As anyone who has tried to quit smoking knows, it is much easier to get off an addictive drug than to stay off it. That applies to virtually all addicts and all types of addictions, whether to alcohol, cocaine, heroin, nicotine or amphetamines. Long after the drug is cleared from the body, it retains a powerful hold on the mind, and despite weeks, months or sometimes even years of abstinence, cravings can linger or suddenly make a shattering comeback. The usual, devastating, consequence is relapse.
"Prolonged drug use changes the brain in fundamental and lasting ways," said Dr. Alan Leshner, director of the National Institute on Drug Abuse. Those long-term effects are not well understood, Dr. Leshner said, and learning more about them may lead to new treatments that offer lasting help to addicts.
Help is certainly needed: The institute estimates that 4 million Americans are drug addicts, including 2 million to 3 million hooked on cocaine and 800,000 on heroin. Millions more, though not addicted, use illegal drugs, and 14 million are alcoholics.
Compared with people who have other mental or physical disorders, addicts have few treatments to choose from. No drug treatment is available for cocaine addiction. Methadone helps some heroin addicts, but by no means all, and two other drugs are useful in only a minority of alcoholics.
In recent years, much addiction research has focused on the reinforcing, or pleasure-producing properties of drugs, which have been traced to their ability to flood certain parts of the brain with dopamine, a substance that nerve cells use to communicate with each other. But even though the rise and fall of dopamine can alter brain cells in ways that contribute to craving, researchers do not think those alterations explain all the long-term mental effects of drug abuse. And there has been no payoff in terms of treatment, in part because the dopamine system is so fundamental to so many types of pleasure that tampering with it to treat addiction may take all the joy out of life.
As a result, the emphasis in addiction research has begun to shift, to move beyond the dopamine pleasure centers to other systems in the brain.
"We've learned a lot about reinforcement," said Dr. Eric J. Nestler, an addiction researcher at Yale University. "But there are other aspects to an addict's life also, having to do with memory and conditioning. Maybe the time is ripe to examine those."
Some changes in the brains of addicts resemble changes that take place in healthy people when certain types of memories are formed.
In some cases, Nestler's research has shown, those changes even include alterations in the functioning of genes.
Dr. Alcino Silva, who studies memory at the University of California at Los Angeles, said, "Addiction may hijack natural systems used for learning and memory."
Addiction researchers have begun to pay particular attention to "emotional memories," which, as the name suggests, are the mental records of events that aroused intense emotions, either wonderful or terrible. "Emotional memories are very powerful, and they're the ones that remain with you the longest," said Dr. Jonathan Pollock, a program officer at the institute. "You remember where you were when Kennedy was assassinated or the Challenger disaster happened. You remember very pleasurable events in your life, like your wedding or the first time you got an A in school."
The intensity of the moment helps to burn emotional memories into brain circuits. The memories are encoded into a part of the brain that operates outside conscious control, and they seem to take on a life of their own, sometimes intruding on the mind when they are not wanted. When emotional memories are reactivated, touched off perhaps by a smell, a taste, a snatch of music, the sight of an old friend or some other signal that a person may not even be consciously aware of, they can evoke the same powerful emotions that helped form them.
Many addiction researchers believe memories of being high on drugs fall into this category of emotional memories, and contribute to craving, compulsion and relapse.
Although a relapse can occur for no apparent reason, many addicts say that cravings are brought on by cues or reminders of past drug use, like seeing a needle or crack pipe or visiting a place where they used to get high. Stress can also rekindle cravings. So, in many people, can just one hit of an addicting drug, even after a long abstinence. The obsessive thoughts that follow, Dr. Leshner said, are "the very definition of an emotional memory."
Last month, Pollock invited 15 researchers to the National Institutes of Health in Bethesda, Md., to discuss the possible role of emotional memory in addiction. He said it was the first time that experts on addiction and experts on memory had been brought together, and at the start of the meeting Dr. Leshner gave the scientists a firm agenda: "What I'm worried about is compulsion. I only care about compulsion."
Much of the interest in emotional memory stems from studies by Dr. Joseph LeDoux, a researcher at New York University. Working with rats that have been trained by means of electrical shocks to fear a certain sound -- a response that qualifies as an emotional memory -- he has found that emotional memories are formed in the amygdala, an almond-shaped structure deep within the brain.
