Statement by Enoch Gordis, M.D., Director
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
Department of Health and Human Services
March 19, 1998
Mr. Chairman and Members of the Committee:
The FY1999 President's budget request for the NIAAA is $230,243,000, an increase of $17.5 million over the FY 1998 appropriation. Including the estimated allocation for AIDS, total support proposed for NIAAA is $245,730,000, an increase of $18.6 million over the FY 1998 appropriation. Funds for NIAAA AIDS research are included in the Office of AIDS research budget request.
THE PROBLEM OF ALCOHOLISM
Alcoholism is one of our country's most serious and persistent health problems. Approximately two-thirds of all American adults (ages 18 and older) drink an alcoholic beverage during the course of a year. At least 13.8 million American adults develop problems from drinking. Our young people, for whom alcohol remains the number one drug of abuse, also are at risk for developing alcohol-related problems. Recently published data from NIAAA's National Longitudinal Alcohol Epidemiologic Survey, which assesses lifetime risk for alcohol use disorders (alcohol abuse and alcohol dependence), provides convincing evidence that the younger the age of drinking onset, the greater the chance that an individual at some point in his or her life will develop a clinically diagnosable alcohol use disorder. As shown on Chart 1, young people who began drinking before age 15 are four times more likely to develop alcohol dependence during their lifetime than those who began drinking at age 21.
The health problems caused by alcohol use include damage to the brain, liver, gastrointestinal tract, and heart. The relative risk for many alcohol-related illnesses rises along with the quantity of alcohol consumed daily. Other consequences of alcohol use include crashes and other injuries, domestic violence, neglect of work and family, and costs to society associated with police, courts, jails, and unemployment. Altogether, the consequences of alcohol abuse and dependence are estimated to cost the nation $100 billion and 100,000 deaths a year.
THE PROMISE OF RESEARCH
NIAAA's research is guided by one fundamental purpose-to develop the necessary knowledge to effectively prevent and treat alcohol abuse and alcoholism and their related consequences. Through its nurturing of the Nation's alcohol research agenda, NIAAA makes an implicit promise-that science will yield practical applications that will help those who suffer as a result of alcohol abuse and alcoholism. In support of this mission, NIAAA conducts and supports a broad-based program of biomedical and behavioral research in areas such as the epidemiology of alcohol use, abuse, and dependence; alcohol's effects on the brain; the genetics of alcoholism, alcohol toxicology; the benefits to health of moderate drinking; the effects of public policies on preventing alcohol use disorders, and clinical trials to develop or evaluate alcoholism treatment therapies.
The activities of the NIAAA are covered within the NIH-wide Annual Performance Plan required under the Government Performance and Results Act (GPRA). The FY 1999 performance goals and measures for NIH are detailed in this performance plan and are linked to both the budget and the HHS GPRA Strategic Plan which was transmitted to Congress on September 30, 1997. NIH's performance targets in the Plan are partially a function of resource levels requested in the President's Budget and could change based upon final Congressional Appropriations action. NIH looks forward to Congress' feedback on the usefulness of its Performance Plan, as well as to working with Congress on achieving the NIH goals laid out in this Plan .
PATHWAY FROM RESEARCH TO APPLICATION
While the promise of research is that science will yield practical applications, some areas of investigation will require a longer time to fulfill the promise than others. For example, the knowledge gained from clinical trials is almost immediately available for application to alcoholism treatment programs whereas complex basic studies investigating alcohol's effects on the brain and the relationship of these effects to behavior, will take longer to develop information that can be used to design new medications. Chart 2 shows the relative time frames in which various areas of research may be expected to yield practical applications and will serve as the basis for my further remarks.
NIAAA-supports clinical trials designed to develop new and evaluate existing treatments. Such trials led to the Food and Drug Administration's approval of the medication naltrexone as an adjunct to traditional treatment. A product of neuroscience research, naltrexone is the first medication since 1949 to be approved to help maintain sobriety after detoxification from alcohol. NIAAA currently is conducting clinical trials to determine which groups of patients are most responsive to naltrexone and the benefits and side effects of long-term use. Based on evidence that naltrexone, used in combination with verbal therapy, can prevent relapse more than standard verbal therapy alone, NIAAA is supporting clinical trials to evaluate the effectiveness of combined behavioral/naltrexone therapy to substantially reduce the current 50 percent relapse rate among those treated for alcoholism.
Two potential medications on the horizon are acamprosate and amperozide. Acamprosate has been clinically tested and used successfully for relapse prevention in Europe. After extensive consultations with the NIAAA, the pharmaceutical industry has launched clinical trials of acamprosate in the U.S. Because of its hypothesized mode of action, Amperozide, which has been shown to successfully reduce alcohol consumption by primates, is expected to be effective in treating human alcoholism. NIAAA also plans to test amperozide in collaboration with the Veterans Administration.
Two recent clinical studies demonstrate that it may be possible to intervene inexpensively with heavy drinkers before they progress to alcoholism. In the first randomized trial of this kind, investigators provided direct evidence that brief physician intervention with problem drinkers can decrease alcohol use and health resource utilization. These studies are important because detecting alcohol abuse at an early stage of development and prior to the onset of alcoholism has both practical and medical benefits.
