Sunday, May 1, 2005

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

Mr. Chairman and Members of the Committee:

I am pleased to present the Fiscal Year (FY) 2006 President's budget request for the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The FY 2006 budget includes $440,333,000, which reflects an increase of $2,056,000 over the FY 2005 enacted level of $438,277,000 comparable for transfers proposed in the President's request.

The Centers for Disease Control and Prevention last year ranked alcohol the number-three preventable cause of death in the country. This finding echoed a report issued by the World Health Organization, which listed alcohol as the third leading preventable cause of healthy years lost to death and disability in developed nations during 2002.

The high rate of death and disability associated with alcohol is the result not only of injury, but also of organ damage, including brain damage. Alcohol's biological actions are widespread in the body, and, when used in excess, it has the potential to contribute to conditions such as cancer and liver disease. Every age group is at risk of alcohol-related problems, from fetuses exposed to alcohol in the womb to the elderly. In the U.S., the estimated annual cost of alcohol-use disorders (alcohol abuse and alcohol dependence), including indirect costs, such as lost productivity, is $185 billion. 1

NIAAA's mission is to develop prevention and treatment interventions that reduce alcohol-use disorders and their consequences. To achieve this goal, we must understand the underlying biological, behavioral, and environmental factors and identify populations at risk. NIAAA research initiatives in four areas, in particular, are essential to this effort: medication development, neuroscience, metabolism, and youth.

MEDICATION DEVELOPMENT

Development of more widely effective medications for alcohol-use disorders and organ damage is among NIAAA's highest priorities; it is among the 28 research outcome goals listed in the NIH Government Performance and Results Act report. Medications help prevent or reduce drinking by acting on one or more of the many brain systems through which alcohol exerts its actions. For example, some medications reduce craving for alcohol. We are testing promising compounds for treatment of alcohol-use disorders, by themselves and in combination with behavioral therapies, and for treatment of liver damage.

Recent advances in science and technology have enabled remarkable progress in our understanding of neurobiological mechanisms that underlie behavior, and are revealing new molecular targets for medications for alcohol-use disorders. Likewise, advances in our understanding of organ injury are providing new opportunities for developing medications. These advances are reflected in unprecedented progress in NIAAA's medication development initiative.

A special challenge for our initiative is to develop strategies that will increase translation of promising medications identified by NIAAA research into clinical applications. The pharmaceutical industry has been reluctant to develop medications for alcoholism, and the medical community has been reticent to use new pharmacotherapeutic modalities as an adjunct to traditional behavioral therapies for the treatment of this disease. For example, only 3 to 13 percent of patients treated for alcoholism receive a prescription for the medication naltrexone, although it has yielded positive results in NIAAA-funded studies published in medical journals. We need to increase the likelihood that compounds we identify as effective and safe will reach the market and that they will reach patients who can benefit from them. Research is underway to identify barriers and strategies to remove them.

Our recently established collaboration with the Food and Drug Administration (FDA) will help to expedite progress. Together, NIAAA and FDA are developing standards for clinical trials of medications to be tested as alcoholism treatments. This will help ensure that NIAAA-supported trials are in line with regulatory requirements, enabling them to proceed.

Our two highest priorities for accelerating our medication program are (1) to develop animal models and human research paradigms that can predict the clinical success of potential medications. Having these predictive models in place will prevent spending time and money on more elaborate testing of compounds that would ultimately fail to be effective. (2) Another priority is to establish a network of sites for early stages of human testing of medications, to reveal whether or not a drug should be pursued in larger, more expensive trials. Medications in this system will be on a fast track, in which scientific elements of safety testing, etc., remain, but elimination of unnecessary administrative roadblocks will expedite the process.

IN THE PIPELINE

Human trials of two particularly promising medications are underway. Among the studies being conducted is a collaboration with the National Institute on Drug Abuse (NIDA), to test the antiseizure drug topiramate's effectiveness in treating people addicted to both alcohol and cocaine. Antiseizure drugs act on neurotransmitter systems that modulate brain-cell activity, to restore their natural balance. Alcohol causes an imbalance in the glutamate and GABA neurotransmitter systems (among others) and topiramate's actions on these receptors are thought to ease some of the symptoms of alcohol withdrawal. The drug rimonabant is directed at a different neurotransmitter system (the cannabinoid system) and has shown considerable promise in animal studies. Several other kinds of medications that have shown promise in research settings are in various phases of clinical studies, including several collaborations with other NIH Institutes.

