STRATEGIC PLAN--FY08-13

National Institute on Alcohol Abuse and Alcoholism

FIVE YEAR
STRATEGIC PLAN
FY08-13

ALCOHOL ACROSS THE LIFESPAN

U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Alcohol Abuse and Alcoholism

Table of Contents

Executive Summary
Introduction
Research Opportunities and Outreach

Chapter I. Overview	Chapter II. Embryo and Fetus	Chapter III. Birth to Age Ten	Chapter IV. Youth and Adolescence	Chapter V. Young Adult	Chapter VI. Midlife	Chapter VII. Senior Adult
Mission and Vision of NIAAA	Background	Background	Definition of Youth and Adolescence	Definition of Young Adult	Definition of Midlife and Epidemiology	Background
Drinking Patterns and Definitions	Epidemiology	Epidemiology	Epidemiology	Epidemiology	Biology	Epidemiology
Prevalence of Alcohol Problems and Consequences	Etiology	Etiology	Biology	Biology	Metabolism and Organ Injury	Etiology
Issues that Transcend Lifespan Perspective	Prevention	Prevention and Intervention	Prevention	Prevention and Treatment	Organ Disease	Treatment and Prevention
Alcohol Metabolism	Treatment	Opportunities	Treatment	Opportunities	Genetic Variants and Pathology	Opportunities
Gene/Environment Interaction, Epigenetics	Opportunities	Outreach	Opportunities	Outreach	Effects of Moderate Alcohol	Outreach
Neurobiology	Outreach		Outreach		HIVAIDS
Diagnostic Criteria			Collaborations		Treatment: Mechanisms of Behavior Change
Alcohol Health Services Research					Treatment: Medications Development
					Opportunities
					Outreach

NIAAA STRATEGIC PLAN

ALCOHOL ACROSS THE LIFESPAN

EXECUTIVE SUMMARY

Introduction

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), a component of the National Institutes of Health, U.S. Department of Health and Human Services, is the lead agency in this country for research on alcohol abuse, alcoholism, and other health effects of alcohol. This document, the NIAAA Strategic Plan for Research, 2008-2013 sets forth a fundamental organizing principle for alcohol research studies and describes research opportunities to deepen and broaden our understanding of alcohol use and alcohol use disorders.

Alcohol use disorders (AUD) is defined as alcohol abuse and alcohol dependence, and arise from drinking too much, too fast and/or too often. Alcohol Abuse is defined as a recurring pattern of high-risk drinking that creates problems for the drinker, for others, or for society. Adverse consequences can also arise from a single instance of hazardous alcohol use. Alcohol dependence, typically considered to be synonymous with alcoholism (alcohol addiction), is a complex disease characterized by persistent and intense alcohol-seeking, which results in a loss of control over drinking, a preoccupation with drinking, compulsion to drink or inability to stop, and the development of tolerance and dependence.

The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recently came to similar conclusions about the toll taken by excessive alcohol use. According to the CDC, excessive alcohol consumption is the number-three cause of preventable death in the United States. The WHO also ranks alcohol third among preventable risk factors for premature death in developed nations. In 2003, the worldwide prevalence of alcohol use disorders (AUD) was estimated at 1.7%, accounting for 1.4% of the total world disease burden in developed countries. In the United States, 18 million Americans (8.5% of the population age 18 and older) suffer from alcohol use disorders. Only 7.1% of these individuals received any treatment for their AUD in the past year. Problems related to the excessive consumption of alcohol cost U.S. society an estimated $185 billion annually.

In addition to the adverse health effects that result directly from excessive alcohol consumption, other medical conditions often co-occur among individuals with excessive alcohol consumption. For example, alcohol abuse and dependence commonly occur in people who abuse other drugs, and in people with mood, anxiety, and personality disorders. An estimated 90% of cocaine addicts have alcohol problems and as many as 60% of patients at community mental health centers have alcohol and other drug abuse disorders. The high co-occurrence of alcohol and tobacco dependence poses special problems. An estimated 50% to 90% of alcohol dependent individuals are smokers who, in general, smoke heavily, become more addicted to nicotine and are less successful at quitting smoking than other smokers. This puts them at a much higher risk for certain cancers and cardiovascular diseases that develop more readily in the presence of both alcohol and nicotine.

