**National Institute on Alcohol Abuse and Alcoholism**

**FIVE YEAR**

**STRATEGIC PLAN**

**FY09-14**

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***"ALCOHOL ACROSS THE LIFESPAN"***

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U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Alcohol Abuse and Alcoholism

**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,
2009-2014* 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.

**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
    *pharmacokineti*cs (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.

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-   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.

-   Explore the phenotypic outcome in immortalized cell lines from the
    interaction of alcohol within the typical relationship of genes,
    proteins, post-translational and metabolic events, using cell lines
    from well-characterized alcohol-consuming human populations. .

> **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.

-   Develop biomarkers for chronic alcohol use, for example through the
    exploration of alcohol on glycoproteomics and lipidomics.

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-   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 consistent
> 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.

-   Continue to explore issues related to access to health services in
    support of youth and adolescent drinkers' alcohol treatment
    programs, including, insurance coverage, provider-training,
    provider-time, and issues of confidentiality between parents and
    children.

**Data Collection Over the Lifespan -** Research on risk factors for
development of alcohol use disorders can exploit the ever increasing
assortment of technological gadgets for recording day-to-day events in
real time. This massive data collection method allows for the analysis
of minute to global influences on the daily behavior of humans that may
lead to the identification of risk factors for various diseases. The
sheer volume and complexity of collected data using real-time technology
would lend itself to modeling of the intricate interplay of
developmental, biological, pharmacological, social, environmental, and
cultural factors in the transition from initial alcohol use to alcohol
dependence.

-   Identify risk characteristics prior to alcohol exposure in order to
    model the interaction of alcohol use patterns with biobehavioral and
    environmental factors in all ages of high risk individuals.

-   Investigate the role of co-factors, such as smoking, diet, drug
    experimentation, and physical activity that could be hypothesis
    generating for basic research into the molecular mechanisms by which
    these factors influence the alcohol dependence transition states.

-   Enhance the understanding of biology by environment exposure (BxE)
    and gene by environment exposure (GxE) to plot the trajectories in
    the development and natural remission from alcohol dependence,
    particularly in adolescent and young adult populations.

    **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**

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-   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.

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-   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.

    **Opportunities: Birth to Age Ten**

A number of significant research opportunities and directions exist for
the birth to age ten years group. The first two are very high priority
since there is little to no information in these areas. The third is
also a very high priority as there is a need to better understand why
drinking is a normative behavior among American adolescents and how
drinking becomes so widespread among youth. The remaining opportunities
represent areas where increased knowledge about known developmental
pathways into alcohol use and AUDs will enhance prevention efforts with
specific groups of youth at high risk.

-   Examine the onset of drinking in young children by instituting
    nationwide surveys of children's alcohol experience beginning in
    grade four. Follow a subset of individuals to determine the
    relationship between early onset of alcohol use and later
    development of problem drinking.

-   Explore parental beliefs and practices concerning childhood alcohol
    use to determine under what circumstances exposure to limited
    drinking at home is protective or a risk factor for later alcohol
    problems.

-   Investigate the ontogeny of attitudes, intentions, and expectancies
    for alcohol use in childhood and through adolescence in order to
    identify the factors influencing the development of alcohol-related
    cognitions.

-   Further characterize the externalizing pathway for the development
    of problematic drinking in adolescence with regard to early
    initiation, alcohol use, and alcohol use disorders. Determine the
    influence of family history of alcoholism, prenatal exposure to
    alcohol, and gender and ethnic/racial variation, and modifiable risk
    factors influencing this pathway that can be targeted in prevention
    efforts. In addition, direct the research effort equally towards the
    characterization of the internalizing pathway for the development of
    alcohol problems, since depression, inhibition, social anxiety,
    social withdrawal, and generalized anxiety all play a role in this
    pathway, and the two pathways are related with respect to gender
    differences in bipolar disorder in adolescence.

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-   Apply the various data collection strategies with state-of-the-art
    technologies in genomics, imaging and statistical modeling to
    determine the relative contribution of biology, environment, and
    genetics to the risk for alcohol dependence or abusive alcohol
    consumption in later life.

In some cases, familial, neighborhood, and peer structures act in
concert to encourage the development of early involvement with alcohol.
Determine the degree to which these concurrent risk factors are
synergistic for the development of risk.

**Outreach: Birth to Age 10**

-   Located in the section on Youth/Adolescence

**Opportunities: Youth/Adolescence**

The beginning of adolescence is demarcated biologically with the onset
of puberty, and is understood to end when an individual assumes adult
roles and responsibilities. Puberty consists of many biological
processes that do not occur at the same chronological age and do not
necessarily progress at the same pace or have the same pattern of
unfolding in every individual. Importantly, brain development, marked by
continuous generation of neurons and connections between neurons, and
the refinement of communication among those neurons, continues during
puberty and into the young adult ages. Drinking alcohol during this
dynamic period of brain development may result in brain effects leading
to an earlier onset of alcohol-induced specific diseases or to an
earlier transition towards the development of alcohol use disorders.
Very important to understanding alcohol use by youth from a
developmental perspective is the fact that, over the past 100 years, the
endocrine changes associated with puberty have been occurring at younger
ages, while the attainment of adult roles such as starting a career,
finding a partner, owning a home and becoming a parent are occurring
much later. The result is the dramatic expansion of the period referred
to as adolescence which prolongs the potential duration of one of the
heaviest drinking periods of the lifespan and therefore may exacerbate
the harmful effects on alcohol on development. In sum, adolescence is a
period of dramatic biological change -- occurring in the context of
equally dynamic socio-environmental change with regard to the
adolescent's school, peer group, family, and social milieu. The majority
(80%) of youth begin to drink by the end of high school, and some
experience significant alcohol-related problems including the
development of alcohol use disorders.

-   Identify alcohol's effects on developing brain structures and
    behavioral regulatory systems.

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-   Use specific modifications in imaging techniques to visualize
    changes associated with white matter tracts, and correlate changes
    in brain structure and function with neuropsychological functioning.

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-   Expand studies on the adolescent decision-making process, including
    the influence of affect, external environmental factors, and
    expectations on those decisions. Use laboratory simulated
    environments as well as animal research, particularly in primates.

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-   Refine definitions of alcohol abuse and dependence currently used
    for adults to apply to youth and adolescents for better diagnosis of
    and screening for adolescent alcohol problems.

-   Identify alcohol behavioral markers for problem alcohol use by
    youth, especially for very early markers of risky drinking.

-   Identify the relationship among reproductive hormones, stress
    hormones, and sex differences in alcohol use and dependence that
    unfolds during late puberty, through longitudinal studies of
    hormonal, electrophysiological and other biological factors over the
    course of puberty.

    **Outreach: Youth/Adolescence**

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-   NIAAA is continually developing and updating its own products
    relevant to underage drinking including scientific reviews,
    brochures for the general public, and web sites, both for adults and
    youth. For example, NIAAA's Underage Drinking Research Initiative
    produced a volume of NIAAA's journal, *Alcohol, Research & Health*
    titled "Alcohol and Development in Youth: A Multidisciplinary
    Overview", which was published in the fall of 2005. A companion
    issue articulating the developmental framework and the state of the
    science for prevention and treatment is planned for late 2007. To
    assist adults in discussing alcohol use with their children, NIAAA's
    parents booklet (available in English and Spanish) *Make a
    Difference, Talk to Your Child About Alcohol* provides helpful
    information in initiating and sustaining the conversation about
    underage alcohol use. The Underage Team, in conjunction with the
    Communications Branch, will be developing concise summaries of the
    state of the science on specific topics of interest. For each topic,
    summaries will be written at various levels of sophistication
    appropriate for specific audiences

-   Several NIAAA web sites provide relevant information for specific
    audiences. The "cool spot" (www.thecoolspot.gov) is an engaging,
    interactive web site for middle school children where they can
    access information directly about the effects and potential
    consequences of alcohol use. NIAAA's college drinking web site
    ([www.collegedrinkingprevention.gov](http://www.collegedrinkingprevention.gov/))
    has resources for high school students and their parents, high
    school administrators, college students and their parents, and
    college presidents. More information on underage drinking including
    statistics, references, and information about the underage drinking
    research initiative can be found on NIAAA's main web site at:
    (<http://www.niaaa.nih.gov/AboutNIAAA/NIAAASponsoredPrograms/underage.htm>).

-   In addition to direct outreach to the public, NIAAA capitalizes on
    opportunities to provide the best available scientific information
    on underage drinking to federal agencies, professional societies,
    and other organizations. For example, NIAAA staff members represent
    the Institute on the Interagency Coordinating Committee on the
    Prevention of Underage Drinking (ICCPUD) thereby informing the
    alcohol-related work of its member federal agencies and departments,
    and their constituencies. Further, NIAAA staff members seek
    opportunities to present at national meetings such as those
    sponsored by the Research Society on Alcohol, the American
    Psychological Association, the Department of Education, the
    Substance Abuse and Mental Health Services Administration, and the
    Community Anti-Drug Coalitions of America.

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-   NIAAA will develop a working relationship with the Department of
    Agriculture's 4-H and other youth programs to determine how these
    programs might be included in efforts to reduce underage drinking.
    The outcomes of pilot projects and activities will be evaluated to
    determine effectiveness.

-   Use state-of-the-art communication strategies and techniques to
    increase awareness of critical alcohol and health messages,
    including -- "Early onset of alcohol use interacts with human
    developmental processes to increase risk for alcohol problems
    throughout the lifespan."

-   NIAAA supports the *Leadership to Keep Children Alcohol Free*, a
    group spearheaded by spouses of current and former Governors,
    dedicated to the prevention of drinking by 9-15 year olds. This
    organization seeks to raise awareness of, and provide science-based
    information to audiences ranging from parents to policy-makers
    about, underage drinking and its consequences.

    **Opportunities: Young Adult**

Entry into young adulthood is defined by a variety of self-directed
transitions that signal an individual's burgeoning independence from
parental care. The pursuit of post-secondary education, enlisting in the
military, and entering the workforce are a few such milestones, which
traditionally have occurred when an individual is in his or her late
teens or early twenties. Other events that traditionally mark this
period include assuming large financial obligations, courtship, and
marriage. In the U.S, most states have adopted age 18 as the legal age
of majority -- the point at which individuals assume responsibility for
their own actions. However, from a developmental rather than a legal
perspective, emerging or young adulthood now comprises an extended
period of unsettled behavior for many individuals, as age of marriage
and age of career initiation in the U.S., for example, have increased
relative to historic norms. Compared to all other age groups, the
prevalence of periodic heavy or high-risk drinking is greatest among
young adults aged 18 to 24. Alcohol use disorders including alcohol
dependence (alcoholism), also peak during this period. While most young
adults transition out of harmful drinking behaviors, a minority will
continue to drink heavily into the later stages of adulthood. These
phenomena raise important research questions. For example, what factors
allow some young adults to discontinue harmful drinking patterns, most
often in the absence of formal alcoholism treatment? Why do others
experience protracted alcohol problems well into their adulthood?

-   Examine the population of non-college and non-military bound young
    adults as they transition from high school into adulthood, as these
    individuals are not exposed to post-secondary educational
    information regarding the consequences of alcohol misuse, nor are
    they in a structured environment that encourages brief interventions
    or treatments.

-   Apply new technologies in neuroscience research to improve
    understanding of how changes in the young adult brain influence
    early onset drinking, with respect to the neural connections
    underlying the decision making process, and to alcohol-induced
    injury in brain versus other organs in young adults.

-   Alcohol Health Services Research: Develop and test models for
    screening and stepped intervention practices with young adults
    across various environmental contexts including primary care, social
    service agencies, mental health care, workplace, schools, and
    juvenile justice.

    **Outreach: Young Adult**

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-   Audience segmentation research conducted at NIAAA has revealed binge
    drinking young urban adults to be a well-delineated group of
    individuals at significant risk for alcohol-related problems. We
    have rich descriptive data about the lives and habits of binge
    drinking in this population, which can provide a strong and unique
    foundation for programmatic prevention intervention research for
    these at-risk young adults.

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-   NIAAA has collaborated with the Office of Juvenile Justice and
    Delinquency Prevention (OJJDP) in evaluating its initiative to
    address underage drinking in rural communities and plans to work
    with OJJDP and the Air Force to evaluate an Air Force Base
    --Community Partnership to reduce drinking among servicemen under
    age 21. NHTSA continues to participate in the NIAAA programs to
    reduce underage drinking in college students. Opportunities exist to
    increase interactions and partnerships with the Department of
    Defense agencies involving collaborations with OJJDP and NHTSA.

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-   NIAAA has attempted to include underrepresented Asian Americans and
    Pacific Islanders as researchers and as study participants. An
    ongoing collaborative alcohol research planning grant at the
    University of Hawaii is one example of NIAAA efforts in this regard.
    NIAAA also is working with the National Association of Asian and
    Pacific Island Families Against Substance Abuse (NAPAFASA) to
    develop culturally and language-appropriate information on alcohol
    use and abuse and health.

-   NIAAA will explore opportunities to work with a new CDC Center of
    Excellence in Health Marketing and Health Communications at the
    University of Connecticut. The University of Connecticut Center
    includes efforts to reduce drug and alcohol use among youth and
    young adults.

-   NIAAA will update/re-issue college drinking report in 2007.

-   NIAAA will use college drinking process/materials as a template for
    developing and disseminating essential alcohol messages and
    materials for the gamut of lifespan stages.

    **Opportunities: Midlife**

A broad spectrum of alcohol-related problems and issues becomes
manifested during the adult period of life often referred to as midlife.
At midlife, many of the pathological consequences of heavy alcohol use
become most evident, and individuals with alcohol dependence are most
likely to seek treatment of their alcoholism at this time.

**Metabolism and Organ Injury**

-   Identify the differing metabolic fates of alcohol, the extent to
    which alcohol metabolism alters other metabolites and the oxidative
    state of the cell, and the consequences of these perturbations on
    organ function and disease.

-   Investigate how alcohol influences the disease course of various
    pathogens, such as Hepatitis C and Hepatitis B.

-   Identify the effects of alcohol at low and moderate dose levels to
    uncover the mechanism underlying both pathologic and potential
    beneficial outcomes of alcohol exposure at these levels.

**Alcohol and HIV/AIDS**

-   Examine whether alcohol's effect on HIV infection and AIDS
    progression varies with age of infection, and how co-infections (TB,
    HepC) alter the disease progression.

-   Identify the alcohol-related factors associated with increased HIV
    infectivity, such as viral shedding, the alteration of HIV variants
    through such processes as epigenetics, and the potential effect of
    alcohol on metabolism of anti-HIV medications.

-   As AIDs patients' life expectancy has increased since the
    introduction of HAART medications, the causes of AIDs mortality has
    changed with liver disease becoming more prominent. As alcohol is
    also a toxic agent for liver and other organs, identify how alcohol
    further contributes to organ and tissue damage in HIV-infected
    individuals. Follow infected individuals longitudinally using
    various tests for organ damage (e.g., neuropathology using MRI) to
    determine the relative role of alcohol consumption pattern (and
    amount) and anti-retroviral drugs on disease progression, and
    morbidity/mortality from opportunistic diseases

-   Determine the implications of alcohol and AIDS basic science
    discoveries for prevention and treatment research.

    **Treatment and Behavioral Change**

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-   Identify biological factors and contextual social factors that
    contribute to the decisional process to change drinking behavior as
    part of the transitional process from alcohol dependence to
    recovery, and the factors underlying sustained recovery among those
    individuals who succeed in both the presence and absence of
    professional treatment.

-   Increase understanding of the role of social context (marital or
    other partners, friendship and kin networks, employment
    environments, legal and economic environment, e.g.) in promoting or
    retarding positive change in drinking behavior.

-   Apply new technologies in neuroscience research to understand how
    acute as well as chronic alcohol use affects neural circuits and how
    neural circuits are modified by treatment and recovery.

-   Apply insights and methods developed in neuroscience, immunology,
    oncology, sociology, genomics, metabolomics and other fields to
    study change in drinking behavior.

    **Medications Development**

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-   Identify new target sites in the brain for which lead compounds
    could be developed.

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-   Develop animal models that more closely reflect the human endo- and
    intermediate phenotype underlying the clinical syndrome phenotype.

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-   Develop paradigms that model surrogate outcomes for alcoholism
    treatment using human laboratory paradigms.

-   Identify characteristics of patients that predict efficacy and
    safety of different medications using pharmacogenetic research
    approaches.

-   Continue research targeted to the prevention and treatment of
    alcohol-related organ pathologies involving anti-oxidant agents, and
    cannabinoid-related agents.

-   Develop collaborative networks among government, academia, and
    industry to overcome the challenges in development of medications to
    treat alcohol problems.

-   Continue research targeted to the prevention and treatment of
    alcohol-related organ pathologies involving anti-oxidant agents, and
    cannabinoid related agents.

    **Outreach: Midlife**

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-   NIAAA has working relationships with many organizations whose
    missions and goals are to help move research results to practice and
    to the public. The NIAAA collaborates with these organizations in
    symposia, workshops and meetings and provides support in the
    distribution of alcohol research knowledge.

-   NIAAA partners with the School of Medicine at Howard University to
    mentor pre-doctoral students in research, seminars, examinations and
    short-term rotations. This partnership allows NIAAA: to explore
    mechanisms and develop hypotheses for alleviating health disparities
    in alcohol related problems; provide education and information to
    the community and to health care providers; increase the
    participation of minorities in research studies at NIAAA and Howard
    University.

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-   Use state-of-the-art communication strategies and techniques to
    increase awareness of critical alcohol and health messages,
    including that: research-based treatments improve the health and
    well-being of individuals with alcohol problems; research promises
    to further elucidate mechanisms of alcohol damage and lead to
    targeted interventions.

-   Partnering with the Office of AIDS Research to continue
    identification of the most prevalent research areas involving an
    interaction between HIV/AIDS and alcohol consumption.

-   Helping Patients Who Drink Too Much: A Clinician's Guide. This
    practical guide to aid physicians and other health care providers in
    the care of patients with alcohol use disorders, the *Guide*
    presents a user-friendly, research-based approach to screening,
    diagnosing, and managing patients with heavy drinking and alcohol
    use disorders. The 2005 version of the *Guide* was updated in 2007
    and offers the following new resources: CME/CE credits for
    physicians and nurses available through Medscape; support for
    medication-based therapy in non-specialty settings; a new handout
    with strategies to help patients cut down on drinking or quit; a new
    dedicated Web page devoted to the *Guide* and supporting resources
    for clinicians and patients
    ([[www.niaaa.nih.gov/guide]{.underline}](../www.niaaa.nih.gov/guide));
    and an updated PowerPoint presentation for educators and
    instructors. NIAAA has worked closely with several organizations to
    disseminate the *Guide* to their memberships including the American
    Medical Association, the American Society of Addiction Medicine, the
    Association for Medical Education and Research in Substance Abuse,
    and the American Academy of Addiction Professionals. In addition,
    copies were sent to the deans of schools of medicine and schools of
    nursing. The *Guide* and related products are also available in
    Spanish. Copies of the Guide are available from NIAAA, and responses
    to the *Guide* have been highly favorable. Of note, thousands of
    physicians and nurses have completed the online CME course.

-   ADDICTION, an HBO documentary: NIAAA along with the National
    Institute on Drug Abuse (NIDA) collaborated with HBO to create a
    90-minute documentary, ADDICTION, which aired on March 15, 2007. One
    of NIAAA\'s key scientific staff, Mark Willenbring, M.D., was one of
    several principal spokespersons for the documentary and was featured
    in a supplementary broadcast on treatment advances. Several NIAAA
    grantees appeared in the documentary. A general-audience HBO book
    accompanied the video.

-   *A Social Work Education Model for the Prevention and Treatment of
    Alcohol Use Disorders.* This comprehensive curriculum is directed
    towards social work educators who prepare professional to practice
    in a variety of settings where they have the opportunity to improve
    outcomes for their clients who either have an alcohol disorder
    diagnosis or are at risk for developing one. Lecture ready modules
    developed by NIAAA-funded alcohol investigators, social work
    researchers, and social work educators support MSW education.
    Materials include Powerpoint presentations, handout materials,
    classroom activities, and accompanying case examples and can be
    found at <http://pubs.niaaa.nih.gov/publications/Social/main.html>
    Modules can be used individually or as a series, and modified to fit
    specific teaching objectives. The curriculum covers current alcohol
    research in epidemiology etiology, prevention, screening,
    assessment, intervention, motivational interviewing, legal and
    ethical issues, coordinated care systems, intimate partner violence,
    adolescence, women, older adults, homelessness, comorbidity, sexual
    orientation, refugees and immigrants, ethnicity, disability, and
    fetal exposure to alcohol. An evaluation of the curriculum, using a
    random sample drawn from every MSW program in the country is
    currently underway and will be completed in 2008. Preliminary
    results have been presented at the Council for Social Work Education
    annual meeting, the Society for Social Work Research, and the
    Research Society on Alcoholism.

-   *Curriculum for BSW Nursing Education.* A curriculum is currently
    under development that is aimed at undergraduate nursing faculty.
    Similar to the Social Work curriculum, it will contain modules that
    can be used as a series or individually, in order to fit specific
    teaching objectives throughout the nursing curriculum. It is being
    written and edited by nursing researchers, nursing educators, and
    experts in addiction nursing. The goal of the curriculum is to
    educate practitioners who will work in a broad array of nursing
    settings, [not]{.underline} addiction specialists. Modules include
    topics in alcohol genetics, prevention and health promotion, the
    neurobiology of addictions, alcohol screening, treatment of high
    risk alcohol use, management of intoxication and withdrawal,
    assessment and treatment of DSM-IV alcohol use disorders, health
    consequences of alcohol use, and legal and ethical issues. In
    addition to the full curriculum which will be available on the NIAAA
    website, an interactive distance learning course is planned. A pilot
    test of the curriculum is scheduled to take place at Howard
    University School of Nursing September 10-11, 2007. An evaluation of
    the curriculum is planned for 2008-2010.

**Opportunities: Senior Adult**

Aging is associated with a variety of changes that place senior adults
at special risk for alcohol-related health problems.  Senior adults are
known to differ in their physiological and behavioral responses to
alcohol in a variety of social contexts, and their ability to develop
tolerance to alcohol is greatly altered during the senior years.
Drinking can aggravate a variety of pathological conditions in the
senior adult including stroke, hypertension, neurodegeneration, memory
loss, mood disorders, and cognitive or emotional dysfunction.  As the
percentage of persons in the senior age category is rapidly growing in
the United States, improving knowledge about the effects of alcohol at
this life stage is becoming increasingly important.

-   Use current technologies of genomics, proteomics, and metabolomics
    to achieve a more detailed understanding of alcohol metabolic
    pharmacokinetics in senior adults.

-   Focus on the effectiveness of emerging medications used to treat
    AUDs in the senior adult population, given the nature of potential
    drug interactions with medications typically prescribed in this
    specific population.

-   Through collaborative efforts across the NIH, conduct longitudinal
    research to assess the use, impact, and consequences of alcohol upon
    the aging population and the development of such disorders as
    Alzheimer's disease, Type II diabetes, and other health problems
    that increase with age.

-   Through animal models of aging and alcohol use, examine the specific
    contributions of alcohol to aging organ pathology (e.g., brain,
    liver, pancreas, heart).

    **Outreach: Senior Adult**

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-   Working with the NIA, Association for the Advancement of Retired
    Persons (AARP) and Medicare, NIAAA will increase the transfer of
    information to practice for seniors through publications and
    assuring that health care providers have appropriate information.
    Co-sponsorship of meetings and conferences will be used to foster
    working relationships.

