HOW WE GET ADDICTED

I was driving up the Massachusetts Turnpike one evening last February
when I knocked over a bottle of water.

I grabbed for it, swerved inadvertently--and a few seconds later
found myself blinking into the flashlight beam of a state trooper.
"How much have you had to drink tonight, sir?" he demanded.

Before I could help myself, I blurted out an answer that was surely a
new one to him. "I haven't had a drink," I said indignantly, "since 1981."

It was both perfectly true and very pertinent to the trip I was
making. By the time I reached my late 20s, I'd poured down as much
alcohol as normal people consume in a lifetime and plenty of
drugs--mostly pot--as well. I was, by any reasonable measure, an
active alcoholic.

Fortunately, with a lot of help, I was able to stop. And now I was on
my way to McLean Hospital in Belmont, Mass., to have my brain scanned
in a functional magnetic-resonance imager (fMRI). The idea was to see
what the inside of my head looked like after more than a
quarter-century on the wagon.

Back when I stopped drinking, such an experiment would have been
unimaginable. At the time, the medical establishment had come to
accept the idea that alcoholism was a disease rather than a moral
failing; the American Medical Association (AMA) had said so in 1950.
But while it had all the hallmarks of other diseases, including
specific symptoms and a predictable course, leading to disability or
even death, alcoholism was different.

Its physical basis was a complete mystery--and since nobody forced
alcoholics to drink, it was still seen, no matter what the AMA said,
as somehow voluntary. Treatment consisted mostly of talk therapy,
maybe some vitamins and usually a strong recommendation to join
Alcoholics Anonymous. Although it's a totally nonprofessional
organization, founded in 1935 by an ex-drunk and an active drinker,
AA has managed to get millions of people off the bottle, using group
support and a program of accumulated folk wisdom.

While AA is astonishingly effective for some people, it doesn't work
for everyone; studies suggest it succeeds about 20% of the time, and
other forms of treatment, including various types of behavioral
therapy, do no better.

The rate is much the same with drug addiction, which experts see as
the same disorder triggered by a different chemical. "The sad part is
that if you look at where addiction treatment was 10 years ago, it
hasn't gotten much better," says Dr. Martin Paulus, a professor of
psychiatry at the University of California at San Diego. "You have a
better chance to do well after many types of cancer than you have of
recovering from methamphetamine dependence."

That could all be about to change.

During those same 10 years, researchers have made extraordinary
progress in understanding the physical basis of addiction.

They know now, for example, that the 20% success rate can shoot up to
40% if treatment is ongoing (very much the AA model, which is most
effective when members continue to attend meetings long after their
last drink). Armed with an array of increasingly sophisticated
technology, including fMRIs and PET scans, investigators have begun
to figure out exactly what goes wrong in the brain of an
addict--which neurotransmitting chemicals are out of balance and what
regions of the brain are affected.

They are developing a more detailed understanding of how deeply and
completely addiction can affect the brain, by hijacking memory-making
processes and by exploiting emotions.

Using that knowledge, they've begun to design new drugs that are
showing promise in cutting off the craving that drives an addict
irresistibly toward relapse--the greatest risk facing even the most
dedicated abstainer.

"Addictions," says Joseph Frascella, director of the division of
clinical neuroscience at the National Institute on Drug Abuse (NIDA),
"are repetitive behaviors in the face of negative consequences, the
desire to continue something you know is bad for you."

Addiction is such a harmful behavior, in fact, that evolution should
have long ago weeded it out of the population: if it's hard to drive
safely under the influence, imagine trying to run from a
saber-toothed tiger or catch a squirrel for lunch.

And yet, says Dr. Nora Volkow, director of NIDA and a pioneer in the
use of imaging to understand addiction, "the use of drugs has been
recorded since the beginning of civilization. Humans in my view will
always want to experiment with things to make them feel good."

That's because drugs of abuse co-opt the very brain functions that
allowed our distant ancestors to survive in a hostile world.

Our minds are programmed to pay extra attention to what neurologists
call salience--that is, special relevance.

Threats, for example, are highly salient, which is why we
instinctively try to get away from them. But so are food and sex
because they help the individual and the species survive.