Lifespan Perspective

Investigators traditionally have pursued solutions to the wide range of alcohol-related issues through studies of alcohol’s effects on biological systems, the genetic factors underlying these biological effects, and the environmental and cultural factors that influence alcohol use. This Plan applies a new organizing principle – the lifespan perspective – to these diverse areas of alcohol research. Scientists now recognize that human biology and behavior continues to change throughout life and changes occurring throughout the lifespan affect individuals' drinking patterns as well as the decisions they may make to change their drinking habits or to seek help for alcohol use problems. A lifespan perspective will allow researchers to identify how the emergence and progression of drinking behavior is influenced by changes in biology, psychology, and in exposure to social and environmental inputs over a person's lifetime, and vice versa. This approach should help researchers discover life stage- appropriate strategies for identifying, treating, and preventing alcohol use disorders.

Contributions to Alcohol Use and Alcohol Problems Across the Lifespan

Numerous factors influence the onset and continuation of alcohol use by an individual. The factors include the individual’s genetic makeup, the environments to which he or she is exposed and complex ways that genes interact with one another and with the environment. These same factors determine an individual's pattern of alcohol consumption and the risks for developing alcohol dependence (alcoholism).

Some of the first evidence of the importance of the lifespan perspective for understanding alcohol use disorders emerged less than ten years ago in an analysis of data derived from NIAAA’s National Longitudinal Alcohol Epidemiologic Study (NLAES). This analysis revealed that people who begin drinking at young ages have a significantly increased risk for developing alcoholism. This finding was confirmed by the recent National Epidemiologic Survey on Alcohol-Related Conditions (NESARC), which showed that 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. This is true for individuals from families where a parent had a history of alcoholism and for individuals with no parental history of alcoholism. Therefore, while parental history clearly contributes to the risk for developing alcoholism, likely a reflection of genetic risk factors, early initiation of drinking is also an important predictor of risk for alcoholism. Researchers hypothesize that early exposure to alcohol may alter brain development in ways that increase an individual’s vulnerability to alcohol dependence. Some other biological factor, perhaps affecting personality, may also be responsible for both the early onset of drinking and the heightened risk for alcoholism.

Alcohol Policy and Public Health

A wide range of alcohol policies may affect alcohol consumption and other behaviors relating to alcohol, and can have important influences on public health outcomes. In the United States, laws, regulations, and jurisprudence address various aspects of alcohol use ranging from alcohol taxation to behaviors affected by alcohol, such as drinking and driving. Scientific research has identified a number of alcohol-related policies that have significant effects on public health outcomes. Examples of these include a reduction in the number of traffic fatalities (raising the minimum drinking age to 21, enforcing stricter drinking and driving penalties), a reduction in child abuse and sexually transmitted diseases (raising taxes on alcohol beverages), and enhancement of access to alcohol treatment programs (State-mandated provision in health care financing). In general, alcohol policies are designed to serve individuals at all levels of the lifespan through harm reduction and prevention of alcohol-related illness or injury.

Lifespan Perspective--Practical Implications

Understanding the interactions of alcohol with stages of life will enable us to address the prevention and treatment of alcohol problems in a life stage-appropriate manner. In particular, such an approach should lead to a better understanding of:

how alcohol perturbs development of the embryo and fetus, which may help reduce the impact of Fetal Alcohol Spectrum Disorders (FASD).

how genetic and environmental factors contribute to drinking initiation and the development of alcohol dependence, which will foster the rational design of prevention strategies that target specific risk factors at appropriate stages of the lifespan.

the factors that influence the common phenomenon of naturally “aging out” of alcohol dependence, to aid in the development of new therapeutic approaches and to help achieve behavioral change in alcoholism treatment.

how alcohol use produces functional and structural changes in the nervous system, which will aid in the development of behavioral and pharmacological therapies directed to specific molecular targets within the brain.

how the products of alcohol metabolism contribute to the development of alcohol-induced diseases of the liver, digestive system, lung, heart, brain, endocrine and immune system. Such knowledge could help develop better preventions and treatments for these disorders.

