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Most  Americans  have  been  affected in some way by addiction to drugs of abuse such as alcohol, nicotine, and illicit substances. Yet addiction to alcohol and other drugs  is  a phenomenon  that  has been clouded by myth, misunderstanding, and moral judgments. The  very nature  of  the problem -- what addiction is -- has long been debated.   Most people probably continue to think of addiction -- particularly to illicit drugs -- as primarily a moral or character problem, something caused by degeneracy or lack of willpower.

Scientific research into addiction, however, has led experts to conclude that addiction is actually a disease, a chronic illness like diabetes or hypertension. The American Medical Association broke new ground approximately forty years ago when it declared alcoholism to be a disease. And in the past decade, dramatic advances in technology have allowed scientists to examine the brain itself in search of the causes, mechanisms, and consequences of addiction. Today, scientists and physicians overwhelmingly agree that while use and even abuse of drugs such as alcohol and cocaine is a behavior over which the individual exerts control, addiction to these substances is something different. Scientists have begun to understand why addicted people may sacrifice everything that's important to them -- their jobs, their families, their homes -- in the quest for a chemical fix.

"When  you  get  into  an  addicted  state, it's  a disease of the brain," says  Alan Leshner,  Ph.D., director  of  the  federal government's National Institute on Drug Abuse (NIDA). Leshner says the stigma associated with alcohol and drug addiction is  one  of the biggest problems experts continually face in dealing with it. Leshner says that the public has little sympathy for addicts, but he adds that "whether you like the person or not, you've got to deal with [their problem] as an illness."

The so-called disease model doesn't mean that addicts cannot stop using drugs -- only that doing so is difficult and often requires treatment and major lifestyle changes. Addiction is a disease that causes changes in the brain, which then drive certain behavior -- taking the drug compulsively -- but addicts can learn to change the behavior. Treatment of and recovery from addiction are possible. Steven Hyman, M.D., who directs the National Institute of Mental Health, compares the disease of addiction to heart disease, which may also necessitate major lifestyle changes. "Take heart patients. We don't blame them for having heart disease," he says, but we ask them to follow a certain diet, to exercise, to comply with medication regimes. So it is with the addicted person -- we shouldn't blame them for the disease, but we should treat them as having responsibility for their recovery. " 

Subject about to undergo a PET scan, a technology that can allow scientists to see the action of drugs in the brain. 





      


Many people assume that addiction is simply an overuse of drugs, and that the addict is just a drug user who chooses to use too much. But research has shown that addiction, unlike casual drug use, is no longer a matter of free choice. "Functionally you've moved into a different state, a state of compulsive drug use," says Alan Leshner, Ph.D., director of the National Institute on Drug Abuse (NIDA). "People have a lot of trouble understanding that addiction is not an issue of choice or will or morality. " The National Academy of Sciences' Institute of Medicine, the American Psychiatric Association, and the American Medical Association all define this state of driven, compulsive use as the essence of addiction. Someone who abuses drugs may suffer negative consequences from using, as the addict does, but generally can and does stop when these consequences become too severe.   The  addict  may  be  unable  to  stop,  even   after   massive   negative consequences, without medical and/or behavioral help. Says Steven Hyman, M.D., director of the National Institute of Mental Health, "An alcoholic taking a drink looks like anyone else engaged in that behavior, but what's happening in his or her head is different.” He or she is in the grip of a powerful compulsion that may lead to a binge.

-- Janet Firshein 


No one becomes addicted the first time they try a drug," says George Koob, M.D., a professor in the neuropharmacology department at The Scripps Research Institute in La Jolla, California. Although there are some cases where a person's reaction to first use is so positive that they immediately begin to abuse a drug, Koob says most addiction has a subtler start. It usually doesn't take place until the person has been using chronically. The person has become an addict when his or her brain has literally been changed by this chronic use of the drug. 


Compared to a normal brain, the brain of
a cocaine abuser shows reduced metabolic
activity, shown in these PET scans in the
warmer colors.
 

