NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

How to Cut Down on Your Drinking If you are drinking too much, you can improve your life and health by cutting down. How do you know if you drink too much? Read these questions and answer "yes" or "no": Do you drink alone when you feel angry or sad? y Does your drinking ever make you late for work? y Does your drinking worry your family? y Do you ever drink after telling yourself you won't? y Do you ever forget what you did while you were drinking? y

and increased damaging effects from use of alcohol (Harris and Buck 1990).
The hallmark of physical dependence is the occurrence of a withdrawal syndrome when alcohol consumption is discontinued after a period of heavy drinking. Alcohol withdrawal symptoms include anxiety; agitation; increased blood pressure; and, in extreme cases, seizures. These symptoms may persist for several days.
Psychological dependence is charac terized by craving, a mental state involv ing a strong need for alcohol that can occur even in the absence of physical dependence (Harris and Buck 1990).
The key question in alcoholism re search is, Why do some people exhibit a pathological appetite for alcohol whereas others do not? Studies using experimental animals have revealed that the actions of alcohol that cause intoxication, reinforce drinking behavior, and lead to addiction are based principally in the brain. NIAAA has dedicated a large proportion of its research effort to this area.
Researchers once believed that alcohol influenced brain function through some general disturbance of nerve cell mem branes. This view has been modified by the growing recognition that alcohol preferen tially affects specific molecular components of nerve cell membranes. These molecular components include receptor proteins cru cial for communication among nerve cells. 1 In one clear demonstration of a specific alcoholreceptor interaction, NIAAA re searchers revealed that alcohol can alter the function of the NmethylDaspartate (NMDA) receptor, one of three subtypes of receptor that respond to the excitatory neurotransmitter glutamate. Significantly, this effect occurs at alcohol concentrations present in the brain after only one drink (Lovinger et al. 1989). The effect of alcohol on this receptor may contribute to the phe nomena of intoxication and withdrawal (Hoffman et al. 1989; for a further discus sion, see the article by Linnoila and col leagues,. NIAAA investigators have found additional associations between alcohol and specific neurotransmitters whose actions might help mediate alcohol rein forcement, intoxication, and dependence (Linnoila 1989;Harris and Buck 1990). For example, a neurotransmitter that appears to enhance longterm memory also maintains tolerance to alcohol after 1 Receptors function by recognizing and responding to specific molecules, called neurotransmitters, released by nerve cells. alcohol consumption has ceased. This suggests that the development of toler ance may be related to the processes of learning and memory (Hoffman et al. 1978;Tabakoff and Hoffman 1988).
Researchers are seeking additional asso ciations between alcohol and specific neuro transmitters. However, the complex mental processes that govern drinking behavior are unlikely to be carried out by a small number of independent neurotransmitterreceptor interactions. The existence within the brain of multiple intersecting pathways of nerve cell communication has generated a new emphasis on the study of neural networksintegrated brain circuits that modulate one another's activity. Alcohol may influence the activity of a given communication pathway by interacting with receptors on nerve cells within the pathway or on nerve cells that modulate these circuits (Dworkin and Smith 1991).

WHY ARE SOME PEOPLE MORE VULNERABLE TO ALCOHOL'S EFFECTS?
A combination of genetic and environ mental factors influence vulnerability to alcoholism.
An important benchmark in the history of alcoholism research was the demon stration that a significant portion of the susceptibility to alcoholism is inherited. Understanding the genetic contribution to the development of alcoholism helps clarify the nature of the disorder and provides the basis for early recognition, treatment, and prevention efforts. From its inception, NIAAA has supported studies in alcoholism genetics utilizing a range of techniques from the investigation of family pedigrees to the latest methods of molecular analysis.