RESEARCH OPPORTUNTIES AND OUTREACH

The following is a brief outline of Research Opportunities and Outreach activities identified by NIAAA that will help guide the Institute’s research program and activities over the next 5 years.

Opportunities that Transcend the Lifespan Perspective

Several scientific issues have impact on all stages of life. While the manner by which they affect an individual may differ depending upon the person's stage of life, these issues are best considered from an overarching perspective and include: alcohol metabolism; genetic and environmental influences including epigenetics; neurobiological effects of alcohol; and improvements in the diagnostic recognition of alcohol use disorder.

Metabolism -- Individuals differ in how fast they metabolize alcohol and in the extent to which they are affected by a given dose of alcohol. These differences affect drinking behavior, the potential for the development of alcohol dependence, and the risk for developing alcohol-induced organ damage.

Enhance understanding of the differences in alcohol pharmacokinetics (the rate by which an individual metabolizes alcohol) and pharmacodynamics (the extent to which an individual is affected by a given dose of alcohol) in their respective contributions to alcohol dependence and organ pathologies arising from alcohol use.

Continue to identify pathways through which alcohol is metabolized, as well as the effects of alcohol and its two main metabolic products, acetaldehyde and acetate, in altering key metabolic events in the body. Emerging metabolomics technologies can be applied to this effort.

Identify unique alcohol metabolites and investigate their involvement in pathologic processes, including the development of AUDs.

Identify metabolic profiles that provide an early indication of alcohol use disorders and alcohol-derived pathologic diseases.

Continue to investigate how alcohol alters the oxidative state of the cell, the pathologic consequences of the changes in oxidative state, and mechanisms by which alcohol alters the cellular defenses against oxidative damage.

Alcohol and Gene/Environmental Interactions -- Neither genes nor environment alone can explain why any particular individual develops alcohol dependence. Rather, as a complex disorder, risk for alcohol dependence is a consequence of the interplay of multiple genes, multiple environmental factors, and the interaction of these genes and environmental factors. The alcohol field has benefited from the ability to model various aspects of alcohol consumption in animal models, but advances in our understanding of neurobehavioral aspects of drinking and its consequences requires the development of new models. The identification of a number of genes contributing to the vulnerability to alcohol dependence in human studies, coupled with technological advances including the ability to conduct genome-wide association studies, offer great promise to further define genetic risk factors and their interactions with environmental factors.

Develop new animal models that more closely resemble diverse human traits regarding alcohol use, to aid the study of alcohol dependence and pharmacotherapy development.

Continue to identify genes associated with vulnerability for alcohol dependence by employing new and emerging technologies, particularly on samples from study populations previously recruited for genetic research on alcohol dependence (e.g., the Collaborative Study on the Genetics of Alcoholism).

Identify, through the study of discordant twin pairs, the relative influence of gene and environment on the risk of developing alcohol dependence or abuse.

Engage investigators and their respective institutions and agencies in efforts to incorporate alcohol-related measures, including alcohol use disorders, family history of alcoholism, and detailed measures of alcohol consumption, into broad-based surveys such as the National Health and Nutrition Examination Survey (NHANES). By doing so, future efforts can be undertaken to study the effects of interactions between alcohol-related measures and environmental factors such as diet, physical activity, smoking, and exposure to toxins, on risk factors for chronic disease.