Drugs of abuse capitalize on this ready-made programming. When
exposed to drugs, our memory systems, reward circuits,
decision-making skills and conditioning kick in--salience in
overdrive--to create an all consuming pattern of uncontrollable
craving. "Some people have a genetic predisposition to addiction,"
says Volkow. "But because it involves these basic brain functions,
everyone will become an addict if sufficiently exposed to drugs or alcohol."

That can go for nonchemical addictions as well. Behaviors, from
gambling to shopping to sex, may start out as habits but slide into
addictions. Sometimes there might be a behavior-specific root of the
problem. Volkow's research group, for example, has shown that
pathologically obese people who are compulsive eaters exhibit
hyperactivity in the areas of the brain that process food
stimuli--including the mouth, lips and tongue.

For them, activating these regions is like opening the floodgates to
the pleasure center. Almost anything deeply enjoyable can turn into
an addiction, though.

Of course, not everyone becomes an addict.

That's because we have other, more analytical regions that can
evaluate consequences and override mere pleasure seeking.

Brain imaging is showing exactly how that happens.

Paulus, for example, looked at methamphetamine addicts enrolled in a
VA hospital's intensive four-week rehabilitation program. Those who
were more likely to relapse in the first year after completing the
program were also less able to complete tasks involving cognitive
skills and less able to adjust to new rules quickly. This suggested
that those patients might also be less adept at using analytical
areas of the brain while performing decision-making tasks.

Sure enough, brain scans showed that there were reduced levels of
activation in the prefrontal cortex, where rational thought can
override impulsive behavior.

It's impossible to say if the drugs might have damaged these
abilities in the relapsers--an effect rather than a cause of the
chemical abuse--but the fact that the cognitive deficit existed in
only some of the meth users suggests that there was something innate
that was unique to them. To his surprise, Paulus found that 80% to
90% of the time, he could accurately predict who would relapse within
a year simply by examining the scans.

Another area of focus for researchers involves the brain's reward
system, powered largely by the neurotransmitter dopamine.
Investigators are looking specifically at the family of dopamine
receptors that populate nerve cells and bind to the compound.

The hope is that if you can dampen the effect of the brain chemical
that carries the pleasurable signal, you can loosen the drug's hold.

One particular group of dopamine receptors, for example, called D3,
seems to multiply in the presence of cocaine, methamphetamine and
nicotine, making it possible for more of the drug to enter and
activate nerve cells. "Receptor density is thought to be an
amplifier," says Frank Vocci, director of pharmacotherapies at NIDA.
"[Chemically] blocking D3 interrupts an awful lot of the drugs'
effects. It is probably the hottest target in modulating the reward system."

But just as there are two ways to stop a speeding car--by easing off
the gas or hitting the brake pedal--there are two different
possibilities for muting addiction.

If dopamine receptors are the gas, the brain's own inhibitory systems
act as the brakes.

In addicts, this natural damping circuit, called GABA
(gamma-aminobutyric acid), appears to be faulty.

Without a proper chemical check on excitatory messages set off by
drugs, the brain never appreciates that it's been satiated.

As it turns out, vigabatrin, an antiepilepsy treatment that is
marketed in 60 countries (but not yet in the U.S.), is an effective
GABA booster.

In epileptics, vigabatrin suppresses overactivated motor neurons that
cause muscles to contract and go into spasm. Hoping that enhancing
GABA in the brains of addicts could help them control their drug
cravings, two biotech companies in the U.S., Ovation Pharmaceuticals
and Catalyst Pharmaceuticals, are studying the drug's effect on
methamphetamine and cocaine use. So far, in animals, vigabatrin
prevents the breakdown of GABA so that more of the inhibitory
compound can be stored in whole form in nerve cells. That way, more
of it could be released when those cells are activated by a hit from
a drug. Says Vocci, optimistically: "If it works, it will probably
work on all addictions."

Another fundamental target for addiction treatments is the stress
network. Animal studies have long shown that stress can increase the
desire for drugs.