Some populations are at particular risk, and we also are conducting studies specific to them. We are testing medications in youth, who have high rates of alcohol abuse. This group poses special challenges, since the biological changes that occur in the brain during adolescence might compromise the pharmacologic actions of medications used for adults.

People with co-occurring alcoholism and psychiatric conditions are another high-risk group. Our studies of this population include collaborations with the National Institute of Mental Health. In a recent trial, a drug already used as an anticonvulsant and to treat bipolar disorder showed promise in treating alcoholism in bipolar people, who are generally resistant to current medications for alcoholism.

A collaboration with the National Cancer Institute and NIDA is helping researchers to understand the biological interactions that occur between alcohol and nicotine, and to develop treatments for alcoholic smokers. Studies suggest that addiction to alcohol and nicotine involves some common underlying mechanisms.
In addition to developing medications to treat alcohol-use disorders themselves, we are developing treatments for alcoholic liver disease. Alcohol is among the leading causes of death from liver disease in the U.S.

Pharmaceutical companies put aside many of the medications they develop. Even though they may be safe, they may not be optimally effective for treating the diseases or conditions for which they were developed. These medications are potentially useful for treatment of other diseases, and some act on neurotransmitters that we have identified as promising targets for treatment of alcoholism. We are encouraging pharmaceutical companies to collaborate with us in developing these compounds as potential alcoholism treatments.

NEUROSCIENCE AND METABOLISM

The biology of the brain contributes to how we make decisions - to the choices we make in life and the behaviors in which they result. Neuroscience research is essential for understanding the biological basis of alcohol-related behaviors and for identifying molecular targets for therapeutic compounds that can alter alcohol's actions in the brain. Many different biological systems in the brain influence how people respond to alcohol, and chronic, heavy exposure results in brain adaptations that form the underpinnings of alcoholism.

NIAAA-funded scientists are making important discoveries about genes and proteins active in these brain systems, whose variant forms increase or decrease the risk of alcohol-use disorders. For example, recent studies suggest that a gene that produces an appetite-regulating protein fragment, neuropeptide Y, also affects tolerance to alcohol, a predictor of alcoholism and a factor in its development.

In 2006, NIAAA will take part in the NIH Blueprint for Neuroscience, a collaboration of 15 Institutes. We are particularly interested in the Blueprint's cross-training programs for the next generation of researchers and clinicians in neuroscience. One component trains physicians and scientists to work together toward translating neuroscience findings into clinical practice; others provide training in computer and neuroimaging technologies that offer unprecedented research capabilities. The Blueprint's project to target all of the genes in the mouse genome, to discover which of them are critical players in health or diseases of the nervous system, will benefit NIAAA research.

Metabolism also has a profound effect on people's responses to alcohol. Variations in the genes and proteins involved in alcohol metabolism can, like those involved in brain function, increase or decrease risk of alcoholism. NIAAA's metabolism initiative is making progress in identifying these gene/protein variations and their impact on alcohol-related behaviors, particularly in regard to enzymes in alcohol-metabolism pathways. The NIH Roadmap Initiative on National Technology Centers for Networks and Pathways is contributing valuable information to the effort. Like our neuroscience research, our metabolism research is helping us to identify potential targets for therapeutic compounds.

YOUTH AT RISK

Last year, we reported that new epidemiology data called for a major scaling up of efforts to prevent underage drinking. The data revealed that youth is the age of greatest risk of alcoholism; people 18-to-25 years old have much higher rates of alcoholism than any other age group in the Nation. Previous studies had shown the extent to which youth engage in risky patterns of drinking, such as occasionally or frequently drinking too much, too fast. Alcohol is the largest contributor to unintentional injury, the leading cause of death of Americans under age 21.

