Statement by Ting-Kai Li, M.D., Director
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
Department of Health and Human Services

April 8, 2003

For the National Institute on Alcohol Abuse and Alcoholism I am pleased to present the President’s budget request for the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for Fiscal Year 2004. The Fiscal Year (FY) 2004 budget includes $430 million, an increase of $14 million over the FY 2003 enacted level of $416 million comparable for transfers proposed in the President’s request.

Alcohol is the third leading preventable risk factor for premature death in developed countries, according to the 2002 World Health Organization report. In the United States, alcohol misuse costs society about $185 billion each year. ¹

The reason alcohol takes such a heavy toll is that its potential to cause harm extends beyond alcoholism and behaviors that lead to fatal injuries, major problems in themselves. Alcohol is not only a psychoactive substance, but also a toxin that can damage any tissue or organ in the body, unlike illegal drugs. Alcohol’s toxic actions cause or contribute to certain cancers, liver and pancreatic disease, brain damage, and disturbances of the immune and endocrine systems, among other conditions.

But alcohol also presents a paradox. While heavy drinking substantially raises the risk of heart disease and stroke, studies suggest that moderate drinking appears to reduce them. Thus a major contributor to disease appears to have the potential to improve certain aspects of health.

VARIATION HOLDS THE ANSWER

The explanation for the paradox lies not only in degree of drinking in terms of the quantity and the frequency of drinking, but also in differences in our biological make-up. When we can answer the question of why alcohol is harmful in some circumstances, but appears to be beneficial in others, we’ll also be likely to find answers to other questions fundamental to our research: Why do only some of the people who drink, but not others, develop alcoholism or tissue damage? Why does the same medication result in sustained recovery from alcoholism in some people, but fail completely in others?

The answers lie largely in variations in our genes and the hundreds of biochemical activities they influence in our cells and, ultimately, our organs and behaviors. Different individuals and different ethnic populations can have different gene variants to yield a four-fold difference in their metabolic and behavioral responses to alcohol.

Much of our research is aimed at identifying and understanding: (1) the genes that influence how our organs and behaviors respond to alcohol, (2) the association of specific variants of these genes with specific alcohol-related outcomes, such as tissue damage or alcoholism; (3) patterns of variation in gene activity, protein activity, and metabolic activity with specific alcohol-related outcomes, and (4) how environmental factors interact with these biological factors to increase or decrease risk of alcoholism and alcohol-related problems.

Findings from this research form the basis on which we develop and test pharmacological and behavioral strategies for prevention and treatment.

Through studies in humans as well as animals, a high-risk, high-technology project currently underway is developing a biosensor that will help us understand vulnerability to alcoholism and organ pathology. This unobtrusive sensor will enable us to continuously measure and integrate over time levels of alcohol and, simultaneously, measure products resulting from alcohol metabolism in a number of bodily processes. One approach is an external skin sensor that periodically and imperceptibly inserts a probe smaller than a human hair into an individual subject’s tissue or the fluid around it. Another is to implant a microchip sensor subcutaneously. The continuous data it generates will provide valuable information about metabolic patterns of vulnerability. Clinically, alcohol levels also will reveal whether patients are complying with treatment regimens, providing clues about which treatment strategies are most effective.

CLINICAL IMPLICATIONS

Data from our basic research will enable us to do several crucial things. We will be able to provide clinicians with reliable biomarkers – laboratory tests – that will tell them which of their patients are biologically and/or genetically at risk of becoming alcoholic or of developing alcohol-induced tissue injury. Clinicians also will have the potential to predict which patients are biologically and/or genetically predisposed to respond to a specific medication for treatment of alcoholism, and which patients will respond to another.

At the same time, this research is helping us to identify molecular targets for new medications to treat both alcoholism and alcohol-induced organ damage, a pressing need in the clinical setting. As we follow the pathways from genes to physical and behavioral outcomes, we’re asking where, within the many biochemical reactions that occur along the way, we can find the best molecular points at which to aim pharmaceuticals that block alcohol’s actions. We also are asking if these points for intervention vary depending on variations in a person’s constellation of genes, necessitating different medications or molecular targets for subtypes of the disorders.