Epigenetics -- Metabolic and environmental factors can influence the manner in which genes are expressed through a process known as epigenetics. Epigenetics refers to stable alterations in the genome, sometimes heritable through cell division, that do not involve the DNA sequence itself. Epigenetic processes act as an additional source of biologic variation beyond that attributable to the genetic code. These processes involve the chemical modification of the constituents of the chromosome, the DNA molecules and the gene-regulating proteins known as histones, and may occur as a consequence of exposures to specific environmental substances and stimuli.

Explore how alcohol alters normal processes associated with chemical modification of DNA and histone proteins, and the consequences of these modifications on gene expression. In addition to epigenetics, identify other mechanisms (e.g., alterations in transcription factors, small inhibitory RNA, etc.) by which alcohol may act to alter gene expression.

Examine epigenetic effects of alcohol across the lifespan, including alterations in embryonic and fetal development, adolescent and young adult brain maturation, the development of alcohol dependence and organ disease, and potential changes occurring in the later years of life.

Neurobiology -- The brain, which is the primary target for alcohol-induced neurotoxic effects including alcohol dependence, continues to develop and mature from conception through birth into early adulthood. Alcohol consumption may affect the normal physiology of the central nervous system at any point throughout the lifespan, and those effects may differ depending on lifespan stage.

Define the full range of pharmacodynamic effects of alcohol on central nervous system function and the variability associated with unique genetic and gene-environment profiles.

Continue to investigate how changes in brain structure and function arise from alcohol use. Such studies could include using the newest imaging technologies, diffusion tensor imaging MRI (dtMRI), for example, to study alcohol-induced changes in white matter tracts in the brain.

Apply new techniques for quantifying neurotransmitters, receptors and transporters to obtain a more complete understanding of alcohol's effects on these systems.

Diagnosis of Alcohol Use Disorders -- While the diagnostic criteria for alcohol dependence and alcohol abuse provided in current diagnostic schemes, including the DSM-IV and ICD-10, have contributed to improved case recognition and served researchers well over the past decade, research has begun to focus on developing quantitative representations of these criteria using statistical methods that provide differential severity weighting for individual AUD symptoms and allow for the inclusion of alcohol consumption variables. The development of quantitative criteria will lead to better understanding of the pathological stage of the disease for any given individual, provide the researcher an improved understanding of the etiology of alcohol dependence, and augment translational research to develop improved treatment approaches for the differing severity levels of alcohol dependence.

Pursue the development and assessment of dimensional or quantitative criteria as an improved indicator of alcohol use disorders, for both categorization and severity determination.

Determine if expression of AUDs differs by age, sex, and race-ethnicity variables and establish criteria for identifying AUDs that takes such differences into consideration.

Alcohol Health Services Research--Alcohol health services research is a multidisciplinary field of applied research that seeks to improve the effectiveness, efficiency and equity of services designed to reduce the public health burden of alcohol use disorders across the lifespan. It does this by examining how social factors, financing systems, service environments, organizational structures and processes, health technologies, and personal beliefs and behaviors affect access to and utilization of healthcare, the quality and cost of healthcare, and in the end our health and well-being. Ultimately the goal of alcohol health services research is to identify ways to organize, manage, finance, and deliver high-quality care conistent with developmental needs of patients and their families.

Identify strategies to enhance screening, brief intervention, and appropriate referral to additional services within primary care and obstetric practices, and examine the application of emerging technologies to expand self-directed interventions and health choices.

Develop and test models for screening and stepped intervention practices with children, youth, adolescents and emerging adults across various environmental contexts including primary care, social service agencies, mental health care, workplace, schools and juvenile justice.

