NO MORE KICKS

There are treatments on the way that promise to destroy the allure of
addictive drugs for good. Problem solved? Philip Cohen discovers it's
not that easy

BILLY wanted to be bad. He just never quite made it. Sure, he'd put in
the hours hanging out with the wrong crowd. He'd snorted what they
snorted, injected what they injected and smoked what they smoked. But
while his friends found bliss or oblivion, Billy was left to watch
from the sidelines, untouched by the drugs.

Billy's parents couldn't have been happier with the result. Years ago,
they'd made the decision to vaccinate their son against addictive
chemicals. Thanks to a few simple injections, Billy's blood was
brimming with antibodies that bind to these substances and stop them
getting to his brain, like a thin red line of defence against life's
vices.

Billy may be fictitious, but the prospect of an anti-drug vaccine
isn't just a rebellious teenager's nightmare. Academic labs and at
least five companies are in the advanced stages of animal testing for
antibody therapies against cocaine, phencyclidine (PCP),
methamphetamine and even nicotine. One anti-cocaine vaccine has
already been tested for safety in drug abusers. By the end of the
year, it could be undergoing its first efficacy trials.

Treating drug abusers may be just the start. The idea that a jab in
the arm could take the kick out of cocaine and other drugs raises some
thorny questions. Should people be vaccinated, for example, simply
because they belong to a group thought to be particularly at risk of
becoming addicted? Should parents be allowed to make that decision for
their children? Might companies screen job applicants for traces of
anti-drug antibodies, in the belief that this would finger former
users? It may be years before the first anti-vice vaccine goes on the
market. But the ethical debate has begun. "I don't think it's too
early to start thinking about these things," says Frank Vocci,
director of the drug dependence research programme at the National
Institute on Drug Abuse (NIDA) in Washington DC.

For now, these therapies are being developed for addicts who want to
kick the habit or who overdose. The problem is particularly acute for
cocaine--a drug for which there is currently no established medical
treatment. In the US alone, millions of people regularly snort, inject
or smoke cocaine, and each year, for 150 000 of them, the pleasure
trip ends with a visit to the emergency room. And cocaine is growing
in popularity in Britain too.

Experiments with rats and monkeys have already shown that an injection
of antibodies can stop cocaine-addicted animals from seeking out the
drug. The hope now is that this will help people who want to quit.
"This isn't a cure, it's like a safety belt," says Michael Owens of
the University of Arkansas for Medical Sciences in Little Rock. "For
people who use it right, we think it will greatly reduce the chance
they get hurt."

But potential misuse of the vaccine seems destined to trigger as much
interest as its benefits. Barbara Fox remembers about six years ago,
when her team at the Massachusetts-based company ImmuLogic presented
their grant request to the NIDA for the cocaine vaccine now in
clinical trials, it was turned down flat. It was considered too
revolutionary, and there were fears that it might be used on people
who hadn't given their consent. "They were worried it would be used
coercively," says Fox, who is now at Addiction Therapies in Wayland,
Massachusetts.

Such fears don't surprise Peter Cohen, a doctor and lawyer at
Georgetown University in Washington DC, who has written on the legal
implications of vaccines against addictive drugs (Drug and Alcohol
Dependence, vol 48, p 167). He thinks that American law would allow
parents to vaccinate rebellious children like Billy against their
will. "You don't need a law degree to see who is going to win that
fight," he says. He is less concerned about the spectre of job
applicants being screened for antibodies. "I doubt that would stand up
to legal challenge," he says. But that doesn't mean companies won't
try, he adds.

The idea of targeting "at risk" groups with an anti-addiction vaccine
may have been one reason why the NIDA panel initially took fright,
according to Charles Schuster, a former NIDA director now at Wayne
State University in Detroit, Michigan. "I think someone called it a
racist plot," he says. But many people are untroubled by such worries,
says Schuster, and he suspects that a vaccine would have wide appeal.
In the 1970s, when he was director of the drug abuse centre at the
University of Chicago, Schuster was the first to show that anti-drug
antibodies, in this case anti-heroin, could work in animals. "When I
published, I got calls and letters from parents all over the world
saying would you please, please immunise my child," he says.

And it's not just parents who think vaccines might be a good idea. Ali
Fattom, a vaccine specialist at the Florida-based company Nabi, thinks
that many kids would volunteer. Fattom recently asked the classmates
of his 16-year-old son about their feelings towards an anti-nicotine
vaccine. "Most of these guys say I'll take it first thing, because
that would relieve the risk of experimenting with cigarettes and
getting addicted," he says.

But the ethical issues surrounding these vaccines run deep. "Should we
be taking away people's pleasures?" asks John St Clair Roberts,
medical director at the British company Cantab Pharmaceuticals, based
in Cambridge, which took over Fox's vaccine programme from ImmuLogic
and now runs the clinical trials. "A person who gives up today might
change their mind tomorrow," he points out. "But you can't turn off
the immune system with a switch."

