An Anti-Addiction Pill?

[Guest guest]

June 25, 2006

An Anti-Addiction Pill?

By BENOIT DENIZET-LEWIS

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, " 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 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 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 , 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

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? "

, 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. " Torrington, an addiction-medicine doctor in Los Angeles who

works with 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, " 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

, 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. "

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, 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 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,

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.

took 16 lucky rats and plopped them into Rat Park, where they were

offered water or a sweet, morphine-based cocktail (rats love sweets).

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 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 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

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. 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? 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. "

Benoit Denizet- is a contributing writer for the magazine. He is working on

a book about addiction in America.

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