Addiction Research

No one raises a glass of alcohol, snorts a line of cocaine, or lights up a nicotine-laden cigarette with a toast: “Here’s to addiction.” When first using these drugs, people simply choose to do something that makes them feel good. But with continued use, these people can find themselves addicted: They depend on the drug not simply to feel good but to feel normal. Using drugs is no longer a choice but a compulsion. These people don’t plan to become addicts; it just happens.

In a recent article, Alan Leshner, PhD, director of the National Institute on Drug Abuse, calls this the “oops phenomenon.” It happens when occasional use of a drug turns into weekly use, then daily use, and then eventually into a surprising, distressing realization: “I’m addicted.”

“Every drug user starts out as an occasional user, and that initial use is a voluntary and controllable decision,” Leshner writes. “But as time passes and drug use continues, a person goes from being a voluntary to a compulsive drug user. This change occurs because over time, use of addictive drugs changes the brain–at times in big dramatic toxic ways, at others in more subtle ways, but always in destructive ways that can result in compulsive and even uncontrollable drug use.” 1

The fact is, drug addiction is a brain disease, Leshner says. “While every type of drug of abuse has its own individual trigger for affecting or transforming the brain, many of the results of the transformation are strikingly similar regardless of the addictive drug used. The brain changes range from fundamental and long-lasting changes in the biochemical makeup of the brain, to mood changes, to changes in memory processes and motor skills.”

The changes Leshner refers to include specific alterations in the structure and function of the brain. Thanks to recent advances in research, we have a much more complete picture of those changes. With these discoveries have come new insights into the role of heredity–findings that may actually identify people at risk for addiction and prompt them to learn behaviors that prevent the disease.

Drugs change brain structure

Begin with structural changes in the human brain. Long-term drinking literally shrinks this vital organ. Autopsies consistently show that chronic alcoholics have lighter and smaller brains than other people of the same age and gender. Researchers have also observed this shrinking effect in living alcoholics through non-invasive medical tests that give a picture of the brain in action. These tests include magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and computed tomography (CT) scans. 2

The same techniques reveal how addiction harms or even kills brain cells. For example, research indicates that methamphetamine (“speed”) damages cells that produce dopamine, a chemical in the brain that helps to create feelings of euphoria. Methamphetamine use can even trigger a process called aptosis, where cells in the brain self-destruct.

In long-term alcoholics, such changes can be devastating. Studies indicate that 50 to 75 percent of these drinkers show some kind of cognitive impairment, even after they detoxify and abstain from alcohol. According to the National Institute on Alcohol Abuse and Alcoholism, alcoholic dementia is the second-leading cause of adult dementia in the United States , exceeded only by Alzheimers disease. 3

Drugs alter brain function

The effects of addiction on the brain don’t stop with brain size. Research over the last decade reveals that addictive drugs also alter the function of the brain–the very way that cells work.

Human beings are “wired” with nerve cells (neurons) that extend from the brain and spinal cord throughout the body. Neurons with the same function group themselves into strands up to four feet long. However, the strands are not continuous. Between neurons is a small space called a synapse.

Researchers used to think that neurons passed signals to each other by sending electrical impulses across synapses–something like the way that electricity jumps the gaps in a car’s spark plugs. Today we know that what crosses the synapse are not “sparks” but chemicals. Those chemicals are called neurotransmitters. The constant exchange of neurotransmitters makes it possible for the brain to send messages through vast chains of neurons and direct our thoughts, feelings and behavior.

Addictive drugs wreak havoc with this normal exchange of neurotransmitters in countless ways. For example, drugs can:

  • Flood the brain with excess neurotransmitters.
  • Stop the brain from making neurotransmitters.
  • Bind to receptors in place of neurotransmitters.
  • Block neurotransmitters from entering or leaving neurons.
  • Empty neurotransmitters from parts of the cells where they’re normally stored, causing the neurotransmitters to be destroyed.
    Increase the number of receptors for certain neurotransmitters.
  • Make some receptors more sensitive to certain neurotransmitters.
  • Make other receptors less to neurotransmitters (leading to tolerance).
  • Interfere with the reuptake system by preventing neurotransmitters from returning to the sending neuron.

A case in point–dopamine

Dopamine, mentioned above, is one of the primary neurotransmitters involved in addiction. All the major drugs of abuse–alcohol, nicotine, opiates and cocaine–increase dopamine levels. That’s a “good news-bad news” scenario. The “good” news, at least temporarily, is that the excess dopamine creates powerful feelings of pleasure. The bad news is that the excess levels take a long-term toll on brain chemistry and promote addiction.

