Abbott in Europe. "We can hardly say in our literature that our drug may be taken safely with heroin, cocaine or whatever but not with ecstasy."

This defence does not go down well with the doctors whose daily business is to prescribe drugs like Ritonavir to patients who use illicit substances. Ray Brettle, who runs the infectious diseases unit at City Hospital in Edinburgh, says the companies are simply trying to protect their corporate image. He maintains they could still make the dangers clear without appearing to support illegal activity. "It's possible to come up with a form of words that makes it clear you're not condoning drug abuse."

There is now an urgent clinical need for openness and research, claims Brettle. Ritonavir is just one of many powerful new medicines for treating people with HIV, many of whom belong to communities in which the use of illegal drugs is endemic. There is also evidence that drug users are deliberately mixing prescription medicines with drugs like LSD and MDMA to modify or enhance their effects.

For example, people have been mixing the antidepressant Prozac with MDMA in a bid to prevent a post-ecstasy depression. According to Geoff Tucker, a pharmacologist at the University of Sheffield, the cocktail could create the same sort of problems as those that may have killed Kay—like Ritonavir, Prozac inhibits the CYP2D6 liver enzyme.

High-risk group

Quantifying the risks of mixing Prozac and MDMA is not easy. Research has been hindered by red tape and the need for special licences, says Tucker. But the little biochemistry that has been done indicates that not everyone is equally at risk. Between 3 and 8 per cent of the population possess a genetic defect that makes them especially poor at metabolising certain drugs.

For these people, mixing drugs like Prozac with MDMA could be especially hazardous, perhaps tipping the balance between a strong reaction and a fullblown overdose. But drug abusers have no way of knowing if they belong to this high-risk group. Nor can researchers like Tucker discover if Kay or any of the other ecstasy users who have died in recent years carried the defective gene. Despite pleas about the need to learn from these tragedies, nobody kept any blood samples.

The prevalence of deaths caused by the interaction between prescribed and illegal drugs is unknown. Very few are ever recorded and there are no schemes in place for monitoring those that do come to light. Michael Rawlins, chairman of Britain's Committee on the Safety of Medicines, says he has never been called on to investigate an adverse interaction of this type. In fact, says Rawlins, it is not even clear whether companies in Britain are legally required to notify officials about such interactions. "Rightly or wrongly, drug safety guidelines relate to normal use."

In the US Curtis Wright, a drug safety expert at the FDA, claims his organisation "makes no distinction between illicit and legal drugs" when monitoring or investigating suspected cases of adverse interactions. But so far, the FDA's interventions have been confined to a tiny number of "problem pharmaceuticals"—medicines that are open to abuse themselves or for which the risks of adverse interactions with street drugs are obvious.

The WHO's internationally accepted guidelines on drug safety information say nothing about adverse interactions involving illicit substances. Ralph Edwards, director of the WHO's drug monitoring unit in Uppsala in Sweden, says the pharmaceuticals industry lobbied to exclude any specific recommendations. Edwards now says he has misgivings about the omission.

Where information about the interactions of illicit and prescribed drugs does exist, there is disagreement over what should be done with it. Wright says the FDA's obligation to the drug abusing community "is to keep them alive, not to provide them with quality control information". Some would not even go that far. "Researchers have their work cut out monitoring licensed drugs," says Joe Collier, editor of Drug and Therapeutics Bulletin and a clinical pharmacologist at St George's Hospital Medical School in London. "If you take illicit drugs you're putting yourself outside the law and you can lump it. You can't expect the state to protect you."

But most experts believe this is a dangerous argument. "Like it or not, a large percentage of the population uses recreational drugs," says Katherine Bonson, a researcher at the US National Institutes of Health who has interviewed people about their experiences of mixing antidepressants and LSD. And Edwards asks: "Are we saying that drug addicts who overdose shouldn't be admitted to hospital?"

Lumb will not be agonising over the niceties of medical ethics when he goes to a coroner's court in London next week to press for an investigation into his partner's death. He says he simply wants doctors and patients to know that mixing Ritonavir with ecstasy could be dangerous. And he wants the drugs company to tell them.

After all, he says, "the drug cost more than £4000 a year, so Phil was worth more to them alive than dead".