AN ANTI-ADDICTION PILL?

Last month, the Picower Institute for Learning and Memory at the
Massachusetts Institute of Technology was host to a conference about
addiction for a small, invitation-only crowd of neuroscientists,
clinicians and public policy makers.

It was an unusual gathering. Addiction conferences are usually sober
affairs, but M.I.T. offered a lavish cocktail reception (with an open
bar, no less). More important, the conference was a celebration of
the new ways scientists and addiction researchers are
conceptualizing, and seeking to treat, addiction.

While many in the treatment field have long called addiction a
"disease," they've used the word in vague and metaphorical ways,
meaning everything from a disease of the mind to a disease of the spirit.

Many assumed that an addict suffers from a brain-chemistry problem,
but scientists had not been able to peer into our heads to begin to prove it.

Now they can, using advances in brain-imaging technology. And they
tend to agree on what they see, although not necessarily on how to
fix it: addiction -- whether to alcohol, to drugs or even to
behaviors like gambling -- appears to be a complicated disorder
affecting brain processes responsible for motivation, decision
making, pleasure seeking, inhibitory control and the way we learn and
consolidate information and experiences. This new research, in turn,
is fueling a vast effort by scientists and pharmaceutical companies
to develop medications and vaccines to treat addiction.

The National Institute on Drug Abuse and the National Institute on
Alcohol Abuse and Alcoholism are studying, or financing studies on,
more than 200 addiction medications.

The search for pharmacology to treat addiction is not new. The
history of addiction treatment in America is rife with supposed
miracle medications and "cures," most of which turned out to be
useless. But there are a handful of drugs -- some developed in the
mid-1900's, others in the last decade or so -- that are being used to
help addicts quit. For heroin addiction, there's methadone and
buprenorphine, both of which bind to and activate opioid receptors in
the brain.

Each essentially substitutes for heroin by activating the same brain
receptors as the drug, but many addiction doctors prefer
buprenorphine, which the Food and Drug Administration approved in
2002, because it causes less of a high and less dependence.

For alcohol, Antabuse, which makes people physically ill if they
drink, has been on the market since 1948, although it isn't widely
used. Addiction scientists are more hopeful about another
anti-alcoholism drug, naltrexone, which was originally developed to
treat opioid addiction but was approved for the treatment of
alcoholism in 1994. Studies have found it can help some alcoholics
abstain from or cut down on their drinking, and two pharmaceutical
companies recently teamed up to produce Vivitrol, a long-acting,
injectable form of naltrexone, which the F.D.A. approved in April.
Some hope Vivitrol will sidestep a huge challenge facing those
seeking pharmacological solutions for addiction: unless they're
getting high from it, most addicts aren't model medicine takers.
(Vivitrol requires a monthly shot from a doctor.)

None of the medications currently approved to treat addiction are
perfect, and in many ways they are the products of some of our
earlier advances in neuroscience. In the last few years, though,
scientists say they've learned a staggering amount about how
addiction affects the brain, and neuroscientists and other addiction
researchers are eagerly testing and developing a new generation of
anti-addiction medications.

"In 5 or 10 years, we will be treating addiction very differently,"
predicts Nora Volkow, a psychiatrist and the director of the
institute on drug abuse, who attended the M.I.T. conference and
presented a lecture, "Addiction: The Neurobiology of Free Will Gone
Awry," in an intense and rapid-fire speaking style. (Besides being a
leading American thinker about addiction, Volkow is the
great-granddaughter of Leon Trotsky.) What Volkow means is that in a
decade or so, we may actually start treating addiction effectively.
Addiction is one of the nation's biggest public health problems,
costing $524 billion (including lost wages and costs to the public
health care and criminal justice systems) each year. The majority of
the estimated 20 million alcoholics and drug addicts in America (and
millions more compulsive gamblers, overeaters and sex addicts, if you
accept an expanded understanding of addiction) never get help. Those
who do often relapse repeatedly, sometimes returning to treatment
centers 5, 10 or 15 times (if they don't die first). And many of
those who "recover" simply trade one addiction for another -- addicts
call this dance "switching seats on the Titanic."