None of this will matter, however, unless the successes of the animal
studies can be translated to humans. And this is far from certain--not
least because researchers don't yet understand exactly how these
vaccines work.

Indeed, the approach was all but abandoned shortly after Schuster's
pioneering work in Chicago. The work began when a colleague pointed
out a newly developed antibody treatment for accidental overdoses of
the heart medicine digitalis, which worked by binding the drug safely
in the blood. Schuster and his team began to wonder whether it might
be possible to treat heroin addiction in the same way.

Constant cravings

The idea seemed straightforward enough. A major problem for recovering
addicts is relapse. After a period of abstinence, they succumb to a
craving for their drug and take a hit. But that taste only reinforces
a greater hankering, and starts an ugly cycle of treatment and
relapse. Schuster reasoned that because antibodies are too big to
cross the blood-brain barrier, any drug they grabbed would be kept
safely away from the brain.

To test the idea, Schuster and his team created a vaccine by
chemically joining a heroin-like molecule to a protein that they knew
would be detected by the immune system and stimulate
antibody-producing cells. Next, they inoculated heroin- addicted
rhesus monkeys that had been trained to self-administer by hitting a
lever which injected heroin straight into their blood. Their results
were dramatic.

At the peak of the vaccine's effectiveness, immunised monkeys found
heroin no more alluring than a salty water control (Nature, vol 252, p
708). But despite this success, there were major drawbacks. In
particular, the animals had to undergo a brutal inoculation regime
several times a day for weeks for the vaccine to be effective, which
caused ulcers to form at the site of the injection. The researchers
were also disappointed that the monkeys' antibody levels seemed to
drop within a few weeks, and that as the drug dose was raised, the
antibodies became saturated, and the animals resumed their heroin habit.

The approach was all but abandoned shortly afterwards because, on top
of these problems, it faced competition from other methods of treating
heroin addiction. It was around this time that other groups were
reporting excellent results using chemicals such as methadone and
naltrexone, which block the action of heroin by competing with the
drug for special receptor sites in the brain. Everyone became
convinced that the true salvation for addicts everywhere lay in this
"small chemical" therapy. One reason they seemed a better bet was that
their molecules are similar in size to the drug they are countering,
so they could be given in doses equal to or greater than the drug,
while antibodies, being large molecules, seemed easier to outnumber.

It was nearly 20 years before researchers seriously reconsidered the
vaccine idea, and for a simple reason: desperation. No drug had
emerged to treat cocaine and its use was reaching new heights. Then a
pharmaceuticals company asked Kim Janda at the Scripps Research
Institute in La Jolla, California to develop a vaccine that would
stimulate animals to produce antibodies which could be used in a
cocaine screening test.

To Janda's surprise, the vaccine his team created dramatically blunted
the psychoactive effects of cocaine in rats, halting the hyperactivity
and sniffing that the drug usually inspired (Nature, vol 378, p 727).
As it turned out, Fox and her colleagues at ImmuLogic were right on
Janda's heels, having decided to take a gamble on a cocaine vaccine of
their own. They soon reported that immunised rats would stop
self-dosing cocaine, much as Schuster's monkeys resisted heroin
(Nature Medicine, vol 2, p 1129).

Advances in vaccine design meant that the treatment worked after just
a small number of injections, and caused no ill effects. So ImmuLogic
pushed ahead with clinical safety trials, ultimately selling the
rights to Cantab. The British company recently reported that there
were no adverse reactions among the 34 recovering cocaine users who
participated in the study. All produced substantial levels of
antibodies to cocaine, and in three of the participants, antibodies
could be detected a year later.

With the prospects for Cantab's cocaine vaccine looking promising,
other labs have gone on to investigate the effects of vaccines on
other addictive drugs. For sheer numbers, the most impressive must be
the study reported this February at the Sixth Annual Meeting of the
Society for Research on Nicotine and Tobacco in Arlington, Virginia,
by Fattom and his colleagues.

Over one week, they infused rats with a dose of nicotine equivalent to
1400 cigarettes, together with antibodies against nicotine. They then
stopped the nicotine infusion and looked for the characteristic signs
of nicotine withdrawal, such as chattering teeth, gasps and tremors.
Even after this enormous dose, the symptoms were reduced by half
relative to unimmunised controls. At a more realistic nicotine intake
rate, the antibody was completely protective. This is encouraging
evidence that the vaccine might not only help people give up
cigarettes, but could stop others from becoming addicted, says Fattom.

Other researchers have shown that vaccines are effective at blocking
the effects of PCP and methamphetamine. The success of these animal
experiments might suggest that the ability of antibodies to mop up the
drug is now beyond doubt. But things are not that simple. Fox's group,
for instance, showed early on that 30 seconds after a dose of cocaine,
the brain concentration of the drug in immunised rats is reduced by
only 30 to 63 per cent. So it is still at a level that would have
given an unimmunised animal a rush. "The paper calculation tells you
it shouldn't work," says Fox. "But the animal behaviour data tell you
it does. So the question is why."