To understand this, remember the biological concept of homeostasis, a word that literally means “same state.” The brain seeks to maintain a constant level of cell activity. That stable level is critical to regulating our behavior. When supplies of dopamine remain constant, we can experience the ordinary pleasures of life–such as eating and having sex–without the compulsion to seek those pleasures in self-destructive ways.

When consistently subjected to artificially high levels of dopamine from use of a drug, however, the brain “downshifts” its internal supply of this neurotransmitter. The brain comes to depend on the presence of a drug in order to maintain homeostasis and function normally.

And that’s the problem. If the extra dopamine supplied by drugs is missing, the alcoholic or drug addict feels much less pleasure. In fact, these people can experience symptoms such as depression, fatigue and withdrawal. To the addict, it seems that the only relief from these symptoms is to use more and more drugs. It all adds up to craving–addicts’ constant drive to obtain their chemicals of choice.

Drugs hijack the brain’s reward circuit

In addiction, craving becomes so powerful that it rules the addict’s life. This power results in part from changes to a specific path of neurons throughout the brain–the “pleasure system” or “reward circuit.” The reward circuit has been studied extensively in rodents. This is significant, since biochemical processes in these animals are strikingly similar to those of human beings. 4

In a classic experimental design, researchers attach electrodes to points in the brains of living rodents–locations that correspond to the reward circuit. When rodents press a special lever in their cages, a small electrical current travels via the electrodes directly to the animals’ reward circuit. Typically, some of the rodents press the lever compulsively–thousands of times, until they finally collapse in exhaustion.

These findings give a clue to the power of the reward circuit in human beings, which extends from the mid-brain to another section called the nucleus accumbens. This is where drugs of abuse create their effect by masquerading as natural chemicals. Steven Hyman, MD, director of the National Institute of Mental Health, described the action of drugs on this part of the brain in an interview with Bill Moyers (aired on public television as part of Moyer’ series on addiction titled Moyers on Addiction: Close to Home):

The nucleus accumbens seems to have a particular role in telling us what might be pleasing, what might be good for us. . . . Cocaine and amphetamine put more dopamine in key synapses over a longer period of time in this brain reward pathway than normal. And because they are so rewarding, because they tap right into a circuit that we have in our brains, whose job it is to say something like, “Yes, that was good. Let’s do it again and let’s remember exactly how we did it,” people will take these drugs again and again and again. 5

For the person who uses chemicals to repeatedly stimulate the reward circuit, the prospect of abstaining from those chemicals can seem as hopeless and absurd as the idea of abstaining from food. An overpowering drive to drink or use other drugs compromises the user’s will, changing what was once a voluntary behavior into an involuntary one.

Heredity influences response to drugs

Not all people who use drugs will experience the changes in brain structure and function described above. Some people can use drugs occasionally and remain occasional users. Other people, however, start using drugs casually and seem to progress inevitably to addiction. Researchers don’t understand why this is so, but they know that heredity plays a role.

Each of us carries about 100,000 genes located in our cells on structures called chromosomes. And each gene directs the body to produce a specific protein (a process that’s influenced by the action of neurotransmitters). The production of these proteins creates a chemical blueprint that shapes every aspect of a human being, from height and weight to personality and behavior.

Unfortunately, the genetic blueprint is not fail safe; chance mutations in genes can produce hereditary diseases. A few of these–such as cystic fibrosis and Huntington’s disease–result from a change in a single gene. Researchers have had some success in pinpointing the exact location of those genes and designing specific treatments in response.

In contrast, alcoholism and other forms of addiction result from changes in many genes. What’s more, the genes that are involved can vary from person to person. These facts make the effort to locate the genes that influence addiction (gene markers) a task of overwhelming complexity.

Still, we have abundant evidence that the predisposition to alcoholism is inherited. Identical twins born to alcoholic parents are more likely to become alcoholic than fraternal twins born to alcoholic parents. (Identical twins share identical genes; fraternal twins do not.) And, adopted children of alcoholic parents show higher rates of alcoholism than adopted children of non-alcoholic parents. This is true even when children of alcoholics are raised by non-alcoholic foster parents.

In a recent review article, A. Thomas McLellan, PhD, professor in the Department of Psychiatry at the University of Pennsylvania in Philadelphia, and his colleagues provide this summary of the relevant research: “Though there is need for more studies of heritability by drug and by gender, the evidence accumulated over the past several years suggests significant genetic contribution to the risk of addiction in approximately the same range as for chronic illnesses such as asthma and hypertension.” 6

Brain waves may predict risk for addiction

A promising development in this area comes from studies by Henri Begleiter, PhD, professor of psychiatry and neuroscience at the State University of New York in Brooklyn , New York . While not able to identify precise gene markers for addiction, Begleiter has discovered another possible marker in the brain waves of people from alcoholic families.