Many substances and activities, from food to sex, exert control over human behavior by motivating us to indulge in them. But addictive drugs, such as alcohol, nicotine, cocaine, and heroin, can affect the structure and function of the brain -- and hence our motivations -- in long-lasting ways. They can actually alter and "usurp," in one scientist's term, the "circuits" in the brain that are involved in the control of emotions and motivation, impairing an addicted person's will. "What addiction really is, is a result of brain changes that over time get translated into behavior changes," says National Institute on Drug Abuse (NIDA) director Alan Leshner, Ph.D.

If a person uses drugs, at a high enough dose, frequently enough and for a long period of time, these drugs change the way the brain works. "You change the way nerve cells communicate in such a way that you develop this compulsive, out-of-control use despite knowing that all kinds of terrible things can happen to you, and despite even experiencing many of those things," says National Institute of Mental Health director Steven Hyman, M.D.

Studies using new technologies show the precise effects of drugs on the brain. "In many cases, we can actually see changes in the structure of synapses and in the shapes of [brain] cells," says Hyman. A NIDA study released in 1996 provided the first direct evidence that chronic use of opiates (such as morphine and heroin) is linked  with  structural  changes  in the size and shape of specific neurons.

Researchers at the Yale University School of Medicine found that rats chronically given morphine experienced marked structural changes in critical brain "circuits." Other NIDA studies have shown that altered brain circuits could be responsible for the major differences in brain functioning between an occasional cocaine user and a cocaine addict.

-- Janet Firshein

Image: Courtesy of NIDA Brain Imaging Center


Animation:  Craving In The Brain
 
When addicted people are shown
 cues related to their cocaine use,
 and they experience craving, PET
 scans show specific areas of their
 brains are activated.

Scientists and medical experts now consider the disease of addiction to be chronic and relapsing. It requires long-term work to recover from addiction, and relapse is common. In this respect, medically, addiction is more like hypertension -- which may require long-term treatment with medication and lifestyle changes, and which often recurs -- than a broken bone, which is set, heals, and is forgotten. 

Alan Leshner, Ph.D., director of the National Institute on Drug Abuse (NIDA), says that it is not reasonable to expect that drug addicts will obtain lifelong abstinence with the first treatment experience. "Just like the diabetic, [an addict] can be given tools to manage the craving, to manage the compulsion; but every once in a while another treatment may be needed," he says. "Even if [addicts] are treated successfully, often there will be occasional relapses." Neuropharmacology professor George Koob, M.D., of the Scripps Research Institute in La Jolla, California, agrees. He estimates that 80 percent of addicts who get off drugs in detoxification go back to drugs within a year. Only 20 percent achieve a stable abstinence from a given detoxification.

Figuring out why addicts are so prone to relapse is a major area of research. One culprit is the phenomenon of craving, or the powerful "hunger" for drugs that can linger months or years after an addict quits using. Scientists have discovered evidence that this craving may be partly a physiological phenomenon, related to the long-term changes in brain function that addiction causes. Now accustomed to functioning in the presence of drugs, the addicted brain, in essence, has become unable to function normally in their absence.

Craving is also partly a conditioned response to powerful cues to use drugs that the (recovering) addict may encounter, such as people, places, and things that are associated with drug use, Leshner says. These cues evoke powerful emotional memories of the "high," and can trigger near-irresistible urges to use. "Even in the absence of drugs, associated stimuli become capable of producing drug craving," he adds. People recovering from addiction usually are therefore advised to avoid friends and locations that have previously been associated with using drugs. "When something is highly rewarding, we are likely to remember it vividly and also to remember the circumstances under which we encountered it," says Steven Hyman, M.D., director of the National Institute of Mental Health. "Even after years of abstinence, people may experience profound cravings and risk relapse if placed in the surroundings of their former drug use."