Genetic Factors
PopulationBased Studies. Genetic alco holism research began with the observa tion that alcoholism "runs in families." To determine the extent to which this relationship is affected by biological inheritance, NIAAA has contributed to a variety of population genetics studies over the past 20 years.
Adoption studies indicate that children of alcoholics raised in nondrinking homes continue to face an increased risk of alco holism (Cloninger et al. 1981;Goodwin et al. 1973). Other studies have shown that the identical twin of an alcoholic has a 60percent probability of also becoming alcoholic, whereas the fraternal twin of an alcoholic has only a 36percent chance of developing alcoholism (reviewed in Pickens and Svikis 1991). These findings suggest that genetic inheritance is a major contributing factor behind the development of alcoholism.
Trait Markers. Certain abnormalities of biochemical function may be inherited along with a predisposition to developing alcoholism. These abnormalities may serve as trait markers for identifying persons at risk for the disease. For exam ple, alcoholics appear to demonstrate differences in certain components of brain electrical activity compared with nonalco holics (Porjesz and Begleiter 1979;Begleiter et al. 1980;Pfefferbaum et al. 1979). Sons of alcoholic fathers display the same differences compared with sons of nonalcoholic fathers in response to a visual stimulus (Begleiter et al. 1984).
The activity of a brain enzyme in volved in neurotransmitter metabolism is another potential trait marker. This en zyme, monoamine oxidase (MAO), also is found in blood platelets, where its activity can easily be determined. The finding that MAO activities are controlled genetically has led to a hypothesis that diminished MAO levels observed in alcoholics may be a biochemical marker for genetic susceptibility to alcoholism (Buchsbaum et al. 1976).

Molecular Genetics Studies
Cooperative Agreement on Genetics of Alcoholism (COGA). A range of genetic research tools is being brought to bear in a current multisite, multidisciplinary genetic study known as COGA. In part nership with NIAAA, COGA will exam ine approximately 3,000 subjects from several hundred families with alcoholic pedigrees. The longterm objective of this research is to pinpoint the chromosomal location of genes that influence suscepti bility to alcoholism. Stateofthe art tech nology is being used to screen the entire length of each chromosome for genes that may be linked to alcoholism. This search relies on the existence of microsatellite repeat markers-short, repeating chromo somal segments that differ from one person to another. To assist the search, scientists are adapting techniques devel oped for studying singlegene diseases to the more complex disease of alcoholism. Results of COGA will help identify per sons at high risk for alcoholism and also will aid in the development of new treat ments for alcoholrelated problems.
Genetic Animal Models. NIAAA has long played an important role in develop ing animal models for alcohol research, particularly in the area of genetics. Many rat and mouse strains have been selective ly bred for sensitivity to various effects of alcohol. The development of such strains demonstrates that the selected trait is, to some extent, genetically determined. In addition, researchers use selectively bred animal lines to investigate the biological mechanisms of alcohol's effects (Crabbe and Phillips 1990).
Genetic animal models display many characteristics of human alcoholics. Li and colleagues (1981) developed an alcoholpreferring (P) line and an alcohol nonpreferring (NP) line of rats that have, respectively, a high and low preference for alcohol. The P rats develop physical depend ence with longterm exposure, exhibiting signs of withdrawal when alcohol is discon tinued (Crabbe and Phillips 1990). More over, alcohol tolerance develops more rapidly and persists longer in P than in NP rats (Li et al. 1987).
Studies in these and other selectively bred strains have demonstrated that toler ance and dependence are probably not controlled by a single mechanism, because it is possible to alter alcohol tolerance without affecting alcohol dependence (Tabakoff and Ritzmann 1977). Moreover, evidence from both human and animal studies suggests that tolerance and depend ence are controlled not only by different genes but by different sets of genes.
As these findings illustrate, suscepti bility to complex behavioral disorders such as alcoholism is not likely to be determined by a single gene. Therefore, NIAAAsupported investigators are using a new technique in animal studies called quantitative trait locus (QTL) mapping. This technique makes it possible to define the contribution of a single gene and its variations to complex behaviors that are determined by the interaction of many genes. Results of QTL mapping in ani mals can then be used to guide the search for similar genes in the human genome.