**CHAPTER I. OVERVIEW**

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 for U.S. research on
alcohol abuse, alcoholism, and other health effects of alcohol. Its role
is enunciated in the Institute Mission Statement:

**A. Mission and Vision of NIAAA**

The **NIAAA Mission** is to provide leadership in the national effort to
reduce alcohol-related problems by:

-   Conducting and supporting research in a wide range of scientific
    areas including genetics, neuroscience, epidemiology, health risks
    and benefits of alcohol consumption, prevention, and treatment

-   Coordinating and collaborating with other research institutes and
    Federal Programs on alcohol-related issues

-   Collaborating with international, national, state, and local
    institutions, organizations, agencies, and programs engaged in
    alcohol-related work

-   Translating and disseminating research findings to health care
    providers, researchers, policymakers, and the public

The Institute's efforts to fulfill its mission are guided by the **NIAAA
Vision** to support and promote, through research and education, the
best science on alcohol and health for the benefit of all by:

-   Increasing the understanding of normal and abnormal biological
    functions and behavior relating to alcohol use

-   Improving the diagnosis, prevention, and treatment of alcohol use
    disorders

-   Enhancing quality health care

This document, the *NIAAA **Strategic Plan** for Research, 2009-2014*,
sets forth research opportunities to increase our understanding of why,
how, and when people drink, as well as why and how some people develop
alcohol use disorders (AUD). Throughout the years, investigators have
pursued answers to these very questions through studies of alcohol's
effects on biological systems, the genetic factors underlying biology,
and through the study of environmental and cultural factors. This Plan,
however, proposes a significantly different direction for alcohol
studies by applying the lifespan perspective \-- the consideration of
how the emergence and progression of drinking behavior is influenced by
multiple changes (in biology, psychology, and in exposure to social and
environmental inputs) over a person's lifetime. These changes occurring
throughout the lifespan affect the pattern of drinking (quantity and
frequency) and the actions individuals may take to modify their drinking
behavior or to seek help for an alcohol use disorder. Viewing alcohol
use and alcohol problems through a lifespan perspective will provide
knowledge that will, through early identification and intervention,
significantly contribute to the ability to decrease the prevalence of
alcoholism and other alcohol-related disorders, and to the treatment of
these disorders.

This overview describes the origins of the lifespan perspective,
highlights the complexity of alcohol issues in health, and provides a
view to why solutions to these problems cannot be approached from any
single discipline but must be approached in a multidisciplinary and
transdisciplinary manner. Further, the findings at any investigative
level (molecular, cellular, animal model, human laboratory, human
clinical to community) must be translated to other levels and eventually
to clinical practice in the world environment. Transdisciplinary and
translational research over the course of the next decade will be aided
by the intellectual and technical developments arising from the NIH
Roadmap and the NIH Neuroscience Blueprint, and their potential
application to address health issues related to alcohol use has been
integrated into this Plan.

**B. Drinking Patterns and their Definitions**

An understanding of the drinking patterns that exist in the population,
as well as the alcohol-use disorders that arise from drinking *too much,
too fast and/or too often,* is important for identifying targets for
future research pursuits.

*Alcohol Abuse* and *Alcohol Dependence* are two clinical disorders
characterized by either a persistent pattern of inappropriate alcohol
use or of adverse consequences. *Alcohol dependence* is typically
considered to be synonymous with *alcoholism*. *Alcohol abuse* and
*alcohol dependence* may be defined as shown in Tables I-1 and I-2. A
proposal has recently been made to use the term addiction to specify the
behavioral, CNS neuroadaptive responses to chronic alcohol exposure vis
a vis loss of control, preoccupation with drinking and compulsion to
drink, as distinct from the physiological dependence symptoms of
tolerance and withdrawal.

**Table I-1. Harmful or Hazardous Alcohol Use (Alcohol Abuse)**

**Table I-2. Alcohol Dependence (Alcoholism)**

While recurrent or persistent harmful or hazardous alcohol use results
in adverse consequences in the long-term situation, adverse consequences
can occur in individuals who may have used alcohol in a harmful or
hazardous manner on only one occasion. These adverse consequences
include alcohol-related traffic crashes, drownings, and alcohol
poisonings, among many others.

Drinking in a manner that will cause intoxication clearly poses risks to
the drinker. A term frequently used to describe this pattern is *binge
drinking.* Different definitions often have been used for this pattern
of drinking. To provide clarification, the National Advisory Council on
Alcohol Abuse and Alcoholism (NAC) in 2004 developed a standard
definition for *binge* drinking as a pattern of drinking alcohol that
brings the blood alcohol concentration to 0.08 gram percent (the legal
limit for drinking and driving in all states) or above. The NAC further
noted that for a typical adult male, this BAC level may be obtained
after the consumption of 5 drinks in a 2 hour period, and for females, 4
drinks in the same period. The Council definition of binge drinking and
recommendations are provided in Table I-3.

**Table I-3. Definition of Binge Drinking**

**Source: NIAAA, National Advisory Council, February, 2004**

Binge drinking is common across most life stages. Fifty percent of
college students who drink engage in binge drinking, and twenty percent
do so twice or more every three weeks. More than two-thirds of binge
drinking episodes in the U.S. occur among adults age 26 and older, and
half of all binge drinking episodes occur among people who otherwise
drink moderately.

The NIAAA also provided a definition of moderate drinking as this term
has been used in many different ways. Moderate drinking is defined by
the NIAAA as consuming up to two drinks per day for men and one drink
per day for either women or senior adults. While moderate drinking is
considered to offer some benefits to some individuals, drinking at this
level poses real risks for others. For example, women who are pregnant
or considering pregnancy, persons driving or operating heavy machinery,
and those taking one or more of the more than 150 medications that
interact with alcohol should not drink even moderately. Persons with a
high vulnerability to develop alcohol dependence may be encouraged to
refrain from alcohol use.

The National Epidemiological Survey on Alcohol and Related Conditions
(NESARC) study completed its first wave of data collection, which
involved recording the responses to questions posed to over 43,000
individuals about alcohol and other drug use, abuse and dependence, and
their associated disabilities. These data were used to develop extremely
valuable information relating quantity and frequency of alcohol use to
the risk of developing alcohol abuse and alcoholism. These data have
been used to establish the following cut points for *risk drinking*,
which mirrors the definition for moderate drinking*:* Exceeding 2 drinks
per day for men, 1 drink for women, and 14 drinks per week for men and 7
drinks per week for women. The NESARC data revealed that, compared with
individuals who adhere to the weekly and daily limits, those who exceed
only the weekly limits have an 8-fold increase in risk for developing
alcohol abuse and a 12-fold increase in risk for becoming alcohol
dependent at some point in their lives (Table I-4). Exceeding daily
limits once a week or more increases risk for alcohol abuse by 30-fold,
and for dependence by 80-fold. Exceeding both weekly and daily limits
increases the risk of alcohol dependence by more than 200-fold.

**Table I-4. U.S. Adult Drinking Patterns and Risks 2001-2002: Odds
Ratios**

+------------------------------+-------------+-----------+------------+
| ***Alcohol screening limits  |             | ***An     |            |
| -- number of drinks:***      |             | Ind       |            |
|                              |             | ividual's |            |
| ***In a typical WEEK−14      |             | Odds of   |            |
| (men), 7 (women)***          |             | Having An |            |
|                              |             | Alcohol   |            |
| ***On any DAY−4 (men), 3     |             | Use       |            |
| (women)***                   |             | Disorder  |            |
|                              |             | Are       |            |
|                              |             | Increased |            |
|                              |             | by a      |            |
|                              |             | Factor    |            |
|                              |             | of:***    |            |
+------------------------------+-------------+-----------+------------+
| **Drinking Pattern**         | **Percent   | **Abuse** | **De       |
|                              | of U.S.     |           | pendence** |
|                              | adults aged | *without  |            |
|                              | 18+**       | de        | *with or   |
|                              |             | pendence* | without    |
|                              |             |           | Abuse*     |
+------------------------------+-------------+-----------+------------+
| **Never** exceeds the weekly | 72%         | Reference | Reference  |
| or daily screening limits    |             | Group     | Group      |
|                              |             |           |            |
|                              |             | (1.0)     | (1.0)      |
+------------------------------+-------------+-----------+------------+
| Exceeds **only** the         | 2%          | 7.8       | 12.4       |
| **weekly** limits            |             |           |            |
+------------------------------+-------------+-----------+------------+
| Exceeds **only the daily**   | 14%         | 17.0      | 33.0       |
| limit **less than once a     |             |           |            |
| week**                       |             |           |            |
+------------------------------+-------------+-----------+------------+
| Exceeds **only the daily**   | 2%          | 31.1      | 82.0       |
| limit **once a week or       |             |           |            |
| more**                       |             |           |            |
+------------------------------+-------------+-----------+------------+
| Exceeds **both weekly** and  | 10%         | 31.1      | 219.4      |
| **daily** limits **once a    |             |           |            |
| week or more**               |             |           |            |
+------------------------------+-------------+-----------+------------+

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: NIAAA 2001-2002 NESARC data**

**C. Prevalence of Alcohol Problems and Their Consequences**

How extensive are the health problems arising from inappropriate alcohol
use and what are those problems? Excessive, long-term alcohol
consumption can cause a variety of adverse health effects, including
alcoholic liver disease, alcoholic pancreatitis, brain damage, and
cardiomyopathy and compromised immune and endocrine functions. Excessive
drinking is also associated with an increased risk for cancers of the
esophagus, liver, and larynx, irregular heartbeats, and can exacerbate
the health consequences of infection with hepatitis C, HIV and other
infectious agents. Alcohol consumption can also alter neuronal function,
resulting in cognitive deficits, and in neuroadaptations that contribute
to the behavioral changes observed with alcoholism (tolerance,
sensitization, loss of control, dependence, withdrawal, and relapse).

Epidemiologic data inform us of the problems associated with alcohol
consumption and, when collected over time, allow us to track our
progress in addressing these problems. 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 alcohol
misuse. 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. The extent of the alcohol use disorders
problem in the U.S. and worldwide is summarized in Table I-5.

**Table I-5. Extent of the Alcohol Use Disorder Problem**

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: World Health Organization, 2003**

Alcohol also contributes significantly to mortality from a wide-range of
acute and chronic injuries and diseases (see Table I-6). In the U.S. in
2001, 75,766 deaths were attributable to alcohol, 40,933 deaths were
attributable to acute conditions primarily unintentional injuries such
as motor vehicle injuries, and fall injuries, and intentional injuries
such as homicide and suicide, and 34,883 deaths were attributable to
chronic conditions especially alcoholic liver disease and liver
cirrhosis. Because alcohol attributable deaths resulting from acute
conditions occur earlier in the life span than chronic alcohol
attributable deaths, they account for nearly twice as many years of
productive life lost (e.g., 1,491,317) compared with chronic alcohol
attributable deaths (e.g., 788,005). Recently, the NIAAA Extramural
Advisory Board (EAB; a working sub-group of the NIAAA National Advisory
Council) recommended that researchers could improve the estimation of
alcohol-attributable factors (AAF) for morbidity and mortality by better
characterizing the relationship between patterns of drinking (e.g.,
binge-drinking) and a variety of outcomes, and by incorporating relevant
indicators of drinking (e.g., medical examiner data).

Injuries are the leading cause of death in the U.S. from ages 1-44, and
alcohol is the leading contributor to those injury deaths. It should be
noted that many people who die from alcohol attributable injury deaths
are persons other than the drinker. For example, 40% of people who die
in crashes involving drinking drivers are persons other than the
drinking driver e.g. passengers in the same vehicle, passengers in
vehicles struck by the drinking driver, bicyclists and pedestrians.
Further, many homicide victims are fatally injured by persons who had
been drinking. This underscores the need to identify, through rigorous
research programs, policies that protect individuals from their own
excessive drinking, as well as from the potential harms excessive
drinking may cause society. One manner in which to get some indication
of how policies affect excessive alcohol consumption leading to harm
would be to undertake systematic studies of key alcohol and other
relevant public policies and their outcomes (Recommendation of the NIAAA
EAB, August 2006).

**Table I-6. Number of deaths and years of potential life lost (YPLLs)
attributable to the harmful effects of excessive alcohol use for
selected conditions, by cause and sex -- United States, 2001**

  -------------------------- ------------ ------------ ------------ --------------- ------------- ---------------
                             **Deaths**                             **YPLLS**                     

  **Cause**                  **Male**     **Female**   **Total**    **Male**        **Female**    **Total**

  **CHRONIC CONDITIONS**                                                                          

  Acute pancreatitis         370          364          734          7,138           6,054         13,192

  Acute cardiomyopathy       443          56           499          10,195          1,552         11,747

  Alcohol-induced chronic    224          71           295          6,209           2,135         8,344
  pancreatitis                                                                                    

  Alcoholic liver disease    8,927        3,274        12,201       221,369         94,952        316,321

  Chronic pancreatitis       126          106          232          2,606           1,952         4,560

  Esophageal cancer          394          53           447          6,213           788           7,000

  Liver cancer               518          172          690          8,640           2,633         11,273

  Liver cirrhosis,           3,917        2,802        6,719        80,616          54,528        135,144
  unspecified                                                                                     

  Oropharyngeal cancer       303          57           360          5,280           889           6,169

  **TOTAL CHRONIC            24,448       10,285       **34,883**   549,396         239,619       **788,005**
  CONDITIONS**                                                                                    

  **ACUTE CONDITIONS**                                                                            

  Alcohol poisoning          253          78           331          8,798           2,952         11,750

  Homicide                   5,963        1,692        7,655        262,379         71,543        333,922

  Motor Vehicle              10,674       3,000        13,674       442,943         136,558       579,501

  Suicide                    5,617        1,352        6,969        186,568         49,297        235,865

  Falls                      2,500        2,206        4,766        41,627          24,288        65,914

  **TOTAL ACUTE CONDITIONS** 30,309       10,534       **40,933**   1,131,028       350,289       **1,491,397**

  **TOTAL---ALL CAUSE**      **54,947**   **20,918**   **75,766**   **1,679,414**   **599,908**   **2,279,322**
  -------------------------- ------------ ------------ ------------ --------------- ------------- ---------------

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: Adapted from the table in Alcohol-Attributable Deaths and
Years of Potential Life Lost \-\-- United States, 2001 MMWR September
24, 2004, 53;866-870**.

**Co-Morbid Conditions**

In addition to the many adverse health effects that result directly from
alcohol misuse, co-morbid conditions often present further complications
for individuals with alcohol abuse problems. Alcohol abuse and
dependence commonly occur in individuals who suffer from mood, anxiety,
and personality disorders as well as the effects of other drugs of
abuse, (see Table I-7). For example, an estimated 90% of cocaine addicts
have alcohol problems. It also has been estimated that as many as 60% of
patients presenting at community mental health centers have co-morbid
alcohol and other drug abuse disorders. Patients suffering from both
disorders often have poorer treatment outcomes and are more likely to
drop out of treatment. Unfortunately, effective pharmacological and
behavioral treatments have yet to be established for the various
conditions of co-morbid AUD and other drug abuse disorders.

The high co-morbidity between alcohol and tobacco dependence poses
special problems. Fifty to ninety percent of alcoholics smoke, a rate
that is three times higher than among the population as a whole.
Alcoholics smoke heavily, are more addicted to nicotine and are less
successful at quitting smoking, which puts them at a greatly increased
risk for the synergistic effects of alcohol and nicotine on the
development of certain cancers and cardiovascular diseases. According to
one study, more individuals with alcoholism die from smoking-related
diseases than alcohol-related diseases. Furthermore, there is
experimental evidence that smoking may lead to a reduction in blood
alcohol concentration for a given amount of alcohol consumed, thus
leading to an increased use of alcohol to achieve the same pleasurable
feelings from alcohol ingestion. Thus, smoking increases the amount of
alcohol consumed and subsequently the risks for short-term and long-term
adverse effects from the increased consumption of alcohol, including the
perpetual cycle of use leading to dependence on both substances.
Finally, there is evidence to suggest that the brain pathways that
underlie the pleasurable feelings derived from alcohol consumption and
smoking are thought to be the same, thus accounting for the increase in
use of both substances, which suggests that treatment programs to reduce
or cease alcohol consumption should also address cessation of smoking.
There are some data indicating that treating one use disorder without
treating the other concurrently leads to a higher relapse rate for
either substance.

**Table I-7. Odds of Current (past 12-month) DSM-IV Alcohol Dependence
Co-Occurring with Selected Psychiatric Conditions and Other Drug
Dependencies**

  ----------------------------------------------------- -----------------
  **Disorder**                                          **Odds**

  Anxiety Disorders                                     2.6x

  Mood Disorders (especially Major Depression)          4.1x

  Personality Disorders                                 4.0x

  Antisocial Personality Disorder                       7.1x

  **Drug Dependence**                                   **36.9x**

  Nicotine Dependence                                   6.4x
  ----------------------------------------------------- -----------------

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: NIAAA 2001-2002 NESARC data**

**Contributions to Alcohol Use and Alcohol Problems Across the
Lifespan**

The initiation and continuation of alcohol use by an individual is
influenced by numerous factors, chiefly the individual's genetic makeup,
the environments to which he or she is exposed, and complex mechanisms
through which 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)
or other alcohol use disorders.

More than three decades of research has firmly established that genes
account for more than half of the risk for alcoholism and environmental
factors account for the remainder. This statement, however, belies the
true complexity of the mechanisms underlying the risk for, and
protection against, alcohol abuse and alcohol dependence. As with many
other complex diseases, there is no single genetic or environmental
factor that can fully account for the risk of alcoholism. The
development of such complex behavioral and other medical disorders
likely depends upon the specific genetic factors interacting with one
another, the interaction of multiple environmental risk factors, and the
interaction of genetic and environmental factors.

Research has also revealed that neither genetic nor environmental
factors are static. That is, the emergence and progression of drinking
behavior and of drinking consequences is influenced by multiple ongoing
changes in biology, physiological and psychological development, and
environment that occur over the course of a person's life. These
observations are in accord with a broader recognition that human
development continues throughout life, rather than stopping after
adulthood is reached. A full understanding of the development of
drinking behaviors and disorders, therefore, requires a lifespan
context, in which the central concept is that the influence of alcohol
on biology and behavior is dynamic and changes as an individual moves
from childhood into adolescence and through the various stages of
adulthood. This conceptual framework is depicted schematically in Figure
I-1.

**Figure I-1. Alcohol Across the Lifespan**

![](media/image5.wmf){width="6.371527777777778in"
height="4.063888888888889in"}

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**Source: Figure created by Brenda Hewitt.**

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 indicated that
persons who begin drinking at younger ages have a significantly
increased risk for the development of alcoholism. This finding was
replicated in the recent NESARC study, as shown in Figure I-2. These
data show that young people who begin drinking before age 15 were four
times more likely to develop alcohol dependence during their lifetime
than those who begin drinking at age 21. This is true for individuals
from families where a parent had a history of alcoholism (Parental
History Positive) and for individuals with no parental history of
alcoholism (Parental History Negative). 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 the eventual
development of alcoholism.

**Figure I-2. Prevalence of Lifetime Alcohol Dependence by Age of First
Alcohol Use and Parental History of Alcoholism**

![](media/image6.wmf){width="5.55in" height="2.6881944444444446in"}

**Source: NIAAA 1991-1992 NLAES data (left panel) and NIAAA 2001-2002
NESARC data (right panel)**

What is the mechanism by which exposure to alcohol in youth or
adolescence increases the risk for alcoholism? Early exposure to alcohol
may alter neurodevelopment through one or more mechanisms to cause
increased vulnerability to alcohol dependence. Alternatively, it is
possible that some other biological factor, perhaps affecting
personality, is responsible for both the early onset of drinking and the
heightened risk for alcoholism. As research continues, new findings will
help to establish how, and the extent to which each of these two
potential mechanisms contribute to the development of alcohol problems.
That knowledge will arise from research on brain development in general,
as well as from research directed specifically to alcohol-related
issues. For example, research on human brain development has revealed
that the brain continues to develop through adolescence and into young
adulthood. Research also has shown that adolescents in treatment for
alcohol dependence have reductions in the size of a brain region known
as the hippocampus. Taken together, these two findings provide support
for the hypothesis that early alcohol exposure perturbs and thereby
alters early brain development which contributes to later
vulnerabilities for alcoholism and other disorders.

What is the prevalence of alcohol problems in other phases across the
lifespan? As Table I-8 shows, the prevalence of alcohol abuse and
alcohol dependence within the past year varies with age. The highest
previous year prevalence of alcohol dependence is found among the young
adult population (defined as 18-29 years of age), particularly between
the ages of 18 through 24. As has been noted, problems with alcohol use
disorders are also very significant in the adolescent population, aged
12-17 years (further discussed in Chapter IV). From its peak in the
young adult years, the prevalence of past year alcohol dependence
declines with increasing age (adolescence, young adult, midlife defined
as 30-59 years of age, and senior), falling below one percent among
senior adults (defined as 60 years of age and older). According to these
data, at any time point, the percentage of individuals who received
treatment for their alcohol use disorder is quite small relative the
numbers experiencing alcohol problems (also see Figure I-5).

**Table I-8. Percentage of U.S. Adults 18 and Over with Past-year
Alcohol Abuse or Dependence and Percentage of Those with Past-year Abuse
or Dependence Who Received Alcohol Treatment, by Type of Treatment**

+----------------+------+----------+---------+-------+------+---------+
| **Age group**  | **P  |          | **Type  |       |      |         |
|                | ast- |          | of      |       |      |         |
|                | year |          | trea    |       |      |         |
|                | di   |          | tment** |       |      |         |
|                | sord |          |         |       |      |         |
|                | er** |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
|                | *    | **Depe   | **Any** | *     | *    | **12    |
|                | *Abu | ndence** |         | *12-S | *Oth | -Step** |
|                | se** |          | **trea  | tep** | er** |         |
|                |      |          | tment** |       |      | **and   |
|                |      |          |         | **o   | **on | Other** |
|                |      |          |         | nly** | ly** |         |
+----------------+------+----------+---------+-------+------+---------+
| All ages       | 4.7  | 3.8      | 7.1     | 1.1   | 2.7  | 3.4     |
+----------------+------+----------+---------+-------+------+---------+
|                |      |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
| Young Adult    | 7.0  | 9.2      | 5.9     | 1.3   | 2.3  | 2.3     |
| (18-29)        |      |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
| 18-24          | 6.7  | 11.6     | 6.4     | 1.4   | 2.8  | 2.2     |
+----------------+------+----------+---------+-------+------+---------+
| 25-29          | 7.3  | 5.7      | 4.9     | 1.0   | 1.2  | 2.7     |
+----------------+------+----------+---------+-------+------+---------+
|                |      |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
| Midlife        | 5.0  | 3.0      | 8.5     | 0.8   | 3.1  | 4.5     |
| (30-59)        |      |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
| 30-44          | 6.0  | 3.8      | 8.9     | 0.7   | 3.2  | 5.0     |
+----------------+------+----------+---------+-------+------+---------+
| 45-59          | 3.9  | 2.0      | 7.5     | 1.0   | 3.0  | 3.5     |
+----------------+------+----------+---------+-------+------+---------+
|                |      |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
| Senior (60+)   | 1.4  | 0.5      | 3.4     | 1.9   | 0.8  | 0.6     |
+----------------+------+----------+---------+-------+------+---------+

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: NIAAA 2001-2002 NESARC data**

Figure I-3 looks at the history of alcohol abuse and alcohol dependence
from a cumulative life-time perspective. The figure shows the cumulative
conditional probability that an individual at a given age would have at
some point in their life met the diagnostic criteria for DSM-IV alcohol
abuse or dependence. As seen from the figure, by age 30 these
probabilities were 10% and 17% respectively for dependence and abuse. By
age 60 they are 14% and 20% respectively.