The Dopamine Connection

For much of the past two decades, Volkow and other neuroscientists
exploring the physiological basis of addiction have tried to explain
it by studying the brain chemical dopamine, which functions as a
neurotransmitter, sending signals between cells in the brain.
Dopamine affects a variety of critical functions, including learning,
memory, movement, emotional response and feelings of pleasure and pain.

Dopamine was originally thought to serve as a kind of pleasure signal
in the brain, telling us when something feels good or rewarding.

But scientists now believe that dopamine is more a predictor of
salience -- that is, it tells us, and then helps us to remember, what
we should focus on. When you see a person you are strongly attracted
to, scientists can now see a spike of dopamine in your brain.

If you are hungry and smell a food you like, dopamine also increases.

But even unpleasant experiences -- like physical pain or the fear of
an intruder in the house -- can cause a dopamine spike. (Some
hypothesize that different dopamine receptor cells are responsible
for firing during rewarding or aversive situations.)

Drugs, particularly cocaine and methamphetamines, cause a large
increase in the amount of dopamine secreted and pooling between brain
cells, leading to feelings of euphoria.

With regular, repeated "addictive" drug use, though, the brain
eventually responds by reducing its normal release of dopamine.

Studies also show a simultaneous decrease in the number of dopamine
receptors created. That, in turn, makes the brain's reward system
less likely to respond to behaviors (romance, a good meal, the
company of friends) that produce a normal dopamine surge.

The addicted brain essentially becomes pathologically selective,
dependent on bigger and bigger blasts of, say, cocaine to feel rewarded.

Perhaps most fascinating to addiction researchers is how an increase
in dopamine creates a craving -- and an expectation of a reward.

In a study published earlier this month in The Journal of
Neuroscience, Volkow used a brain scan to look at the dopamine
releases in 18 cocaine addicts while they watched two videos: one of
nature scenes, the other of people using cocaine.

Volkow found that dopamine increased while the addicts watched the
cocaine video and that the severity of the increase matched their
self-reported level of craving for the drug. "For these people, their
lives and experience had taught them that when they see others using
cocaine, they're probably about to get rewarded with drugs, too,"
Volkow told me. "So even though they consciously knew that they
weren't going to get cocaine after watching the video, their brains
had learned to expect the reward." Scientists posit that cue-induced
dopamine spikes and craving essentially overpower the brain's
well-meaning frontal cortex, which is responsible for planning and
decision making.

The institute on drug abuse is currently financing studies of
medications that could potentially blunt that process, interfering
with the release of dopamine when an addict sees a conditioned cue.

Dopamine also travels to the parts of the brain responsible for
solidifying memory, like the amygdala, which learns and stores
emotional memories (including the high of drugs). Some researchers
hypothesize that through a combination of medicine and behavioral
therapy, addicts could "unlearn" these powerful memories and
associations, making them less likely to relapse when they see a cue.
"Potentially, you could put an addict in a virtual-reality situation
where you show them videotapes of friends they used to use drugs
with, or whatever their strongest triggers are," Eric Nestler, a
neuroscientist and addiction specialist at the University of Texas
Southwestern Medical Center, told me earlier this month. "But now,
the cue isn't associated with any kind of rewarding response.

So then you can give a medication, which we're making progress on
developing, that enhances memory formation.

Essentially, you'd be teaching them something new -- that a line of
white powder means nothing special."

Dopamine may also make some people more vulnerable to addiction.
Recent studies in both animals and humans have indicated that those
with low levels of dopamine D2 receptors, which regulate the release
of dopamine in the brain, are more likely to find the experience of
taking drugs pleasurable. Some researchers, like Volkow, suggest that
people with fewer D2 receptors experience a less intense reward
signal, causing them to overindulge in order to feel satisfied.

In one experiment, Volkow increased the level of dopamine D2
receptors in rats that had low levels.

After the increase, the rats significantly curtailed their intake of
alcohol, which they had eagerly gulped down before.

Unfortunately, we don't yet know how to safely increase the number of
dopamine D2 receptors in humans.

In fact, we don't yet know how to do much when it comes to dopamine
and addiction.

Understanding how the neurotransmitter works may help us to
understand addiction better, but it hasn't led to any effective
medications, the ultimate goal of many researchers. Because addiction
seems to disrupt so many different brain regions, neuroscientists are
now casting a wider net in their pursuit of effective medications.
For some, the new frontier involves the brain's two major "workhorse"
neurotransmitters: GABA and glutamate.