Environmental Factors
Sociocultural factors provide a framework for beliefs and attitudes about alcohol that encourage drinking and may lead to ad diction. NIAAA has sponsored studies on risk factors and determinants of drinking in the home and in society at large as well as those based on ethnicity and gender.
In the past decade, NIAAAsponsored researchers have investigated mental processes involved in drinking, including decisionmaking, learning, and expectan cies. For example, expectancies, particu larly beliefs about the positive effects of alcohol, have been found to predict drink ing behavior. Findings also indicate that children have positive expectations about alcohol's effects as early as age 8 (Miller et al. 1990).
The role of both genetic and environ mental factors in alcoholrelated behavior can be determined more precisely when NIAAAsupported research led to the issuance in 1981 of the Surgeon General's health advisory on risks of drinking during pregnancy.
studied together. Moreover, in addition to influencing drinking behavior directly, environmental factors may affect the actual structure and function of the ner vous system. Thus, the distinction be tween behavioral and biomedical science is rapidly disappearing. The interplay among genetics, neuroscience, and behav ior will form the basis for promising new approaches to prevention and treatment.

ALCOHOL'S MEDICAL EFFECTS
Research in the past 25 years has brought about an increasing awareness of the multiplicity of alcohol's medical effects and the mechanisms by which these ef fects occur. Some of these effects include alcoholic cirrhosis; cancer; immune de fects; cognitive impairment; fetal alcohol syndrome (FAS); and alcoholrelated trauma, including accidents, traffic crash es, and personal violence. Some preven tion efforts aimed at alcoholinvolved driving also are discussed below.

Alcoholic Cirrhosis and Other Organ Damage
Alcoholic liver disease is one of the most serious medical consequences of chronic alcohol use. Moreover, chronic, excessive alcohol use is the single most important cause of illness and death from liver disease in the United States (Grant et al. 1988). The most advanced form of alco holic liver injury is alcoholic cirrhosis. This condition is marked by progressive development of scar tissue that chokes off blood vessels and distorts the liver's internal structure. Although alcoholic cirrhosis can stabilize with abstinence, the disease is often progressive and fatal (NIAAA 1993a). Before the 1970's, scientists generally attributed alcoholic cirrhosis to the nutri tional deficiencies common among heavy drinkers. Research subsequently proved that alcohol is toxic to the liver, even when nutrition is adequate (Lieber 1989).
NIAAAsponsored research suggests that alcohol is directly toxic to other tissues as well, including bone marrow (Ballard 1993), testicular cells, and both heart and skeletal muscle (Rubin 1989). Research emphasis has shifted from documenting individual organ effects to determining mechanisms of injury at the cellular level.
These and other discoveries suggest that the bewildering diversity of alcohol's medical effects may be explained by a relatively small number of molecular mechanisms (Rubin 1993). Elucidating these mechanisms may provide the basis for successful treatments for the medical effects of alcoholism.

Cognitive Impairment
The incidence of alcoholrelated organic brain disease accounts for approximately 10 percent of adult dementia cases in the United States (Oscar Berman 1990). Alcoholic dementia is characterized by a global loss of intellectual abilities. Wernicke's disease is an alcoholrelated brain degeneration that produces general confusion, abnormal gaze and gait, loss of muscle coordination, and incoherent speech. This disorder is associated with a deficiency of the vitamin thiamine. Abstinence and vitamin supplementation can reverse this disorder. About 80 percent of alcoholic patients who recover from Wernicke's disease are left with a residual severe memory disturbance known as Korsakoff's syndrome, characterized by a permanent state of cognitive dysfunction and an inability to remember recent events or to learn new information (Oscar Berman 1990).
NIAAA is a pioneer in applying so phisticated techniques to produce images of the living human brain for examining brain structure and function in alcoholic organic brain disease. The longterm goals of these studies include predicting alcoholinduced brain damage in time to reverse it and providing rapid feedback on the effectiveness of medications in individual patients (Tabakoff 1989).