**Figure I-3. Cumulative Probability of Onset of DSM-IV Alcohol Abuse or
Alcohol Dependence by Age**

![](media/image7.png){width="4.999305555555556in"
height="2.5006944444444446in"}

**Source: Substance Abuse and Mental Health Services Administration
(SAMHSA) 2002 National Survey on Drug Use and Health (NSDUH) data (ages
12-17) and NIAAA 2001-2002 NESARC data (ages 18-60+)**

**Alcohol-Related Policy and Public Health Outcome**

A wide range of public policies may affect alcohol consumption and other
behaviors relating to alcohol, and therefore can have important
influences on public health outcomes. In the United States, laws,
regulations, and jurisprudence address (1) alcoholic beverage
production, packaging, transportation, marketing, taxation, sales, and
consumption, (2) financing and delivery of alcohol-related treatment and
preventive services, and (3) behaviors that may be affected by alcohol,
such as driving and boating. In many of these topic areas, policies are
established by governments at all levels (Federal, State, county, and
municipal).

Scientific research has identified a number of alcohol-related policies
that have significant effects on public health outcomes. Among the
policies with the best evidence of effectiveness is the minimum legal
drinking age of 21, which has been shown to reduce consumption and
traffic crash deaths among youth 16-21. This policy may also have other
benefits, as studies have shown that deferring the initiation of
drinking reduces both the risk and severity of subsequent alcohol use
disorders. Although every state now sets the minimum age for possession
and purchase of alcoholic beverages at 21, there is still substantial
variation in states' policies toward underage drinking. Many states
afford significant exceptions to the laws against possession and
consumption (e.g., except for in a private residence, or only in a
public place).

Policies addressing drinking and driving have been shown to reduce
traffic fatalities. Every State has now established a law against
driving with a blood alcohol concentration (BAC) of .08 or above. All
States have also adopted so-called "zero tolerance" laws that set BAC
limits for drivers under the age of 21 at no more than .02 percent.
These laws, combined with a variety of other policies designed to deter
driving after drinking, have helped reduce rates of alcohol-related
traffic fatalities in the United States by 50% since 1982.

Alcoholic beverage taxes are another policy for which there is strong
evidence of effectiveness. Although tax rates are most often established
for fiscal rather than public health purposes, a number of studies have
found significant relationships between higher taxes on alcoholic
beverages and lower rates of traffic crash fatalities or drunk driving,
particularly among younger drivers or during nighttime hours. Other
research has found associations between higher alcoholic beverage taxes
and lower rates of some types of violent crime, reduced incidence of
physical child abuse committed by women, and lower rates of sexually
transmitted diseases and liver cirrhosis mortality, as well as with
increases in college graduation rates.

Public policies affecting the delivery and financing of alcohol-related
treatment and preventive services may have important effects on access
to treatment services. Most states now require health insurers to cover
treatment for alcoholism, and a number of other states require such
coverage to be offered but not necessarily included in every insurance
contract. However, no Federal laws require coverage for alcoholism
treatment, and Federal law exempts many large employers from state laws
with such requirements. As a result, many insurance policies may not
include coverage for alcoholism treatment.

Many states have laws, known as "Uniform Accident and Sickness Policy
Provision Laws," or UPPL, that permit health insurers to deny payment
for losses that are the result of the insured person being intoxicated.
Researchers have suggested that these policies create a disincentive for
health care providers in emergency and primary care settings to screen
for alcohol problems, with the result that fewer individuals in need of
treatment for alcohol problems are referred to treatment just when such
referrals might be most effective. While studies have not yet
established the true effects of UPPL provisions on treatment referrals,
a few states have recently enacted laws that prohibit exclusion of
insurance benefits on the basis of intoxication.

Because of the complexity of alcohol-related public policies,
researchers face a challenge in identifying how specific policy measures
may affect health outcomes. The Alcohol Policy Information System
(APIS), developed by the National Institute on Alcohol Abuse and
Alcoholism (NIAAA), provides reliable, detailed, and comparable
information on alcohol-related public policies in the United States at
both the state and Federal levels. The APIS Web site
([http://alcoholpolicy.niaaa.nih.gov](http://alcoholpolicy.niaaa.nih.gov/))
provides public access to detailed information on a wide variety of
alcohol-related public policies. Intended primarily as a tool for
researchers, APIS features compilations and analyses of alcohol-related
statutes and regulations designed to simplify the process of
ascertaining the state of the law for studies on the effects and
effectiveness of alcohol-related policies

**D. Issues that Transcend the Lifespan Perspective**

There are six issues that provide significant background perspectives
necessary for the accurate interpretation of previous results and the
formulation of research hypotheses with respect to alcohol use across
the lifespan. These issues are alcohol metabolism, alcohol and
gene/environment interactions including the expanded use of
lymphoblastoid cell lines, the neurobiology of alcohol, the diagnostic
criteria for alcohol abuse and dependence, alcohol health services
research, data collection over the lifespan, and social, legal and
ethical issues of alcohol research. They are presented in this overview
as they transcend the full lifespan.

**D.1. Alcohol Metabolism**

Individuals differ in how fast they metabolize alcohol
(pharmacokinetics) and in the extent to which they are affected by a
given dose of alcohol (pharmacodynamics). These individual differences
affect drinking behavior, the potential for the development of alcohol
dependence, and the risk for developing alcohol-induced organ damage.
These individual differences in females also contribute to the extent
that alcohol metabolism affects the fetus during development. Therefore,
understanding these differences will provide important information about
alcohol's health effects throughout the lifespan.

The major pathway for the metabolism of alcohol is found in the liver
and involves the enzyme alcohol dehydrogenase (ADH) (see Figure I-6).
Alcohol is metabolized to acetaldehyde, a highly reactive and
potentially toxic molecule. In most circumstances, acetaldehyde is
rapidly metabolized by another enzyme, aldehyde dehydrogenase (ALDH) to
acetate. Because of the rapid enzymatic conversion of acetaldehyde to
acetate, the concentration of acetaldehyde in the cell is typically a
thousand-fold lower than that of alcohol, and the eventual product of
this pathway, acetate. Both alcohol and acetate are found at millimolar
levels following drinking, while acetaldehyde is found at micromolar
concentrations. \[The legal intoxicating blood alcohol level in all
states in the U.S. is 80 mg%, which is 17.4 mM. The normal baseline
level for acetaldehyde in humans is 9 µM, or 40 µg%. After alcohol
ingestion, the acetaldehyde level in most individuals will increase to
20-30 µM, or 90 -- 130 µg%. Metabolism of a dose of alcohol achieving a
blood alcohol concentration of 80 mg% may result in elevation of tissue
acetate levels to 2mM\] When the level of acetaldehyde increases, an
individual may experience very dysphoric feelings and the potential for
toxic reactions with various cellular components increases. Men and
women differ with respect to the rate of alcohol metabolism based
primarily on differences in total water body content, and potentially
changes associated with the menstrual cycle. The extent of difference in
alcohol metabolism between pregnant and non-pregnant women is not well
studied, although it has clear implication for the amount and duration
of alcohol available to the fetus during pregnancy.

**Figure I-6. Alcohol Metabolism in the Liver**

![](media/image8.wmf){width="4.908333333333333in"
height="3.4055555555555554in"}

**Source: Figure created by Brenda Hewitt**

There are a number of variants of the ADH and ALDH enzymes, and the
differences in the profile of the variants present can influence an
individual's drinking behavior. The various functional variants of ADH
and ALDH are shown in Table I-9.

**Table I-9. Human ADH and ALDH Isozymes**

  ---------------------------- ----------- ------------------ ---------- ---------------------
                               **Class**   **Nomenclature**   **Km       **V~max~(min^-1^)**
                                                              (mM)**     

  Alcohol Dehydrogenase (ADH)  I           ADH1A              4.0        30

                                           ADH1B\*1           0.05       4

                                           ADH1B\*2           0.9        350

                                           ADH1B\*3           40.0       300

                                           ADH1C\*1           1.0        90

                                           ADH1C\*2           0.6        40

                               II          ADH4               30.0       20

                               III         ADH5               \>1000     10

                               IV          ADH7               30.0       1800

                               V           ADH6               ?          ?

  Aldehyde Dehydrogenase                   ALDH2\*1           3          0.4
  (ALDH)                                                                 

                                           ALDH2\*2           \~300      \--
  ---------------------------- ----------- ------------------ ---------- ---------------------

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: ADH: Km and V~max~ values from Hurley et al., 2002; ALDH
V~max~: Yin & Li (pp. 227-247), In Sun et al., Molecular Mechanisms of
Alcohol: Neurobiology and Metabolism, Humana Press, 1989; ALDH Km: Mizoi
et al., 1994.**

Most of the alcohol consumed by humans is metabolized by the Class I and
Class II ADH enzymes (Table I-9). While only one functional form of the
Class II ADH is known, the Class I ADHs exist in a number of polymorphic
forms, and differences in individual Class I ADHs contribute to
variation in the alcohol metabolic rate (Table I-9). Of particular
importance are the three known functional variants of *ADH1B.* The
*ADH1B\*2*, found in the majority of Asians and 25 percent of people of
Jewish ancestry, and the *ADH1B\*3*, found in some African Americans,
oxidize alcohol at a faster rate than the *ADH1B\*1* variant which
predominates in most European Americans. Two functional forms of the
*ADH1C* gene also exist (*ADH1C\*1* and *ADH1C\*2*)*.* The Class I ADH
enzymes are found primarily in the liver in the cytosol compartment of
the cell.

There are other enzyme pathways that can metabolize alcohol to
acetaldehyde, including cytochrome P450 and catalase (Figure I-7). The
cytochrome P450 isozyme CYP2E1 is the form which is predominantly
involved in alcohol oxidation. It is present in an internal cellular
structure known as the endoplasmic reticulum and particularly comes into
play after chronic, heavy, alcohol exposure. Alcohol metabolism by
CYP2E1 also produces highly reactive oxygen species (ROS) with the
potential to cause tissue damage. Unlike most Class I ADH enzymes that
are primarily found in the liver, CYP2E1 is found in a number of tissues
and organs including liver, brain, heart, lung, and the neutrophils and
macrophages of the immune system. Therefore, the generation of
acetaldehyde and ROS within these tissues poses risks for injury to
these systems. The enzyme catalase (Figure I-7), located in the
intracellular structure known as the peroxisome, is also capable of
oxidizing alcohol in the presence of a hydrogen peroxide
(H~2~O~2~)-generating system. However, catalase appears to be a minor
pathway for alcohol metabolism.

**Figure I-7. Minor Oxidative Pathways of Alcohol Metabolism**

![](media/image9.wmf){width="4.634722222222222in"
height="2.892361111111111in"}

**Source: Figure created by Dr. Ting-Kai Li and Dr. Samir Zakhari.**

The acetaldehyde that is produced from alcohol oxidation through any of
these enzyme systems is typically metabolized rapidly to acetate. ALDH
catalyzes the oxidation of many aldehydes, and under conditions of
ethanol exposure, ALDH enzymes specifically convert acetaldehyde to
acetate. Genetic polymorphisms in the ALDH genes have been linked to
decreased risk of alcoholism and increased risk of alcohol-induced
cancers. A variant of the mitochondrial aldehyde dehydrogenase enzyme
*(ALDH2\*2)* is found in about 50 percent of Taiwanese, Han Chinese, and
Japanese populations. The enzyme expressed by *ALDH2\*2* is virtually
inactive. Consequently, individuals with one, and particularly two
copies of this allele show elevations in acetaldehyde after consuming
alcohol (see Figure I-8). Individuals with both *ADH1B\*2* and
*ALDH2\*2* genes have been shown to have virtually complete protection
against developing alcoholism, presumably due to the adverse effects of
elevated acetaldehyde. This allelic combination is curiously absent in
Native American Indian populations, who have a high prevalence of
alcoholism, suggesting that other combinations of ADH and ALDH genes may
confer various forms of protection or susceptibility to alcohol use
disorders.

**Figure I-8. Blood Acetaldehyde Concentrations of Han Chinese Men with
Different ALDH2 Allelotypes (0.2 g/kg ethanol)**

![](media/image10.wmf){width="5.020833333333333in"
height="2.5076388888888888in"}

**Source: Chen et al. Interaction between the functional polymorphisms
of the alcohol-metabolism genes in protection against alcoholism. Am J
Hum Genet 65:795-807, 1999**

Most of the acetate arising from ethanol metabolism departs the liver
via the circulatory system and is eventually metabolized to carbon
dioxide (CO~2~) and water by way of the tricarboxylic acid cycle (TCA)
in heart, skeletal muscle, brain, and liver. Further, acetate itself is
not an inert product; in addition to being a metabolic source of energy,
it can increase portal blood flow in the liver, and potentially in other
organs, and contributes to the biosynthesis of adenosine which has its
own effects on cortical and coronary blood flow in response to need.

The oxidation of alcohol through ADH, and acetaldehyde through ALDH, is
accompanied by the conversion of the co-enzyme nicotinamide-adenine
dinucleotide (NAD^+^) to its reduced form NADH (Figure I-7). When
sufficiently large amounts of alcohol are consumed, alcohol metabolism
can change the reductive-oxidative state of the cell (redox state),
expressed as the ratio of NAD^+^/NADH. The change in the NAD^+^/NADH
ratio, in turn, can affect a number of metabolic pathways within the
cell. Further, the NADH generated through alcohol and acetaldehyde
oxidation is subsequently re-oxidized to NAD^+^ through the
mitochondrial electron transport chain, a process that involves the
generation of the energy intermediate ATP. Enzymes within the electron
transport chain also have the potential to generate ROS. In a cellular
environment low on antioxidant defense mechanisms (e.g., glutathione),
such as occurs after heavy alcohol exposure, these ROS have the
potential to disrupt developmental processes and to cause tissue damage.

In addition to the oxidative pathways of alcohol presented above,
alcohol can also be non-oxidatively metabolized by at least two
pathways. One leads to the formation of fatty acid ethyl esters (FAEE)
and the other to phosphatidyl-ethanol. Both oxidative and non-oxidative
pathways of alcohol metabolism are inter-related, and may result in
tissue injury throughout the lifespan.

***Opportunities for Research in Alcohol Metabolism Across the
Lifespan***

-   The field of metabolomics has increased in depth and breadth during
    the last five-year period, and there is an emerging opportunity to
    explore how changes in metabolism affect brain, other organs, and
    functional outcomes of alcohol use on all ages of individuals. The
    products of this research may further uncover the mechanisms by
    which alcohol is involved in the development of pathologies at all
    stages of the lifespan, from the fetus to the elderly, and may lead
    to the identification of biomarkers for early pathology recognition
    thus facilitating more effective intervention and treatment
    implementation.

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-   Enhance understanding of the differences in alcohol
    *pharmacokineti*cs (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.

-   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.

**D.2. Alcohol and Gene/Environment Interaction, Epigenetics, and
Cellular Phenotyping**

Neither genes nor environment alone can explain why any particular
individual develops alcohol dependence. Rather, as a complex disorder,
risk for the development of alcohol dependence will be a consequence of
the interplay of multiple genes, potentially multiple environmental
factors, and the interaction of these genes and the environmental
factors. Similarly, it is not likely that any single mechanism of
gene-environmental interaction will explain all vulnerability to alcohol
dependence. While in the past decade investigators have sought to define
both genes and environmental factors underlying risk, this effort had
been limited due to a lack of powerful technologies and methodologies
that could be applied to the genetic study of complex disorders such as
alcoholism. One manner in which NIAAA has accelerated its involvement in
exploring gene-environment interactions is through its active
participation in the NIH-wide Genes and Environment Health Initiative
(GEI: http://genesandenvironment.nih.gov/). This NIH-initiative focuses
on both genetic analyses and the development of new tools to measure
environmental exposures that affect health, such as alcohol consumption.
One focus of the genetic program of the GEI is on using advanced
technologies, such as single nucleotide polymorphisms (SNPs) and
haplotype maps, to enable scientists to identify genes associated with
alcohol-related disorders. Although a few genes, such as GABRA2, ADH,
ALDH, CHRM2, OPRM1 and NPY, have been linked to alcohol dependence and
its related disorders, it is apparent that more genes will be rapidly
identified through NIAAA's extramural programs as will as through the
GEI. Table 1-10 presents a number of candidate genes in animals and
humans. However, it is clear from the content of Table I-10 that there
are significant opportunities to advance the field with respect to
determining how these genes are functionally significant for alcohol use
disorders in both humans and various animal model systems.

**Table I-10. Genes Contributing to Alcohol-Related Behaviors in both
Rodents and Humans**

  --------------- -------------------------- ---------------------------------
  Gene            Rodent                     Human

  *a-synuclein*   QTG for alcohol preference Associated with alcohol
                  (Liang et al., PNAS 2003)  dependence (Bonsch et al., Hum
                                             Mol Genet. 2005)

  *BDNF*          BDNF levels in the NAc are Association of val66met
                  lower in P rats than NP    polymorphism with alcohol
                  rats (Yan et al., Brain    dependence and violence in males
                  Res. 2005)                 (Tsai et al., Neurosci Lett.
                                             2005)

  *NMDA NR1*      Mutant mice show           The A allele is associated with
                  attenuated alcohol effects type I alcohol dependence
                  on behavior (Kiefer et     (Wernicke et al., Biol Pyschiat.
                  al., Biol Psychiat. 2003)  2003)

  *CB1*           KO showed decreased        1359G/A polymorphism confers
                  alcohol consumption        vulnerability to alcohol
                  (Hungund et al., J         withdrawal (Schmidt et al., Drug
                  Neurochem. 2003)           Alc Dep. 2002)

  *CCK-AR*        KO showed increased        -81A/G polymorphism is associate
                  alcohol consumption        with alcohol dependence in a
                  (Miyasaka et al., Alcohol  Japanese population (Miyasaka et
                  & Alcohol 2005)            al., Alcohol & Alcohol 2004)

  *5-HTT*         Alcohol intake decreased   Associated with lower risk of
                  in KO mice (Kelai et al.,  binge drinking (Olsson et al.,
                  Alcohol Alcohol 2003)      Mol Psychiat. 2005)
  --------------- -------------------------- ---------------------------------

The search for both genetic and environmental risk factors includes both
human population genetics investigation, as well as studies involving
animal models. Specifically, selected animal strains are used to model
the endo- and intermediate phenotypes (see Table I-11) involved in the
development of human alcohol dependence. While animal models of alcohol
tolerance and alcohol preference have been developed in the past,
refinement of current models is still required in order for them to more
closely parallel those features of the clinical syndrome phenotype,
including modeling such contributing traits as anxiety, propensity for
relapse, and obsessive-compulsive behaviors such as craving.

**Table I-11. Definition of Endophenotype, Intermediate Phenotype, and
Clinical Syndrome Phenotype**

**Endophenotype**: innate or biological host factors that may predispose
an organism to alcohol dependence (e.g., temperament, gene expression,
electrophysiology, developmental biology)

**Intermediate phenotype**: host factors interact with environmental
factors to facilitate the development of alcohol dependence (e.g.,
sensitivity, tolerance, reward)

**Clinical Syndrome Phenotype**: the transition from voluntary to
nonvoluntary, obsession with and compulsion to use alcohol

**Epigenetics**

One additional route by which alcohol may affect the development of
alcohol disorders, from alcohol dependence to organ disease is through
epigenetics, which refers to stable alterations in the genome, sometimes
heritable through cell division, that do not involve permanent changes
to 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. Alcohol and its metabolites could be important environmental
factors contributing to epigenetic processes. For example, alcohol has
been shown to cause acetylation at specific histone sites in the rat
chromosome, resulting in increased expression of the ADH gene. Further,
alcohol has the ability to alter the normal biochemical pathways by
which DNA and histones might be modified in response to other events
occurring in the environment. For example, alcohol can interfere in the
metabolic pathways leading to the biosynthesis of the intermediates
required to modify DNA, by altering biosynthetic pathways involving
folate, and inhibiting the synthesis of a "methyl donor" known as
S-adenosyl methionine (see Figure VI-1 in Chapter VI).

Related to such metabolic alterations, alcohol may influence epigenetic
processes in ways opposite to that necessary for normal functioning, and
in the case of the fetus, to that required for normal development.
Epigenetic events also may contribute to the development of alcohol
tolerance and sensitization, obsessive-compulsive drinking, craving,
cognitive effects of chronic drinking and organ damage associated with
heavy drinking.

**Cellular Phenotypes/Immortalized Cell Lines**

Recent advances in rapid molecular biology techniques coupled with the
sequencing of the human genome, and the genomes from select animal model
systems, has provided the opportunity to identify the complex
relationships that inter-connect genotype and phenotype underlying the
progression 'from sequence to function.' A thorough understanding of
biological systems requires a complete assessment of not only gene-gene
interactions, but protein-protein interactions, post-translational
modifications, and metabolic effects. One approach to understanding
these complex interactions involves the phenotypic characterization of
immortalized cell lines (of known genetic background) from organ systems
of interest following the application of a manipulation, such as alcohol
exposure under conditions within the physiological range of normal and
binge human alcohol consumption. Gene targeting experiments can further
elucidate the molecular signals in temporal sequence by perturbation of
the cell line through knockdown/inactivation or over-expression of genes
in isolation combined with microarray techniques that allow expression
of phenotypic changes in the response to alcohol exposure. Recently,
NIAAA hosted a trans-NIH workshop on gene expression in immortalized
cell lines with the focus of exploring the potential utility of human
immortalized lymphoblastoid cell slines (LCLs) and establishing
standardized methods for gene by environment interaction studies using
LCLs. The recommendations from the expert panel convened for this
workshop are posted in the box to the right.

***Opportunities for Exploring Alcohol and Gene/Environment Interaction,
Epigenetics, and Cellular Phenotyping Across the Lifespan***

There are many opportunities to explore the effects of alcohol exposure
on the interaction of genes and environment across the lifespan, even
though the effects of heavy alcohol consumption may differ significantly
given the age of exposure, and with respect to alcohol's direct or
indirect effects.

-   The contribution of animal models to genetics research is limited by
    the relevance of current animal models to the actual phenotype of
    human alcohol dependence. The technologies exist to develop new
    animal strains that model both the endophenotypes (e.g.,
    electrophysiological trait risk factors) and intermediate phenotypes
    (e.g., cue response to alcohol) associated with alcohol exposure.
    New animal models may also be developed through resources emerging
    from the NIH Roadmap and the Neuroscience Blueprint including animal
    knock-out lines, knock-in lines, and transgenic animals, where
    specific pathways involved in the CNS actions of alcohol are
    altered. These lines can be subjected to genetic analysis for
    uncovering key pathways involved in the development of alcohol
    dependence.

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-   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.

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-   As new and more powerful approaches to genetic analysis emerge from
    the Human Genome Program and the NIH Roadmap, these technologies,
    including whole genome SNP and haplotype scans, new methods for
    quantitative trait gene identification, may be applied in both human
    population genetics research and on animal model studies in the
    identification of genes contributing to the risk for alcohol
    disorders.

-   Exploit the use of twin registries (e.g., identical twins discordant
    for disease) and existing cohorts of twins (e.g., Australia's
    cohort) to identify relative weight of gene/environment influence in
    developing alcohol dependence or alcohol abuse

-   The effect of alcohol on epigenetic processes typically involves
    undesirable changes in gene expression that have the potential to
    alter anatomy, function, and risk of disease at any age. For
    example, there may be direct effects of alcohol on fetal
    development, resulting in the characteristic FAS facial features, or
    the effect of alcohol on maternal gene expression at or near
    conception which may alter embryo survival or result in severe birth
    defects to the fetus. In alcohol consuming youth, the effects of
    alcohol may be to alter the expression of specific genes controlling
    the growth and maturation of organs (including brain). Adults may
    also experience the direct effects of alcohol through epigenetic
    mechanisms with consequent organ and tissue damage. The study of
    epigenetic mechanisms on phenomena across the lifespan can provide
    valuable insights into the mechanisms by which alcohol contributes
    to both the development of alcohol dependence and of other
    alcohol-related pathologies.