The job of the amygdala, LeDoux said, is to react instantly when it detects a danger signal -- the sound, in the case of the rats -- sending out messages that prepare the body for fight or flight and that create a state of fear. The human amygdala works in much the same way. It reacts in a few thousandths of a second, independent of the cortex of the brain, which means that people may respond to cues that they are not consciously aware of.
Although LeDoux has worked mainly on fear, that is not all the amygdala mediates. It includes 13 areas, called nuclei, only two of which are known to be involved in fear. The other areas may process other types of emotional memory.
"The amygdala is showing up in a lot of addiction studies," LeDoux said.
When addicts who say they are in the throes of a craving are given brain scans, the images suggest that the amygdala is involved, according to studies by Dr. Hans Breiter of the Massachusetts General Hospital and Dr. Annarose Childress of the University of Pennsylvania in Philadelphia.
Other researchers, working with animals, have also found that the amygdala is important in responding to cues associated with rewards like cocaine and food. Dr. Barry Everitt, a psychology professor at the University of Cambridge in England, said that an "amazing property" of stimulant drugs like cocaine and amphetamines was their capacity to stimulate exceptionally powerful responses to cues that have been associated with them. "They amplify the control of behavior by environmental events," Everitt said.
Dr. Michaela Gallagher of Johns Hopkins University in Baltimore suggested that drug abuse might also affect the cortex of the brain, inhibiting a region that would normally help keep the amygdala in check. That, she said, may make the amygdala extra responsive to all sorts of environmental cues, including those associated with drugs.
Other factors may also give cues more power to evoke emotional memories, according to research by Dr. Jane Stewart of Concordia University in Montreal. One is stress, which increases levels in the brain of a hormone called C.R.F., or corticotropin releasing factor, which may act on the amygdala.
"Dr. Stewart and her colleagues are showing that C.R.F., released during stress, causes anxiety," Dr. Leshner said. "Maybe C.R.F. released during abstinence exaggerates anxiety in addicts. We're going to look at things that block C.R.F. to see if that will help. We haven't tried it in humans yet, but it has been done in animals. It looks good to me, and we're in negotiations with a pharmaceutical company about it, and we'll run clinical trials."
Ultimately, Leshner said, he expects that treatment of addiction would combine behavioral therapy and drugs that combat craving and compulsion. Addicts may not be able to control their cravings, but therapy may teach them to control the way they respond to them.
"Prolonged drug use changes the brain in fundamental and lasting ways," said Dr. Alan Leshner, director of the National Institute on Drug Abuse. Those long-term effects are not well understood, Dr. Leshner said, and learning more about them may lead to new treatments that offer lasting help to addicts.
Help is certainly needed: The institute estimates that 4 million Americans are drug addicts, including 2 million to 3 million hooked on cocaine and 800,000 on heroin. Millions more, though not addicted, use illegal drugs, and 14 million are alcoholics.
Compared with people who have other mental or physical disorders, addicts have few treatments to choose from. No drug treatment is available for cocaine addiction. Methadone helps some heroin addicts, but by no means all, and two other drugs are useful in only a minority of alcoholics.
In recent years, much addiction research has focused on the reinforcing, or pleasure-producing properties of drugs, which have been traced to their ability to flood certain parts of the brain with dopamine, a substance that nerve cells use to communicate with each other. But even though the rise and fall of dopamine can alter brain cells in ways that contribute to craving, researchers do not think those alterations explain all the long-term mental effects of drug abuse. And there has been no payoff in terms of treatment, in part because the dopamine system is so fundamental to so many types of pleasure that tampering with it to treat addiction may take all the joy out of life.
As a result, the emphasis in addiction research has begun to shift, to move beyond the dopamine pleasure centers to other systems in the brain.
"We've learned a lot about reinforcement," said Dr. Eric J. Nestler, an addiction researcher at Yale University. "But there are other aspects to an addict's life also, having to do with memory and conditioning. Maybe the time is ripe to examine those."
Some changes in the brains of addicts resemble changes that take place in healthy people when certain types of memories are formed.
In some cases, Nestler's research has shown, those changes even include alterations in the functioning of genes.
Dr. Alcino Silva, who studies memory at the University of California at Los Angeles, said, "Addiction may hijack natural systems used for learning and memory."