Fetal Alcohol Syndrome
A research milestone of the 1970's was the identification of FAS, a pattern of birth defects in children of heavydrinking mothers. FAS is the leading known pre ventable cause of mental impairment, affecting 1 to 3 infants per 1,000 live births in the United States (NIAAA 1991). The adverse effects of prenatal alcohol expo sure exist along a continuum, with com plete FAS at one end of the spectrum and incomplete features of FAS, including more subtle cognitivebehavioral deficits, at the other (NIAAA 1991).
NIAAAsponsored researchers have conducted studies using experimental animals to answer many important ques tions about FAS. One of the first issues that researchers addressed was whether alcohol itself is responsible for FAS. Alcoholic women frequently smoke to bacco, have poor health, and are malnour ished, any of which factors can cause birth defects. Two different laboratories reported that alcohol administration to pregnant mice resulted in birth defects similar to those of FAS (Chernoff 1977;Randall et al. 1977), suggesting that alcohol itself caused the defects.
Additional animal research has demon strated that critical periods occur during pregnancy in which different organ sys tems are most susceptible to damage. The specific type of birth defect produced appears to depend on which organ sys tems are undergoing development at the time of alcohol exposure (Webster 1989).
The existence of critical periods for fetal damage suggests the importance of the mother's drinking patterns in produc ing fetal injury. Animal research has shown that peak blood alcohol level, rather than total amount of alcohol con sumed, may represent the critical dose of alcohol above which an adverse effect will occur (West et al. 1990). This finding implies that drinking pattern is critical: Rapid consumption of alcohol produces a higher blood alcohol level than does slower consumption of the same amount over a long period. These results sug gest the importance for researchers and clinicians of asking women about their drinking patterns in addition to the total number of drinks they consume.
In 1974 NIAAA initiated the first in a series of studies examining the effects of light to moderate alcohol consumption by pregnant women. The offspring of women who drank moderately during pregnancy were found to be smaller in weight, height, and head circumference (Day and Richard son 1994). The effects of prenatal exposure to low levels of alcohol on intellectual development fall along a continuum; the decrement in intellectual function may persist until at least age 7 (Streissguth et al. 1990). Researchers are attempting to deter mine the threshold alcohol concentration below which these effects might not occur. An average of seven drinks per week may be the threshold for some neurological and behavioral symptoms (Jacobson and Jacobson 1994).
NIAAAsupported research led to the issuance in 1981 of the Surgeon General's health advisory on risks of drinking dur ing pregnancy.

Cancer
Alcohol is strongly associated with can cers of the esophagus, pharynx, and mouth; a more controversial association links alcohol with liver, breast, and col orectal cancers. Together these cancers kill more than 125,000 people annually in the United States (NIAAA 1993b).
Researchers have identified an enzyme system in the liver that metabolizes alco hol and other ingested chemicals. The normal function of this system is to detox ify harmful chemicals. However, in some cases the effect may be the reverse, in creasing the transformation of nontoxic environmental chemicals into substances that may cause cancer (Lieber 1992).

AlcoholRelated Trauma
Alcoholinduced impairment is associated with a variety of serious and fatal injuries, including those incurred in aviation, boating, cycling, and motor vehicle crash es; drownings; fires; and household acci dents. In addition, incidents of personal violence-including domestic violence, suicides, and homicides-are often associ ated with alcohol use. An important source of alcoholrelated trauma is drinking and driving. Of the 40,115 traffic fatalities that occurred in 1993, 17,461 were alcohol related (U.S. Department of Transportation [USDOT] 1994). Statistics indicate that almost two in five Americans will be involved in an alcoholrelated crash at some time in their lives (USDOT 1994). NIAAA research has provided the basis for prevention efforts, as described below.

Immune Defects
NIAAAsponsored studies have shown that chronic use of alcohol impairs the body's immune system, possibly setting the stage for respiratory and liver infec tions as well as AIDS (Roselle 1992;Rosman 1992;Kruger and Jerrells 1992).

PREVENTION OF ALCOHOLRELATED PROBLEMS
During recent years investigators have placed increasing priority on researching the prevention of alcoholrelated prob lems. Until recently, prevention efforts were essentially limited to educational programs to inform people of the dangers of alcohol abuse and alcoholism. During the past 10 to 15 years, there has been an explosion of interest in complementing educational approaches with strategies aimed at altering the social, legal, and economic context in which drinking occurs (Holder and Wallack 1986).