In rats trained to self-administer a substance, stressors such as a
new environment, an unfamiliar cage mate or a change in daily routine
push the animals to depend on the substance even more.

Among higher creatures like us, stress can also alter the way the
brain thinks, particularly the way it contemplates the consequences of actions.

Recall the last time you found yourself in a stressful
situation--when you were scared, nervous or threatened. Your brain
tuned out everything besides whatever it was that was frightening
you--the familiar fight-or-flight mode. "The part of the prefrontal
cortex that is involved in deliberative cognition is shut down by
stress," says Vocci. "It's supposed to be, but it's even more
inhibited in substance abusers." A less responsive prefrontal cortex
sets up addicts to be more impulsive as well.

Hormones--of the male-female kind--may play a role in how people
become addicted as well. Studies have shown, for instance, that women
may be more vulnerable to cravings for nicotine during the latter
part of the menstrual cycle, when the egg emerges from the follicle
and the hormones progesterone and estrogen are released. "The reward
systems of the brain have different sensitivities at different points
in the cycle," notes Volkow. "There is way greater craving during the
later phase."

That led researchers to wonder about other biological differences in
the way men and women become addicted and, significantly, respond to
treatments. Alcohol dependence is one very promising area. For years,
researchers had documented the way female alcoholics tend to progress
more rapidly to alcoholism than men. This telescoping effect, they
now know, has a lot to do with the way women metabolize alcohol.
Females are endowed with less alcohol dehydrogenase--the first enzyme
in the stomach lining that starts to break down the ethanol in
liquor--and less total body water than men. Together with estrogen,
these factors have a net concentrating effect on the alcohol in the
blood, giving women a more intense hit with each drink.

The pleasure from that extreme high may be enough for some women to
feel satisfied and therefore drink less. For others, the intense
intoxication is so enjoyable that they try to duplicate the
experience over and over.

But it's the brain, not the gut, that continues to get most of the
attention, and one of the biggest reasons is technology. It was in
1985 that Volkow first began using PET scans to record trademark
characteristics in the brains and nerve cells of chronic drug
abusers, including blood flow, dopamine levels and glucose
metabolism--a measure of how much energy is being used and where (and
therefore a stand-in for figuring out which cells are at work). After
the subjects had been abstinent a year, Volkow rescanned their brains
and found that they had begun to return to their predrug state.

Good news, certainly, but only as far as it goes.

"The changes induced by addiction do not just involve one system,"
says Volkow. "There are some areas in which the changes persist even
after two years." One area of delayed rebound involves learning.
Somehow in methamphetamine abusers, the ability to learn some new
things remained affected after 14 months of abstinence. "Does
treatment push the brain back to normal," asks NIDA's Frascella, "or
does it push it back in different ways?"

If the kind of damage that lingers in an addict's learning abilities
also hangs on in behavioral areas, this could explain why
rehabilitation programs that rely on cognitive therapy--teaching new
ways to think about the need for a substance and the consequences of
using it--may not always be effective, especially in the first weeks
and months after getting clean. "Therapy is a learning process,"
notes Vocci. "We are trying to get [addicts] to change cognition and
behavior at a time when they are least able to do so."

One important discovery: evidence is building to support the 90-day
rehabilitation model, which was stumbled upon by AA (new members are
advised to attend a meeting a day for the first 90 days) and is the
duration of a typical stint in a drug-treatment program.

It turns out that this is just about how long it takes for the brain
to reset itself and shake off the immediate influence of a drug.
Researchers at Yale University have documented what they call the
sleeper effect--a gradual re-engaging of proper decision making and
analytical functions in the brain's prefrontal cortex--after an
addict has abstained for at least 90 days.

This work has led to research on cognitive enhancers, or compounds
that may amplify connections in the prefrontal cortex to speed up the
natural reversal.

Such enhancement would give the higher regions of the brain a
fighting chance against the amygdala, a more basal region that plays
a role in priming the dopamine-reward system when certain cues
suggest imminent pleasure--anything from the sight of white powder
that looks like cocaine to spending time with friends you used to
drink with. It's that conditioned reflex--identical to the one that
caused Ivan Pavlov's famed dog to salivate at the ringing of a bell
after it learned to associate the sound with food--that unleashes a craving.

