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In the Experience of Doubt, a Possible Cure for Alcoholism

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For many alcoholics, drinking is a compulsion. They know it’s ruining their lives, and yet they continue to drink.

A study out this month in the print version of Nature Neuroscience suggests that this phenomenon — the internal struggle against one’s better angels — may contain the seeds of a new treatment.

The paper reminded me of a man I met a few years ago, when I was working on another story about scientific research into alcoholism.

I met Joe at an alcohol treatment center at the San Francisco VA Medical Center where he had come to dry out. Joe was 71 when we spoke, but he remembered his first drink — a ginger and seven, he told me — and the “warm feeling” it gave him.


Joe’s drinking became chronic. It got so bad that it scared his wife, he said. Especially when he started having blackouts.

“You just don’t remember,” he said, “and then you get told what you did.”

“Like what?” I asked him. The question seemed to bother him.

“Things I don’t really even want to mention,” he answered. “Ok?”

It was obvious there were huge consequences to Joe’s drinking. And yet he kept doing it. For scientists who study alcoholism and other addictions, this is really interesting behavior. It’s the ability to recognize something is a bad idea, but to do it anyway.

“Something switches where our immensely capable brain is still immensely capable, but we’re just not in the driver’s seat anymore,” says Woody Hopf, a co-author on the paper and a scientist at the Gallo Center, a research institution affiliated with the University of California, San Francisco.

Hopf says that – in addicts, and perhaps other people, though it’s too soon to say — the act of overriding our better judgment can be traced to a specific set of places in the brain.

“These are certain areas that mostly are there to tell you, ok there’s something bad, get away. But they have been co-opted to do exactly the opposite. Normally they’d help you avoid what’s bad; here they’re helping you rush right into what’s bad.”

These areas seem to be most active in a certain type of addict: one who feels conflicted about his or her drug use, but feels a compulsion to keep using.

“Not all drug seeking is the same,” says Nasir Naqvi, a researcher at Columbia University Medical Center who is unaffiliated with the study, but whose earlier work on the the neural pathways at work in addicts who feel conflicted about their drug use inspired the Gallo team.

“Drug seeking under risk is different from drug seeking without risk in terms of the specific brain systems involved,” says Naqvi.

The question facing Hopf and others was this: Now that they knew where these parts of the brain are, how could they stop them from being co-opted? In other words, could you take someone who is making bad decisions about drinking alcohol and essentially get them to make good decisions instead?

So, they started with rats. And in this month’s Nature Neuroscience paper, they say they’ve been able to do this.

According to lead author and Gallo scientist Taban Seif, “the experiments in this study may provide the first direct evidence of a novel direct pathway that mediates compulsive alcohol intake.”

I asked Hopf to start from the beginning.

How do you make an alcoholic rat? I asked him.

“Rats actually do it themselves,” Hopf says. “We give them [something like] a vodka on the rocks. Rats like to drink. Monkeys like intoxication, elephants, horses. Part of our brain is in search of the perpetual buzz. Hedonism is cross species.”

Liking alcohol isn’t enough. To create a rat that will drink compulsively, you have to do something else: You have to give them alcohol, and then take it away.

“Every other day,” Hopf explains, “they get access to drinking for an overnight session.”

Hopf says this kind of binge drinking is particularly insidious, both in rats and in humans.

“You learn ‘I’d better drink now because now I have the opportunity,’” he says.

After about a month of this, the researchers take another step: They add quinine to the alcohol to give it a bitter taste. Later, they deliver a small electric shock to the rats whenever the animals take a sip of alcohol.

The idea, says Hopf, is to make it so that drinking comes with a conflict, to associate bad consequences with alcohol in a way that’s analogous to a person who continues to drink, even though it’s causing problems in his or her life.

After a month of the binge drinking, the rats continue to drink, despite the costs.

At that point, says Hopf, “they have biochemical, molecular changes in their brain. A whole different brain circuit is involved.”

The next step was changing that brain circuit. And this is where a recent technology called optogenetics, developed nearby at Stanford University, comes in. It lets researches turn brain cells off and on remotely, using a beam of light.

“We can shine light into these connections and specifically turn off just a few of the many thousands of wires of the brain,” says Hopf. “That’s sufficient to dramatically reduce their compulsive drinking.”

Suddenly, the rats drink alcohol when it tastes good, and stop drinking when it tastes and feels bad.

“What is new, and very exciting, about this finding,” says Columbia’s Nasir Naqvi, “is that it uses very elegant, state of the art techniques to prove this hypothesis to a pretty good level certainty, which you can only do in animal models.”

“If there’s no conflict with the alcohol,” says Hopf, the rats are “still happy to drink it. It’s just that period where if you add a conflict to it — when you’re modeling that compulsive aspect which is so potent in driving relapse in humans — now we can sever that connection.”

You can’t do this in humans, at least not yet. Optogenetics is still a research tool, used in rats and other animals.

But what excites Seif, Hopf, and others is that there are existing drugs, currently used in other mental disorders such as Alzheimer’s Disease, that – again, in rats – seem to affect the same part of the brain in similar ways.

“What’s great for us is that we have FDA-approved drugs that will block the action of those excitatory molecules,” says Hopf.

But in order for them to work the key will be doubt — what Seif describes as the act of “facing a negative outcome to your drinking,” or, simply “caring enough.”

“You have to be in conflict about your addiction,” says Hopf. “Because if you’re not in conflict you don’t recruit these cortical areas.”

In other words, the drug would be targeting a part of the brain that isn’t really active.


Clinical trials on humans can take about five years. The team hopes to get started soon.

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