There are at least two ideas in circulation. One is linked to the
notion that a drug's addictive effect is related to the speed at which
it enters the brain. Cocaine is more addictive when smoked as crack
than when snorted because the lungs have a larger surface area than
the nose. So for the antibody to work, it might not need to hang on to
the drug, just slow its progress to the brain. By contrast, the
negative or "dysphoric" effects of cocaine such as anxiety and nausea
seem to come from its final concentration in the brain. So antibodies
might take away all the good effects of cocaine and leave only the
bad.

Owens has other data suggesting that antibody therapy ends up
targeting the brain selectively. His lab has done extensive work on
the kinetics of PCP interactions in the brains of rats. When the
researchers infuse the animals with extremely high doses of purified
anti-PCP antibodies, the brain concentration of the drug drops to
zero, even though levels remains high in other parts of the body (The
Journal of Pharmacology and Experimental Therapeutics, vol 292, p 831).

Mind-altering

Owens suspects that PCP wouldn't have the psychoactive effects it did
if it wasn't able to penetrate the blood-brain barrier rapidly. This
may explain why a little bit of antibody works far better than
expected--it mops up the drug in the blood vessels and the resulting
drug diffusion gradient causes the drug to leak rapidly back from the
brain into the blood vessels. "If one organ is preferentially
protected, isn't it wonderful that it's the brain?" says Owens.

But even given immunotherapy's mysterious success, researchers are
eager to improve on it further by changing the method of immunisation.
Inoculation with a vaccine, made from a drug linked to a protein,
causes active immunity, a natural antibody response which triggers the
body to produce a wide array of molecules with varying abilities to
grab the drug. It's a method that can remain effective for a few
months to a couple of years. By contrast, the animal can also be given
passive immunity by infusing it with monoclonal antibodies, a single
species of molecule produced from an antibody-producing cell cultured
in the laboratory. Monoclonals can be selected to have very specific
properties, such as very tight binding of the drug, but they are
short-lived, lasting just a few weeks.

In a paper just published (Proceedings of the National Academy of
Sciences vol 97, p 6202), Janda describes how he has combined the
active and passive approaches to deliver what he calls a "one-two
punch". The vaccine alone is able to stop rodents from
self-administering the drug until high doses are available. But with
monoclonals included, even doses equivalent to three hits of cocaine
are blunted and the animals stop pushing the lever after a few tries.
Janda compares the natural antibody response to a group of workers of
varying strengths trying to capture the drug. But the monoclonal
antibody is in a different league: "It's like sending in Superman to
help," he says.

At Columbia University in New York City, Donald Landry and his
colleagues have even found that some monoclonals can destroy cocaine
molecules. His team developed these "catalytic" antibodies by creating
a vaccine that mimics cocaine's "transition state", a fragile form of
the molecule which breaks down into fragments--ecgonine methyl ester,
or EME, and benzoic acid--which aren't toxic or psychoactive. They
used the vaccine to isolate monoclonal antibodies that bind to the
cocaine and twist it into its fragile state, making it more likely to
snap apart (click on thumbnail graphic below ).

Shooting up: a protein-bound drug prompts the immune system to make a
variety of antibodies which mop up the drug. Alternatively, a vaccine
can take just the best of these antibodies. A newer approach is to
make catalytic antibodies that distort and break up the drug.

This ability to break down cocaine seems to give the antibody extra
potency. For one thing, the broken fragments just slip away, leaving
the antibody free to work again. At concentrations at which a
comparable cocaine-binding antibody had no effect in rats, Landry's
catalytic antibodies increased the lethal threshold for cocaine
threefold and also dramatically blunted self-dosing of cocaine by
addicted animals (Proceedings of the National Academy of Sciences, vol
95, p 10 176).

The vaccines are at last looking as though they might be a more
promising treatment than the small chemicals. Antibodies don't mess
with brain chemistry the way blocking drugs do, so there should be
fewer side effects. And antibodies are expected to be long-lived--from
weeks to years--compared with a single day for a dose of naltrexone.
"Right now, an addicted patient has to ask themselves every day if
they should take their medicine or get high," says Colin Brewer of the
Stapleford Clinic in London. "If they only have to make that decision
every few weeks, it would be a great relief." He thinks antibodies
would be a big help to recovering addicts who have trouble sticking
with their therapy.

Researchers are confident they can push the vaccine technology even
further. And they have another reason to be optimistic. It's only
anecdotal, but the story is often told of two men from the Cantab
trial who started doing hits of cocaine after their treatment--to no
avail. One experienced nothing from the drug, the other felt his heart
race, but didn't achieve a high.

Tom Kosten, a psychiatrist at Yale University who conducted the trial,
says that if this anecdote foretells that effective immunotherapy is
possible, then he, for one, will gladly confront the moral and medical
morass that will follow. "In my thinking," he says, "if we have a real
vaccine to argue about, we would be very lucky."