People who begin drinking earlier in adolescence have a much higher risk of alcoholism as adults, as compared with late starters. Children are beginning to drink at earlier ages, and youth from secondary-school age to college age have substantial rates of risky drinking. In the military, more than 26 percent of underage personnel engage in "binge drinking" (five or more drinks in a row), according to a recent Department of Defense report.

These and other epidemiology data indicated to us that (1) the problem of underage drinking required renewed emphasis and coordination in the research and service communities, and (2) we should approach alcoholism as having a developmental trajectory that begins in childhood and adolescence. In a recent report, Reducing Underage Drinking: A Collective Responsibility, the Institute of Medicine called for strategies to ameliorate these problems. Last year, NIAAA announced the addition of a major new initiative to its ongoing research on youth.

YOUTH INITIATIVE

Research shows that brain development and maturation occur over a longer period than previously thought. A key question we are asking is: What brain systems differ in adolescents and adults such that youth tend to binge drink? The brain receives and sends chemical messages that influence when an individual has "had enough" and stops drinking. Are the brain systems that regulate these "stop mechanisms" not yet mature in the adolescent brain? Does alcohol alter their development? A collaboration with NIDA is stimulating studies on consequences of alcohol exposure and drug abuse on development of the brain and behavior.

NIAAA has formed a steering committee that includes both scientists and policy and communication experts. The former chairman of the IOM committee on underage drinking is a member, as are two of the 60 current and former governors' spouses leading a national NIAAA-sponsored prevention campaign. In addition, the NIAAA sits on the newly established Interagency Committee on Prevention of Underage Drinking. This Committee cuts across agencies, from research to service, including the Substance Abuse and Mental Health Services Administration, in a major coordination of effort.

Our initiative also is reaching out to health-care systems and communities. An area in critical need of attention is the response of health care systems to underage drinking. NIAAA's youth initiative is beginning to address this need, in part, with a project called Underage Drinking: Building Health Care System Responses. Rural academic health centers will use existing services and clienteles to conduct the studies.

The youth initiative is responding to crisis levels of risky drinking on college campuses, as well. It includes fast-track approval of grant applications in response to campuses that request help, a recommendation issued in the NIAAA Task Force on College Drinking - a collaboration between scientists and college presidents. Seven approved and funded projects are underway; another application is nearing approval, and others are under review. The Task Force is about to release an updated report, which will reflect the latest research findings. Another new program under the youth initiative, the Mississippi River Delta Project, is examining whether a prevention strategy recommended for college students by the Task Force is effective for rural adolescents.

One major question that must be addressed regarding underage drinking and its consequences is whether enforcement of existing laws can reduce these problems by reducing youths' access to alcohol. We recently began collaborating with the Office of Juvenile Justice and Delinquency Prevention to address this question in rural communities. NIAAA's role in this joint effort is to provide the research required for evaluation of the effectiveness of the three-year program. Four projects are underway; three more are nearing approval.

The leadership of the youth initiative is discussing collaborations with other potential partners. In Spring 2005, we will meet with leaders in the radio and television media about the effects of alcohol portrayal on youth behaviors. Navy leaders have requested a meeting with NIAAA, also to be held in Spring 2005, to discuss prevention and treatment strategies. We have begun discussions with the Department of Agriculture about the possibility of conducting research and outreach through the 4-H Club organization.

AT THE CROSSROADS

The results of our research will be useful to the public to the extent that clinicians and communities apply them. We are at a crossroads, in which we are able to identify new medications, for example, while the pharmaceutical and medical communities are relatively unresponsive to new findings in alcohol research, and prevention and treatment are not reimbursed adequately by private insurers.

At this juncture, a high priority for our Institute is to develop strategies that will increase the likelihood that clinicians, communities, and health-care systems will adopt findings from our investigations. Efforts are underway.

Thank you Mr. Chairman. I would be pleased to answer any questions that the Committee may have.

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1 Harwood, H.; Fountain, D.; and Livermore, G. (2000). The Economic Costs of Alcohol and Drug Abuse in the United States 1992 (updated for 1998). Report prepared for the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services. NIH Publication No. 98-4327. Rockville, MD: National Institutes of Health.

Prepared: May 2005