Effects of Reduced Access to Alcohol
A common approach to preventing alco hol problems is to decrease the availabili ty of alcohol through manipulation of price or restrictions on the sale of alco holic beverages. Some scientists have argued that availability restrictions affect only light and moderate drinkers, because alcoholics will accept any inconvenience or expense to satisfy their addiction. Ledermann, a French medical demogra pher, challenged this assumption, suggest ing for the first time that heavy drinking is sensitive to changes in the same supply anddemand factors that govern consumer behavior in general. NIAAAsponsored research has confirmed that reduced access to alcoholic beverages can be associated with reductions in the medical and social consequences of heavy drink ing, especially among youth (Chaloupka 1992;Grossman et al. 1987;Coate and Grossman 1988). Based on computer modeling studies, Grossman and col leagues (1991) predicted that increases in alcoholic beverage taxes might be an effective means of reducing alcohol involved driving and related traffic fatali ties. Researchers have not yet determined whether manipulation of price would have an equal effect on different beverage types and on different subpopulations of drinkers.

Integrating Targeted and BroadBased Prevention Approaches
Once it was assumed that most alcohol related problems result from heavy drink ing by alcoholics, who were therefore viewed as the appropriate target for pre ventive and treatment efforts. However, many people who experience alcohol related problems are light to moderate drinkers who are not addicted to alcohol. Although these people are at far less risk individually than are heavy drinkers, they form a much greater proportion of the population (Kreitman 1986). Indeed, even a single episode of alcohol misuse can have adverse consequences-including death, as in the case of drinking and driving. Researchers are therefore seeking ways to complement targeted interven tions that focus on highrisk populations with strategies aimed at the entire popula tion of drinkers.

Prevention of Traffic Fatalities
NIAAA research provided the scientific basis for the Federal Uniform Drinking Age Act of 1984, which specified that Federal highway funds would be withheld from any State that did not set 21 as the minimum legal drinking age (MLDA) for purchase or public possession of all alco holic beverages. Subsequent studies have reported that raising the MLDA from 18 to 21 years of age has dramatically re duced alcoholrelated driving deaths, especially among persons ages 16 to 20 (NIAAA 1993c;O'Malley and Wagenaar 1991;Hingson and Howland 1989).

Liver Transplantation for Alcoholic Liver Disease
Scientific data also were conclusive in shaping policy concerning liver transplants for persons with alcoholic liver disease. Liver transplantation is the only effective treatment for patients with endstage cir rhosis. However, many clinicians believed that alcoholic liver recipients would re lapse into drinking, thereby destroying their new liver. Data showed that the survival of alcoholic cirrhosis patients after transplant was no worse than that for patients with nonalcoholic liver disease (Starzl et al. 1988). In addition, the rate of relapse to drinking among transplant recip ients was low. 2 Based on these data, medi care rules were revised to include alcoholic liver disease as a condition for which liver transplantation is considered accepted medical practice.

Fetal Alcohol Syndrome
Beginning in 1989 Federal law has re quired that all alcoholic beverage con tainers sold or distributed in the United States bear warning labels. One such label addresses pregnant women as fol lows: "According to the Surgeon General, women should not drink alcoholic bever ages during pregnancy because of the risk of birth defects." Meanwhile, for the past decade, NIAAA has sponsored a nation wide effort to alert clinicians and expec tant mothers of the risks of maternal drinking to the fetus.