Getting the Brain's Brakes to Work

Walter Ling, a neurologist and the director of the Integrated
Substance Abuse Programs at U.C.L.A., likes to explain complex brain
processes using simple metaphors.

GABA, he says, is to a brain what a braking system is to a car. "The
brain works by inhibition," he told me recently. "At some point you
realize that your car is a great car not because of its engine but
because it has a great braking system. GABA is the brakes.

If your brakes don't work well, you crash."

GABA (gamma-aminobutyric acid) is the brain's major inhibitory
transmitter, and its role, in essence, is to keep glutamate, the main
excitatory transmitter, from overwhelming us. In the extreme, too
much glutamate can cause a seizure and too much GABA can put us in a
coma. Researchers are particularly interested in the brain's critical
balance of GABA and glutamate -- some hypothesize that addictive
craving is the result of too much glutamate or too little GABA.
"We've been able to measure GABA in living brains for some time, but
measuring glutamate in living human brains has just become feasible
in the last few months," says Frank Vocci, the director of the
division on pharmacotherapies and medical consequences at the
institute on drug abuse. "What's been shown is that people with
alcohol and cocaine problems have less GABA in their brains, and we
do know that medications that increase GABA have shown some efficacy
in treating addiction." (Vocci says that it isn't yet clear whether
the absence of GABA is a cause of addiction or a result.) The seizure
medication topiramate, for example, works on both GABA and glutamate
and has helped some alcoholics in initial trials quit or cut back on
their drinking.

The muscle relaxant baclofen, which essentially mimics the effects of
GABA, may also help some cocaine addicts quit. Both are being tested
further by the institute.

Hythiam, a Los Angeles-based health care services management company
that made national news in the spring when it plastered Chris
Farley's face -- with the words "It Wasn't All His Fault" -- on a
series of Los Angeles billboards, is particularly interested in
GABA's role in addiction.

The company is aggressively marketing its Prometa protocol for
cocaine, alcohol and methamphetamine addiction, which involves
therapy and medications, both oral and intravenously injected, not
usually used to treat addiction: flumazenil, approved by the F.D.A.
to treat overdoses of Valium and Xanax, and gabapentin, approved to
relieve neuropathic pain. While no double-blind placebo studies have
tested Prometa's effectiveness (two are under way),
addiction-medicine doctors around the country who have administered
the protocol report encouraging results.

Prometa appears to reduce anxiety and craving by enhancing the
brain's GABA receptors, says David Smith, the former president of the
American Society of Addiction Medicine and now the director for
medical affairs at Hythiam and the head of a Prometa treatment center
in Los Angeles. Sanjay Sabnani, Hythiam's senior vice president for
strategic development, says: "It's all hypothesis at this point,
because we haven't sliced open anyone's brain yet, but it seems that
normalizing the GABA receptor takes away the craving and anxiety that
one would typically experience in the absence of the drug. And it
doesn't appear to be happening because of will power, love, God,
discipline, family support or anything else. It seems to be happening
because the protocol resets a faulty mechanism in the brain." Yet,
several addiction scientists told me they were skeptical that Prometa
works, and some criticized Hythiam for promoting it before it has
been rigorously tested.

The Prescription Model

Hythiam was among a handful of companies publicizing their
anti-addiction medications last month at the American Society of
Addiction Medicine conference in San Diego. Several were armed with
charts, graphs and clinical-study results (particularly the ones that
found their medications most effective), and their eager young
marketing and sales teams talked about doing for addiction what the
pharmaceutical industry did for depression: medicalizing it, and
destigmatizing it in the process.

They know it won't be easy. A series of recent surveys sponsored by
the National Council on Alcoholism and Drug Dependence and by Faces
and Voices of Recovery, a recovery advocacy group, found that half
the public called addiction a personal weakness.

Among those who did see addiction as a disease, most put it in a
special category of diseases that people get by making poor choices.

In a 2004 poll of the general public, two-thirds said they believed
that a stigma -- usually defined as a thing that disgraces a person
or injures one's reputation -- exists for people in recovery from addiction.

