A NEW RX FOR ADDICTION:

New 'Anti-High' Drugs Fight Fire With Fire

Experts hope cutting-edge treatments will block the need and end the
drive for the 'rush'

One morning more than a quarter of a century ago, scientists Alan
Cowan and John Lewis folded themselves into a small observation box at
an industrial laboratory outside London. Fingers crossed, they peered
through a hazy one-way mirror at three patas monkeys playing in a room.

For weeks, the monkeys had been injected three times daily with an
experimental painkiller and opiate called RX 6029-M. Now, the animals
had been injected with another drug, naloxone, which normally provokes
instantaneous withdrawal in subjects taking opiates.

Over the next hour, Cowan, a pharmacologist, and Lewis, a chemist,
waited for the classic signs of drug withdrawal -- sweating, nausea,
itching, agitation. With every other compound they had tried, that's
what had happened. This time, nothing adverse happened. This was one
strange drug, they agreed.

On that day, a quixotic quest to find the best use for the mystery
drug RX 6029-M now known as buprenorphine, was born.

A few years later, it would take a pioneering addiction researcher,
Donald Jasinski of Johns Hopkins University School of Medicine, to
make the leap in logic that buprenorphine might be a potent treatment
for heroin addiction. His research showed that it blocks heroin from
connecting with the pleasure receptors in the brain, eliminating the
high that junkies crave.

Once Jasinski realized that this odd opiate wasn't addictive, the idea
stirred other brain researchers to turn to pharmacology manuals in
hopes of designing other drug treatments.

An examination of the kinds of drugs now in the development stage --
ones to treat heroin and cocaine addiction, to combat alcoholism and
to vaccinate people against nicotine addiction -- illustrates the
progress that is being made by scientists in finding so-called cures
for addiction.

HEROIN

Buprenorphine has been edging its way toward U.S. government approval
ever since the British researchers discovered its unusual powers.

Its backers -- scientists, drug policy wonks, government officials and
industry executives -- say buprenorphine is one of the most effective
treatment options for heroin addicts.

"From a scientific point of view, there is no question in anyone's
mind that buprenorphine is going to be useful," said Martin Adler,
director of the Center for Substance Abuse Research at Temple
University's School of Medicine in Philadelphia, noting that the drug
has been approved as a treatment for heroin addiction in more than a
dozen other countries. "We're way behind the world on this one."

Fears by governmental anti-drug authorities that buprenorphine could
turn into another problem street drug and that it could unseat the
prevalent treatment, methadone, has slowed its advance, officials said.

"Buprenorphine is important both in terms of what it means for addicts
and what it means for the larger field of addiction research," said
Jasinski, the physician-scientist credited with first seeing
buprenorphine's potential. Many patients who have gone through
detoxification and more extended treatments at his Bayview clinic in
Baltimore have been helped by the drug.

Since the 1930s, government scientists had been searching for pain
medications that were not as addictive as morphine, like codeine.

Cowan and Lewis, the scientists who had been spying on the monkeys,
were the first to realize that buprenorphine was a new kind of
powerful, nonaddictive painkiller, mimicking morphine in some ways and
not in others. There was more to this drug, they said, than met the
eye.

Jasinski suggested in a 1977 paper that a painkiller that did not
produce a high, did not produce withdrawal and did not dangerously
suppress respiration might be useful in treating heroin addicts. The
drug merited study, he said.

His idea ignited a bitter argument among addiction and drug policy
experts in industry and government circles over what to do about the
enigmatic compound and whether it needed to be strongly regulated as a
controlled dangerous substance, dispensed in clinics with intense
government oversight like methadone.

Those divisions led to further delays.

While the addiction uses were being studied, executives at Cowan and
Lewis' firm, Reckitt & Colman, a British household products company,
looked for more traditional uses. In 1981, they won approval from the
U.S. Food and Drug Administration for buprenorphine to be used as an
analgesic for post-operative pain.

Efforts to develop the drug as a substance abuse treatment continued
to stall. Meanwhile, scientists at the federal National Institute for
Drug Abuse approached Reckitt officials in 1990 about sponsoring
clinical trials for the drug, even offering to share the costs.

Charles O'Keefe, a former drug policy official in the Carter
administration who now heads Reckitt's pharmaceutical division,
agreed. "It was a very difficult decision for the company to make,"
O'Keefe said, explaining that developing addiction drugs is not a
popular choice for a pharmaceutical firm. "We made it not on the basis
of the bottom line but because it was the right thing to do."

The firm, now known as Reckitt Benckiser, is best known for producing
Woolite, Lysol and French's mustard. Its American headquarters is in
Wayne.

Buprenorphine, unlike methadone, is not addictive, blunts the effects
of withdrawal and provides a feeling of well-being, although not
euphoria. The result is that people who are on buprenorphine are able
to stop taking heroin and, gradually, stop taking buprenorphine as
well.