Brain waves are recorded by a common medical device called an electroencephalograph and printed out as an electroencephalogram (EEG). When subjected to a significant sensory stimulus, such as a loud sound, most people respond with a common pattern: Between 300 and 500 milliseconds after the stimulus, their EEG shows a characteristic peak in brain waves. This part of the EEG is called the P3 amplitude. (The term amplitude refers to the height of the waves on the EEG.)

In numerous studies that have been replicated by other researchers, Begleiter and colleagues discovered that the P3 amplitude tends to be lower in alcoholics–even those who have been abstinent for up to 10 years. In effect, people with this wave pattern often do not distinguish significant stimuli (those that are unique and unpredictable) from insignificant stimuli (those that are repeated and predictable). These people tend to process each sensory stimulus as new, a characteristic called hyperexcitability. This characteristic plays a key role in conduct disorders and other forms of impulsive behavior. 7

The lowered P3 amplitude has another implication: It has been discovered in non-alcoholic relatives of alcoholics, including their children. This fact suggests that the unusual brain wave pattern is inherited, and that it may help predict people who are at risk to develop addiction. Begleiter suggests that people at risk for alcoholism inherit a general state of hyperexcitability, and that drinking alcohol relieves this state. Yet the relief is only temporary and depends on drinking increasing amounts of alcohol over time. 8

Research has treatment applications

Begleiter believes that his findings have clear applications in treating and preventing addiction. “There are several approaches that may be implemented,” he says. One is “using behavioral and pharmacological means to reduce this hyperexcitability in young adolescents at risk to develop substance dependence. The other approach deals with prevention initiatives involving intense education starting at a very early age.”

Each of these strategies holds promise. For one, knowing the effects of addictive drugs on the brain holds the hope of developing medications to reduce craving. This has already been done with methadone for heroin addicts, naltrexone for alcoholics, and buproprion for nicotine addicts.

In addition, research can shape the way we educate people about addiction. “Research gives us information to use with patients and families in treatment to understand what has happened to them, why the addiction has occurred, and how it is not a matter of lack of willpower,” says Patricia Owen, PhD, director of the Butler Center for Research at Hazelden. Also, people who know that they’ve inherited a risk for addiction can learn to abstain from alcohol and other drugs early on.

Equally important is placing people in treatment programs that reinforce changes in addictive behavior. To say that addiction involves biological factors does not mean that addicts are victims of biology. Indeed, the addict’s initial behavior–casual drug use–sets biological factors in motion. And, we can expect addicts to enter and comply with a treatment program.

Besides , it’s not only drugs that change the brain; stable changes in behavior can also alter brain function. For example, recovering alcoholics know that it’s wise to avoid the people, places, and things that they used to associate with drinking. This new behavior weakens the link between drinking and pleasure that’s been encoded in their brains.

Biology and behavior, then, must share the billing when it comes to explaining addiction and promoting recovery. According to the National Institute on Drug Abuse, the most effective treatment programs blend an array of strategies–medication, therapy, social services, rehabilitation, and self-help groups. 9

Leshner believes that these programs succeed because they treat the whole person. “Their treatment strategies place just as much emphasis on the unique social and behavioral aspects of drug addiction treatment and recovery as on the biological aspects. By doing so, they better enable those who have abused drugs to surmount the unexpected consequences of drug use and once again lead fruitful lives.”


  1. Leshner, A. Oops: How casual drug use leads to addiction. National Institute on Drug Abuse web site,, accessed September 2000.
  2. National Institute on Alcohol Abuse and Alcoholism. Imaging and Alcoholism: A Window on the Brain. Alcohol Alert No. 47, April 2000.
  3. National Institute on Alcohol Abuse and Alcoholism. Tenth Special Report to the U.S. Congress on Alcohol and Health, NIH Pub. No. 00-1583, 2000.
  4. Rubenstein, M, et al. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90(6):991-1001, 1997.
  5. Web site, Public Broadcasting Service,, accessed Dec. 8, 2000 .
  6. McLellan AT, Lewis DC, O’Brien CP, and Kleber HD. Drug dependence, a chronic medical illness: Implications for treatment, insurance, and outcomes evaluation. JAMA 284(13):1689-1695, 2000.
  7. Slutske WS, et al. Common genetic risk factors for conduct disorder and alcohol dependence. J Abnorm Psychol 107(3):363-374, 1998.
  8. Begleiter H, Porjesz B. What is inherited in the predisposition toward alcoholism? A proposed model. Alcohol Clin Exp Res, Vol. 23, No 7, 1999: pp 1125-1135.
  9. National Institute on Drug Abuse. Principles of drug addiction treatment: a research-based guide. NIH Pub. No. 99-4180, 1999.

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