The pharmaceutical companies came to San Diego to argue that
addiction is a chronic and recurring disease like diabetes or
hypertension -- and no one, they say, tells a diabetic to try to
tough it out without insulin.

They don't discount the importance of environment in inducing
addictive behavior or psychosocial interventions as part of the
recovery process; in fact, most stress therapy as an essential
adjunct to their products.

But they insist that medications will stabilize addicts and make the
deeper therapeutic and spiritual work more effective.

In the exhibition hall, the prime booth location near the entrance
belonged to Alkermes and Cephalon, the two pharmaceutical companies
producing and marketing Vivitrol, the recently approved, injectable
form of naltrexone, prescribed for alcoholics. Alkermes and Cephalon
are initially focusing on doctors who specialize in addiction, but
they plan eventually to market the drug directly to primary care
physicians, most of whom are used to sending their addicted patients
to treatment centers and groups like Alcoholics Anonymous. "It would
require a complete paradigm shift," Doug Neale, a product director at
Cephalon, told me, "but we'd like to see the day when a patient who
is struggling with alcoholism can walk into their primary care
doctor's office, say, 'Doc, I'm drinking too much and can't seem to
stop,' and the doctor will have a handful of options for medications
that he could prescribe."

But Ling, the U.C.L.A. researcher, cautions that we still have a way
to go before we can effectively treat most addicts medically. "In
general, we have a pretty good handle on dealing with opioid
addiction," he says. But "if you look at the various studies of
alcohol-abuse drugs, the results are mixed at best," he continues,
adding: "These kinds of mixed findings mean that the drug maybe works
for some people, but it's not working all that great.

And we're still far off from having a handle on treating people
addicted to stimulants like cocaine and methamphetamine."

A Higher Power Versus Medicine

John Schwarzlose, the president of the Betty Ford Center, says he
isn't convinced that treating alcoholics and drug addicts with more
drugs -- particularly if they aren't proved effective -- is a good
idea. He points out that millions of addicts around the world have
recovered without the help of medication. "We're open to medications
that will actually work, but the fact is that today 12-step treatment
is still the best treatment there is," he told me. "Nothing even comes close.

And until something does, we like to try to keep most of our patients
as drug-free as possible."

Many addiction treatment centers share that view, which made for a
strange scene in the exhibition hall at the society of addiction
medicine conference. The treatment centers, most of which advocate a
behavioral and spiritual solution to addiction, promoted their
centers right next to pharmaceutical companies boasting novel medical
solutions. "Why can't these two camps come together?" Smith, the
medical director of Hythiam, said as he sat in front of the company's
booth. "They need to come together.

In medicine, if something isn't working, you try something new. In
addiction, if someone goes to treatment and fails, for years we've
just sent them back again and again and expected different results.

That's insanity.

And we're starting to realize that. The field of addiction treatment
is changing right before our eyes, and it's only going to continue to
change. Advances in neuroscience and pharmacology will change everything."

Those changes could lead to addiction vaccines.

Several are already in development. The British company Xenova Group
Plc has created what it says are effective vaccines for cocaine and
nicotine addiction (NABI Biopharmaceuticals in Florida has also
developed a nicotine vaccine). The vaccines, which the institute on
drug abuse and others are testing, work by producing antibodies to a
specific drug, binding to the drug when it enters the bloodstream and
keeping it from entering the brain.

An effective vaccine won't stop craving or treat any underlying
pathology (making it an inadequate solution, some say), but it will
make it nearly impossible for an addict to get high on that
particular substance.

And if it is combined with medications that could blunt craving, some
addiction specialists believe that we'll stop using the word "treat"
and start using the word "cure." Matthew Torrington, an
addiction-medicine doctor in Los Angeles who works with Smith at his
Prometa center, attended the society's conference and told me that he
believes we can essentially eliminate addiction in America.

"With the scientific advances we're making in understanding how the
human brain works," he says, "there's no reason we can't eradicate
addiction in the next 20 or 30 years.

We can do it by fixing the part of the brain that turns on you during
drug addiction and encourages you to kill yourself against your will.
I think addiction is the most beatable of all the major problems we
face. And I think we will."