Charles O'Brien, M.D., Ph.D., a professor and chief of psychiatry at the University of Pennsylvania Veterans Medical Center, says studies have shown the precise effect of environmental cues in triggering physical "anticipatory reactions" in addicts, such as changes in heart rate, blood pressure, and pupil size. (These physical reactions before the drug is even ingested are specific to the type of drug the particular addict used, O'Brien says: Cocaine addicts don't react to stimuli associated with heroin use, and vice versa.)


Computer imaging of drug craving in the brain of an addict.

Anna Rose Childress, Ph.D., a psychologist who directs the VA Addiction Research Center at the University of Pennsylvania School of Medicine, has used positron emission tomography (PET) scans to see the system of the brain that is involved when craving occurs in cocaine abusers. (See craving animation above.) She has found that particular areas of the limbic system -- the part of the brain, including the hypothalamus and the amygdala, that is linked to emotion and motivation -- "light up" during scans, showing these areas are being activated.

But relapse is usually preceded by other problems that make a recovered addict vulnerable. Most relapses among addicts occur when they are in a "negative mood state," says Leshner. In other words, other things are impacting their lives that lead them back to using drugs, such as the death of someone close, a loss of a job, or other economic or social stresses. A recovering addict isn't likely to relapse simply by reconnecting with their drug-using past or seeing someone get high, says Leshner.

If not halted, however, relapse can plunge addicts back to former levels of drug use. When alcoholics relapse, they often overdrink almost as if they are making up for lost time, experts say. Koob has discovered that when alcohol is removed from addicted rats for three or four days and then returned, the rats will drink 50 percent more than they did before. This phenomenon is not well understood.

However, if caught in time, relapse can be merely a stumble on the pathway to recovery. If the addict identifies why a relapse has occurred, he or she may be better able to avoid it the next time. Part of the recovery process is learning how to avoid, or "talk back to," these urges, situations, and cues, and wait out the cravings until they recede again. The search to identify where and how in the brain drug cravings are produced may also enable scientists to develop useful medical treatments for the phenomenon. Childress says it's important to understand what stimulates these cravings, in order to develop strategies or medications that help recovering addicts avoid relapse.

--Janet Firshein

Top: PET scans for animation courtesy of Addiction Research Center of the University of Pennsylvania
Bottom: Courtesy of NIDA Brain Imaging Center
 


People who use drugs, including alcohol, do so because they like what the drugs do to their brains. All drugs of abuse, from alcohol to nicotine to heroin, cause a series of temporary changes in the brain that produce the "high."

One of these changes is the rise in available levels of certain neurotransmitters associated with feelings of pleasure. Key among these is dopamine, a naturally occurring neurotransmitter that some scientists now think is implicated in most of the basic human experiences of pleasure.

The pleasure of a kiss, a bowl of favorite ice cream, and a compliment may all be related to a rise in dopamine levels in the normal person's brain. Drugs of abuse also boost dopamine levels. When a person takes a hit of crack cocaine -- or a drag on a cigarette -- the drugs cause a spike in dopamine levels in the brain, and a rush of euphoria, or pleasure. While it's not the only chemical involved in drug abuse, experts have come to believe that dopamine is the crucial one.

A 1997 study led by researcher Dr. Nora Volkow of the Brookhaven National Laboratory in Upton, NY, found a significant relationship between the intensity and duration of the rush associated with cocaine and the degree to which the drug blocks one of the key mechanisms that control the amount of dopamine in the brain. Previous animal studies have shown that cocaine occupies or blocks dopamine transporter sites and prevents dopamine from returning, as it normally would, to the brain cells that release it. This allows high concentrations of dopamine to remain available in the brain longer than normal, which is believed to cause the high associated with cocaine use. (See animation.) Elevated dopamine levels make a person feel omnipotent. "You get a sense of power, a sense of being able to do things, an immediate feeling of pleasure associated with moving and getting going and being unusually capable," says George Koob, M.D., a professor in the neuropharmacology department at the Scripps Research Institute.


PET scans showing that the brain of a smoker has less of the enzyme MAO B than that of a non-smoker. MAO B breaks down the "pleasure chemical" dopamine in the brain.