"I would never have been able to kick heroin without buprenorphine,"
said Odis Rivers, 52, who took buprenorphine for a year, kicking a 28-
year heroin habit. "It's probably why I'm alive today. It took away
all those rough, hard feelings."

Rivers, who now lives in Baltimore, took buprenorphine as part of a
nationwide clinical trial at Wayne State University in his hometown of
Detroit. For the past two years, he has been attending weekly
Narcotics Anonymous meetings.

Buprenorphine is taken in pill form under the tongue. Now under review
by the Food and Drug Administration, it has been altered to contain
naloxone, the withdrawal-producing drug. If addicts take the pill
under the tongue like they're supposed to, naloxone won't have any
effect. If they try to inject the compound, naloxone will make them
sick.

Company executives expect the inclusion of naloxone will appease
government authorities worried that street addicts will grind up the
buprenorphine pill and shoot it up.

Physicians who have been treating addicts with buprenorphine in
experimental trials report that beyond showing great effect, the
medication is drawing a new kind of heroin addict, one from the upper
and middle classes, normally loath to be seen at a methadone clinic.

Unlike methadone, which can only be dispensed at clinics,
buprenorphine, if approved by the FDA, may legally be prescribed in a
doctor's office. Congress in 2000 amended the 1914 Harrison Narcotics
Act to allow physicians to directly prescribe an opiate. To do so,
physicians must receive special training. Organizations offering the
seminars, such as the American Psychiatric Association, have reported
that the sessions have been standing-room-only.

"It's the most exciting time ever in the field," said Paul Casadonte,
director of substance abuse treatment programs at the Manhattan
Veterans Administration Hospital in New York. Many of his patients who
have participated in the experimental clinical trials on buprenorphine
are actors, writers, lawyers and stockbrokers. They are anxious, he
said, for the drug to be approved so they can continue to take it and
stay clean.

Alcohol

Like heroin addiction, alcohol abuse has baffled researchers seeking
to find medications to thwart its assault upon the brain.

Donald Elbel, a Texas rancher, considers himself lucky. In 1999, after
decades of uncontrolled drinking, Elbel spotted an ad in a local
newspaper suggesting he could get help from a brain researcher. At the
University of Texas Health Science Center in San Antonio, he met
neuroscientist Bankole Johnson, who told him: "You'll never drink again."

Elbel was enrolled in a clinical trial testing the drug ondansetron in
treating alcoholics like him who started drinking in their teens.
Johnson, it appears, was right: Elbel has not had a drop of the stuff
since.

His family regards his resurrection as a miracle, he said. "I was on
the road to hell," said Elbel, 47. "I thought God had turned his back
on me. I was wrong."

Long deterred from his dream of being a NASCAR racing driver, Elbel is
fixing up an old Camaro and is looking for sponsors. "That's his dream
and I'm going to encourage it with every lick of what I've got," said
Joanne Elbel, his wife of 20 years.

According to Johnson's hypothesis, ondansetron, which is already on
the market as an anti-nausea medication for cancer patients, corrects
an imbalance in a brain chemical called serotonin in some drinkers,
taking away the urge to drink.

Other drugs are being studied for alcoholism. While not a cure-all,
naltrexone, sold as Revia, has been found in studies to be effective
in preventing single drinks from triggering binges. It reduces
craving, scientists said.

Scientists working in a federal study called COMBINE are investigating
whether a combination of Revia and Campral, also known as acamprosate,
can help addicts to stop drinking.

Naltrexone and Campral seem to be useful in reducing craving and
preventing relapses, said Barbara McCrady, director of the clinical
division of the Center of Alcohol Studies at Rutgers University in
Piscataway.

Naltrexone works by jamming up the brain's opiate receptors, blocking
pleasure signals. In studies of alcoholics taking naltrexone who were
trying to stop drinking, "if they drank, they did not drink as much,"
McCrady said.

The California biotech Drug Abuse Sciences also is developing
Naltrexone Depot, a form of the drug that is injected but lasts for
weeks, designed to overcome alcoholics' resistance to taking a daily
pill.

Acamprosate, marketed in the United States by Forest Laboratories in
New York and under review by the FDA, seems to increase the chances,
at least in those motivated to stop drinking, that they won't drink at
all, McCrady said.

FDA officials declined to approve the drug for alcohol treatment in
July, contrary to industry expectations. Though clinical trials in
Europe showed the drug's effectiveness, an American clinical trial
produced less convincing data. Company officials were asked to
redesign the trial and try again.

Cocaine

Several scientists are seeking to close the gap between their research
into addicts' brains and treatment for one of the banes of America --
cocaine addiction. Cocaine is the second most commonly abused drug
after marijuana. There is currently no FDA-approved treatment.

Cocaine, a natural substance found in coca leaves, has a powerful grip
on users. Monkeys given unlimited access to the substance have been
shown to binge, giving up sleep and any other activity until they die.

