BusinessWeek APRIL 11, 2005

Your Brain On Alcohol
Can Alcoholism Be Treated? Research
shows how stubborn addictions are
-- and how medications may help

By Catrherine Arnst
r. Olivier Ameisen is a 51-year-old cardiologist in Paris. He is also an alcoholic. Between 1997 and 2004, Ameisen was hospitalized numerous times for drinking. He went through years of rehabilitation programs and attended two Alcoholics Anonymous meetings a day, some 700 a year, for seven years. All to no avail. His craving for drink always overwhelmed his desire to quit.

By January, 2004, Ameisen came to believe his only hope would be a drug that could dampen those cravings. But despite the fact that alcoholism is widely recognized as a medical condition, there were only two medications available, and neither had worked for him. Ameisen researched the literature and came across rat studies showing that
baclofen, a generic drug used to control muscle spasms, could suppress the desire to consume alcohol by interfering with the reward circuitry in the brain. It is also used to treat anxiety disorders, which afflict large numbers of alcoholics, including Ameisen.

The doctor decided to self-prescribe the drug at high doses. And he took the unusual step of writing himself up as a case study this past December in the journal
Alcohol & Alcoholism. After nine months on baclofen, he reported that he had not had a drink since Jan. 9, 2004, and, more important, that he had experienced "no craving or desire for alcohol for the first time in my alcoholic life. Even in a restaurant with friends, I was indifferent to people drinking. This had never occurred before."

Ameisen's detailed report adds to a growing body of evidence that alcoholism -- and addiction itself -- has unique pathologic traits that can be corrected through chemical intervention. Drug researchers are now striving to bring science to bear on what was long treated as a social problem rather than a medical one. Over the last decade, sophisticated brain-imaging technologies have demonstrated that constant use of alcohol significantly alters the structure of the brain in ways that can last for months and even years, creating a chronic brain disease. With this knowledge in hand, the search is on for drugs that can restore the brain to its pre-drinking state.

Forest Laboratories Inc. (FRX ) started marketing one promising medicine in the U.S. in January.
Campral, the first alcoholism drug to win Food & Drug Administration approval in 10 years, is designed to suppress alcohol cravings by targeting specific brain chemicals thrown out of balance by drinking. Alkermes Inc. (ALKS ) filed for FDA approval of its own anti-craving drug, Vivitrex, on Apr. 1.

Neither drug is new. Campral has been on the market in Europe for 15 years, and Vivitrex is a once-a-month, injectable form of naltrexone, a daily pill approved for alcoholism in 1994. Nor are Campral and Vivitrex miracle cures. Dr. Ameisen tried both, to no effect. Clinical trials have shown that they can help patients remain abstinent two to three times longer than those on placebo, but the relapse rate is high.

Still, these medicines prove the principle: Drugs that target the brain's addiction pathways can curb drinking. Scientists have also discovered that almost any addiction, be it alcohol, cocaine, nicotine, even gambling, involves many of the same pathways. A drug that treats one addiction may be effective against others. As a result, research in this field is rapidly accelerating. "I've been treating addiction for over 20 years, and for the first time I believe there is a convergence of various forces that will get medications out there," says Dr. Richard N. Rosenthal, chairman of the Psychiatry Dept. at St. Luke's-Roosevelt Hospital Center in New York. "The pharmaceutical industry is finally getting interested."

Drug companies have good reason to be pay attention -- alcoholism is one of medicine's largest unmet needs. The National Institute on Alcohol Abuse and Alcoholism estimates that almost 18 million people in the U.S. abuse or are addicted to alcohol. They cost the nation some $185 billion a year in medical services, lost wages, and law enforcement resources. Yet each year only two million alcohol-dependent people seek treatment, and up to 90% relapse within four years.

Despite the huge number of sufferers, alcoholism was "underscienced" for years, says Alkermes CEO Richard F. Pops. Since 1935, when Alcoholics Anonymous was founded, the vast majority of treatment efforts in the U.S. were based on AA's 12-step program, requiring behavioral changes and faith in a higher power. "The history of treatment in this country was not consistent with the idea that medicines could help," says Dr. Klye M. Kampman, associate professor of psychiatry at the University of Pennsylvania. "We were very moralistic."

For decades the only alcoholism drug in the U.S. was Antabuse, which causes people to vomit when they drink. Even now, only some 140,000 alcoholics in the U.S. receive medication for their disease, ranging from Antabuse to anti-depressants to anti-seizure drugs. There was no move to introduce Campral in the U.S. until Forest licensed it from Germany's Merck in 2001.

A clearer understanding of the biological underpinnings of alcoholism is opening the way to better drugs. Scientists have identified a number of genes that confer a predisposition to alcohol addiction. They have also found that the brain goes through profound changes when a person starts drinking to excess.

Alcohol releases a neurotransmitter called GABA (gamma-aminobutyric acid), instrumental in creating a sense of euphoria. Too much GABA can impair muscle control and slow reaction times, so the brain releases a stimulating chemical called glutamate to keep it in check. When alcohol is cut off, glutamate levels remain high and can cause irritability and discomfort. To relieve those feelings, the brain craves another drink. As more GABA and glutamate are released, brain cells change their structure to accommodate the excess chemicals, making them dependent on these levels. When alcohol is withdrawn, painful emotional and physical reactions are set off.

GABA may be the reason people drink, but glutamate is the reason they can't stop. This powerful neurotransmitter is a key player in the brain's learning centers, and excess amounts create deeply embedded memories of drinking. Years after a person quits, these memories can be triggered by a place, person, or even smell associated with drinking, setting off intense cravings. Such cue-induced cravings are the main reason for relapse. "They're why it can be easy to get off a drug, but it's very hard to stay off," says Dr. Herbert D. Kleber, director of the division on substance abuse at Columbia University.

Campral helps alcoholics resist these cravings by checking production of glutamate, bringing the brain's chemistry back into balance. Clinical studies of Campral have shown that after six months of treatment, 36% of patients were still abstinent, compared with 23.4% on placebo. Vivitrex dampens cravings by a slightly different mechanism, calming opioid receptors in the neurons that are overstimulated by alcohol. A recent study showed that Vivitrex can help people cut way down on alcohol bingeing. That's not the same as abstinence, but Dr. James C. Garbutt, an alcoholism researcher at the University of North Carolina at Chapel Hill, says reduced drinking is still meaningful in a disease that is remarkably resistant to treatment. "If you significantly reduce the number of heavy drinking days, you've made a big impact." Treatment specialists believe that Campral and Vivitrex may be most effective when used in combination.

Existing drugs approved for other purposes may end up being part of that combination. The field got a jolt in May 2003 from
a study in The Lancet that showed that Topamax, an anti-seizure medicine from Johnson & Johnson (JNJ ), helped 13 of 55 patients abstain from drinking for a month. Dr. Bankole A. Johnson of the University of Texas Health Science Center at San Antonio, who headed the study, said the patients all started on the drug while still drinking, a significant breakthrough. Campral is taken after the patient quits.

Still, no drug is recommended in a vacuum. "We are developing better and better medications, but they need to be taken in a therapeutic context," says Kleber -- which may include AA and other types of behavioral therapies. Dr. Ameisen, for one, found it much easier to use the techniques he learned at AA while on baclofen. But it was the drug that changed his life. "At the end of my ninth month of complete liberation from symptoms of alcohol dependence, I remain indifferent to alcohol," he writes. "Abstinence has become natural to me."