Scientists are now able to actually see this happening. The Brookhaven study, which included researchers from State University of New York at Stony Brook   and Columbia University, examined PET scans of 17 current cocaine users. Researchers found that high doses of cocaine blocked from 60 to 77 percent of the users' dopamine transporter sites. (For the user to perceive cocaine's effects, about half of the sites had to be blocked, the study found.) Methamphetamine, or speed, produces a similar effect, dramatically boosting the supply of dopamine at brain synapses, which results in increased stimulation and feelings of euphoria.

New research has also revealed that a chemical in cigarette smoke may keep dopamine in synapses by blocking an enzyme (called monoamine oxidase or MAO)  designed  to  break  it down.  A  study  by  the  Department of Energy's Brookhaven Laboratory found that smokers had an average of 40 percent less of the enzyme MAO B (a subtype of MAO) than non-smokers and former smokers. Less  MAO  B  could  result  in  enhanced  dopamine  activity,  rewarding  and reinforcing the behavior that caused the increase in dopamine behavior such as smoking.

-- Janet Firshein


Scientists now think that all drugs of abuse directly or indirectly affect the so-called "reward pathway," a linked set of areas deep in the brain. All these drugs converge on the same brain regions, masquerading as natural chemicals -- including dopamine, a neurotransmitter involved in the experience of pleasure -- in those reward circuits.

Animation:    
Areas of the
brain of a
cocaine user
"light up" in
PET scans
as the drug
acts on
it.            
       

The "reward pathway" in the brain that is activated by natural rewards and by artificial rewards such as addictive drugs.


-Janet Firshein


Addiction to drugs of abuse occurs partly because, over time, the drugs cause long-lasting -- possibly permanent -- changes in the way users' brains experience pleasure and reward.  "The problem is these drugs are like a sledgehammer in the brain," says National Institute of Mental Health director Steven Hyman, M.D. "While the person is feeling this euphoria, other things are happening in the brain."

George Koob, M.D.,a professor of neuropharmacology
at Scripps Research Institute who has been trying to
understand the reward system, thinks that pumping up
one's dopamine levels through drug abuse can be likened to overdrawing a bank account. "The system
has to self-regulate.  If you spend these pleasure
neurochemicals in one lump sum,such as with a crack binge, you use your supply of pleasure for a certain
period.  You have bankrupted the system.  There's
no pleasure in your account," says Koob.

Then, when the person stops using the drug, they can't feel pleasure -- a state known as anhedonia -- and may experience very negative feelings, such as depression, anxiety, and agitation.

Koob thinks that addicts have compromised their natural pleasure-reward systems in long-lasting ways. Chronic use of a drug to stimulate certain neurotransmitters may reduce the brain's natural ability to produce the neurotransmitters without the drug. People who are addicted initially take the drug because it makes them feel good. But over time they take it just to return to feeling "normal." The "essence of addiction is that a person has created an artificial but negative state," says Koob. The addict is striving to feel stable, not necessarily high, but the effort becomes futile. "After a while the system has become so compromised that a person is taking the drug to return to a normal state. . . . In effect, you spend most of your time not trying to get some extra bliss, but just trying to feel normal," he adds.

-- Janet Firshein

Dopamine Does Not Work Alone: The Role of Other Brain Chemicals

Dopamine is one of the most important neurotransmitters that drugs of abuse affect, but there  are  other  reward  neurotransmitters  that  have  been  linked with "getting high."   Some  drugs  of  abuse,  such  as  the  opiates   (heroin,  morphine), --  probably   also affect endorphins, which are other important neurotransmitters associated with feelings of pleasure. Nicotine has been implicated in activating opiate  peptide  systems in the brain  that  release  other  chemicals  affecting  mood.   A  neurotransmitter  linked with withdrawal  from  chronic  drug use is corticotropin-releasing factor, or CRF, which is a chemical  naturally  released  in  the  experience  of stress. Koob has found that during acute drug withdrawal, levels of corticotrophin increase, presumably causing feelings of stress.