Study the development of an integrated addiction specialty sector with fully integrated medical, psychiatric, and substance abuse programming aimed at managing severe co-morbidities using disease management and other chronic disease responses

Opportunities: Embryo and Fetus

The earliest stages of life are periods of great vulnerability to the adverse effects of alcohol. Embryonic and fetal development are characterized by rapid, but well-synchronized patterns of gene expression, including epigenetic imprinting, which makes the embryo/fetus particularly vulnerable to harm from alcohol, a known teratogen (an agent capable of causing physical birth defects). Alcohol's teratogenic effects were recognized over three decades ago, and it is now the leading known environmental teratogen. Alcohol may also damage neurological and behavioral development even in the absence of obvious physical birth defects. Alcohol-induced birth defects are known as fetal alcohol spectrum disorders (FASD). The severity of defects depends on the dose, pattern, and timing of in utero exposure to alcohol. Research in animal models has demonstrated that the potential for adverse effects increases with the maternal blood alcohol concentration (BAC). Research has also suggested that alcohol's causative role in FASD can be influenced by maternal hormones, nutrition, age, parity, years of drinking, and genetic factors. The most serious adverse consequence of prenatal alcohol exposure is fetal alcohol syndrome (FAS), a devastating developmental disorder characterized by craniofacial abnormalities, growth retardation, and nervous system impairments that may include mental retardation. Children and adults with FAS have irreversible neurobiological deficits that affect multiple systems, ranging from motor control to executive function.

Apply genetic and proteomic technologies to examine alcohol’s effects on gene expression patterns involved in normal development.

Identify alcohol's role in epigenetic modifications of DNA and histone structure.

Examine the interaction of alcohol with additional factors, such as maternal stress and nutritional stress, in altering epigenetic patterns, and identify the sites where the interaction of these factors changes the genetic expression pattern.

Identify the mechanisms through which alcohol impairs the functioning of various neurotransmitter systems, second messenger signaling systems, and cell adhesion communication systems.

Use knowledge gained in uncovering target sites for alcohol's action on the embryonic and fetal stages of life to begin developing potential therapeutic or preventative interventions, including dietary supplements (e.g., antioxidants and choline) that are safe for use in pregnant women.

Apply metabolomics technology to the search for a metabolic profile that may serve as a marker for risk or vulnerability for FASD.

Use computer technologies for the analysis of 3-D facial images and MRI brain scans to identify changes in FASD and other disorders of children to refine the understanding of the neurodevelopmental signature of FAS and FASD.

Refine and increase knowledge about specific structural alterations in various brain regions for identifying fetal alcohol CNS deficits, and explore the potential for developing low-cost or modest-cost approaches for identifying these structural deficits through prenatal ultrasound and transfontanelle ultrasound of newborns.

Identify barriers to implementing alcohol screening in primary care and obstetric practice, and explore the acceptability of new screening technologies, such as computer assisted interviewing.

Continue to develop and refine approaches for selected and indicated prevention, to decrease the potential for FASD births among the women at greatest risk for these disorders.

NIAAA will co-sponsor, with NICHD, NCI, and NCCAM, an initiative for a multi-center international research network designed to conduct randomized clinical trials of interventions to reduce the major risks to maternal, neonatal, infant and early childhood health in resource-poor countries. NIAAA seeks to include alcohol screening and interventions in the health care of women in prenatal care and the screening of children from birth through early childhood for the disabilities that result from prenatal exposure to alcohol.

Outreach: Embryo and Fetus

NIAAA will continue to support the meetings and work of the Interagency Coordinating Committee on Fetal Alcohol Spectrum Disorders (ICCFAS), which is developing a strategic plan with actions that involve the participation of alcohol researchers and research administrators. NIAAA and other ICCFAS agencies will co-sponsor Research to Practice Meetings on diverse FASD issues. NIAAA will continue to work with the Substance Abuse and Mental Health Services Administration (SAMHSA) on the development of guidelines and training materials for criminal justice personnel.

NIAAA will partner with the Health Resources and Services Administration (HRSA) and the National Organization on Fetal Alcohol Syndrome (NOFAS) in an effort to include alcohol screening in maternal care programs and beyond and to identify research-based interventions that can be implemented in a cost effective manner in health care facilities.