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/