-   Explore the phenotypic outcome in immortalized cell lines from the
    interaction of alcohol within the typical relationship of genes,
    proteins, post-translational and metabolic events, using cell lines
    from well-characterized alcohol-consuming human populations.

**D.3. Neurobiology of Alcohol**

Since the brain is a significant target for alcohol-induced toxic
effects, and the brain undergoes development and maturation continuously
from conception to birth and into adulthood, the effects of alcohol on
neurobiology and neural processes in general are observed throughout
life. Therefore, at any point in the lifespan, alcohol consumption may
affect the normal physiology of the CNS, which makes the topic of
alcohol's detrimental effects on the brains of any age of importance for
comprehensive examination.

Alcohol has complex pharmacodynamic effects on the body, primarily
through its interactions with the brain within the central nervous
system (CNS).   Alcohol's pharmacologic effects typically begin with
mild stimulation, followed by CNS depression as shown in Figure I-9. 
Disinhibition and anxiolysis may also be experienced in the early phase
following alcohol ingestion.  As is noted in Figure I-9, as breath
alcohol concentration (BrAC) increases, the likelihood and severity of
functional impairments increases, ranging from impaired motor function
to respiratory depression and death. 

**Figure I-9. Pharmacodynamics of Ethanol on the Central Nervous
System**

![](media/image11.wmf){width="4.496527777777778in"
height="3.2583333333333333in"}

Among the physiological or behavioral consequences of chronic alcohol
use, that is, *drinking too much, too fast and/or too often*, are the
disorders of alcohol abuse, and alcohol dependence.  However, there are
other pathologic consequences to both the CNS and the peripheral nervous
system (PNS) that can arise from drinking over long periods of time. 
These usually do not clinically manifest themselves until the midlife
period. Alcohol neurotoxicity can result from heavy alcohol consumption
beginning as early as adolescence, which may be critical to
understanding why certain individuals drink excessively and what
biological factors continue to prompt them to drink. Furthermore,
alcohol neurotoxicity affects the fetus with long-term consequences.
Therefore, a discussion of alcohol's effect on the brain involves all
ages of individuals.

Alcohol's effect on the brain can have immediate, direct, and
wide-ranging ramifications, from effects on normal physiology (patterns
of sleep-wake, thermoregulation), to effects on basic motor functions
(balance, gait, coordination), to effects on thoughts and emotions
(cognition). Of particular interest are physical or chemical alterations
in the brain that may cause changes in cognition leading to a variety of
responses that manifest as, for example, the decision to start or stop
drinking alcohol or the decision to seek help for an AUD. The
adaptations that occur in the development of alcohol dependence occur
within the CNS as well. Therefore, it is important to explore the
effects of alcohol on the brain at many levels, from cellular and
molecular biology to cognitive effects, using the range of techniques
and methods of neuroscience. Some relevant research topics that may
advance the knowledge about the effects of alcohol on brain include an
examination of synaptic protein adaptation, the differential temporal
vulnerability (differences across the lifespan) of various brain regions
and neuronal cell types to long-term consequences of alcohol-induced
toxicity, changes in frontal lobe function associated with
alcohol-induced cognitive alterations, impairments of neuroimmune and
neuroendocrine function that predispose individuals to organ damage, and
neuronal plasticity. These areas can be approached from a variety of
perspectives in both clinical (human) and experimental (animal models)
settings using imaging and functional imaging, electroencephalography,
and cellular and molecular biology techniques.

***Opportunities for Examination of the Neurobiology of Alcohol Across
the Lifespan***

The central nervous system is a major target for adaptive, as well as
toxic effects of alcohol across the lifespan, e.g., alterations in
developing neurons, changes in neurotransmitter systems that alter
neuronal function. Therefore, there is a wealth of information to be
gained from researching the basics of the neurobiology of alcohol across
various ages of subjects and experimental systems.

-   Alcohol can directly affect the brain among those who drink
    excessively in terms of physical anatomy, and this has the end
    consequence of changes in function. One technical method that is
    relatively new for investigators in this field is diffusion tensor
    imaging, a form of magnetic resonance imaging (dtMRI). This
    technique allows a visual tracking of changes in white matter tracts
    in the brains of humans at any age. For example, fetal exposure to
    alcohol can result in alterations to the corpus callosum (a large
    fiber bundle connecting the two halves of the brain), while changes
    in the chemical constituents of white matter from alcohol exposure
    may accelerate the progression of white matter-specific diseases.
    Furthermore, excessive alcohol consumption in youth and young adults
    could significantly affect the *maturation* of their white matter
    ultimately leading to changes in neural circuitry (communications)
    involved in decision-making abilities and other aspects of altered
    cognitive function.

-   Alcohol also affects neurotransmitters, their receptors and
    transporters, which are involved in neural communication and in
    brain development (in fetus). Alcohol-induced depletions of specific
    neurotransmitters have been shown to affect the development of
    specific brain regions in experimental animal models, while changes
    in the levels of neurotransmitters affect global neuronal
    communication. In addition to alcohol dependence, these changes may
    contribute to the expression of disorders co-morbid with alcoholism
    such as depression and anxiety. Technologies have emerged for
    improved quantification of alcohol's effects on neurotransmitters,
    receptors and transporters at all ages, including senior adult.

-   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.

**D.4. Diagnostic Criteria for Alcohol Abuse and Dependence**

Since the early 1900s, numerous definitions of AUDs have been proposed.
Currently, in the United States, the clinical standard used for defining
and diagnosing AUDs is the American Psychiatric Association's Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).

Definitions of alcohol abuse (see Table I-1) and dependence (see Table
I-2) appearing in the DSM-IV both describe maladaptive patterns of
alcohol use leading to clinically significant impairment or distress.

*DSM-IV alcohol abuse* requires at least one of the following four
symptoms to occur within a 12-month period:

-   drinking resulting in failure of the affected individual to fulfill
    major role obligations,

-   recurrent drinking in situations in which it is physically
    hazardous,

-   recurrent alcohol-related legal problems, or

-   continued drinking despite social or interpersonal problems.

*DSM-IV alcohol dependence* requires that at least three of the
following seven criteria be met in a 12-month period:

-   tolerance,

-   withdrawal or relief drinking,

-   drinking in larger amounts or for longer periods than intended,

-   persistent desire or unsuccessful attempts to cut down or stop
    drinking,

-   much time spent in obtaining alcohol, drinking, or recovering from
    its effects,

-   important social, occupational, or recreational activities given up
    in favor of drinking, or

-   continued drinking despite knowledge of physical or psychological
    problems caused or exacerbated by drinking.

Several issues have been raised concerning the applicability of the
DSM-IV diagnostic definitions. With regard to dependence, the
categorical nature of the diagnosis has been criticized as failing to
represent the degree of severity inherent in the phenomenon. Each
diagnostic symptom criterion carries equal weight in the classification,
when clearly some criteria subsume symptoms that are more severe or
disabling than others. The DSM-IV dependence diagnosis has also been
questioned due to the absence of alcohol consumption measures,
especially those consumption measures related to excessive drinking that
have been found to increase individuals' risks for a variety of physical
and psychiatric disorders. To address these issues, research has begun
to focus on developing quantitative representations of AUD diagnostic
criteria using statistical methods that provide differential severity
weighting for individual AUD symptoms and allow for the inclusion of
alcohol consumption variables (Saha et al., 2007).

**Figure I-10. Severity of Alcohol Use Disorder: Comparison of Frequency
of Risk Drinking (5+/4+) with Average Daily Ethanol Intake**

![](media/image12.wmf){width="5.997222222222222in"
height="7.076388888888889in"}

**Source: Dawson, D. Laboratory of Epidemiology and Biometry, NIAAA,
2007.**

As part of this effort, the relationship of average daily volume of
alcohol consumption to severity of AUD, as well as the relationship
between risk drinking and AUD was analyzed from the NESARC data. As seen
in Figure I-10, the increase in severity of AUD is non-linear with
respect to average daily alcohol consumption or the frequency of risk or
binge drinking, but rather increases at a rate greater than linear. One
interesting observation is that the severity of AUD attained is about
the same for individuals who engage in risk drinking once a month (5
drinks per occasion for males/4 drinks per occasion for females) as it
is for individuals whose overall average daily alcohol consumption is 1
standard drink per day (30 drinks per month) (the blue bars in the two
graphs in Figure 1-10).

Another important issue related to the current DSM-IV formulation of
alcohol abuse and dependence concerns the relevance of some of the
criterion items to certain subgroups of the population. For example,
some researchers have questioned the applicability of DSM-IV symptom
items to females, a result of the historical definitions of diagnostic
criteria based on clinical samples that have been composed largely of
middle-aged males. The need to determine if differential case
identification for AUDs exists for males versus females will be
paramount for future prevention and intervention efforts. Biases
attributable to language, differences in response tendencies (e.g.,
trait desirability, social approval, or acquiescence), or cultural
expectations and experiences can also lead to differential reliability
and validity of the AUD diagnoses across race-ethnic subgroups of the
U.S. population.

Further, questions have been raised about the applicability of specific
diagnostic symptom items across the lifespan, particularly among youth,
young adults, and the elderly. Whether some symptoms of AUDs may be more
relevant to different stages of the life course is an important research
question. Given the relationship between early-onset drinking and the
increased risk of developing an AUD, identifying criterion symptom items
specific to youth and young adults will be critical to prevention and
intervention efforts. Similarly, identifying AUD symptoms of greatest
relevance in the elderly can increase our ability to recognize serious
alcohol problems among this important subgroup of the population, which
is projected to increase dramatically over the next 10 years.

***Opportunities Related to the Diagnostic Criteria for Alcohol Abuse
and Dependence***

-   Develop continuous representations of AUDs, with particular emphasis
    on severity and the inclusion of additional diagnostic criteria
    related to alcohol consumption measures.

-   Identify differential case ascertainment for AUDs with respect to
    age, sex, and race-ethnicity, and determine if differences exist in
    the expression of AUDs among these subgroups of the population.

-   Develop biomarkers for chronic alcohol use employing such
    technologies as glycoproteomics, metabolomics, and lipidomics.

**D.5. Alcohol Health Services Research Across the Lifespan**

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
consistent with developmental needs of patients and their families.

NIAAA supports a broad program of scientific research that helps inform
decisions that policy-makers, payors, clinicians, and consumers will
make regarding the prevention and treatment of alcohol use and related
disorders. The focus then is to continue to advance the evidence base
that can bridge the gap between research and community-based
implementation that will lead to improvements in access to appropriate,
high quality, and effective services for people who have or are at risk
for alcohol use and related disorders.

One of the most consistent findings in the research literature is the
fact that only a small percentage of those with alcohol use disorders
seek and receive treatment in the specialty sector. Findings from the
National Epidemiological Survey on Alcohol and Related Conditions
(NESARC) show that individuals with an alcohol disorder are most likely
to seek treatment from professionals other than AA, EAP and clergy.
Findings from the National Survey of Substance Abuse Treatment Services
(N-SSATS) show that only 1% of the treatment programs nationally are
exclusively alcohol treatment programs (i.e. programs with 90% or more
alcohol patients) and only 5% are predominately alcohol treatment
programs (i.e. between 50% and 89% alcohol patients). From the lifespan
perspective, a very small percentage of individuals at the younger ages
(12-17) seek and receive treatments for alcohol consumption problems
even though this age group has the highest rate of mortality and
morbidity associated with their alcohol consumption pattern. Therefore,
age-specific health services are an important area of health services
research that requires further development. A review of the health
services research portfolio for the years 1997 to 2006 showed that NIAAA
funded 153 health services research projects totaling \$159 million. The
majority were categorized as outcome/effectiveness studies (32%),
economic and financing studies (15%) and technology studies (14%).
However the NIAAA portfolio is deficient in a number of areas, as
described in the recommendations from the Extramural Advisory Board
recommendations (see box). Those deficiencies, in general, include
outcome and effectiveness studies, health disparities, research on
dissemination and implementation, economics and financing, access to
care, technology, methodology, and infrastructure.

***Opportunities Related to Alcohol Health Research Services Across the
Lifespan***

-   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.

-   Similarly, once youth and adolescents are identified as high-risk
    drinkers or alcohol dependent, access to health services in support
    of their alcohol treatment suffers from barriers to service
    including, insurance coverage, provider-training, provider-time, and
    issues of confidentiality between parents and children. This lack of
    understanding with respect to the barriers to treatment of youth for
    alcohol use disorders may contribute to the under-identification or
    under-recognition of high-risk drinking in youth.

**D.5. Data Collection Over the Lifespan: The New Face of Longditudinal
Studies**

Research on risk factors for development of alcohol use disorders can
exploit the ever increasing assortment of technological gadgets for
recording day-to-day events in real time. This massive data collection
method allows for the analysis of minute to global influences on the
daily behavior of humans that may lead to the identification of risk
factors for various diseases. The sheer volume and complexity of
collected data using real-time technology would lend itself to modeling
of the intricate interplay of developmental, biological,
pharmacological, social, environmental, and cultural factors in the
transition from initial alcohol use to alcohol dependence.

***Opportunities Related to Data Collection Across the Lifespan***

-   Identify risk characteristics prior to alcohol exposure in order to
    model the interaction of alcohol use patterns with biobehavioral and
    environmental factors in all ages of high risk individuals.

-   Investigate the role of co-factors, such as smoking, diet, drug
    experimentation, and physical activity that could be hypothesis
    generating for basic research into the molecular mechanisms by which
    these factors influence the alcohol dependence transition states.

-   Enhance the understanding of biology by environment exposure (BxE)
    and gene by environment exposure (GxE) to plot the trajectories in
    the development and natural remission from alcohol dependence,
    particularly in adolescent and young adult populations.

**D.6. Ethical, Legal and Social Issues in Alcohol Research**

The consumption of alcohol, more than any other substance, is governed
by a variety of complex social and legal conditions. The complexity
around alcohol consumption by humans adds important ethical, social, and
legal issues (ELSI) to alcohol research. Each researcher using human or
animal subjects must ensure that the research is being conducted in an
ethical manner. NIAAA recognizes that adequate consideration of ethical,
legal and social issues in alcohol research requires that the home
institution provide support and guidance for the researchers as they
carry out their research programs. NIAAA continues to approach this
challenge though such activities as:

-   Website information \-- on Certificates of Confidentiality and
    HIPAA;

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-   Publications - Guidelines on Alcohol Administration to Human
    Subjects

-   Workshops at relevant meetings such as the Research Society on
    Alcoholism and others.

**CHAPTER II. The Embryo and Fetus**

**A. Background**

The earliest stages of life, in particular, embryonic and fetal
development, are periods of great vulnerability to the adverse effects
of alcohol. A known teratogen (an agent capable of causing physical
birth defects), alcohol may also damage neurological and behavioral
development even in the absence of obvious physical birth defects.
Alcohol's teratogenic effects were recognized over three decades ago,
and it is now the leading known preventable environmental teratogen.

Ranging from mild to severe, 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). As such, the peak dose, as measured by BAC, is a
more important determinant of harm than is the total dose consumed.

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. Consequently, many secondary disabilities may occur, such as
learning disabilities, attention disorders, failure in school, poor
social skills, delinquent or criminal behavior, psychiatric
co-morbidities, and premature and/or promiscuous sexual activity.
Prenatal alcohol exposure itself may be a risk factor for subsequent
alcohol and other drug use disorders later in life. The disabilities of
FAS are life-long and place heavy emotional and financial burdens on
individuals, families, and society.

Another *fetal alcohol spectrum disorder* is *partial FAS*, which
includes the facial and neurodevelopmental deficits of FAS but not the
growth deficits. Other FASD outcomes include *alcohol-related birth
defects* (ARBD), where physical attributes of FAS are seen in the
absence of the full syndrome, and *alcohol-related neurodevelopmental
disorder* (ARND) in which neurobehavioral deficits are consistent with
FAS, but the facial or physical features of FAS are absent.

By virtue of the lifelong learning and neurobehavioral deficits that
characterize FAS and other types of FASD, many consider the central
nervous system to be most critically affected by prenatal alcohol
exposure. Imaging and neurobehavioral research in individuals with FAS
and FASD reveals that some brain regions appear to be more sensitive to
prenatal alcohol while other areas apparently are spared adverse
effects. Particularly vulnerable regions include the frontal cortex,
hippocampus, corpus callosum, and components of the cerebellum,
including the anterior cerebellar vermis. Obviously, the extent of
damage to any brain area may be related to the timing of alcohol
exposure relative to the rapid development or neurogenesis of a
particular brain region, and the stage of embryonic development.

Epidemiological studies have revealed other adverse outcomes of prenatal
alcohol exposure, including an increase in the risk for spontaneous
abortion, pre-term delivery, stillbirth, and sudden infant death
syndrome (SIDS).

**B. Epidemiology**

Despite alcohol's potent teratogenicity, only a small proportion of
women who drink heavily give birth to children with FAS. The prevalence
of FAS and FASD are presented in Table II-1 for selected countries. In
the U.S., the prevalence of FAS has been estimated at 0.5-2.0 cases per
1000 births, with FASD projected to occur at several times that
prevalence (10 per 1000 births). In some parts of the world the rate of
FAS is far greater than in the U.S. This is particularly true in
countries where alcohol consumption during pregnancy is more common than
in the U.S. For example, in parts of South Africa, where farm wages once
were paid in part, with alcohol, a heavy drinking culture is quite
prevalent among the mixed ancestry farm workers. The incidence of FAS in
this region exceeds 60 cases per 1000 individuals.

**Table II-1. Prevalence of FASD, FAS and Associated Disorders (FAE,
ARND, ARBD) by Country (per 1000 cases)**

  -------------- -------------------------------- ------------------------
  **Country**    **Fetal Alcohol Spectrum         **Fetal Alcohol
                 Disorders**                      Syndrome**

  Canada         25 -- 46\^                       10.3\^

  France         6.0 (FAS and ARBD)               1.2 -- 2.9

  Italy          20 -40                           3.7 - 7.04

  South Africa   \-\-\-\--                        65-74^\*^

  Sweden         3.3 (FAS and ARBD)               1.7

  United States  10                               0.5 -- 2.0
  -------------- -------------------------------- ------------------------

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

Source: Canada: Habbick et al., 1996, Williams et al., 1999, Boland et
al., 1998; South Africa: Viljoen et al., 2005; Italy: May et al., 2006;
Sweden, France, and the United States: IOM Report, 1996.

Fetal Alcohol Spectrum Disorders include FAS, ARND, ARBD and FAE.

\^ Among Aboriginal populations in Northern British Columbia and Yukon
territory

\*Western Cape Province, Republic of South Africa

Given that alcohol consumption is the prime factor responsible for FASD,
the extent of drinking in pregnancy is an important epidemiological
question. Despite a number of prevention efforts, including point of
sale warning signs and bottle labeling, surveillance data indicate that
10% of pregnant women drink some alcohol and 2% are binge drinking. More
than 12% of women who are not using contraception and are at risk of
becoming pregnant are drinking at levels that exceed 7 drinks per week
or 4 or more drinks per occasion.

**C. Etiology**

Research has shown that, in the development of FASD, alcohol's causative
effect can be influenced by a number of maternal factors, including
amount of alcohol consumed, pattern of consumption, timing of
consumption relative to developmental stages of the embryo/fetus,
hormone status (e.g., thyroid hormones), nutrition, age, parity, and
drinking history.

Research shows that genetic factors influence adverse pregnancy outcome
in both humans and animal models. Animal research has also shown that
the genetic profiles of the mother and the fetus are important for
determining the potential for risk of physical birth defects, prenatal
mortality, learning and other neurobehavioral deficits in the offspring.
In humans, the presence of a specific variant of the alcohol
dehydrogenase gene, *ADH1B\*2*, in either the mother or child, has been
shown to decrease risk for FAS. Other studies have shown that the
presence of the *ADH1B\*3* variant decreases risk for neurodevelopmental
deficits associated with ARBD. Both of these ADH variants have kinetic
properties that make them more efficient at oxidizing alcohol to
acetaldehyde, a noxious intermediate metabolite, suggesting that
elevated acetaldehyde levels may contribute to decreased alcohol
consumption to lessen the risk FAS and FASD.

With respect to environmental risk factors, parents' socio-economic
status (SES) has been shown to be inversely associated with adverse
prenatal outcomes. However, the mechanisms accounting for this finding
remain to be established and the possibility exists that some factor
associated with SES such as drinking pattern, paternal drinking, or
nutrition may account for the observation.

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. Hence, this stage of life provides fertile ground for the
gamut of teratogenic consequences. As noted in this Plan's Overview,
alcohol has the ability to affect epigenetic pathways directly by
disruption of metabolic events in the biosynthesis of metabolites
involved in epigenetic modification (for example, the methyl donor
S-adenosyl methionine) resulting in altered gene expression and
consequent developmental injury. In addition, alcohol-induced errors in
gene imprinting at the level of the gamete may be heritable across
multiple generations. Therefore, the effect of alcohol on
embryonic/fetal development is similar to shooting a moving target
whereby development is differentially vulnerable at different stages of
development following different durations and patterns of alcohol
exposure.

Although there is both clinical and experimental evidence that maternal
history of drinking in the absence of direct alcohol exposure to the
embryo does result in intrauterine growth retardation (one
characteristic of FAS/D), much of the research to date has focused on
the effects of alcohol on the embryo per se, since a diagnosis of FAS
cannot occur in the absence of direct fetal alcohol exposure (maternal
alcohol consumption during pregnancy). Evidence for alcohol-induced
alterations has been found as early as the embryonic stage of
development. Research with a frog model of FASD has demonstrated that
alcohol can induce developmental injury at alcohol concentrations that
are attainable in heavy or binge drinking. Embryonic alcohol exposure
decreased the expression of several key neural genes necessary for
development (Pax6, Otx,6, Sox 3 and NCAM, TBX5, VAX2 among others). The
effect of these alterations in gene expression produced outcomes
consistent with the types of deficits seen in FAS including microcephaly
and micro-ophthalmia as well as other ocular abnormalities, overall
growth retardation, as well as delayed gut development. This research
further demonstrated that reactive oxygen species (ROS) and potentially
reactive nitrogen species (RNS) were involved in the mechanisms by which
alcohol caused these developmental effects. The anti-oxidant ascorbic
acid (vitamin C) was capable of protecting against microcephaly and
overall growth impairment.

Further evidence for detrimental effects of alcohol exposure on early
development has been demonstrated in research using the zebrafish embryo
model system. Zebrafish embryos exposed to alcohol of various
concentrations show alcohol-induced facial dysmorphologies (especially
deficits involving the eye), defects in brain, somatic growth, limb, and
cardiac development, abnormalities in gene expression, and behavioral
abnormalities (learning and memory, startle reflex) in adult fish
exposed during embryogenesis. Of interest, the behavioral abnormalities
occur at concentrations lower than those that caused cell death.
Furthermore, the timing of the embryonic alcohol exposure appears to be
related to differential adverse developmental outcome.

Other research studies have implicated ROS in the mechanisms by which
teratogenicity develops following prenatal alcohol exposure, including
programmed cell death. Programmed cell death, or apoptosis, is an
essential process for normal development. Specific cells required only
at a particular stage of development undergo apoptosis once their
developmental function is completed. An apoptotic event occurring either
too early, or too late, can alter the developmental process. Both *in
vivo* and *in vitro* studies have demonstrated that alcohol can alter
cellular responses to regulatory mediators of apoptosis in susceptible
cell populations. Alcohol induction of oxidative stress may cause
apoptosis, in part by reducing intracellular antioxidant capacity. This
increase in ROS enhances the permeability of the mitochondrial membrane
which, in turn, leads to induction of an apoptotic signaling cascade
involving the enzyme caspase. These findings led investigators to test
whether antioxidant agents could prevent fetal alcohol injury. Results
of such studies to date have been mixed, with decreased cell death in
animal and tissue culture models but no change in neurobehavioral
deficits observed in the offspring.