One such point for intervention is about to be tested in human clinical trials. Our scientists used several approaches to test a hypothesis that blocking a specific receptor on brain cells – the CB1 receptor, a docking site for the brain’s own version of marijuana-like substances called endocannabinoids – reduces desire for alcohol. In each approach, the CB1-receptor blocker (Rimonabant) reduced drinking. Pending results of the clinical trials, Rimonabant could become an important addition to our currently limited arsenal of effective treatments for alcoholism. We have identified another 16 compounds that are potential candidates for further development.

Our research also can help us isolate the biological mechanisms that underlie alcohol’s apparent beneficial effects. Since we don’t yet have clinically useful biomarkers that tell us who can benefit from moderate alcohol use and who is at risk of alcohol-related problems, and because alcohol carries with it so many well-documented risks, a recommendation to drink moderately for those who do not drink would be irresponsible at this point. If we can isolate the mechanisms that underlie whatever benefits alcohol might have, we have a chance of designing pharmaceuticals that mimic the actions of these mechanisms, but don’t have alcohol’s many deleterious effects.

BRAIN RESEARCH

Alcohol exerts its principal actions in the brain. It is here that heavy alcohol use results in brain-cell adaptations that lead to alcohol addiction. We’re approaching this crucial area of brain research with our Integrative Neuroscience Initiative on Alcoholism (INIA). This initiative is extending beyond traditional models of collaboration to capture the potential of input from the many fields that necessarily contribute to alcohol research, including genetics, imaging, molecular biology, and behavior – each of which may use different methods and attach different significance to findings.

At the scientific level, INIA has provided its investigators with technologies and standardized animal models which ensure that the significance of findings from each field are placed in the context of alcohol research. INIA collaborations are occurring not only across fields of research, but also across universities and organizations, nationally and internationally.

More than that, INIA has created an operational structure that enables us to pursue the most productive research, relatively unencumbered by inflexible funding mechanisms. INIA’s funding strategy allows us to pursue productive investigations as they emerge, to continue them, and to discontinue those that prove to be less promising or have reached their potential. In short, INIA has removed roadblocks to progress. This is enabling us to identify the structure and function of neural circuits, networks of brain cells that work in concert as intermediaries of alcohol’s behavioral outcomes.

Molecular imaging techniques are permitting INIA investigators to link alcohol-induced molecular responses with behaviors, in real time. Through computational biology, INIA researchers are creating models that predict how different brain structures and functions will respond to alcohol under different scenarios. This kind of research can help us determine optimal points for therapeutic intervention. A recent expansion of INIA will enable us to conduct translational research, to test whether neurobiological changes that occur in our animal models of alcohol-related behavior also occur in humans.

UNDER-AGE DRINKING

Drinking by children and adolescents is a concern reflected not only in our research, but also in parents and the media. Young brains are still forming nerve-cell connections, and they appear to be more sensitive to the deleterious effects of alcohol. Researchers are investigating how alcohol affects this and other processes in the developing brain, and for how long. Early indications are that adolescents who have gone through alcohol addiction and withdrawal risk long-term deficits in learning ability and memory. Research also shows that people who begin drinking at young ages are much more likely than those who begin later to become alcoholic at a later point in life.

Children and adolescents also are still developing decision-making capabilities, so important in formulating responses to environmental influences, such as peer pressure, that are powerful contributors to their choices about drinking. Almost 30 percent of 9th-12th graders surveyed report that they have had five drinks in a row at least once in the previous month. ²

An important question in alcohol research is how different drinking patterns affect risk of developing alcohol-related problems. Heavy, episodic drinking (sometimes referred to as "binge drinking") appears to be popular among some youth – notably college students, as newspaper headlines frequently attest. A study widely publicized in the media last year estimated that 1,400 college students die each year from alcohol-related causes and that 500,000 are injured. ³

In addition to our investigator-initiated research in this area, we have formed the Task Force on College Drinking, a collaboration between college presidents and scientists. The Task Force has released recommendations on prevention strategies, literature for various audiences, and a website, and has organized regional workshops. The Institute recently issued a research announcement calling for scientists with expertise in underage drinking to form rapid-response partnerships with colleges that request help.