The Stress Culture

It's not the first time a doctor has predicted the end of addiction.
In his book "Slaying the Dragon: The History of Addiction Treatment
and Recovery in America," William L. White recounts how in the
1800's, countless "medications" like Knights' Tonics for Inebriates
promised to remove "the craving for a stimulant that those who have
been addicted to the use of ardent spirits know so well." In the 1905
Sears, Roebuck & Company catalog, a person struggling with opium or
morphine addiction could buy a bottled "cure" for 69 cents.

Most of these miracle potions were promoted as a result of important
scientific and medical breakthroughs. Science, it seems, has always
been just about to save us from addiction. "But it has never lived up
to its promise," says Bruce Alexander, emeritus professor of
psychology at Simon Fraser University in British Columbia, "and I
don't believe the science will live up to its promise now, either.
Addiction doesn't demand a scientific solution."

Alexander is among a vocal group of addiction researchers who argue
that focusing on a pill to treat addicts fails to address the primary
cause of becoming and staying hooked: our unhappy, disconnected
lives. Beginning in the late 1970's, Alexander and his team of
researchers at Simon Fraser set out to study the role of our
environment on addictive behavior.

Until that point, most scientists studying addiction put rats in
small, individual cages and watched as they eagerly guzzled
drug-laced solutions and ignored water and food, sometimes dying in
the process.

This phenomenon was noted -- first by researchers, then drug czars,
then parents trying to keep their children off drugs -- as proof of
the inherently addictive quality of drugs and of the inevitable
addiction of any human who used them. This was false, of course.

Most people who use drugs don't become addicted.

So what made all those lab rats lose their minds?

Bruce Alexander and his research team had a rather simple hypothesis:
The rats had awful lives. They were stressed, lonely, bored and
looking to self-medicate. To prove it, Alexander created a lab-rat
heaven he called Rat Park. The 200-square-foot residence featured
bright balls and tin cans to play with, painted creeks and trees to
look at and plenty of room for mating and socializing.

Alexander took 16 lucky rats and plopped them into Rat Park, where
they were offered water or a sweet, morphine-based cocktail (rats
love sweets). Alexander offered the same two drinks to the control
group of rats he left isolated in cages.

The results?

The rat-parkers were apparently having too much fun to bother with
artificial highs, because they hardly touched the morphine solution,
no matter how sweet Alexander and his colleagues made it. The
isolated and arguably depressed rats, on the other hand, eagerly got
high, drinking more than a dozen times the amount of the morphine
solution as the rats in paradise.

When I spoke with Alexander recently, he predicted that unless we
undergo a "cultural renaissance" and all start living in a human
version of his rat park (which he conceded isn't likely), we won't be
eradicating addiction anytime soon. While Volkow of the institute on
drug abuse doesn't agree with Alexander that developing addiction
medications is a fruitless enterprise, she does say that a positive
and nurturing environment, particularly during childhood and
adolescence, is a strong protector against addiction.

Volkow says that addicts are more likely to have been unnecessarily
stressed during childhood (from neglect; emotional, physical or
sexual abuse; or poverty) and that they're less able to deal with
stress as adults.

Studies show that animals who are stressed during early development
are more likely to self-administer drugs later in life and that
living in an enriched environment -- one with a minimal amount of
strain and anxiety, like Rat Park -- appears to protect animals from
developing addictive behavior.

And remember the dopamine D2 receptors that some hypothesize may
protect us from abusing drugs?

There is evidence that our environment can affect those, too. In
2003, researchers at the Wake Forest School of Medicine measured the
levels of dopamine D2 receptors of 20 macaque monkeys while they were
housed in isolation.

They then assigned the monkeys to social groups of four monkeys each,
letting natural social hierarchies develop.

Three months later, they tested the levels of D2 receptors again.

The dominant monkeys -- who, the theory goes, were much less stressed
and anxious than the subordinate ones -- had 20 percent higher D2
receptor function, while the submissive ones were unchanged.

The monkeys were then taught how to self-administer cocaine by
pressing a lever, with researchers finding that the dominant monkeys
took significantly less cocaine than the subordinate ones.

Interestingly, though, when the animals that seemed to be protected
from addiction were given cocaine repeatedly, the number of their D2
receptors eventually went down, and they then became addicted.

The moral of the monkey story, Volkow says, is that environment -- if
good or bad enough -- can sometimes trump genetics and biology.