Cocaine was placed under extreme legal restrictions in the Harrison
Narcotic Act of 1914. Used as a powerful local anesthetic in the early
20th century, it was replaced by its synthetic cousins, Novocain and
lidocaine, which deaden local nerves but do not enter the brain as
readily.

Cocaine overstimulates brain receptors for dopamine and serotonin,
scientists believe, and, over the long term, decreases the number of
those receptors. This, they say, causes the depression that follows
withdrawal. Sometimes the damage can't be reversed, allowing relapses
after long periods of abstinence.

Stephen Dewey, a 42-year-old brain scientist at Brookhaven National
Laboratory on the eastern tip of Long Island, has spent more than a
decade looking at the brain images of drug addicts. The images are so
dramatic and the brain changes so graphically clear that he often
shows them to schoolchildren as part of an anti-drug speech.

One night in 1991, he had a thought: Vigabatrin, a drug prescribed in
Europe for symptoms of epilepsy, might be useful to treat cocaine addiction.

Drugs of abuse elevate levels of dopamine, a chemical messenger in the
brain. Vigabatrin controls another brain chemical, GVG, which flips
the "off" switch for dopamine. Vigabatrin would elevate GVG (gamma-
vinyl gamma-aminobutyric acid). GVG would shut off dopamine. Addicts,
he reasoned, would no longer feel the craving caused by dopamine. As
an added plus, vigabatrin was not addictive.

In experiments conducted in his laboratory, rats trained to take
cocaine rejected the drug when they were given vigabatrin.

Dewey and executives at Catalyst Pharmaceutical Partners of Coral
Gables, Fla., have been meeting with FDA officials over the summer to
set up clinical trials with human subjects. "I'm very hopeful," Dewey
said.

In Connecticut, Thomas Kosten, professor of psychiatry at Yale School
of Medicine, has been working to develop another cocaine treatment --
this time, a vaccine.

Immunologic Pharmaceutical Corp., a California biotech startup,
developed the vaccine and first approached Kosten in April 1998 to do
human studies. The next year, the company sold the vaccine to Cantab
Pharmaceuticals plc, a British concern. When Cantab executives sold
the rights to the vaccine the next year to Xenova Group plc during a
merger, Kosten found himself with his third partner.

The vaccine has been advancing ever so slowly through the various
regulatory hurdles that make up the U.S. drug approval process, based
on data provided by trials supervised by Kosten.

The vaccine works by binding the cocaine to antibodies on entering the
bloodstream, preventing the cocaine from crossing the blood-brain
barrier and blocking the euphoric rush caused by the substance.

The vaccine, Kosten said, would be most effective for those drug
abusers who are motivated to stop using cocaine. It is possible that
someone intent on getting high can override the vaccine's binding
action by taking more cocaine.

Currently in Phase II of FDA-approved trials, the drug has been tested
on eight patients. Six of them reported using cocaine once or twice
during six months of follow-up treatment. Two other patients used
cocaine on a regular basis during that period.

"These are very good results for people who use cocaine," Kosten said.
He hopes to enroll a total of 150 patients in the trial over the next
few years.

Elizabeth Greetham, chief executive officer of Drug Abuse Sciences,
the eight-year-old California biotech firm also working on a drug for
alcoholics, said her company also is developing a cocaine vaccine but
is waiting to see what happens with the rival product.

"We're waiting to see how it does, sort of as a test case, " Greetham
said. "If it does well, then we'll go ahead. We think we've got better
chemistry -- a more effective mousetrap, if you will."

Nicotine

When cigarette smokers inhale, they hold the smoke in their lungs
before exhaling. Very quickly, the smoke, like a ghost moving through
a wall, crosses through the partition between the air sac in the lung
and the blood rushing by. From there it is carried quickly to the
brain, where it moves out of the capillary network into brain tissue
and finds its destination: the nicotinic acetylcholine receptors. The
process takes seconds.

Each puff produces a spike of satisfaction in the brain, reinforcing
the smoking behavior. Though its complete method of action in the
brain is not fully known, it is clear that nicotine creates high
levels of dopamine in the brain, like other addictive substances.

Nicotine is metabolized quickly, meaning that the smoker in a few
hours will possess only residual levels. Smoking again will bring
relief from that withdrawal discomfort.

Scientists at Nabi Pharmaceuticals of Rockville, Md., have started
early trials in humans to test whether a tobacco vaccine works to ward
off addiction to smoking. The vaccine encourages the human body to
make antibodies that will soak up nicotine like a sponge before it
reaches the brain.

"By reducing the amount of nicotine available to stimulate the brain's
pleasure centers, an immunized tobacco user would theoretically
receive no positive reinforcement from nicotine use," said Robert
Naso, a vice president at Nabi.

For many, stopping smoking could be the key to renewed enjoyment of
life. "I can play my saxophone again," said Steve Ryden, a Somerville
management consultant who quit smoking in May after seeking treatment
at a state-sponsored tobacco treatment center in New Brunswick. "It
means a lot."

Tomorrow : Will power and addiction.