Photo: Sue Young Wilson 


Despite the reinforcing properties of drug use, however, many people drink alcohol and/or experiment with illegal drugs without becoming addicts. Only a small percent of users turn into alcohol and other drug abusers, and an even smaller number become alcoholics and drug addicts. For instance, a large proportion of people who use heroin don't become heroin addicts. Scripps Research Institute professor George Koob, M.D., says that for every one heroin addict there are two or three "chippers," individuals who use opiates only on the weekend or less frequently.

"Pretty much everyone enjoys having their dopamine levels shoot up dramatically, which can happen without the use of drugs, as with the 'runner's high,'" says Alan Leshner, Ph.D., director of the National Institute on Drug Abuse. "However, not everybody craves the experience so much that it consumes them." Nor does everyone experience the same changes in brain function.

What makes for the difference between someone who can drink or dabble in illicit drugs  without  developing  dependence  or  many  negative  consequences,  and someone   who  becomes  an  addict?   Researchers  believe that  there  is  great variability  among  individuals  when it comes to their vulnerability to becoming addicted. Vulnerability is affected by many factors. Leshner says that one of the major predictors of becoming addicted is the level of stress a person is trying to cope with. "The more stress, the more likely it is you will get addicted," he says. But risk of addiction is also driven by the individual's genetic background, other biological factors, the environment, and the social context in which drug use is occurring.

In addition, new studies are showing that many smokers who have been unable to quit are suffering from serious psychiatric problems. Cynthia Pomersleau, Ph.D., with the University of Michigan's Substance Abuse Research Center and Nicotine Research  Laboratory,  says  she  has found  mounting evidence that smoking is becoming  increasingly  concentrated  in  people  at  risk  for  major  depressive disorder,  adult attention-deficit  hyperactivity  disorder,  anxiety  disorders,  and bulimia, or binge eating  and purging. Her link between smoking and psychiatric disorders  could  yield  the  development  of  new  types  of  smoking  cessation strategies tailored to treating the psychiatric problem before or at the same time as the smoking problem. The drug buproprion -- already used as an anti-depressant -- is now being marketed for smoking cessation as well, under the name Zyban.

--Janet Firshein


Although the brain of an addict is demonstrably different from the brain of a non-addict, researchers are still searching to see whether the brain of a potential addict has  unique  characteristics,  or  whether  all  the  differences  are  caused  by  the addiction. The addiction process "is a complex interaction between what the drug is doing to the brain, and what the state of the brain was when you started using drugs," says Alan Leshner, Ph.D., director of the National Institute on Drug Abuse.

George  Koob,  M.D., a  professor in the  neuropharmacology  department at the Scripps   Research   Institute  in  La  Jolla,  California,  thinks ----  that  the  same neurotransmitter systems that are compromised once a person gets addicted may already be abnormal in people vulnerable to addiction. For example, maybe the future  addict  already  has  a  higher  level  of  stress  hormones or  a  deficit  in dopamine function. Koob predicts that in the next 10 to 15 years there will be even greater advances in identifying who is at risk for addiction.  Work  with PET scans and other imaging technologies, and the ability to visualize neurochemical activity in the brain, will contribute.

Other  physical  problems such  as  chronic   pain,  and mental disorders such as depression,  attention-deficit  disorder,  and  chronic  anxiety  that  may  have  a physical basis in the brain, can also increase vulnerability to addiction.


Genetic predisposition is another likely culprit. Researchers have shown relatively conclusively that people with a particular kind of severe, early-onset alcoholism are genetically predisposed to it. In some young men, for example, the risk may be as much as 10-fold greater than in people without that genetic predisposition. In general, children of alcoholics are two to four times more likely to become alcoholics or addicts themselves, reports the federal government's Center for Substance Abuse Prevention. Studies involving adoption have shown that if a person's biological parents were alcoholics, a greater risk for alcoholism persists even if the person was raised by non-alcoholics. And, according to the Addiction Science Research and Education Center at the University of Texas at Austin, more than 60 percent of alcoholics have family histories of alcoholism.