"Some people may be naturally better protected against addiction than
others," Volkow says, "but that's not enough to keep someone from
becoming addicted.

The same thing is true for those who are genetically predisposed. We
know from twin and family studies that about 50 percent of a person's
vulnerability to addiction is genetic. But if you're never exposed to
illegal drugs, or if you grow up and live in an environment without
trauma and too many stressors, you probably won't become addicted."

If It's Not One Addiction, It's Another

What Volkow and other researchers can't yet explain is why we choose
one particular manifestation of addiction over another.

Why do some of us become addicted to cocaine, while others are hooked
on alcohol or cigarettes? Researchers hypothesize that environmental
availability and genetic predisposition both play a part, but they
don't know for sure.

Further complicating the question is that many people are addicted to
more than one thing.

Howard Shaffer, director of the division on addictions at the
Cambridge Health Alliance, an affiliate of Harvard Medical School,
suggests a "syndrome model" of addiction: each outwardly unique
manifestation of addiction is actually part of the same underlying disorder.

Shaffer's syndrome model argues that behavioral addictions (like
gambling, sex and eating) can be just as powerful as an addiction to
heroin or crystal meth, and his belief is gaining acceptance among
neuroscientists and addiction researchers, many of whom used to
dismiss this idea as a product of an American culture that's addicted
to calling everything an addiction.

But by studying the brain's reward and pleasure systems, researchers
are discovering that drugs and powerfully rewarding behaviors like
gambling and sex affect it in similar ways. Neurologists at the
University Medical Center Hamburg-Eppendorf in Germany, for example,
found that pathological gamblers, like drug addicts, have a sluggish
reward system that doesn't react normally to pleasing stimuli.

The scientists used an M.R.I. scanner to compare the brain responses
of 12 gambling addicts and 12 nonaddicted people to a card-guessing
game. Subjects were told to pick a playing card, and if the card
turned out to be red, they won a euro.

The game activated the ventral striatum, an important part of the
brain's reward system.

Those nonaddicts who picked a winning card had increased blood flow
to the striatum, but the gambling addicts who picked the right card
had much less of it (their reward system was less active). It was as
if their brains, which were accustomed to powerful rewards, were
saying, "You call this silly prize a reward?" The same kind of
indifference to basic rewards has been seen in the ventral striatum
of cocaine addicts.

"People addicted to gambling and drugs look a lot alike," Shaffer
told me when I visited him in his office in March. "Gamblers have to
increase their bets to get the same level of excitement, just like
someone addicted to drugs who has to keep using more to get an
effect. When addicted gamblers cut back, they experience withdrawal
symptoms that look like stimulant withdrawal. They get depressed,
they're irritable and they have trouble sleeping.

And if they gamble again, they can make the symptoms go away for the
short run."

While Shaffer focuses much of his recent behavioral addiction
research on gamblers, Volkow studies overeaters and also finds many
similarities to drug addicts and alcoholics -- including the fact
that obese subjects have lower levels of dopamine D2 receptors than
those who eat normally. "Because we know that many people are
addicted to more than one thing and that many people switch
addictions," she told me at the M.I.T. conference, "in my own
research I'm mostly interested in developing medications that could
work across a variety of addictions."

An Addict's Perspective

What do addicts think about all this focus on their brains?

William C. Moyers, a recovery advocate (and the son of the journalist
Bill Moyers) who for 12 years has been free of crack and alcohol, was
invited to speak at the M.I.T. conference. In a room full of
scientists and addiction researchers obsessed with the intricacies of
the human brain, Moyers read a lecture that reminded them that
treating addiction might be even more complicated than they thought.

"I have an illness with origins in the brain. . .but I also suffered
with the other component of this illness," he told the gathered
researchers and scientists, some of whom dutifully took notes. "I was
born with what I like to call a hole in my soul.. . .A pain that came
from the reality that I just wasn't good enough.

That I wasn't deserving enough.

That you weren't paying attention to me all the time. That maybe you
didn't like me enough."

The conference room was as quiet as it had been all day. "For us
addicts," he continued, "recovery is more than just taking a pill or
maybe getting a shot.. . .Recovery is also about the spirit, about
dealing with that hole in the soul."