And it's that phenomenon that was the purpose of my brain scans at
McLean, one of the world's premier centers for addiction research.

In my heyday, I would often drink even when I knew it was a terrible
idea--and the urge was hardest to resist when I was with my drinking
buddies, hearing the clink of glasses and bottles, seeing others
imbibe and smelling the aroma of wine or beer. The researchers at
McLean have invented a machine that wafts such odors directly into
the nostrils of a subject undergoing an fMRI scan in order to see how
the brain reacts.

The reward circuitry in the brain of a newly recovering alcoholic
should light up like a Christmas tree when stimulated by one of these
alluring smells.

I chose dark beer, my absolute favorite, from their impressive stock.
But I haven't gotten high for more than a quarter-century; it was an
open question whether I would react that way. So after an interview
with a staff psychiatrist to make sure I would be able to handle it
if I experienced a craving, I was fitted with a tube that carried
beer aroma from a vaporizer into my nose. I was then slid into the
machine to inhale that still familiar odor while the fMRI did its work.

Even if the smells triggered a strong desire to drink, I had long
since learned ways to talk myself out of it--or find someone to help
me do so. Like the 90-day drying-out period that turns out to
parallel the brain's recovery cycle, such a strategy is in line with
other new theories of addiction.

Scientists say extinguishing urges is not a matter of getting the
feelings to fade but of helping the addict learn a new form of
conditioning, one that allows the brain's cognitive power to shout
down the amygdala and other lower regions. "What has to happen for
that cue to extinguish is not for the amygdala to become weaker but
for the frontal cortex to become stronger," says Vocci.

While such relearning has not been studied formally in humans, Vocci
believes it will work, on the basis of studies involving, of all
things, phobias.

It turns out that phobias and drugs exploit the same struggle between
high and low circuits in the brain.

People placed in a virtual-reality glass elevator and treated with
the antibiotic D-cycloserine were better able to overcome their fear
of heights than those without benefit of the drug. Says Vocci: "I
never thought we would have drugs that affect cognition in such a
specific way."

Such surprises have even allowed experts to speculate whether
addiction can ever be cured.

That notion goes firmly against current beliefs. A rehabilitated
addict is always in recovery because cured suggests that resuming
drinking or smoking or shooting up is a safe possibility--whose
downside could be devastating. But there are hints that a cure might
not in principle be impossible. A recent study showed that tobacco
smokers who suffered a stroke that damaged the insula (a region of
the brain involved in emotional, gut-instinct perceptions) no longer
felt a desire for nicotine.

That's exciting, but because the insula is so critical to other brain
functions--perceiving danger, anticipating threats--damaging this
area isn't something you would ever want to do intentionally. With so
many of the brain's systems entangled with one another, it could
prove impossible to adjust just one without throwing the others into imbalance.

Nevertheless, says Volkow, "addiction is a medical condition.

We have to recognize that medications can reverse the pathology of
the disease. We have to force ourselves to think about a cure because
if we don't, it will never happen." Still, she is quick to admit that
just contemplating new ideas doesn't make them so. The brain
functions that addiction commandeers may simply be so complex that
sufferers, as 12-step recovery programs have emphasized for decades,
never lose their vulnerability to their drug of choice, no matter how
healthy their brains might eventually look.

I'm probably a case in point.

My brain barely lit up in response to the smell of beer inside the
fMRI at McLean. "This is actually valuable information for you as an
individual," said Scott Lukas, director of the hospital's behavioral
psychopharmacology research laboratory and a professor at Harvard
Medical School who ran the tests. "It means that your brain's
sensitivity to beer cues has long passed."

That's in keeping with my real-world experience; if someone has a
beer at dinner, I don't feel a compulsion to leap across the table
and grab it or even to order one for myself.

Does that mean I'm cured? Maybe. But it may also mean simply that it
would take a much stronger trigger for me to fall prey to addiction
again--like, for example, downing a glass of beer. But the last thing
I intend to do is put it to the test. I've seen too many others try
it--with horrifying results.