Addiction researchers have begun to pay particular attention to "emotional memories," which, as the name suggests, are the mental records of events that aroused intense emotions, either wonderful or terrible. "Emotional memories are very powerful, and they're the ones that remain with you the longest," said Dr. Jonathan Pollock, a program officer at the institute. "You remember where you were when Kennedy was assassinated or the Challenger disaster happened. You remember very pleasurable events in your life, like your wedding or the first time you got an A in school."
The intensity of the moment helps to burn emotional memories into brain circuits. The memories are encoded into a part of the brain that operates outside conscious control, and they seem to take on a life of their own, sometimes intruding on the mind when they are not wanted. When emotional memories are reactivated, touched off perhaps by a smell, a taste, a snatch of music, the sight of an old friend or some other signal that a person may not even be consciously aware of, they can evoke the same powerful emotions that helped form them.
Many addiction researchers believe memories of being high on drugs fall into this category of emotional memories, and contribute to craving, compulsion and relapse.
Although a relapse can occur for no apparent reason, many addicts say that cravings are brought on by cues or reminders of past drug use, like seeing a needle or crack pipe or visiting a place where they used to get high. Stress can also rekindle cravings. So, in many people, can just one hit of an addicting drug, even after a long abstinence. The obsessive thoughts that follow, Dr. Leshner said, are "the very definition of an emotional memory."
Last month, Pollock invited 15 researchers to the National Institutes of Health in Bethesda, Md., to discuss the possible role of emotional memory in addiction. He said it was the first time that experts on addiction and experts on memory had been brought together, and at the start of the meeting Dr. Leshner gave the scientists a firm agenda: "What I'm worried about is compulsion. I only care about compulsion."
Much of the interest in emotional memory stems from studies by Dr. Joseph LeDoux, a researcher at New York University. Working with rats that have been trained by means of electrical shocks to fear a certain sound -- a response that qualifies as an emotional memory -- he has found that emotional memories are formed in the amygdala, an almond-shaped structure deep within the brain.
The job of the amygdala, LeDoux said, is to react instantly when it detects a danger signal -- the sound, in the case of the rats -- sending out messages that prepare the body for fight or flight and that create a state of fear. The human amygdala works in much the same way. It reacts in a few thousandths of a second, independent of the cortex of the brain, which means that people may respond to cues that they are not consciously aware of.
Although LeDoux has worked mainly on fear, that is not all the amygdala mediates. It includes 13 areas, called nuclei, only two of which are known to be involved in fear. The other areas may process other types of emotional memory.
"The amygdala is showing up in a lot of addiction studies," LeDoux said.
When addicts who say they are in the throes of a craving are given brain scans, the images suggest that the amygdala is involved, according to studies by Dr. Hans Breiter of the Massachusetts General Hospital and Dr. Annarose Childress of the University of Pennsylvania in Philadelphia.
Other researchers, working with animals, have also found that the amygdala is important in responding to cues associated with rewards like cocaine and food. Dr. Barry Everitt, a psychology professor at the University of Cambridge in England, said that an "amazing property" of stimulant drugs like cocaine and amphetamines was their capacity to stimulate exceptionally powerful responses to cues that have been associated with them. "They amplify the control of behavior by environmental events," Everitt said.
Dr. Michaela Gallagher of Johns Hopkins University in Baltimore suggested that drug abuse might also affect the cortex of the brain, inhibiting a region that would normally help keep the amygdala in check. That, she said, may make the amygdala extra responsive to all sorts of environmental cues, including those associated with drugs.
Other factors may also give cues more power to evoke emotional memories, according to research by Dr. Jane Stewart of Concordia University in Montreal. One is stress, which increases levels in the brain of a hormone called C.R.F., or corticotropin releasing factor, which may act on the amygdala.
"Dr. Stewart and her colleagues are showing that C.R.F., released during stress, causes anxiety," Dr. Leshner said. "Maybe C.R.F. released during abstinence exaggerates anxiety in addicts. We're going to look at things that block C.R.F. to see if that will help. We haven't tried it in humans yet, but it has been done in animals. It looks good to me, and we're in negotiations with a pharmaceutical company about it, and we'll run clinical trials."
Ultimately, Leshner said, he expects that treatment of addiction would combine behavioral therapy and drugs that combat craving and compulsion. Addicts may not be able to control their cravings, but therapy may teach them to control the way they respond to them.