One area where prenatal alcohol exposure may bring about a life-long
consequence involves the fetal programming of the
hypothalamic-pituitary-adrenal axis (HPA) axis and its response to
stress. Research in animal models has shown that alcohol exposure during
fetal development can reprogram the HPA axis such that HPA tone is
increased throughout life. The consequent sustained elevations of stress
hormones can produce adverse effects on behavioral, cognitive,
emotional, physiological and metabolic functions. Changes in
immunological function can increase vulnerability to illnesses
throughout life. While this particular research demonstrates an effect
of prenatal alcohol on fetal programming of adult HPA responding, other
research has demonstrated that *postnatal* maternal behaviors can
permanently alter offspring through imprinting or epigenetics. In this
particular study, maternal-infant interactions resulted in permanent
variations in specific gene expression directly through an imprinting
process. Therefore, a potential mechanism exists for epigenetic or fetal
programming in the offspring of mothers exposed to alcohol during
pregnancy

Another area where prenatal alcohol exposure may cause life course
problems involves disturbances of circadian rhythm. Prenatal alcohol
exposure has been shown to alter the circadian rhythm of biological
processes, which may contribute to long term effects on health,
including sleep disturbances and psychiatric disorders.

Components of many neurotransmitter systems appear to be involved in
prenatal alcohol-induced fetal injury. For example, several studies
implicate the NMDA glutamate receptor system in alcohol teratogenesis.
Prenatal alcohol exposure on gestational day 8 of the mouse caused an
eventual change in the expression pattern of NMDA receptors, with a
decrease in the NR2B receptor and an increase in the NR2A receptor.
Researchers have hypothesized that this change could contribute to
learning deficits in FASD as NR2A is less modifiable than NR2B. Also,
the alcohol withdrawal-induced excitotoxicity of the NMDA glutamate
system that follows heavy exposure to alcohol has been proposed as
another mechanism by which injury to the fetal hippocampus may occur.
Research has shown that the NMDA receptor blocker, MK-801, could
attenuate the reductions in fetal hippocampal cell numbers in the rat
associated with alcohol withdrawal. Similarly, the selective NMDA
antagonist, eliprodil, was shown to reduce the severity of learning
deficits in rats observed after exposure and withdrawal from alcohol,
with alcohol administered on postnatal day 6 (corresponding to mid-third
trimester in the human) and eliprodil administered the following day.
Both of these findings indicate that glutamate/NMDA excitotoxicity can
contribute to alcohol-induced fetal brain injury.

Prenatal alcohol exposure has been shown to affect the serotonergic
system of the rodent, by reducing the quantity of serotonin acting as a
growth factor during organogenesis and neurogenesis, and by depleting
the amount of serotonin available for use as a neurotransmitter in older
offspring, resulting in aberrant neural tube development and depletions
in the density of serotonergic neurons, respectively Alcohol exposure in
the prenatal period has also been demonstrated to affect other
neurotransmitter systems including the muscarinic acetylcholine system,
catecholaminergic (DA, NE), and GABA-ergic systems through various
mechanisms that alter the availability of the neurotransmitter (e.g.,
depletion of neurotransmitter producing neurons, changes in baseline or
stimulated release or uptake of neurotransmitters, or changes in the
sensitivity of the neurotransmitter receptors).

Another important functional system altered by prenatal alcohol is the
L1 cell adhesion system. Alcohol potently inhibits the cell adhesion and
axonal growth properties of L1. Of particular interest is that children
who are born with mutations involving the L1 molecule develop birth
defects with a phenotype that is similar to FAS.

One striking observation is that short peptide fragments from two of the
brain's neuropeptides, *activity-dependent neurotrophic factor* (ADNF)
and *activity-dependent neurotrophic protein* (ADNP) have been found to
afford significant protection from fetal alcohol injury at
concentrations as low as the femtomolar (10^-15^) range. Peptide
fragments from ADNF and ADNP could prevent alcohol-induced alterations
in the function of L1. These peptide fragments have also been found to
protect against reactive oxygen injury in the developing fetus.

**D. Prevention**

Researchers have pursued two paths for preventing FASD. The most
desirable route for prevention involves eliminating or significantly
reducing alcohol consumption by women during pregnancy. Other efforts
have explored the possibility of minimizing the damage caused by
prenatal alcohol exposure.

The Institute of Medicine addressed the issue of prevention of FASD in
the mid-1990s and proposed three approaches that differed in degree of
intensity depending on the level of risk of the pregnant woman.

The broadest approach involves **universal** prevention measures
targeted to the global community of men and women, and conveys general
education on risks and information to abstain from alcohol in pregnancy.
Examples include notices in bars, restaurants and other points of sale,
broad media campaigns, and labels on alcohol beverage containers. While
these efforts raise the level of overall awareness, research to date has
not demonstrated that universal approaches decrease alcohol use among
the group at highest risk for having an FASD child. The next level
involves **selected** prevention efforts which are directed to those
women who are in special risk groups, for example, a population that is
known to have a greater percentage of women who drink during pregnancy,
or who frequently engage in binge drinking. An example may be a
screening effort in primary care or prenatal clinics in a community
known to have a high prevalence of risk drinking. **Indicated**
prevention is at the highest level of intensity and is directed at
*individuals* known to be more vulnerable because of a high prevalence
of drinking in a high risk manner, including frequent binge drinking,
having a diagnosis of alcoholism, or having previously given birth to a
child with an FASD. To date, the limited research on *selecte*d and
*indicated* prevention efforts has shown that these methods can produce
changes in drinking behavior that would be expected to decrease risk for
an adverse fetal outcome. Indeed, research has shown that both screening
for alcohol use and administration of brief interventions in the clinic
(*selected* prevention) have positive effects on drinking reduction
during pregnancy. Also, conducting a single postpartum follow-up session
showed promise for maintaining the gains made possible by the
intervention during pregnancy. Several screening instruments have been
demonstrated to have good sensitivity and specificity in identifying
women at risk, and their effectiveness may be enhanced by computerized
self-interview.

Pharmacological intervention during pregnancy is an alternative approach
to prevention that may have applicability when there is early alcohol
exposure before a woman recognizes that she is pregnant, or otherwise
fails to stop drinking in pregnancy. Unlike many other teratogens that
have a limited period of exposure vulnerability, there are many periods
during gestation when alcohol can produce embryonic and fetal injury.
While some agents have shown intriguing results with respect to the
prevention of FASD associated injury, to date no agents have progressed
to the point of consideration for human trials. Therefore, this area
would best be described as at an early stage of development. However,
among the promising potential agents tested in animal models are
anti-oxidants that have been shown to reduce fetal cell toxicity,
anti-inflammatory agents such as prostaglandin inhibitors; the
nutritional co-factor choline; and agents that interfere with alcohol's
action in disruption of the functioning of the L1 cell adhesion
receptor. Also, two neuropeptides derived from the neurotrophic factors
ADNF and ADNP have been shown to exert significant protection from
alcohol-induced fetal injury in cell culture and animal models, and
derivatives of these factors may offer significant potential as future
preventive agents.

**E. Treatment**

**Diagnosis**: Important to the implementation of treatment is the
identification of the infant or child with FAS or FASD. Diagnosis of FAS
and FASD often has been difficult due to the lack of a biological
marker, nonspecific and often subtle symptomatology, differences in the
severity and timing of the insult, individual differences in response
and resiliency, and the overall complexity and plasticity of brain
development. Diagnosis in neonates and infants is further complicated
because neurodevelopmental deficits important to case identification may
not be discernable in infancy, and facial features may not be prominent
in the neonate. Because the physical signs of FAS moderate with age, and
behavioral manifestations of FASD change according to developmental
stage, diagnosis during later childhood (puberty and beyond) is even
more difficult than at younger ages. However, with more recent advances
in the application of complex, detailed facial imaging, researchers have
been using the facial dysmorphology associated with FAS as a biomarker
for CNS damage following confirmed maternal gestational alcohol
consumption. So, while a definitive biomarker is still lacking, the use
of an objective measure, facial imaging, may confirm the use of facial
dysmorphology as a biomarker for gestational alcohol exposure.

Analysis of magnetic resonance images (MRI) of the brains of adolescents
and adults with FAS, FASD, and normal subjects reveals that the shape of
the corpus callosum is much more variable in the brains of
alcohol-affected subjects. Statistical analysis of this excess
variability reveals that it can discriminate affected individuals with
good sensitivity and specificity. Further, the altered shape of the
corpus callosum serves as a permanent record of brain damage, even in
subjects suspected of FAS or FASD relatively late in life, or who lack
the physical signs of FAS. More recently, a pilot study has provided
evidence for the use of ultrasound in infants, through the infant's
fontanelle, in determining the shape of the corpus callosum. This
approach may offer the potential to assess the corpus callosum in
infants as a diagnostic indicator for FAS. Early case recognition is
important in the quest for early initiative of therapy.

**Therapeutics for FASD behavioral deficits:** Several promising
approaches to restoration or improvement of neurobehavioral deficits are
being explored in animal models. Twenty days of complex motor skill
training in adult rats was shown to restore performance deficits on a
motor task that resulted from binge exposure to alcohol in the neonatal
period. Recent results showed that this training stimulates
synaptogenesis in the cerebellum. Thus, Purkinje cells that survive the
initial alcohol insult are capable of experience-induced plasticity.
Other forms of directed activity may have similar beneficial effects in
other neuronal cell populations.

Prenatal alcohol exposure produces functional changes in the cholinergic
system of the hippocampus, leading to hyperactivity, passive avoidance
deficits, and impairments in spatial and working memory. Dietary
supplementation with choline, a precursor of the neurotransmitter
acetylcholine, was shown to decrease hyperactivity and improve spatial
and working memory in young rats that had been exposed to alcohol
prenatally. The choline treatment had no effect on alcohol-induced
deficits in motor balance and coordination, which are controlled by the
cerebellum rather than the hippocampus. Thus, choline's ameliorative
effects may be selective for hippocampal dysfunction.

Of particular importance are educational and skill oriented
interventions to address the learning and neurobehavioral deficits of
FASD children. Pilot studies with these populations are showing
improvements in performance that can enhance the life skills of
individuals with FAS and other FASD.

**F. Opportunities**

-   Apply genetic and proteomic technologies to examine alcohol's
    effects in altering the gene expression patterns involved in normal
    development, particularly with reference to systems and organs that
    are affected in FASD such as the central nervous system.

-   Apply the technologies for the study of epigenetic modifications of
    DNA and histone structure to uncover alcohol's potential role in
    altering the normal course of gene expression, as well as the
    physiological and behavioral consequences of such alteration.
    Undertake such studies at various points in embryogenesis and fetal
    development that have to date been demonstrated to be particularly
    sensitive to the effect of prenatal administered alcohol, for
    example, during the development and closure of the neural tube.

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

-   Continue to explore the mechanisms through which alcohol impairs the
    functioning of various neurotransmitter systems (glutamate,
    serotonin, muscarinic acetylcholine), second messenger signaling
    systems, and cell adhesion communication systems, in the development
    of fetal alcohol injury.

-   Use the knowledge gained in uncovering target sites for ethanol's
    action on the embryogenic and fetal stages of life to begin the
    development of potential therapeutic or preventative interventions.
    In this context, focus explorations on the dietary supplements
    (e.g., antioxidants and choline) that are safe for use in pregnant
    women and identify the concomitant levels of vitamins that may be
    useful in pregnant women relative to those used in animal
    experiments for the same level of benefit. Continue to explore the
    potential of antagonists of alcohol's interferences with cell
    adhesion molecules, and of ADNF and ADNP derived peptides as
    potential protective agents from fetal alcohol injury in
    experimental model systems. It is known that choline deficiency
    during pregnancy does harm fetal brain development (hippocampus is
    one target) through decreased global methylation in fetal brain and
    methylation of specific genes, and in normal pregnancy, choline
    levels steadily increase from early gestation through parturition to
    account for increased need with respect to placental transfer, but
    to date, no studies have looked at whether alcohol causes a decrease
    in choline levels during pregnancy. Iron deficiency has been shown
    in high FAS risk populations, e.g., South Africa.

-   Apply technologies arising from the NIH Roadmap program on
    metabolomics to the search for a metabolic profile that may serve as
    a marker for either risk levels of alcohol consumption, or of
    particular vulnerabilities for the development of FASD.

-   Refine the current understanding of the neurodevelopmental signature
    of FAS and FASD, their relationships to and differences from other
    neurodevelopmental disorders such as William's syndrome. Identify
    indicators of these deficits at increasingly earlier ages to enable
    earlier interventions with FASD affected individuals. Use
    "self-educating' computer technologies for the analysis of 3-D
    facial images and MRI brain scans to identify changes in these
    images not recognized by the human eye. Explore the structural and
    functional underpinning of these alterations in deciphering targets
    for alcohol's teratogenesis, and to improve case recognition of FASD
    versus other disorders. Neurobehavioral deficits specifically
    associated with FASD, and those associated with other disorders,
    will improve the diagnosis of FASD, but can be used in the
    development of therapeutic interventions for both groups of affected
    children.

-   Increase knowledge on the structural alterations in various brain
    regions such as the cerebellar vermis, corpus callosum, hippocampus,
    brain stem arcuate nucleus, alone or in combination, for
    identification of fetal alcohol CNS deficits. Explore the potential
    of this knowledge to the understanding of prenatal alcohol induced
    functional deficits, and potential therapeutic interventions.
    Examine the potential for development of low to modest cost
    approaches for the identification of these structural deficits
    through prenatal ultrasound and transfontanelle ultrasound of
    newborns, to facilitate their adaptation into diagnostic approaches
    for clinical care.

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

**G. Outreach**

-   The meetings and work of the Interagency Coordinating Committee on
    Fetal Alcohol Spectrum Disorders (ICCFAS) will continue to be
    supported by the NIAAA. The ICCFAS is developing a strategic plan
    with actions that involve the participation of alcohol researchers
    and research administrators. Over the next five years relevant
    research results will be transferred to practice. Research to
    Practice Meetings on Prevention, Treatment, Educating Affected
    Children and FASD and Criminal Justice will be co-sponsored with
    ICCFAS organizations. NIAAA will continue to work with SAMHSA on the
    development of guidelines and training materials for criminal
    justice personnel.

-   The Health Resources and Services Administration (HRSA), a member
    organization of the ICCFAS, has provided funding to the National
    Organization on Fetal Alcohol Syndrome (NOFAS) to work with maternal
    care programs and gain the inclusion of alcohol screening. NIAAA
    will be involved in providing advice and guidance for this effort.
    The opportunity exists to partner with NOFAS and with HRSA to work
    within an ongoing program to identify research-based intervention
    that can be implemented in a cost effective manner in health care
    facilities. NIAAA will work with the HRSA Network and SAMHSA to
    improve the chances that alcohol screening will be selected for
    implementation beyond maternal care.

**Chapter III. Birth to Age Ten**

**A. Background**

The period from birth to age 10 is perhaps the most remarkable of all
developmental periods with respect to the sheer extent of the changes
that take place. It encompasses infancy, the toddler and preschool
years, and middle childhood. By age 10, many of the most basic human
systems for adapting to the world have developed and have some
stability. These include the ways in which the individual will perceive
and learn, problem solve, communicate, regulate emotion and behavior,
respond to stress, and relate to other people.

As children traverse the period from birth to age 10 there are a number
of key transitions that they must negotiate and developmental milestones
they must achieve. These include: attachment to caregivers and others;
understanding the language of the family; preschool entry and the
transition to elementary school; understanding, speaking, reading and
writing the language of the culture/school; sitting, walking, skipping
and other developmental motor milestones; compliance with rules for
conduct and impulse control; toilet training; playing with peers; and
acceptance among peers in key community or school contexts.

A child's development takes place in multiple contexts. Key contexts
from birth to age 10 include: caregiver relationships; the family, home,
and neighborhood; daycare, preschool, and kindergarten; the primary
grades of elementary school; peer play and activity groups; classrooms
and playgrounds; friendships; and the media (television, music,
electronic toys and games, computers, and movies).

**Figure III-1. Systems that influence child and adolescent behavior.**

![](media/image13.wmf){width="3.4972222222222222in"
height="3.082638888888889in"}

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: Surgeon General's Call to Action to Prevent and Reduce
Underage Drinking
(http://www.surgeongeneral.gov/topics/underagedrinking/calltoaction.pdf)**

**B. Epidemiology**

There is little information available on alcohol use by those aged 10
and under. Only limited survey data are available and retrospective
recall by adolescents about early drinking is not very reliable, with
the age of first use increasing the older the adolescents are when
questioned.

According to the most recent Partnership Attitude Tracking Study (1999
PATS; sponsored by the Partnership for a Drug-Free America) which
surveyed a national probability sample of nearly 2,400 youth, 9.8% of
4^th^ graders, 16.1% of 5^th^ graders, and 29.4% of 6^th^ graders had
had more than just a sip of alcohol in their life. According to the
2003-2004 PRIDE Survey, which summarizes school district surveys
performed across the U.S., 4.2% of 4^th^ graders, 5.6% of 5^th^ graders,
and 8.7% of 6^th^ graders had consumed a beer in the past year. Slightly
more had consumed wine coolers (4.4%, 6.7%, and 10.3%, respectively),
and approximately half as many reported drinking liquor in the past year
(1.9%, 2.8%, and 5.2%, respectively). The PRIDE data are based on a
large convenience sample of children from many school districts across
the country rather than on a representative national sample and so
contain an unknown level of bias. (Note that most 4^th^ graders are 9 or
10 years old and some 5^th^ graders are 10 years old.)

There is little evidence that children under 10 have alcohol abuse or
alcohol dependence problems, despite some clinical reports and anecdotal
stories of child alcoholics. In the few studies that examined very early
alcohol abuse and dependence, rates of diagnosed alcohol use disorders
was close to zero in the general population, but other studies have
found alcohol problems among youth under 10. For example, one study
found that 0.5% of fourth graders in rural New Hampshire qualified as
problem drinkers, which was defined as drinking at least once a month
and having been drunk to the point of falling down or vomiting.

**C. Etiology**

**Non-specific to Alcohol Risk Factors in Childhood.** A number of
non-specific-to alcohol risk factors from birth to age 10 predict the
early onset of drinking and the development of alcohol problems and
alcohol use disorders in adolescence or adulthood. These risk factors
for subsequent alcohol involvement are considered nonspecific because
they also influence a broad range of other behavioral outcomes. The
primary non-specific risk factors include the following:

-   Externalizing behaviors reflecting emotional/behavioral/attention
    undercontrol expressed as conduct disorder, impulsivity, attention
    deficits, aggressiveness, and antisocial personal disorder. To a
    lesser extent, internalizing behavior expressed as anxiety, sadness,
    and depression.

-   Negative affectivity

-   Neglectful or poor parenting, especially a family history of
    antisocial behavior and experiences of abuse and trauma

-   Early exposure to alcohol and other drug use by parents and peers

-   Sleep problems

-   Attention problems

-   Deficits in reading and other academic achievement

Because of this cluster of non-specific factors, the pre-pubertal period
is important for understanding and preventing adolescent alcohol use.
There is evidence, for example, that some risk factors for later alcohol
dependence can be identified as early as age three.

**[The Externalizing Pathway]{.underline}.** Children who show early
difficulties with impulse control and paying attention, exhibit
unusually high levels of aggression during the preschool years, and
develop early academic problems related to their behavior once they are
in school are said to exhibit externalizing behaviors. During late
childhood and early adolescence, some of these children disengage from
school, begin to associate with deviant peers, engage in increasingly
risky behaviors, and become involved in delinquent behavior. These same
youth are at high risk for early alcohol use and other negative
behaviors, including early and risky sexual activities and truancy.

**The Internalizing Pathway.** A second pathway toward underage drinking
that may have its beginnings in childhood is associated with depressive
spectrum disorders and related antecedents, including anxiety and
shy/inhibited personality. The evidence is weaker for this internalizing
pathway in relation to earlier alcohol use than for the externalizing
pathway. However, there does appear to be a link between depression in
adolescence and risk for alcohol initiation and considerably stronger
evidence for an internalizing pathway to alcohol use disorders.

**Alcohol-Specific Risk Factors in Childhood.** The dynamic interplay of
biological, psychological, and social processes from birth through age
10 shapes overall development including the risk for alcohol problems.
Research has identified a number of risk factors that can be identified
between birth and age 10 that predict risk for later alcohol use and
abuse. Unlike non-specific risk factors that predict a spectrum of
problems as well as alcohol use, these risk factors are specific to
alcohol. They include:

-   How children understand alcohol as an object in the social
    environment, e.g., its effects, use in social settings, and
    expectancies about use

-   Brain development and biological processes related to appetite,
    rewards, planning, forethought, affective and behavioral control

-   Genetic influences and effects

-   Environmental factors such as the family, school, peers, and social
    norms

-   Social contexts that encourage children to use alcohol

-   Families with alcohol problems.

-   Prenatal and early postnatal alcohol exposure, which increases
    alcohol preference and consumption in adolescence.

-   Early onset of alcohol use (age 12 and under), which is associated
    with a greater likelihood of developing both problem drinking in
    adolescence and alcohol abuse or dependence in adulthood.

-   Societal levels of alcohol use, with alcohol the most used and most
    pharmacologically used drug in American society.

**Development of Children's Beliefs and Expectancies about Alcohol.** As
they develop, children become aware of alcohol as an object in their
social environment through a variety of mechanisms. These include
drinking by their parents and other adults in the family context as well
as alcohol use by adolescents and adults portrayed in the mass media
(television, movies, print media, and advertising). In the absence of
their own experience with alcohol, this vicarious learning is the major
influence on children's attitudes toward alcohol and their expectancies
about the effects of drinking. As children grow older, they learn that
alcohol produces changes in cognition, feeling, and behavior and that it
has a role in social relationships. They discover who uses it and why,
and, ultimately, develop expectancies about its use.

Expectancies about alcohol and its use have been shown to play an
important role in determining if and when youth will consume alcohol,
and how much they will consume if they choose to drink. Studies of
normal samples over a twenty-year period show that children's ratings of
adults depicted drinking alcohol are basically neutral at age 6, and
become more negative until about age 10. In one recent study, the
researchers found that between ages 8 and 12, both positive and negative
expectancies increase suggesting increasing ambivalence about the
effects of alcohol. A number of studies indicate that between ages 10
and 14, children's attitudes about alcohol become more positive. This is
important because positive expectancies have been shown to predict onset
of drinking in adolescence.

**The Role of Childhood Social Contexts in the Risk for Drinking.**
Parents are a major source of children's exposure to alcohol use. When
children are asked the source of their first drink, they overwhelmingly
cite their parents or home. For example, 78% of the third- through
sixth-grade children participating in the 1993-94 Bogalusa Heart Study
who had tried alcohol took their first drink with someone in the family.
Among children, self-reports of alcohol use correlate significantly with
child perceptions of parental drinking. Research over the past 40 years
consistently shows that children are more likely to eventually become
drinkers if their parents are drinkers.

In addition to their observation of parental drinking, children learn
about alcohol use and its effects through their exposure to movies,
television content, and advertisements. On average, children aged 2-11
saw 99.4 alcohol advertisements on television between January and
October of 2004 (81% for beer and ale, 11% for spirits, 5% for alcopops,
3% for wine). Alcohol advertisements are not the only source of alcohol
portrayals on television, however. Portrayals of alcohol use (and
typically its lack of consequences) are common on television programs
aired in prime time (8-11pm) when children may be watching. An estimated
71% of sampled episodes from the 1998-99 season included alcohol use by
characters on the shows. Approximately 38% of the shows with a TV-G
rating, which makes them appropriate for most children, depicted alcohol
use. More episodes characterized drinking as a positive experience
rather than a negative experience. Negative consequences were portrayed
or mentioned in only 23% of the episodes. Moreover, a recent study
provides evidence for an association between exposure to movie alcohol
use and early-onset teen drinking.