The complex mental processes that govern drinking behavior are carried out in the brain by many independent interactions among neural systems comprised of neurotransmitters and their receptors. Two main processes involved in drinking are being studied: positive reinforcement, or the pleasurable feedback an individual receives from alcohol use; and negative reinforcement, the discomfort associated with being deprived of alcohol. In positive reinforcement, alcohol appears to interact with the brain's "pleasure" or reward system to stimulate continued use. Negative reinforcement, which appears to involve separate neural systems, may result from the brain's chronic exposure to alcohol. Such exposure causes the brain's cells, or neurons, to adapt to the presence of alcohol and to "miss it when it is not present." Clarification of these processes will enable scientists to develop specifically designed medications tailored to individual physiology. The study of the mechanisms of action of the two medications currently used to prevent relapse-naltrexone and acamprosate- is informing this effort. These two drugs appear to work through different mechanisms to achieve the same effect; naltrexone by blocking positive reinforcement and acamprosate by acting on negative reinforcement.
Alcohol scientists are using advanced neuroscience techniques (e.g., patch clamping, imaging, electrophysiology, neurochemistry, and cognitive neuroscience) to understand the fundamental phenomena associated with alcoholism, i.e., physical dependence, tolerance, impaired control over drinking, and the craving for alcohol. However, investigating the specific effects of alcohol is challenging; alcohol interacts with and alters the activities of many different brain cell components and, consequently, may have diverse and profound effects on nerve cell function. For example, alcohol can affect various neuroreceptors causing the neuron to react by increasing or decreasing its usual functions. These receptors are divided into subunits. The different ways in which subunits combine affects the brain's sensitivity to alcohol, and quite possibly, the sensitivity to alcohol among different individuals. How an individual's pattern of subunits affects his or her initial sensitivity to alcohol and how alcohol influences the way in which subunits combine to affect sensitivity are both under study. Transgenic animals have been bred with different brain receptor compositions to determine which constitute those that are most vulnerable to alcohol. As we learn which subunit variations account for addiction, we will be able to develop new medications designed to interfere in the addictive process by acting on specific brain chemicals.
New Approaches to Medications Development
Medications have been traditionally developed either by lucky accident, or by finding new uses for established medicines. We are now moving into a new era in which our understanding of the shape and structure of important molecules in the body is dramatically improved with techniques such as crystallography and nuclear magnetic imaging. With the help of computers and powerful methods of combinatorial chemistry to create hundreds of new potential compounds rapidly, it will become increasingly possible to design new medications specifically to fit known biological structures and alter their function. The crystal structure of the alcohol metabolizing enzyme, aldehyde dehydrogenase seen in Chart 3, was reported by NIAAA grantees this year. It is a fine example of how new insight into structure explains function, and is a prototype of what future medication development will exploit.
There is ample evidence that a significant portion of the susceptibility to alcoholism is inherited. Genetics researchers are now actively engaged in identifying the genes that confer this vulnerability and developing ways to apply this information to clinical populations. The task is difficult because alcoholism is likely to be polygenic, with each gene contributing only a portion of the vulnerability. The search for the relevant genes is now actively pursued in several settings.
Through the Cooperative Study on the Genetics of Alcoholism (COGA), a multisite study at six centers, hundreds of probands and families have been interviewed, a complex computerized pedigree database has been incorporated, and statistical genetics and molecular biology techniques are being applied to "informative" families. Phenotypic markers shown previously to be relevant to alcohol are incorporated in the study, including biochemical markers, evoked potential responses, and tests of initial sensitivity to alcohol (the latter being a strong predictor of later alcoholism). COGA scientists have recently located chromosomal "hot spots," areas of potential linkage of alcohol dependence, on chromosomes 1, 7, 8, and 16. Also, the possibility of protective factors is suggested by possible linkage on chromosomes 4 for resilience to alcoholism. In addition, locations for the genes involved in the expression of evoked potential responses, a high-risk marker for alcoholism, have been tentatively identified. Because replication of genetic findings in independent populations is essential for their verification, NIAAA has funded two new genetic linkage studies. Although smaller in scale than COGA, the relative genetic, cultural, and phenotypic homogeneity of these studies' subject samples should enhance their likelihood of success.
Once we know which proteins are coded by the genes for alcoholism, alcohol researchers will be able to study the effect of various combinations of neurochemicals on these proteins and design medications that are targeted specifically to interrupt those processes which result in the development of alcoholism.
WHERE ARE WE GOING?
Research has diversified and consolidated our knowledge of alcohol problems. We will continue this progress into the new millennium by focusing on research to determine which aspects of the vulnerability to alcoholism are inherited; how genetic and non-genetic factors interact in the development of alcoholism; how biology and behavior interact in the development of alcohol use disorders; and by developing and testing new prevention and treatment and methods to reduce the risk for alcoholism, improve the chance for recovery and reduce the risk of relapse. NIAAA also will continue to pursue research aimed at preventing fetal alcohol syndrome, reducing drunk driving; understanding the effects of alcohol advertising on our nation's youth; improving adolescent alcohol treatment, and clarifying the health effects of moderate drinking.
My colleagues and I will be happy to respond to any questions you may have.
Prepared: March 19, 1998