TREATMENT RESEARCH
Alcoholism treatment methods tradition ally had been developed on the basis of clinical experience and intuition, with little rigorous validation of their effective ness (Woody et al. 1991). The rise of health care costs has accelerated the need for research to document which treat ments succeed, for whom, and how. Over the past 10 years, alcoholism treatment research has employed modern standards of outcome evaluation, such as the use of control groups for comparison purposes, random assignment of subjects to treat ments, multiple and objective measures of treatment effects, adequate followup to confirm results, and appropriate statistical analysis (Fuller 1990). Results of these studies will permit researchers to improve treatments and will ensure that clinicians can provide the best available treatment to their patients.
An important development in treat ment research is a new emphasis on 2 Recent research suggests that outcome is enhanced by appropriate patient selection procedures and continu ous followup care (reviewed in Beresford 1994). patienttreatment matching. Because no single treatment approach is effective for all people with alcohol problems, NIAAA is sponsoring Project MATCH to develop practical guidelines for assigning patients to appropriate treatments based on rele vant patient characteristics. Involving 1,700 patients at 9 sites, Project MATCH is the largest and most complex trial of patienttreatment matching and treatment effectiveness ever undertaken. Although the first 5 years of the program concluded in the fall of 1994, researchers are contin uing to analyze the extensive data collect ed (Mattson 1994).
Modern research standards also have been applied to determine the effectiveness of disulfiram (Antabuse ® ), a medication used since 1949 to discourage drinking without convincing evidence of efficacy. In a large, multisite, doubleblind con trolled clinical trial conducted by the Veterans Administration (Fuller et al. 1986), researchers found that disulfiram itself was not associated with increased total abstinence. However, despite lack of compliance among many patients, subjects who remained in the study and continued to take their disulfiram exhibit ed a significantly decreased number of drinking days.
Controlled clinical trials supported by NIAAA have led to the Food and Drug Administration's recent approval of the use of naltrexone to assist alcoholics in treat ment to maintain abstinence (O'Malley et al. 1992;Volpicelli et al. 1992). A product of neuroscience research, naltrexone is the first new medication in 45 years approved to help maintain sobriety after detoxifica tion from alcohol.
The longterm goal of NIAAAsponsored clinical research is to develop a knowledge base for improving the efficiency and effectiveness of treatment delivery for alcoholrelated problems. NIAAA current ly funds multidisciplinary studies on the impact of organization, financing, manage ment, and delivery of alcoholrelated health care on service accessibility, quality, utilization, cost, and outcome. Ultimately these studies should ensure that the public is offered the highest quality of alcohol related prevention and treatment services at the lowest possible cost.

WHERE ARE WE NOW?
The past 25 years of research have both diversified and consolidated our knowledge of alcohol problems. On the molecular scale, it appears that the diversity of alco hol's addictive and medical effects can be attributed to its interference with a small number of key molecular processes com mon to all cells of the body. As basic re search expands our knowledge base, a consistent pattern appears to be emerging that ultimately will help guide improved prevention and treatment efforts.
On both individual and societal levels, however, alcoholrelated problems display a heterogeneity that challenges historical notions of alcoholism as a onedimensional problem. The causes and manifestations of alcoholism differ from one person to another, sometimes markedly. Multiple genes may each make contributions to ward the disorder, and some researchers have suggested that certain families may have their own unique mixture of genes responsible for alcoholism susceptibility (Plomin 1990). In addition, the relative contributions of genetic and environmen tal factors to the development of alco holism differ in different patients. Genetic influences appear to predominate for some people, whereas environmental influences appear to predominate for others (Pickens and Svikis 1991). These interactions appear to fluctuate over time, and risk for alcoholism or problem drink ing may emerge at any age.

WHERE ARE WE GOING?
The potential for synergism among the various scientific disciplines in alcohol research is greater than ever since NIAAA has become part of the National Institutes of Health. As we approach the beginning of a new century, research efforts will concentrate on the following: • Determining which aspects of the vul nerability to alcoholism are inherited. Linking specific traits with specific genes or groups of genes may support innovative ways to interfere with the development of alcoholism.
• Determining how genetic and non genetic factors interact in the devel opment of alcoholism. The ability of some nerve cells to undergo longterm adaptive changes in re sponse to environmental stimuli suggests that nature and nurture can not be considered separately in the development of alcoholism.
• Increasing efforts to address the spe cial treatment needs of traditionally underserved populations. For example, NIAAA supports the largest and most intensive study of women's drinking habits over time ever conducted in the United States as well as research to develop effective treatments aimed at ethnic and racial minorities, older individuals, and youth.
• Developing new treatment methods.
For example, NIAAA researchers are searching for medications that act to impede the progression of alcoholism and lessen the risk of relapse in recov ering alcoholics. In the near future, this research may be aided by computer assisted molecular technology for predicting the therapeutic effects of potential medications.
Finally, alcohol research will help remove the stigma associated with alco holism as it provides hope for the millions of people affected by this disease, their families, and society. ■