**Children in Alcoholic Families and/or with a Family History of Alcohol
Dependence.** According to National Longitudinal Alcohol Epidemiologic
Survey (NLAES) data approximately 6.8 million children age 11 or younger
were living in households with one or more adults classified as having a
current diagnosis of alcohol abuse or dependence and thereby would meet
the formal definition of children of alcoholics (COA). Children of
alcoholics are between 4 and 10 times as likely to develop alcohol
dependence themselves. But prior to that, they are also at elevated risk
for earlier onset of drinking and for earlier progression into drinking
problems.

Some of the elevated risk of the COA is attributable to environmental
risk, including exposure to an alcoholic parent as well as socialization
effects found in alcoholic households, some to genetically transmitted
differences in response to alcohol that make drinking more pleasurable
and/or less aversive, and some to elevated transmission of risky
temperamental and behavioral traits that lead the COA into greater
contact with earlier and heavier drinking peers. Both genetic
vulnerability and environmental risk are important as are the length of
exposure and the developmental period(s) during which the exposure(s)
take place. For example, studies show that children with an alcoholic
biological parent who were raised by non-alcoholic adoptive parents were
still significantly more likely to develop alcoholism later in life than
were control children with no genetic risk for alcoholism. In addition,
a substantial number of alcoholic men marry alcoholic women further
compounding risk for their offspring through increased genetic exposure
and impaired martial interactions. Environmental risk for COAs involves
both familial and neighborhood exposure. Families with an alcoholic
member tend to be more dysfunctional and experience higher levels of
psychiatric comorbidity. They are also more likely to be poor and to
live in poorer neighborhoods where the risk of a child's exposure to
deviant peers is higher.

**Fetal Alcohol Exposure.** An additional potential risk for early onset
drinking as well as for the development of risk factors for later
alcohol problems is the exposure of the child to alcohol *in utero*.
Given the number of alcoholic men who marry women with the same problem,
some children will be affected not only by genetic risk and by
socialization risk associated with being a child of alcoholic parents,
but also by the risk arising from the effects of heavy alcohol exposure
during fetal development (i.e., teratogenic effects). The teratogenic
risks are discussed in detail in the section on the Fetus. What is
relevant for this age group is the possibility that prenatal alcohol
exposure itself increases the risk of the exposed child for developing
alcohol problems of his own.

**D. Prevention and Intervention**

**Resilience .** Considerable evidence indicates that later alcohol use
can be predicted from developmental patterns evident well before 10
years of age, suggesting that young children have already started down
developmental paths leading toward or away from early use and abuse of
alcohol. In some cases, high risk pathways are so well established that
these pathways are clear targets for preventive intervention, although
such pathways are always probabilistic and not certain roads to underage
drinking. In fact, there are children who appear to be on the same
high-risk pathways who do *not* begin to drink early or who take a turn
for better development.

**Protective and Promotive Factors .** "Protective factor" has had two
meanings in the literature on risk and resilience. The first meaning
refers to a positive correlate of a desirable outcome (i.e., it is a
simple predictor of better outcomes). For alcohol use, therefore, a
protective factor is one that predicts lower rates of use or dependence
(i.e., it is negatively correlated to the outcome). With this
definition, a bipolar predictor of the outcomes could be labeled either
as a risk or a protective factor depending on how it is scored or named.
Parenting is a classic example, where good parenting can be viewed as a
protective factor, and bad parenting can be viewed as a risk factor for
underage drinking. Rearing environments that are high in warmth,
moderate in discipline, and lower in stress level are the most effective
in instituting lower levels of externalizing behavior in children and
adolescents, and ultimately, in producing lower drug involvement in
adolescence. Parents who are responsive to their child's needs gradually
increase the self regulatory capacity of the child.

The second meaning of protective factor refers to a factor that has a
buffering effect on the outcome, so that the factor is associated with
better-than-expected outcomes in the context of risk. For alcohol use,
such a factor would be associated with lower-than-expected
alcohol-related outcomes given the level of risk for alcohol use or AUDs
present in the individual. Thus, among children living in poverty in bad
neighborhoods surrounded by deviant peers who encourage underage
drinking (where risk for underage drinking appears to be high),
effective parenting may be particularly important and may have
protective effects beyond the generally positive effects of good
parenting on child outcomes. These concepts are clarified in the
resilience literature, where the term "promotive" factor is often used
to mean a simple predictor of risk and "protective" factor is one that
plays a moderating role when risk is present. Little research has been
performed to establish the operation of protective factors among
children under the age of 10 years.

**Developmentally Influenced Interventions**

A number of opportunities exist for developmentally-related
interventions prior to the initiation of alcohol use in childhood. These
interventions focus not only on the children but on their parents as
well.

**Child-Focused Interventions**

1.  Among those children identified as having prenatal exposure to
    alcohol, early childhood interventions should be instituted prior to
    school entry. Such interventions should teach child and parental
    behaviors that improve the child's functioning at academic tasks,
    enhance response inhibition, and reduce inattention.

2.  Better surveillance systems in the schools, pediatric medicine,
    social services, and public safety (police) will identify children
    already displaying evidence of externalizing disorders, which are
    risk factors for earlier onset of drinking and the development of
    alcohol problems in adolescence.

3.  Develop a program to enhance or enable collaboration between alcohol
    researchers and other developmental researchers in allied fields who
    may already have successful prevention or intervention programs to
    reduce conduct problems in children and preadolescents. Important
    considerations would include determining at what ages interventions
    are likely to be most efficacious, what are the most engaging and
    least stigmatizing venues for such interventions, and how best to
    reduce barriers to parental involvement in the programs.

4.  Although childhood onset of alcohol use is less likely affected by
    affiliation with deviant peers, associating with such peers is a
    major risk factor for early adolescent onset of drinking and for
    movement into problematic drinking in adolescence. The pathways
    toward later affiliation with deviant peers begin in childhood and
    are influenced by a variety of family risk factors, including harsh
    and inconsistent discipline, low levels of parental warmth, low
    parental support, less parental monitoring, and low parental
    attachment and identification. Research suggests that the most
    effective interventions involve parent education in school family
    resource centers, rather than child interventions that group and
    segregate children at risk.

**Parent-Focused Interventions**

The goal in parent-focused interventions is to make the
intergenerational transmission of alcoholism less likely. Given the
importance of genetic risk for alcoholism and its associated
socialization risks, these interventions:

1.  Emphasize treatment for the alcoholic parent(s) to reduce the
    parent's problem drinking and thereby reduce the children's exposure
    to such drinking in the home

2.  Train parents in more effective parenting practices to reduce
    instances of child neglect and maltreatment

3.  Provide marital or couples' counseling to reduce conflict in the
    home. Such parental training and counseling should be offered as
    part of the parents' alcoholism treatment.

**E. Opportunities**

A number of significant research opportunities and directions exist for
the birth to age ten years group. The first two are of importance since
there is little to no information in these areas. The third is also of
importance as there is a need to better understand why drinking is a
normative behavior among American adolescents and how drinking becomes
so widespread among youth. The remaining opportunities represent areas
where increased knowledge about known developmental pathways into
alcohol use and AUDs will enhance prevention efforts with specific
groups of youth at high risk.

-   Examine the onset of drinking in young children. One potential
    approach would be through nationwide surveys of children's alcohol
    experience beginning in grade four. Following a subset of
    individuals to determine the relationship between early onset of
    alcohol use and later development of problem drinking would be
    particularly informative.

-   Explore parental beliefs and practices concerning childhood alcohol
    use to determine under what circumstances exposure to limited
    drinking at home is protective or a risk factor for later alcohol
    problems.

-   Investigate the ontogeny of attitudes, intentions, and expectancies
    for alcohol use in childhood and through adolescence in order to
    identify the factors influencing the development of alcohol-related
    cognitions.

-   Further characterize the externalizing pathway for the development
    of problematic drinking in adolescence with regard to early
    initiation, alcohol use, and alcohol use disorders. Determine the
    influence of family history of alcoholism, prenatal exposure to
    alcohol, and gender and ethnic/racial variation, and modifiable risk
    factors influencing this pathway that can be targeted in prevention
    efforts. In addition, direct the research effort equally towards the
    characterization of the internalizing pathway for the development of
    alcohol problems, since depression, inhibition, social anxiety,
    social withdrawal, and generalized anxiety all play a role in this
    pathway, and the two pathways are related with respect to gender
    differences in bipolar disorder in adolescence.

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-   Apply the various data collection strategies with state-of-the-art
    technologies in genomics, imaging and statistical modeling to
    determine the relative contribution of biology, environment, and
    genetics to the risk for alcohol dependence or abusive alcohol
    consumption in later life.

In some cases, familial, neighborhood, and peer structures act in
concert to encourage the development of early involvement with alcohol.
Determine the degree to which these concurrent risk factors are
synergistic for the development of risk.

**F. Outreach**

Outreach activities for the Birth to Age Ten category are located in the
Youth/Adolescence Outreach section.

**CHAPTER IV. Youth/Adolescence**

**A. Definition of Youth and Adolescence**

Adolescence is a period of life characterized by dramatic changes in
biological processes, as well as physical and social contexts. For the
purpose of this document, we define the age range of adolescence as
spanning the period between 12-17 years old. There are many factors that
impinge on the development of the individual as they progress through
the adolescent period. Biological changes include substantial physical
growth, endocrine changes, and brain maturation that continue into the
third decade of life. Important psychosocial changes include spending
more time with peers and less time with family, a change in the level
and type or supervision (parental or otherwise), the development of
sexuality and romantic interests, and increasing independence and
self-reliance. At the same time, the environments with which youth
interact - schools, peers, parents and family, neighborhoods and the
larger society-- are changing as are the multiple ways in which youth
interface with and relate to these environments. As youth traverse this
complex period of life, they are expected to successfully negotiate
important transitions (such as from elementary to middle school and from
middle school to high school), take on new roles (such as employee),
master new tasks (such as driving), develop increased self-regulation,
and set long-term goals. During this time the majority of youth begin to
drink (80% by the end of high school), and some experience significant
alcohol-related problems including the development of alcohol use
disorders.

The beginning of adolescence is demarcated biologically with the onset
of puberty, and, by convention, is understood to end when an individual
assumes adult roles and responsibilities. Puberty was once thought to be
initiated by hormonal events triggered by neuroendocrine changes in the
brain. Furthermore, puberty is not a single entity, but consists of many
biological processes that may not occur at the same time, and do not
necessarily progress at the same pace or have the same pattern of
unfolding. As already mentioned the brain itself continues to mature
during adolescence and into the mid 20s with early adolescence marked by
proliferation of neurons and connections between neurons and later
adolescence characterized by pruning of neural connections and increased
myelination. Very important to understanding alcohol use by youth from a
developmental perspective is the fact that, over the past 100 years, the
endocrine changes associated with puberty have been occurring at younger
ages, while the attainment of adult roles such as starting a career,
finding a partner, owning a home and becoming a parent are occurring
much later. The result is the dramatic expansion of the period referred
to as adolescence.

Adolescents are the healthiest cohort in the population in terms of
organic disease but, at the same time, they experience relatively high
rates of mortality and morbidity due to their behavior, including the
use of alcohol. Across many species including humans, adolescence is a
time of heightened risk-taking and for many young people in our society,
some of that risk-taking involves alcohol use. Further, adolescence is a
period of increasing socialization often involving alcohol. For some,
the increased social demands of adolescence may be accompanied by
increased anxiety heightening the risk for alcohol use. In this way,
alcohol use has become intertwined with the normal developmental
processes of adolescence. And alcohol use both affects development and
is affected by developmental processes. Therefore, an overarching
developmental framework will provide a useful vantage point for
advancing our understanding of underage drinking.

**B. Epidemiology**

Alcohol is the drug of choice among youth, used by far more young people
than cigarettes, marijuana, or illicit drugs (see Figure IV-1)

**Figure IV-1. Alcohol as the Drug of Choice Among Youth**

![](media/image14.wmf){width="4.997916666666667in"
height="2.9138888888888888in"}

**Source: SAMHSA 2002 National Survey on Drug Use and Health (NSDUH)
data**

As a result, underage drinking is a leading public health problem in
this country, as young people create problems for themselves, for people
around them, and for society as a whole by drinking *too much, too
often*, at too early an age. A number of studies have found that early
initiation of alcohol use (usually defined as starting to drink at age
13 or younger) is a risk factor for escalation of alcohol use in
adolescence, and that both are risk factors for the development of
alcohol-related problems in adulthood.

Nationwide surveys indicate that adolescent males and females between
the ages of 12 and 17 have similar patterns of alcohol use (frequency
and quantity) as well as prevalence of DSM-IV alcohol abuse and
dependence. By late puberty, however, sex specific patterns and
prevalence begin to diverge, with females exhibiting fewer drinking days
in the past month, fewer episodes of heavy drinking, and lower
prevalence of alcohol abuse and dependence. Research also suggests that
early puberty, particularly in girls, is associated with higher rates of
substance use and abuse (including alcohol) independent of age and
school grade. The usual interpretation of this finding is that social
factors and environmental stressors mediate the relationship between
maturational changes during puberty and the onset of alcohol/substance
use. However, hormonal mechanisms that could explain the progression of
sex differences in alcohol drinking patterns during puberty, such as
activation of reproductive hormones, stress responses, and their effects
on brain developmental processes, remain relatively unexplored.

Even though this chapter focuses on youth from ages 12-17 and their
alcohol consumption and consequences, it is important to note that
alcohol is a leading cause of death for people under age 21. Each year,
approximately 5,000 persons under the age of 21 die from causes related
to underage drinking. These deaths include about 1,500 homicides and 300
suicides. Alcohol is also often associated with unintentional burns,
falls, drownings, and other fatal and non-fatal events, and is a
frequent factor in physical and sexual assault and in
unwanted/unintended sexual activity. Underage drinking also causes
second-hand consequences. Half of all persons who die in traffic crashes
involving drinking drivers under age 21are persons other than the
drinking driver. Among college students under age 21 alone, 50,000
experience alcohol-related date rape, and 43,000 are injured by another
student who has been drinking.

While the prevalence of drinking among youth has decreased since the
1970s, available information from a number of national surveys indicates
that rates of consumption have remained stable, at quite high levels,
during the past decade.

Particularly worrisome among adolescents is the high prevalence of binge
drinking. In fact, the majority of youth who drink are binge drinkers.
In the figure, below, heavy drinkers are those who binge drink five
times a month or more, so among youth who drink, 60.5% binge drink (see
Figure IV-2).

**Figure IV-2. Three Broad Types of Drinkers**

![](media/image15.wmf){width="3.435416666666667in"
height="2.4166666666666665in"}

**Source: SAMHSA 2002 NSDUH data. Data based on responses to questions
about drinking within the past 30 days from 4.37 million adolescents
ages 12-17.**

**Figure IV-3. Frequency vs. Quantity of Alcohol Consumption in Youth**

![](media/image16.wmf)**­­­­­­­­­­­­­­­­­­­­­­­­­­­­­\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: SAMHSA 2000 National Household Survey on Drug Abuse (NHSDA)**

As seen in Figure IV-3, underage drinkers (aged 12-20) consume, on
average, 4 to 5 drinks per occasion about 5 times a month. By
comparison, drinkers age 26 and older consume 2 to 3 drinks per
occasion, about 9 times a month.

**C. Biology**

Adolescence is a period of rapid growth and physical change; a central
question is whether consuming alcohol during this stage can alter
development in ways that have long-term consequences. As noted above,
brain development and maturation continue during adolescence, and even
into the mid 20s. Limited research with animals and humans suggests that
alcohol may perturb normal brain development in adolescence and young
adulthood, thereby altering neurophysiology and associated behavioral
functioning.

Imaging studies have shown that the hippocampus, a brain region that
plays an important role in learning and memory, is smaller in
adolescents who begin drinking at an earlier age than in those who begin
drinking later. Researchers have found that memory problems are common
among adolescents in treatment for alcohol withdrawal. Since so many
youth use alcohol on a regular basis, and often in a "binge" pattern of
consumption, we must understand more about the impact of alcohol on the
physiological, neurophysiological and functional development of the
brain. In general, adolescents are less sensitive to the acute, negative
effects of alcohol, such as sedation and motor impairment, which would
normally serve to limit alcohol consumption. This may partially explain
the heavy, binge-like pattern of drinking undertaken by adolescents.
However, on tasks with which youth are unfamiliar or less experienced,
such as driving a motor vehicle, they are more susceptible to the
negative effects of alcohol (this effect could be due to processes
related to state dependent learning or the development of tolerance).The
heavy, binge pattern of alcohol consumption places adolescents in
repeated exposures to, and withdrawals from, the high (medically
damaging) concentrations of alcohol that are thought to make individuals
more vulnerable to alcohol's detrimental and toxic effects. Although
withdrawal symptoms normally associated with abstinence from alcohol
abuse are rare in adolescents, subsyndromal effects from binge-like
alcohol exposure may still initiate harmful consequences.

**D. Prevention**

Prevention of alcohol problems in adolescents poses special challenges
due to the unique physical, psychological, and social maturation
processes occurring during this period. As the developing adolescent
advances through middle/junior high and high school, and becomes active
in sports and other after-school activities, he or she will likely be
granted more freedom of movement and use of discretionary time, and have
access to resources like money and a motor vehicle. As greater degrees
of independence are obtained, the adolescent becomes exposed in a
greater degree to the influences of the larger culture, including
significant peer pressure, which becomes increasingly important in
shaping attitudes, beliefs and tastes in clothing, music, and behavior.
These intense pressures on the adolescent, in combination with their
developing attitudes and beliefs, make them "moving targets" for
intervention and treatment. These external influences may, or may not,
be in synchrony with the competencies, interests, and capacities of any
particular adolescent. In tandem with these biological and environmental
changes, progressive demands are made on the developing youth for
academic progress, self-regulation, and self-governance, in the face of
increasing freedom to choose one's own day-to-day and life directions.
Recent studies point to developmental processes intrinsic to adolescence
that may support or even encourage alcohol use, abuse, and dependence.
The challenge is then to reduce underage drinking despite strong
psychosocial influences that may lead young people toward alcohol use
since long--term consequences may result from alcohol exposure during
this time of accelerated neural, endocrine, behavioral and social
maturation.

Current prevention efforts approach the issue of youth drinking in two
ways. *Environmental-level interventions* seek to reduce the
availability of alcohol to youth and opportunities to drink, increase
penalties for violation of minimum legal drinking age laws, and reduce
community tolerance for alcohol use by youth. *Individual-level
interventions* seek to change knowledge, attitudes, and skills so that
youth are better able to resist influences that support drinking.

At the environmental level, the most comprehensive interventions to date
encompass coordinated school, family, and community programs. One such
universal prevention program, implemented in the last decade called
Project Northland, included school curricula, peer leadership, parental
involvement programs, and communitywide efforts to address community
norms and alcohol availability. The intervention was delivered to a
single cohort from grades 6 through 12. Comparisons in such measures as
"tendency to use alcohol" and drinking five or more drinks in a row
revealed differences between intervention and comparison communities.

At the individual level, the ability of parents to influence whether
their children drink is well documented and is consistent across
racial/ethnic groups. Family interventions encourage parents to be aware
of the risks from underage drinking, communicate with children, clarify
expectations, set rules and consequences about alcohol use, and monitor
children's activities. In addition to changing the knowledge and skills
of young people, families can create an environment that reduces alcohol
availability and increases the costs associated with drinking.

Another type of individual intervention uses the contact time with the
medical system following an alcohol-related adverse event that
represents a "teachable moment." Recent studies in pediatric and other
emergency departments and with college age and other populations have
indicated screening and brief interventions can reduce current drinking
and related problems. For example, in a study of alcohol-involved teens
in an urgent care setting, those who participated in a brief
motivational interview showed significantly greater improvement as
reflected in significantly lower incidence of drinking and driving,
fewer alcohol-related social and legal problems, and fewer
alcohol-related injuries during follow-up compared to those receiving
standard care. Another study in a similar population found that those
adolescents receiving a brief motivational intervention had
significantly fewer drinking days per month and lower frequency of
high-volume drinking compared with adolescents who received standard
care.

**E. Treatment**

The rates of problematic drinking and serious consequences are high
among adolescents, and many have problems, such as alcohol dependence,
appropriate for intervention by the alcoholism treatment system. Data
from the National Household Survey indicate that 1.47 million youth ages
12-17 met the criteria for alcohol dependence or alcohol abuse in 2003
(5.9% of adolescents in this age group). The same survey showed a major
unmet need for alcohol treatment in this group. Only 216,000 (15%)
received any type of treatment for their alcohol problem (see Table
IV-1).

**Table IV-1. Percent Youth Meeting DSM-IV Criteria for Alcohol
Dependence and Seeking Treatment**

  ----------------------- ----------------------- -----------------------
  **Age**                 **Alcohol Dependent**   **Seeking Treatment**

  12-17                   5.9%                    15%
  ----------------------- ----------------------- -----------------------

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: National Household Survey, 2003**

Youth prefer easy access, low threshold approaches that accentuate
strategies adolescents normally use to stop drinking and treatments that
do not remove them from their primary home or academic settings. Youth
perceive traditional services (e.g., alcoholism treatment programs,
Alcoholics Anonymous) as less helpful than brief interventions tailored
to salient adolescent concerns. Consequently, alternative formats,
attention to developmental transitions, and use of social marketing are
needed to more adequately address alcohol problems emerging in
adolescence.

Adolescents in treatment for alcohol use disorders (AUDs) are likely to
have more than one substance use disorder and may have other psychiatric
co-morbidities; the success of treatment is lower with those who have
multiple problems than with other subgroups of youth. To date, treatment
for adolescent addiction has involved adapting adult treatments to
youth. Ongoing research is testing some innovative and developmentally
tailored interventions aimed at improving treatment outcomes.

Research has shown that adolescents in treatment for alcohol dependence
have deficits in neural function and structure demonstrated through
neuropsychological assessments and structural imaging. The question of
whether the adolescent brain is more or less vulnerable than the adult
brain to alcohol's acute and chronic effects remains to be determined.
Recovery of function may also provide insight on whether such deficits
may have been causative rather than consequential to the development of
the alcohol use disorder.

The changes that occur in the endocrine systems during adolescence may
significantly contribute in processes associated with the development of
alcohol problems. Therefore, an important element for research
investigation is to identify the relationship among reproductive
hormones, stress hormones, and sex differences in alcohol use and
dependence that unfolds during late puberty.

**F. Opportunities**

-   Brain imaging and neurobehavioral correlations. Identify alcohol's
    effects on developing brain structures and behavioral regulatory
    systems. Techniques can be employed to examine specific brain
    structures in individuals who engage in drinking as compared to
    non-drinking controls, and to mark the progression of changes that
    occur with continued drinking behavior. Important targets for study
    include tasks related to executive functioning such as spatial
    working memory. As ongoing research identifies other tasks and areas
    of the brain that may be vulnerable to alcohol's effects, fMRI
    studies can be used to examine those domains. Data obtained from the
    NIH Neuroscience Blueprint and Program on Normal Brain Development
    will provide important reference data to guide the direction of
    these studies.