Episodic heavy drinking of alcohol has been ritualized and is an accepted part of life at certain celebratory events in our society, not only among youth, but also among adults. Among the questions we’re asking are: How does this kind of drinking practice become ritualized in our society in spite of its deleterious consequences? How can we change the culture that leads to it?

Meanwhile, our initiative on the biological mechanisms of adolescent alcohol abuse is using imaging techniques that correlate brain structure with function and behaviors, in addition to other techniques, to reveal how alcohol affects specific brain areas, in human and nonhuman primate and rodent animal model studies. We’re also asking how developmental and environmental factors and the interplay between genes and environment affect youths’ choices to drink and their physical and behavioral responses to alcohol.

PREVENTION and RISK REDUCTION

Alcohol prevention research is aimed at reducing the causes and consequences of alcohol abuse and alcoholism. For example, whether the relationship between early onset of drinking and subsequent alcoholism is one of cause and effect or the result of factors that predispose people to both those behaviors, and others, is unclear. Our investigators are studying this issue, and their findings will help us understand why people become alcoholic. Meanwhile, preventing youth from drinking and reducing the harm it causes are essential, not only because early onset drinking predicts subsequent alcoholism, but also because of the immediate harm that alcohol misuse can cause – injury, violence, early introduction into the criminal justice system, legal repercussions, derailed scholastic careers, and death, to name a few.

We are conducting studies that develop and test strategies to prevent drinking by youth of different ages and backgrounds. Particularly important among these are longitudinal studies that can tell us whether strategies that show promise among a given subgroup of youth, such as rural adolescents, are successful or can be adapted for others, such as urban youth. These studies examine the impact of a number of factors, such as school programs, parental and family influence, peer influence, alcohol advertisements, and community policies and practices.

Prevention research at NIAAA also focuses on the general population and segments with unique needs. Among them are pregnant women (and their unborn children, who are at risk of fetal alcohol syndrome) and the elderly, who may be prone to depression and dangerous interactions between alcohol and prescription drugs. One of our initiatives is determining if community-based approaches successful in preventing alcohol-use disorders in the short-term can result in long-term prevention at different life stages.

OUTREACH

Public and private partnerships are helping us send our prevention messages to the community. The Leadership to Keep Children Alcohol-Free, a prevention campaign in which the Robert Wood Johnson Foundation has joined us, has recruited 33 governors’ spouses to act as spokespersons.

Other partners in our efforts to prevent under-age drinking include the National Highway Traffic Safety Administration, the Department of Justice, the Department of Education, and the Substance Abuse and Mental Health Services Administration.

Our outreach efforts also target clinicians, including physician groups such as the National Hispanic Medical Association, and the National Medical Association, that serve special populations. A science-to-service program provides clinicians with information about current research, and links them with scientists who advise them on specific areas of practice, at the clinician’s request. We work with States to engage their treatment providers and administrators. After exchanging information about our current research findings and the practitioners' obstacles to providing treatment, we place experts in temporary residencies in treatment programs that have identified specific areas of need. Medical schools generally aren’t thorough in their coverage of alcohol-related problems, and we have produced a physician’s guide to help fill the gap. Through these efforts, we promote the practical application of our research where it’s most needed.

_{¹ National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. The Economic Costs of Alcohol and Drug Abuse in the United States, 1992. Analysis by the Lewin Group, Harwood, H.; Fountain, D.; and Livermore, G. Bethesda, MD: DHHS, NIH, NIH Publication No. 98-4327 (September 1998)}

_{² Centers for Disease Control and Prevention, Youth Risk Behavior Survey. http://www.cdc.gov/nccdphp/dash/yrbs/2001/youth01online.htm}

_{³ Hingson, R.W.; Heeren, T.; Zakocs, R.C.; Kopstein, A.; Wechsler, H. Magnitude of alcohol-related mortality and morbidity among U.S. college students ages 18-24. Journal of Studies on Alcohol, 63(2):136-144, 2002. (164269)}

Prepared: April 2003