Pubdate: Sat., 17 April 1999 Source: Economist, The (UK) Copyright: 1999. The Economist Newspaper Limited. Contact: http://www.economist.com/ Note: The Economist includes related web links below on it's website. They may not appear in the print edition. NEW DRUGS FOR OLD HABITS Advances In Both Science And Social Attitudes Could Lead To Novel Treatments For Drug And Alcohol Addiction IN THE world of addiction, ingenuity knows few bounds. People have always had a knack for getting high, and sometimes hooked, on the most unlikely substances, from mushrooms to poppies. But though modern pharmacology has created hundreds of new drugs, both legal and illicit, for would-be junkies, it has offered few that can deal with the problem of addiction itself. Until now. Advances in the understanding of how alcohol, cocaine, heroin and nicotine affect the brain at the cellular and molecular level are leading to new approaches to treating substance abuse. The challenge, say addiction experts, is to persuade drug companies to develop these bright ideas into marketable products with the same enthusiasm they have for drugs to treat cancer, say, or depression. A few companies have taken the plunge, at least for alcohol abuse. Consider acamprosate, a new drug made by Merck Lipha, a company based in Lyons, France. The compound, which helps reformed alcoholics stay off the bottle after detoxification, is finishing late-stage clinical trials in America, and has been on the market in Europe since 1995. How it works is still uncertain. Acamprosate is known to bind to a protein on nerve cells in the brain called the NMDA receptor, which is normally involved in relaying excitatory signals between nerve cells. Alcohol withdrawal boosts the receptor's activity and reduces the effects of other inhibitory proteins, sending the brain into a twitter, and the drinker in search of liquor. Joseph Volpicelli, a researcher at the University of Pennsylvania, reckons that acamprosate may act by dampening the hyperactive NMDA receptor, restoring the balance between excitation and inhibition in the brain, so keeping reformed alcoholics on the wagon. At any rate, in large-scale clinical trials in Europe, twice as many alcoholics taking acamprosate stayed dry after a year of daily dosing compared with those receiving a placebo. Acamprosate may prove a good partner for naltrexone, another anti-alcoholism drug launched by America's DuPont in 1995. Naltrexone has been found to lower the high associated with drinking and to diminish craving. It is not a new drug: it was approved 15 years ago to treat heroin addiction. But old drugs, often developed for quite different disorders, tend to find new uses in addiction medicine, largely because of the lack of drugs tailor-made to deal with substance abuse. Another difficulty, says Dr Volpicelli, is that most alcoholics and doctors are largely unaware of these new medical treatments. And many Americans believe that, unlike other diseases such as cancer, addiction is a moral rather than a medical problem. Even such long-established drugs as methadone, for treating heroin addiction, are controversial in America, and new drugs take much longer to be accepted than in Europe. There is also plenty of room for improvement in administering the drugs. One big problem with naltrexone is that users often forget, deliberately or otherwise, to take their pills. One solution, now being tested by Drug Abuse Sciences, a biotechnology company in Menlo Park, California, is to repackage naltrexone from pill form into microspheres that can be implanted under the skin. In animal tests, this slow-release system sustained steady levels of the compound for one month. Drug Abuse Sciences is hoping to try it on human volunteers in clinical trials later this month. Similarly, experts are hoping for a technical fix to one of the most offputting aspects of methadone treatment for middle-class heroin addicts, namely the nuisance and humiliation of queuing up at a down-at-heel clinic in the inner city. Drug experts like Westley Clark, director of the Centre for Substance Abuse Treatment in Rockville, Maryland, are hoping to introduce more amenable means of distributing newer, potentially more effective drugs for heroin treatment (such as buprenorphine, now in clinical trials in America) to these addicts. These drugs could, he suggests, be prescribed to some patients by their own doctors. Kicking the habit The urge to drink or take drugs is, neurochemically speaking, linked to endorphins (natural morphine-like molecules) or dopamine, a neurotransmitter that is involved in bits of the brain that control reward behaviour. A better grasp of how such reward pathways work is leading to new drugs to treat even the enfant terrible of narcotics, cocaine. According to Frank Vocci, a director of medications development at America's National Institute of Drug Abuse, several drugs are on the way that block the drug-induced craving associated with cocaine. And the range of drug therapies will grow, he believes, as new genes associated with drug and alcohol addiction are found. Among the new approaches is a cocaine-like molecule now in clinical safety trials from Neurosearch, a Copenhagen-based biotechnology firm. This drug attaches itself to a protein that is responsible for pumping dopamine back into nerve cells after its release. This same pump is targeted by cocaine, which rapidly blocks it and so boosts dopamine levels, causing an intense high. Neurosearch's compound stops cocaine from binding to the receptor by getting in the way and gradually brings dopamine levels back to normal. Cocaine-addicted baboons treated with the molecule stopped injecting themselves, with no sign of becoming hooked on the treatment instead. An even more intriguing approach to cocaine addiction uses the immune system--which can be coaxed into producing antibodies to just about anything--to attack drugs. Drug Abuse Sciences has been generating antibodies to cocaine in horses and using them to mop up cocaine in the bloodstream of other experimental animals before it reaches the brain and heart. The company believes that these antibodies might one day be useful for treating cocaine overdoses. Donald Landry and his team at Columbia University in New York have also developed antibodies to cocaine, but with a twist. As well as sticking to cocaine, their antibodies also break it up into bits, which more thoroughly removes it from the system. Cocaine-addicted rats lost their appetite for the drug after receiving a few doses of Dr Landry's catalytic antibodies. And Cantab Pharmaceuticals, a Cambridge-based biotechnology firm, has almost finished safety trials with its anti-cocaine vaccine designed to stimulate an addict's own immune system to fight off the drug, just as it might a bacterial infection. The company plans to try a similar approach for nicotine addiction. Weaning smokers from their weed is an alluring prospect for large pharmaceutical companies interested in millions of customers and billions of dollars in sales. But developing drugs for other addictions is a riskier commercial proposition, largely because so many addicts are poor and, in America at least, their health insurance will not always pay the bill. Yet every dollar spent on drug-abuse treatment could save as much as seven times that in medical and social costs. With such a prize at stake, all it may take to get more drug companies into the business of addiction, according to Dr Volpicelli, is one success story, such as Prozac. Until that happens, though, academics and biotechnology firms will remain busy trying to lift addiction drug development out of depression. LINKS Acamprosate, the compound which helps reformed alcoholics stay off the bottle after detoxification, is produced by Merck Lipha. DuPont is the manufacturer of naltrexone, another anti-alcoholism drug. The issues surrounding addiction medicine can be found at the American Society of Addiction Medicine. Information on the issues of drug-dependence can be found at the Lindesmith Center and the National Institute on Drug Abuse. More general substance abuse information is available at the Substance Abuse & Mental Health Services Administration. The National Institute on Alcohol Abuse and Alcoholism is here. The White House website on drugs policy is here. A web links resource on addiction related topics is here. Additional information can be found at the Addiction Resource Guide. Merck Lipha: http://www.lipha.com/ Dupont: http://www.dupont.com/ American Society of Addiction Medicine: http://www.asam.org/ Lindesmith Center: http://www.lindesmith.org/ National Institute on Drug Abuse: http://www.nida.nih.gov/ Substance Abuse & Mental Health Services Administration: http://www.samhsa.gov/ The National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/ The White House website on drugs policy: http://www.whitehousedrugpolicy.gov/ A web links resource on addiction related topics: http://www.well.com/user/woa/aodsites.htm Addiction Resource Guide: http://www.hubplace.com/addictions/ - --- MAP posted-by: Richard Lake