However, not every child of an alcoholic will become alcohol-dependent. Most will not. "Nobody is predestined to become an alcoholic," says Marc Schuckit, M.D., a psychiatrist  who  teaches  at  the  University  of  California  at San Diego's Medical School. "[Genetics]  is  one  of  many  factors  that you need to look at in order to evaluate your chances of becoming an alcoholic."


Finally, researchers  acknowledge  that  behavior  plays  a  part  in  triggering addiction. As Leshner points out, many people exposed to multiple risk factors never try drugs of abuse. How frequently, for how long, and how much of a drug  is used also helps determine if someone will become addicted. And addicts can learn new behaviors that allow them to recover from their addictions.

-- Janet Firshein


Gateway drugs" is a term for drugs that supposedly lead to abuse of other substances. Marijuana, for instance, is considered by some to be a gateway to harder drugs. George Koob, M.D., of the Scripps Research Institute says that studies of long-term exposure to cannabinoids, the active ingredient in marijuana, suggest that addiction to one drug could make a person vulnerable to abuse and addiction to other drugs. Cannabis abuse, he says, appears to activate corticotropin-releasing factor, a brain chemical that increases during periods of stress. Consequently, Koob says, this could "lead to a subtle disruption of brain processes that are then 'primed' for further and easier disruption by other drugs of abuse."

Whether there is such a thing as a gateway drug is still very controversial, however. Critics of the idea note that even if people who use cocaine started with marijuana, it is not clear that the marijuana use caused or encouraged the cocaine use: The person may simply have encountered marijuana first, and/or is the sort of person more inclined than others to experiment with a variety of illegal drugs. Fewer than one percent of marijuana users go on to become cocaine addicts. What is known is that long-term use of marijuana can produce changes in the brain comparable to that seen after long-term use of other major drugs of abuse such as cocaine, heroin, and alcohol. 

PET scans show long-term changes
in glucose-metabolism in the brain
of a marijuana abuser compared to
that of a normal brain.

However,   there  does  appear  to  be  a  link  of  some kind  between  nicotine dependence  and  alcohol  dependence. Whether  the link is causal or not is still unclear. Some researchers hypothesize that since alcohol can cause depression, alcoholics may be using nicotine as an anti-depressant. "Most alcohol-dependent people are nicotine-dependent.  I don't  understand  why that association is, but there  are  a  bunch  of  theories  being  tested,"  says  Marc  Schuckit,  M.D., a psychiatrist  who  teaches  at the  University  of  California at San Diego Medical School.

-- Janet Firshein

Scans: Courtesy of Brookhaven National Laboratory Center for Imaging and Neurosciences


Prolonged drug use can change the brain in fundamental and possibly permanent ways, say experts. National Institute of Mental Health director Steven Hyman, M.D., says there are some changes that happen in the brain that "may be irreversible, especially [some] emotional memories" associated with drug use. But he notes that just as people with strokes are able to, addicts can recover by using other parts of their brain that weren't affected by the drugs.

These PET scans show that changes in the way a cocaine abuser's brain metabolizes glucose persist long after the person has stopped using the drug. But the brain does appear to be slowly returning towards normal.

The research into cocaine by Mark Gold of the Florida-based Brain Institute has found that changes in the number and functioning of dopamine receptors and transporters in the brain persisted for many months after abstinence. However, Gold says, there is ongoing research into the ability of brain cells to recover from damage caused by drugs. And many recovering addicts can certainly learn to live happy, productive lives drug-free. Therefore, the brain must possess some ability to return to a state that allows normal experience of pleasure. (If it was an inability to experience pleasure normally  -- e.g., chronic depression -- that drove the person to drug use in the first place, of course, quitting substance use may not be enough to rectify this co-existing problem. The person might need treatment with antidepressants or other help.)  This is an area of important ongoing research.

--Janet Firshein 

Modified:  July 2, 2005

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