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-   In the longer term, as improvements in technology increase, more
    sophisticated techniques will undoubtedly allow the imaging of
    individual molecules or biomarkers of recovery in individual brains
    and brain regions. However, until those methods are perfected,
    specific modifications in imaging techniques, such as diffuser
    tensor imaging -- dtMRI -- should allow the visualization of
    specific changes associated with white matter tracts. Furthermore,
    the quality of image gained by using a 3.0T MRI (rather than the
    1.5T) may enhance the visibility of specific brain structures
    potentially affected by youth alcohol drinking or by treatment for
    youth alcohol consumption. Furthermore, the use of alternative
    measures to determine brain patterns, such as event related
    potentials, may gain prominence in the field with improvements in
    localization of specific areas that are affected by alcohol
    drinking. All of these incremental improvements in technique could
    substantially advance the field with respect to the degree of
    deficit and or amelioration afforded by treatment.

> Correlate changes in brain structure and function with
> neuropsychological functioning using current and newly emerging
> neuropsychological tools from the NIH Normal Brain Development
> Project.

-   Adolescent decision-making. The decision to initiate drinking, and
    to continue drinking are important elements in the pathway leading
    to alcohol-use disorders. Currently, researchers rely on data
    collected in surveys to provide information about factors that
    influence adolescents' decisions to use alcohol. Recognizing the
    limitations of self-report, for example that individuals may not be
    aware of everything that factors into their decision-making, it is
    important to utilize multiple methodologies to assess
    decision-making about alcohol use.

> Research in this area needs to be pursued through the expansion of
> investigations on the adolescent decisional process overall, and the
> influence of affect, external environmental factors, and expectations
> on those decisions. Important in the context of alcohol use is the
> observation that alcohol is typically used in a social rather than an
> individual context, by both adolescents and adults (with the exception
> of those who have become physically dependent on alcohol). Examining
> the interplay of environment, and biological traits related to
> temperament, and socialization, through longitudinal research and
> clinical study, is a direction that may uncover important factors in
> decisional processes about alcohol. These human studies can employ the
> use of time-line follow backs as one tool to assess decisional
> changes.
>
> Some of the needed decision making investigations can be carried out
> in laboratory simulated environments similar to those used in other
> human decision making research. In addition, animal research,
> particularly in primates, can be used to examine decisional processes
> related to alcohol. Through such investigations, it may also be
> possible to understand how alcohol affects the valence of the various
> factors that contribute to decision making in adolescence and whether
> those effects are different for adolescents than they are for adults.

-   Diagnosis of and screening for adolescent alcohol problems. In order
    to intervene with high risk adolescent drinkers and adolescents who
    have alcohol-use disorders, the target individuals must be
    identified in a clinical or other setting. Proper identification
    requires diagnostic instruments that are highly sensitive and
    specific. While the definitions of alcohol abuse and dependence
    currently in use are the same for youth and adults, these two
    periods of the lifespan are quite different. As such, the current
    criteria which were developed to identify adults with alcohol
    disorders may not have the same diagnostic value for adolescents. An
    important objective is the development of diagnostic criteria for
    alcohol use disorders that take the special characteristics of
    adolescents into account. Epidemiological assessment of existing and
    newly derived data offers opportunities for the development of such
    criteria. Adolescent specific criteria may then be used to develop
    screening instruments that more accurately identify high-risk
    adolescent drinkers and adolescents who are dependent on alcohol.
    Youth in both groups are appropriate targets for intervention and/or
    treatment. The predictive utility of adolescent diagnostic criteria
    and screening instruments can be tested in real world settings.

-   

-   Define and study alcohol behavioral markers (endophenotypes and
    intermediate phenotypes) for problem alcohol use by youth. An
    important goal is to identify very early markers for drinking risk
    and to determine if the relationships between these markers and
    problem alcohol use are correlative or causal. Of potential interest
    are relationships between externalizing disorders, internalizing
    disorders, and prenatal alcohol exposure (as discussed in the fetal
    section), and the development of alcohol problems. Identifying
    factors that play into vulnerability for very early initiation can
    help to identify high-risk populations that may benefit from
    targeted early interventions. The identification of these
    endophenotypes requires longitudinal study of youth as they develop
    through adolescence and into young adulthood. Such longitudinal
    studies, particularly in high-risk children, offers the potential to
    dissociate brain and behavioral abnormalities that are predisposing
    factors for alcohol abuse and dependence from those that are the
    consequence of chronic alcohol exposure Longitudinal studies also
    offers the opportunity to identify behavioral, cognitive, and
    emotional processes and neurobiological mechanisms of social
    behavior as they related to preadolescent and adolescent drinking
    pathways including the development of abuse and dependence Major
    collaborative opportunities exist to partner with other NIH
    institutes in such developmental studies where multiple genetic and
    environmental influences may be followed in a common research
    population that provides a basis for the study of various
    developmental disorders, including alcoholism, drug abuse,
    psychiatric disorders, obesity and eating disorders. Efforts
    underway in the NIH Program on Normal Brain Development will also
    contribute to this effort.

-   The changes that occur in the endocrine systems during adolescence
    may significantly contribute in processes associated with the
    development of alcohol problems. Therefore, an important element for
    research investigation is to identify the relationship among
    reproductive hormones, stress hormones, and sex differences in
    alcohol use and dependence that unfolds during late puberty. One
    approach to examine these relationships is through longitudinal
    studies of hormonal, electrophysiological and other biological
    factors over the course of puberty. In humans, such an effort may be
    undertaken in collaboration with other institutes of the NIH as part
    of a more global examination of the biological and behavioral
    changes occurring throughout adolescence. Modeling in animals, both
    rodents and particularly primates, could contribute to answer to
    answer these questions.

-   Research has shown that adolescents in treatment for alcohol
    dependence have deficits in neural function and structure
    demonstrated through neuropsychological assessments and structural
    imaging. The question of whether the adolescent brain is more or
    less vulnerable than the adult brain to alcohol's acute and chronic
    effects can be determined through the continued assessment after
    successful alcoholism treatment of the recovery of neural and
    behavioral function in adolescents, in comparison to recovery of
    function in adults. Recovery of function may also provide insight on
    whether such deficits may have been causative rather than
    consequential to the development of the alcohol use disorder.

**G. Outreach**

The preceding two sections of the NIAAA Strategic Plan have provided
research information pertaining to drinking by young people in two broad
age groups: Birth to Age 10 and Youth/Adolescence (\~ages 12-17). The
NIAAA outreach activities for these two age groups are presented in this
particular section because they target young people of both ages, and
the adults who interface with them. NIAAA's Underage Drinking Research
Initiative has framed the issue of underage drinking in a developmental
context. This framework also informs NIAAA's outreach approach. While
some materials and activities are best suited to a particular age group,
many are appropriate for both children and adolescents, and their
parents.

-   NIAAA is continuously developing and updating its own products
    relevant to underage drinking including scientific reviews,
    brochures for the general public, and web sites, both for adults and
    youth. For example, NIAAA's Underage Drinking Research Initiative
    produced a volume of NIAAA's journal, *Alcohol, Research & Health*
    titled "Alcohol and Development in Youth: A Multidisciplinary
    Overview", which was published in the fall of 2005. A companion
    issue articulating the developmental framework and the state of the
    science for prevention and treatment is planned for late 2007. To
    assist adults in discussing alcohol use with their children, NIAAA's
    parents booklet (available in English and Spanish) *Make a
    Difference, Talk to Your Child About Alcohol* provides helpful
    information in initiating and sustaining the conversation about
    underage alcohol use. The Underage Team, in conjunction with the
    Communications Branch, will be developing concise summaries of the
    state of the science on specific topics of interest. For each topic,
    summaries will be written at various levels of sophistication
    appropriate for specific audiences

-   Several NIAAA web sites provide relevant information for specific
    audiences. The "cool spot" (www.thecoolspot.gov) is an engaging,
    interactive web site for middle school children where they can
    access information directly about the effects and potential
    consequences of alcohol use. NIAAA's college drinking web site
    ([www.collegedrinkingprevention.gov](http://www.collegedrinkingprevention.gov/))
    has resources for high school students and their parents, high
    school administrators, college students and their parents, and
    college presidents. More information on underage drinking including
    statistics, references, and information about the underage drinking
    research initiative can be found on NIAAA's main web site at:
    (<http://www.niaaa.nih.gov/AboutNIAAA/NIAAASponsoredPrograms/underage.htm>).

-   In addition to direct outreach to the public, NIAAA capitalizes on
    opportunities to provide the best available scientific information
    on underage drinking to federal agencies, professional societies,
    and other organizations. For example, NIAAA staff members represent
    the Institute on the Interagency Coordinating Committee on the
    Prevention of Underage Drinking (ICCPUD) thereby informing the
    alcohol-related work of its member federal agencies and departments,
    and their constituencies. Further, NIAAA staff members seek
    opportunities to present at national meetings such as those
    sponsored by the Research Society on Alcohol, the American
    Psychological Association, the Department of Education, the
    Substance Abuse and Mental Health Services Administration, and the
    Community Anti-Drug Coalitions of America.

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-   NIAAA will develop a working relationship with the Department of
    Agriculture's 4-H and other youth programs to determine how these
    programs might be included in efforts to reduce underage drinking.
    The outcomes of pilot projects and activities will be evaluated to
    determine effectiveness.

-   Use state-of-the-art communication strategies and techniques to
    increase awareness of critical alcohol and health messages,
    including -- "Early onset of alcohol use interacts with human
    developmental processes to increase risk for alcohol problems
    throughout the lifespan."

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-   NIAAA supports the *Leadership to Keep Children Alcohol Free*, a
    group spearheaded by spouses of current and former Governors,
    dedicated to the prevention of drinking by 9-15 year olds. This
    organization seeks to raise awareness of, and provide science-based
    information to audiences ranging from parents to policy-makers
    about, underage drinking and its consequences.

**H.** **Collaborations**

-   NIAAA is involved in a joint RFA with the National Institute on Drug
    Abuse and National Institute on Aging at NIH, and the Institute of
    Neurosciences, Mental Health and Addiction in Canada on *Social
    Neuroscience*. The purpose of this initiative is to stimulate
    research on the brain mechanisms underlying social behaviors,
    including social decision making, interpersonal/peer relationships,
    self-regulation, and emotional regulation as they relate to the
    development of adolescent alcohol abuse and dependence.

-   The developmental framework articulated as part of the Underage
    Drinking Research Initiative is also reflected in the Surgeon
    General's *Call to Action to Prevent and Reduce Underage Drinking*,
    released in March 2007, and in the companion Guides for Families,
    Educators and Communities. These materials contain comprehensive
    information about underage drinking appropriate for a wide range of
    audiences. NIAAA provided the scientific foundation for the
    document, the Guides, the initial release of the *Call to Action*
    and follow-on activities, and will continue to work closely with the
    Office of the Surgeon General in promoting and disseminating the
    *Call to Action* and the underlying science.

-   NIAAA supports the *Leadership to Keep Children Alcohol Free*, a
    group spearheaded by spouses of current and former Governors,
    dedicated to the prevention of drinking by 9-15 year olds. This
    organization seeks to raise awareness of, and provide science-based
    information to audiences ranging from parents to policy-makers
    about, underage drinking and its consequences.

**CHAPTER V. Young Adult**

**A. Definition of Young Adult**

Many factors contribute to the definition of young adult. For this
purpose, the ages of 18-29 are used to delineate this period, although
this time frame can be further broken down into 18-24, and 25-29. For
example, the late teens and early 20s see the completion of major
maturational changes to the prefrontal cortex of the brain and
optimization of goal-directed behavior, yet the transition from
adolescence to early adulthood is not otherwise demarcated by the kind
of overt biological events that typify entry into adolescence. Rather,
young adulthood entry into this life stage has come to be defined by a
variety of self-directed transitions that signal an individual's
burgeoning independence from parental care. The pursuit of
post-secondary education, enlisting in the military, and entering the
workforce are a few such milestones, which traditionally have occurred
when an individual is in his or her late teens or early twenties. Other
events that traditionally mark this period include assuming large
financial obligations, courtship, and marriage. In the U.S, most states
have adopted age 18 as the legal age of majority -- the point at which
individuals assume responsibility for their own actions. However, from a
developmental rather than a legal perspective, emerging or young
adulthood now comprises an extended period of unsettled behavior for
many individuals, as age of marriage and age of career initiation in the
U.S., for example, have increased relative to historic norms.

**Table V-1. Percentage of U.S. Adults 18 and Over with Past-year
Alcohol Abuse or Dependence and Percentage of Those with Past-year Abuse
or Dependence Who Received Alcohol Treatment, by Type of Treatment**

+----------------+------+----------+---------+-------+------+---------+
| **Age group**  | **P  |          | **Type  |       |      |         |
|                | ast- |          | of      |       |      |         |
|                | year |          | trea    |       |      |         |
|                | di   |          | tment** |       |      |         |
|                | sord |          |         |       |      |         |
|                | er** |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
|                | *    | **Depe   | **Any** | *     | *    | **12    |
|                | *Abu | ndence** |         | *12-S | *Oth | -Step** |
|                | se** |          | **trea  | tep** | er** |         |
|                |      |          | tment** |       |      | **and   |
|                |      |          |         | **o   | **on | Other** |
|                |      |          |         | nly** | ly** |         |
+----------------+------+----------+---------+-------+------+---------+
| Young Adult    | 7.0  | 9.2      | 5.9     | 1.3   | 2.3  | 2.3     |
| (18-29)        |      |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
| 18-24          | 6.7  | 11.6     | 6.4     | 1.4   | 2.8  | 2.2     |
+----------------+------+----------+---------+-------+------+---------+
| 25-29          | 7.3  | 5.7      | 4.9     | 1.0   | 1.2  | 2.7     |
+----------------+------+----------+---------+-------+------+---------+

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: Adapted from Table I-8 in the Overview.**

Compared to all other age groups, the prevalence of periodic heavy or
high-risk drinking is greatest among young adults aged 18 to 24. Alcohol
use disorders, including alcohol dependence, also peak during this
period (see Table V-1 above). While most young adults transition out of
harmful drinking behaviors, a minority will continue to drink heavily
into the later stages of adulthood. For example, recent NESARC data has
shown that, while the prevalence of past-year DSM-IV alcohol dependence
is more than 12 percent for 18-20 year olds and more than 10 percent for
21-24 year olds, by age 25-29 prevalence has dropped to less than 6
percent and is less than 4 percent for adults ages 35 and over (see
Figure V-1). These phenomena raise important research questions. For
example, what factors allow some young adults to discontinue harmful
drinking patterns, most often in the absence of formal alcoholism
treatment? Why do others experience protracted alcohol problems well
into their adulthood?

**Figure V-1. Prevalence of Past-year DSM-IV Alcohol Dependence by Age
in the United States**

![](media/image17.wmf){width="5.0in" height="2.448611111111111in"}

**Source: NIAAA 2001-2002 NESARC data (18-60+ years of age) and SAMHSA
2003 NSDUH (12-17 years of age)**

**B. Epidemiology**

Figure V-2 illustrates that problematic drinking behaviors are prevalent
among college, non-college, military, and civilian young adult
populations. A recent review by NIAAA researchers found that from 1998
to 2001 the nationwide number of alcohol-related deaths among
18--24-year-olds rose at a rate that significantly exceeded that age
group's proportional population increase. Whereas the population
increased 7% from just over 26 million to almost 28 million,
alcohol-related unintentional injury deaths rose 12% from 4771 to 5367.
Thus, alcohol-related deaths per population of 18--24-year-olds rose 5%
from 1998 to 2001.

**Figure V-2. Prevalence of Heavy and Binge Drinking in Young Adults by
Specific Institution (Military, College)**

![](media/image18.png)

**Source: Ames and Cunradi. [Alcohol Use and Preventing Alcohol-Related
Problems Among Young Adults in the
Military](http://pubs.niaaa.nih.gov/publications/arh284/252-257.htm)
Alcohol Res Health 28: 252-257, 2005. (Military data: Bray, et al.,
2003; Civilian data: SAMHSA 2002 NSDUH)**

According to NESARC data, in 2001--2002 over three-quarters of young
adults ages 21--24 were current drinkers, as were nearly two-thirds of
those ages 18--20, despite the fact that the legal drinking age is 21.
More than half of young adult men exceeded the recommended daily
drinking limit, as did two-fifths of young adult women (see Figure V-3).
Although the prevalence of exceeding the daily limit is higher for those
ages 21--24 than for those ages 18--20, it also is substantial for those
ages 18--20. Because drinking more than the recommended per-occasion
maximum is likely to impair mental and physical performance, the
increase over the past decade in the prevalence among young adults of
drinking five or more drinks 12 or more times per year may help explain
the increased risk of injury and other acute negative consequences
commonly observed among college students ages 18--24.

Of the various sub-populations of young adults, college students have
received perhaps the greatest research scrutiny regarding alcohol
consumption in recent years. As we have learned much about alcohol use
in the transitional roles through college, there is a need to expand our
knowledge on the similarities and differences that occur among the young
adults who enter the military or the workforce. We must also continue to
explore similarities and differences in drinking behaviors of young
adults from different racial and ethnic sub-populations.

**Figure V-3.** **Percentage of Individuals Exceeding the Daily Drinking
Limit for Ages 18--20 and 21--24, by Gender, Race-Ethnicity, and College
Enrollment Status**

![](media/image19.png){width="5.34375in" height="3.834722222222222in"}

**Source:** NIAAA 2001-2002 NESARC data. AIAN = American Indian/Alaska
Native, \*\* NHOPI = Native Hawaiian/Other Pacific Islander

**College**

Research on the college-attending population has shown that some 1,700
college students between the ages of 18 and 24 die every year as a
result of hazardous drinking. In addition, nearly 600,000 college
students suffer unintentional injuries under the influence of alcohol,
and another 700,000 are assaulted by fellow drinking students.
Alcohol-related assaults include nearly 100,000 sexually assaults or
date rapes.

The proportion of college students who drink varies with where they
live. Drinking rates are highest in fraternities and sororities followed
by on-campus housing (e.g., dormitories, residence halls). Students who
live independently off-site (e.g., in apartments) drink less, while
commuting students who live with their families drink the least.

Although the existing literature on the influence of collegiate
environmental factors on student drinking is limited, a number of
environmental influences working in concert with other factors may
affect students\' alcohol consumption. Colleges and universities where
excessive alcohol use is more likely to occur include schools where
Greek systems dominate (i.e., fraternities, sororities), schools where
athletic teams are prominent, and schools located in the Northeast.

Some first-year students who live on campus may be at particular risk
for alcohol misuse. During their high school years, those who go on to
college tend to drink less than their noncollege-bound peers. But during
the first few years following high school, the heavy drinking rates of
college students surpass those of their noncollege peers, and this rapid
increase in heavy drinking over a relatively short period of time can
contribute to problems with alcohol and with the college transition in
general.

**Military and Non-College Civilians**

Researchers have noted that heavy drinking is common among those who
enlist in the military. A study that tracked high school students into
adulthood found that those who entered the military were more likely
than other young adults to have been heavy drinkers in high school.

A 2002 survey by the Department of Defense found that, among the 193,000
active duty military personnel between the ages of 17 and 20, 26 percent
are heavy drinkers who consume five or more drinks per drinking occasion
at least once a week. As shown in the table below (Table V-2), a
comparison of data from military and civilian surveys found that rates
of heavy drinking among 18- to 25-year-olds in the military are higher
than for civilians of the same age (32 percent vs. 18 percent for men
and 8 percent vs. 5 percent for women).

**Table V-2. Standardized Comparisons of the Prevalence of Heavy Alcohol
Use Among 18- to 25-Year-Old Military Personnel and Civilians, Past 30
Days, by Gender, 2001--2002**

**Source: Ames and Cunradi. [Alcohol Use and Preventing Alcohol-Related
Problems Among Young Adults in the
Military](http://pubs.niaaa.nih.gov/publications/arh284/252-257.htm)
Alcohol Res Health 28: 252-257, 2005. (Military data: Bray, et al.,
2003; Civilian data: SAMHSA 2003 NSDUH)**

NOTE: Table entries are percentages. Civilian data have been
standardized to the U.S.-based military data by gender, age, education,
race/ethnicity, and marital status. Data for the total Department of
Defense and the individual services are U.S.-based population estimates
(including personnel in Alaska and Hawaii). ^a^ Significantly different
from the civilian estimate at the 95-percent confidence interval.

**C. Biology**

Research in college students has found short-term health-related
consequences of heavy drinking such as hangovers, nausea and vomiting
are experienced by a large minority, if not the majority, of such
students. One survey of students at 89 schools across the nation
produced a self-report result of 40% with at least one hangover (47% of
drinkers) and 47% (56% of drinkers) having nausea or vomiting as a
result of alcohol or other drug use within the year. In one study at a
New England university where almost all students (97%) drank alcohol
within the year, 29% of the student sample reported that anywhere from
one-half to 24 hours of their normal functioning were lost "in recovery"
from drinking in the last week. Alcohol poisoning, alcohol-induced coma,
and the fatal outcomes resulting from extremely high blood alcohol
levels induced by excessive alcohol consumption are occasional, but not
unfamiliar incidents in campus health centers and local hospital
emergency rooms, although systematically collected data on the
prevalence of student alcohol poisoning are not available in the
research literature.

Longer term consequences of heavy alcohol use to one\'s health may
include reduced resistance to illnesses. Self-reported illnesses were
correlated with drinks consumed per week among undergraduates enrolled
in a general education course at a large mid-western university.
Although light to moderate consumption was not significantly associated
with increased health risks, consuming an average of 22 drinks or more
per week was associated with increased upper respiratory infections, and
consuming 28 drinks or more was associated with greater acute illness on
an aggregate measure, thus suggesting that heavy alcohol consumption
contributes to lowered resistance to common illnesses among students.

With respect to young adults in the military, one study found that the
highest levels of negative effects---serious consequences (e.g., missing
a week or more of duty because of a drinking-related illness or being
arrested for driving while impaired), productivity loss, and dependence
symptoms---occurred among military personnel in the lowest pay grades.
Other serious consequences included not being promoted, receiving a low
performance rating, being arrested for another alcohol-related reason,
being involved in a traffic crash resulting in injury or property
damage, and fighting while drinking. These pay grades generally
correspond to the youngest enlisted service members, who typically lack
a college education. During 2002, 20.2 percent of junior enlisted
personnel reported serious alcohol-related consequences, 27.2 percent
reported lost productivity, and 22.6 percent reported symptoms of
dependence.

**D. Prevention and Treatment**

Researchers have noted that young adults rarely identify themselves as
problem drinkers, suggesting that proactive screening approaches may be
necessary to identify problem drinkers in young adult populations.

With respect to college populations, a 2002 review of college drinking
prevention strategies found that campuses would best serve the student
population by implementing brief, motivational or skills-based
interventions, targeting high-risk students identified either through
brief screening in health care centers or other campus settings or
through membership in an identified risk group (e.g., freshmen, Greek
organization members, athletes, mandated students). More recently,
researchers have analyzed the effects of interventions on college
students. In an examination of a multi-site environmental prevention
initiative, investigators reported significant although small
improvements in alcohol consumption and related harms at colleges that
most closely implemented a particular program model. Other investigators
found that environmental DUI campaigns similar to those validated in
community prevention trials can be effective in college settings, but
noted that further research is needed to determine the robustness of the
changes associated with such campaigns. The issue of determining
effective strategies for identifying, recruiting and retaining students
in efficacious individually focused prevention services remains, as is
the determination of the effectiveness of mandated student prevention
services.

With respect to young adult military populations, current strategies to
prevent alcohol problems include instituting and enforcing policies that
regulate alcohol availability and pricing, deglamorizing alcohol use,
and promoting personal responsibility and good health. The U.S. military
has implemented policies and programs designed to reduce alcohol use and
related problems among personnel. However, there has been little formal
evaluation of these programs.

Several studies indicate that the non-student population of emerging
adults is an important target for preventive interventions, especially
because people in this segment of the population may be less likely to
mature out of heavy drinking patterns established during adolescence.
Although the non-students' risks for alcohol-related problems in their
early twenties may not be as high as those of students', recent research
has shown that the risk for alcohol-related problems in non-student
young adults is steadily increasing towards those of college students.
Unlike students, however, the risks for non-students appear to increase
over time. This population does not have the benefits of campus health
care centers or institutionally based programs that college students
have. Similarly, students who do not live on campus may not have the
benefits of campus alcohol prevention programs (which often are designed
for residents) or the protective benefits of campus organizations and
peer groups. Furthermore, in addition to limited exposure to
alcohol-related services, the non-student/non-military population of
individuals may not have exposure to mental health services that are
available to the individuals in a structured setting such as college or
the military. The lack of access to mental health care or health care in
general may predispose these individuals to comorbidities associated
with excessive alcohol consumption.

**E. Opportunities**

-   Intervening with emerging adults as they make the transition out of
    high school will ensure that interventions reach people who would
    not otherwise receive them. The period following high school
    graduation is an ideal time for interventions intended to prevent
    the problems that may result from such escalations in use, given
    that alcohol use increases and specific patterns of alcohol use
    change considerably around this time. Furthermore, non-college bound
    individuals are not likely to be exposed to campus-wide alcohol
    education programs and subsequent interventions, thus their risk for
    early onset of problem drinking may be higher than college-bound
    individuals. Because most of the research on drinking among emerging
    adults has focused on college students, an increased understanding
    of non-student populations can now be obtained to better inform the
    design of appropriate prevention efforts.

-   Apply new technologies in neuroscience research to further
    understand how young adults with alcohol use disorders differ from
    other age groups in terms of brain functions linked to alcoholism.
    Since the physically debilitating effects of alcohol-induced organ
    damage are rarely expressed in this age group, it would be important
    to determine if the brain, also a target of the toxic effects of
    alcohol, shows signs of alcohol-induced injury earlier than other
    organs, and, in those young adults who stop drinking, whether the
    brain shows a return to baseline level of function. Using objective
    measures of brain function such as EEG, ERP and specific brain
    imaging techniques (e.g., diffusion tensor imaging) to identify
    neural changes that will provide direction with respect to why young
    adults may increase their drinking during this particular period of
    time, and how their brains differ from, for example, young adults
    who just began drinking versus those who stopped drinking after
    adolescence. Once these biological changes are documented, the
    benefits of individualized therapies for intervention may be
    developed.

-   Alcohol Health Services Research: Develop and test models for
    screening and stepped intervention practices with young adults
    across various environmental contexts including primary care, social
    service agencies, mental health care, workplace, schools, and
    juvenile justice.

**F. Outreach**

-   Audience segmentation research conducted at NIAAA has revealed that
    urban-dwelling young adults comprise a major segment of U.S. society
    that binge drinks two or more times a month. Thus, binge drinking
    young urban adults are a well-delineated group of individuals at
    significant risk for alcohol-related problems. This research has
    also revealed their primary cities of residence, their beliefs,
    social norms, their mass media viewing habits, their shopping
    habits, food preferences, health habits and typical sports and
    leisure activities. Thus, we have rich descriptive data about the
    lives and habits of binge drinking young adults. This information
    can provide a strong and unique foundation for programmatic
    prevention intervention research for these at-risk young adults.

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-   Government entities such as Office of Juvenile Justice and
    Delinquency Prevention (OJJDP), National Highway Traffic Safety
    Association (NHTSA), and the military share an interest with NIAAA
    and SAMHSA in reducing underage drinking and its consequences. NIAAA
    collaborated with OJJDP in evaluating its initiative to address
    underage drinking in rural communities and plans to work with OJJDP
    and the Air Force to evaluate an Air Force Base --Community
    Partnership to reduce drinking among servicemen under age 21. NHTSA
    continues to participate in the NIAAA programs to reduce underage
    drinking in college students. Opportunities exist to increase
    interactions and partnerships with the Department of Defense
    agencies involving collaborations with OJJDP and NHTSA.

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-   A collaborative alcohol research planning grant at the University of
    Hawaii is one example of NIAAA attempts to include underrepresented
    Asian Americans and Pacific Islanders in our programs, as
    researchers and as study participants. The Institute is working with
    the National Association of Asian and Pacific Island Families
    Against Substance Abuse (NAPAFASA) to develop culturally and
    language appropriate information on alcohol use and abuse and
    health. The Institute supports an Alcohol Research Center in
    California with a researcher of Asian heritage as the principal
    investigator. This Center will be active in promoting outreach and
    research activities relevant to the Asian community.

-   The Institute has long supported research at Hispanic Serving
    Institutions. The objective is to use the Spanish translations of
    publications and the research capacity developed in these
    institutions to improve alcohol prevention and treatment strategies
    in the Latino community. NIAAA program administrators are actively
    involved with the NIDA Latino Research Initiative.

-   NIAAA will explore opportunities to work with a new CDC Center of
    Excellence in Health Marketing and Health Communications at the
    University of Connecticut. The University of Connecticut Center
    includes efforts to reduce drug and alcohol use among youth and
    young adults.

-   NIAAA will update/re-issue college drinking report in 2007.

-   NIAAA will use college drinking process/materials as a template for
    developing and disseminating essential alcohol messages and
    materials for the gamut of lifespan stages.

**CHAPTER VI. Midlife**

**A. Definition of Midlife and Epidemiology**

While some may view the underage and young adult life stages as perhaps
the most problematic periods for alcohol abuse and dependence, a much
more complete spectrum of alcohol-related problems and issues becomes
manifested during the adult period of life often referred to as
mid-life. At midlife, many of the pathological consequences of heavy
alcohol use become most evident, and individuals with alcohol dependence
are most likely to seek treatment of their alcoholism at this time.

As with young adulthood, entry into midlife is not signaled by specific
biological events. But unlike young adulthood, there is no legal
construct analogous to the "age of majority" associated with midlife.
Typically, a person in mid-life has assumed one or more "stable"
responsibilities of career, marriage, and family life. Chronologically,
this period may be viewed as encompassing the 30-59 year old age, but
these boundaries are not exact and will vary among different
individuals. Table VI-1 shows that percentage of individuals in their
midlife meeting criteria for alcohol dependence or alcohol abuse within
the past year, at 3 and 5 percent, respectively, and that the percent of
those individuals receiving any type of treatment during their lifetime
for their alcohol use disorder is only 8.5 percent.

**Table VI-1. Percentage of U.S. Adults 18 and Over with Past-year
Alcohol Abuse or Dependence and Percentage of Those with Past-year Abuse
or Dependence Who Received Alcohol Treatment, by Type of Treatment**

+----------------+------+----------+---------+-------+------+---------+
| **Age group**  | **P  |          | **Type  |       |      |         |
|                | ast- |          | of      |       |      |         |
|                | year |          | trea    |       |      |         |
|                | di   |          | tment** |       |      |         |
|                | sord |          |         |       |      |         |
|                | er** |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
|                | *    | **Depe   | **Any** | *     | *    | **12    |
|                | *Abu | ndence** |         | *12-S | *Oth | -Step** |
|                | se** |          | **trea  | tep** | er** |         |
|                |      |          | tment** |       |      | **and   |
|                |      |          |         | **o   | **on | Other** |
|                |      |          |         | nly** | ly** |         |
+----------------+------+----------+---------+-------+------+---------+
| Midlife        | 5.0  | 3.0      | 8.5     | 0.8   | 3.1  | 4.5     |
| (30-59)        |      |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
| 30-44          | 6.0  | 3.8      | 8.9     | 0.7   | 3.2  | 5.0     |
+----------------+------+----------+---------+-------+------+---------+
| 45-59          | 3.9  | 2.0      | 7.5     | 1.0   | 3.0  | 3.5     |
+----------------+------+----------+---------+-------+------+---------+

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: Adapted from Table I-8 in the overview.**

**B. Biology**

Chronic diseases associated with alcohol abuse and alcoholism
predominate among mid-life rather than any other age group. Alcohol
abuse and alcohol dependence are but two of the disorders that result
from the chronic heavy use of alcohol. Many other alcohol-use disorders
also manifest in the mid-life stage of life, including several types of
alcoholic liver disease, alcoholic pancreatitis, several types of
cancer, such as esophageal, larynx, colon, and liver, disorders of the
heart and vascular system including alcoholic cardiomyopathy,
alcohol-related brain disorders, as well as other adverse effects upon
the endocrine and immune system (see Table I-6 in the Overview Section).
An alcohol attributable factor (AAF) indicates the relative significance
of alcohol as a causal factor in the onset and progression of certain
diseases or its role in specific types of injury. Table VI-2 shows that
several diseases, including cancer, have an alcohol attributable factor
ranging from 25% to 75%, while the alcohol attributable factor for
injuries, including those involving motorized vehicles, is just over
40%. These data show that alcohol has a tremendous impact on the human
population in a multi-faceted manner.

**Table VI-2. Selected Alcohol-Related Diagnoses, Diseases, and Injuries
with Alcohol-Attributable Fractions (AAFs), and Age Ranges Included in
the Calculation of AAFs**

  -------------- ---------------------------------------- --------- ----------
  **ICD-9-CM     **Diagnosis**                            **AAF**   **Age**
  Code**                                                            

                 **Alcohol-related diagnosis with AAF               
                 equal to 1**                                       

  303            Alcohol dependence syndrome              1.00      15 and
                                                                    older

  305.0          Nondependent abuse of alcohol            1.00      15 and
                                                                    older

  425.5          Alcoholic cardiomyopathy                 1.00      15 and
                                                                    older

  571.0          Alcoholic fatty liver                    1.00      15 and
                                                                    older

  571.1          Acute alcoholic hepatitis                1.00      15 and
                                                                    older

  571.2          Alcoholic cirrhosis of liver             1.00      15 and
                                                                    older

                 **Alcohol-related diseases with                    
                 AAFs\<1**                                          

  011, 012       Pulmonary and other respiratory          0.25      35 and
                 tuberculosis                                       older

  140-149        Malignant neoplasm of lip, oral cavity,  0.50      35 and
                 and pharynx                                        older

  150            Malignant neoplasm of esophagus          0.75      35 and
                                                                    older

  151            Malignant neoplasm of stomach            0.20      35 and
                                                                    older

  155            Malignant neoplasm of liver and          0.15      35 and
                 intrahepatic bile ducts                            older

  571.5          Cirrhosis of liver without mention of    0.50      35 and
                 alcohol                                            older

                 **Alcohol-related injuries with                    
                 AAFs\<1**                                          

  E810-E825      Motor vehicle traffic and nontraffic     0.42      All
                 accidents                                          

  E960-E969      Homicide and injury purposely inflicted  0.46      15 and
                 by other persons                                   older
  -------------- ---------------------------------------- --------- ----------

**Source: Adapted from: McDonald AJ 3rd, et al. US emergency department
visits for alcohol-related diseases and injuries between 1992 and 2000.
Arch Intern Med 164(5):531-7, 2004**

**C.1. Metabolism and Organ Injury**

The routes by which alcohol causes organ pathologies continues to be of
great interest as an understanding of these mechanisms is key to the
development of both preventive and treatment approaches to these
disorders that, as noted above, exact high morbidity and mortality in
the U.S. population. Alcohol may cause tissue and organ injury via many
mechanisms, and researchers in recent years have gained an increased
understanding of several factors contributing to the development of
these conditions. But a complete understanding of the mechanisms
underlying these diseases, whether they are common across multiple
organs, or specific to only one organ, requires exploration and
identification of new knowledge.

Alcohol by itself, or through its metabolites, can elicit various
pathologic conditions. Alcohol also may serve to perturb other metabolic
pathways thereby changing the relative concentrations of other
biological intermediates in eliciting the development a particular
pathologic condition. For example, alcohol may alter pathways involved
in the biosynthesis of methyl donors, or in generating reactive oxygen
species or in depleting antioxidants all of which may be detrimental to
cells, tissues and organs.

One of the direct routes by which the alcohol molecule contributes to
organ pathologies is through its actions on the intestinal mucosa, an
action that increases the permeability of the intestine to the bacterial
endotoxin lipopolysaccharides (LPS) into the circulatory system. LPS is
an important factor in the development of alcoholic hepatitis, which in
turn may contribute to the development of other liver pathologies such
as liver cirrhosis and cancer.

The alcohol metabolite acetaldehyde also may serve as a potential source
of organ cell toxicities. Acetaldehyde is the first metabolic
intermediate in the oxidative metabolism of alcohol. Acetaldehyde can
form adducts with various proteins and other molecules potentially
disrupting their normal physiological function. Individuals with
specific variants of the two major enzymes in alcohol metabolism,
alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) achieve
elevated levels of acetaldehyde when they consume alcohol. These ADH
variants are the alleles *ADH1B\*2* or *ADH1B\**3, and the ALDH variant
is the allele *ALDH2\*2*. The consequence of possessing one of these
enzyme variants, especially the ALDH variant, can produce a dysphoric
state that includes facial flushing and nausea. Experiencing these
unpleasant reactions can limit the desire to consume alcohol. It has
been shown that Individuals with the *ALDH2\*2* variant have a greatly
reduced risk for alcohol dependence. Most likely related to the
decreased drinking, individuals with the *ALDH2\*2* variant have over a
70% reduction in alcoholic cirrhosis, presumably due greatly reduced
frequency and quantity of alcohol consumption. While individuals
possessing both the ADH and ALDH variants are at lower risk alcohol
dependence (alcoholism), when they do drink, they are likely at higher
risk for tissue and organ pathology from acetaldehyde.

Another route to alcohol-induced tissue injury is through the generation
of reactive oxygen species (ROS). As presented in an earlier section,
the cytochrome P450s, as well as the mitochondrial oxidative chain are
capable of generating ROS as a consequence of alcohol metabolism. When
sufficient levels of ROS are generated they can deplete the cells
reserve of antioxidants, among which is glutathione, thereby increasing
the likelihood of oxidative injury.

Elevated levels of ROS have been shown to lead to the peroxidation of
lipids, proteins, and DNA. The products of lipid peroxidation include
two aldehydes, malonedialdehyde (MDA) and 4-hydroxynonenal (HNE). As is
the case with acetaldehyde, both of these aldehydes can form adducts
with proteins. As well, acetaldehyde and MDA can react with proteins in
a synergistic manner to generate a stable adduct,
MDA-acetaldehyde-protein adduct (MAA). MAA has been demonstrated to be
immunogenic and it can induce inflammation and autoimmune reactions in
various systems, including the circulatory system, and alter
neuroendocrine functioning.

Another consequence of the elevated levels of ROS is the potential for
mitochondrial damage which affects cell survival by inducing programmed
cell death (apoptosis). ROS may further cause organ injury through the
alteration of gene expression. ROS are capable of stimulating
transcription factors such as NFB and AP-1, which in turn increases the
genetic transcription of inflammatory cytokines (part of the disruption
of mitochondrial signaling pathways) leading to tissue damage.

Fatty acid ethyl esters (FAEE) are another class of metabolic products
arising from alcohol metabolism, in this case via a non-oxidative
esterification between fatty acids and alcohol. FAEEs may accumulate in
significant concentrations in some organs, including the pancreas where
they may contribute in the development of acute and chronic alcoholic
pancreatitis.

Alcohol use may also lead to the development of organ pathologies by
altering the mechanisms through which normal epigenetic regulation
occurs (see Figure VI-1). For example, in a rat model alcohol has been
shown to cause an increase in the acetylation of one particular histone
protein, H3, in a site-specific manner. The consequence is an increase
in transcription of a number of genes, including the gene for the rat
class I ADH enzyme. This research further showed that acetate, an
alcohol metabolite, was responsible for this effect by acting upon the
enzyme histone aceteyltranferase (HAT).

**Figure VI-1. Epigenetic Implications for Alcohol Metabolism**

![](media/image20.wmf){width="4.684722222222222in"
height="2.2083333333333335in"}

**Source: Garro et al ACER 15:395, 1991; Lu et al., Am J Physiol
Gastrointest Liver Physiol 279:G178, 2000; Lu and Mato, Alcohol 35:227,
2005; Mason and Choi Alcohol 35:235, 2005.**

In another example, alcohol, at high intoxicating doses, has also been
demonstrated to bring about a significant reduction in tissue levels of
the metabolite, S-adenosylmethionine, required for the methylation of
both histones and DNA. By inhibiting the biosynthesis of methionine at
the level of the enzyme methionine synthase (MS) (Figure VI-1) the
synthesis of the methyl donor S-adenosyl methionine will be impaired,
and in turn the methylation of histones and DNA. In this manner, alcohol
has the potential to cause significant disruption in gene expression
altering many biological processes that may result in various disease
states. Decreased DNA methylation has been linked to tumor formation,
although it is not known whether this is the route by which alcohol
increases the risk for the development of cancer in such organs as the
liver, throat, larynx, and esophagus

As noted in an earlier chapter, the oxidation of alcohol to acetaldehyde
and subsequently to acetate is accomplished by the reduction of the
co-factor nicotinamide adenine dinucleotide (NAD^+^) to its *reduced*
form, NADH. This changing in the oxido-reductive (redox) state itself
has the potential to cause metabolic changes, including those that
involve gene expression. One example of this has been demonstrated in
yeast and rat studies of caloric restriction. Caloric restriction
increases NAD^+^ relative to NADH. The yeast enzyme histone deacetylase,
Sir2, and the rat version of this enzyme, SIRT1, respond to this
increase in NAD^+^ by significantly increasing their catalytic activity.
The function of histone deacetylase is to remove acetyl moieties from
specific sites on histone proteins. In turn, the removal of the acetyl
moieties silences selected genes in the region of the affected histone
proteins. Among the genes silenced are those that code for enzymes
involved in the deposition of lipids into fat cells, a desired effect
during a period of starvation. While the shift in the NAD+/NADH ratio
resulting from alcohol metabolism, which would be in the opposite
direction to that arising from calorie restriction, has yet to be shown
to have an effect on gene expression mechanisms, the possibility of
observing this phenomenon is worthy of pursuit.

**C.2. Organ Disease**

Many of the major systems and organs of the body may develop a disease
state from heavy and long-term use of alcohol. Several of these
disorders are presented in the section on epidemiology (above). While
advances in our understanding of all of the diseases are not discussed
here, particular note is made of research findings on alcoholic liver
disease because of its identification as the leading cause of death from
alcohol.

**Liver Damage.** The multiple disorders of the liver that can arise
from alcohol use are collectively referred to as *alcoholic liver
disease*. Among these is fatty liver, a condition once considered to be
benign. Other alcohol-derived diseases in the liver include an
inflammatory disease, alcoholic hepatitis, and alcoholic cirrhosis, a
disease characterized by marked scarring of the liver. Other agents,
such as a variety of other chemicals and various bacterial and viral
agents may also bring about liver disease, and alcohol has generally
been considered to accelerate the progress of liver disease arising from
viral agents such as hepatitis C, one of the other major causes of liver
disease in the U.S. However, while individuals with hepatitis C who
drink clearly have increased risk for progression to cirrhosis, whether
there is an interactive as compared to a simple addition effect of the
alcohol exposure, or whether there is a threshold dose above which
alcohol accelerates viral liver diseases remains to be determined.

Alcohol-induced liver disease (ALD) occurs in only about 15-20% of heavy
alcohol consumers suggesting that genetic factors may contribute to this
process. Recent research has suggested that such genetic factors as the
presence of mutant c2 allele of CYP2E1 may increase the risk of
alcoholic liver disease.

# C.3. Genetic Variants and Alcohol Pathology 

Genetic factors have also been considered to underlie the risk for other
alcohol-related disorders, beyond alcohol dependence itself which was
discussed previously (Chapter V. Young Adult). Research has suggested
that individuals with the *ADH1C\*1* allele have an increased risk to
develop breast cancer from moderate amounts of alcohol. However, a
putative mechanism to explain this association has not been established.
It is also possible the genetic risk factor is not *ADH1C\*1* but
*ADH1B\*2*, a variant of ADH which is in linkage disequilibrium with
*ADH1C\*1*. Also, several polymorphisms of *CYP2E1* have been identified
and a few preliminary studies have been undertaken to determine their
effect on alcohol metabolism and tissue damage. In one study, an
association between the m2/m2 *CYP1A1* genotype and alcoholic liver
cirrhosis was found. Another study found a relationship involving
glutathione S-transferase where the Val/Val *GSTP1* variant was
associated with chronic pancreatitis.

**C.4. The Effects of Moderate Alcohol**

In addition to the development of pathologic conditions, many years of
epidemiological studies have produced findings to suggest that moderate
alcohol use (defined as no more than one drink per day for women and two
drinks/day for men) may afford a degree of protection from a number of
disease conditions including coronary artery disease (CAD), type 2
diabetes, dementia, and ischemic stroke. Recently, the results of many
such studies in the literature have been re-analyzed by several groups
of researchers in a meta-analysis examining the effects of moderate
alcohol consumption and total mortality in both men and women. It
appears that J-shaped relationship between moderate alcohol consumption
and total mortality is similar for both sexes, and that low to moderate
levels of alcohol consumption do confer some protection for mortality.
Although some mechanisms of action for this epidemiological finding have
been studied, more basic research offers the potential to confirm these
initial findings and more fully understand the means by which protection
is afforded. Such findings could guide the development of pharmaceutical
approaches for the prevention and treatment of these disorders.

Of all of the disorders that may benefit from moderate alcohol
consumption, CAD has been the most studied. Mechanisms that appear to
underlie alcohol-induced cardioprotection include changes in serum
lipids, blood clotting proteins, platelets, anti-oxidant polyphenols and
inflammatory cytokines. In addition, several reports suggest that
moderate alcohol consumption lowers systemic markers of inflammation,
e.g., C-Reactive Protein (CRP) associated with increased risk for CHD.
Also, exposure of the myocardium to a moderate alcohol dose before an
ischemic insult resulted in up to an 80% reduction in cardiac damage.
Enhanced recovery appears to be is associated with sustained activation
of ε-Protein Kinase C (PKC).

One potential mechanism underlying alcohol-induced reduction of risk for
Type II diabetes is an increase in insulin sensitivity. Formation of
advanced glycation end products (AGE's) and their binding to vascular
wall components contributes to atherogenesis. The anti-atherogenic
effect of moderate alcohol consumption may be linked to acetaldehyde,
which can react with nucleophilic precursors of AGE's to prevent AGE
formation and lipoprotein oxidation.

Some research to date on the mechanisms underlying alcohol-induced
reduction of risk for age-related dementia have focused on constituents
of alcoholic beverages including wine such as polyphenols, tannins, and
anthocyanin pigments that have antioxidant and anti-inflammatory
properties. In degenerative diseases of the brain, alterations in
consciousness are associated with regional deficits in the cholinergic
system. Moderate alcohol consumption has been shown to enhance the
release of acetylcholine in the hippocampus which may underlie its
neuroprotective effect.

A complete understanding of the biological mechanisms underlying the
protective or beneficial effect of alcohol consumption may improve our
understanding of the molecular targets that could lead to development of
therapies for coronary artery disease, dementia and diabetes.

**C.5. Alcohol and Human Immunodeficiency Virus (HIV)/Acquired
Immunodeficiency Syndrome (AIDs)**

The acquired immunodeficiency syndrome (AIDS) was first reported in the
United States in 1981 and has since become a major worldwide epidemic. 
Caused by the human immunodeficiency virus (HIV), AIDS has killed more
than 500,000 people in the United States, and as many as 950,000 people
in the U.S. may be infected with HIV.  Between 40,000 and 60,000 new HIV
infections occur each year in this country.

The epidemic is growing most rapidly among minority populations and is a
leading killer of African-American males ages 25 to 44. According to the
Centers for Disease Control and Prevention (CDC), AIDS affects nearly
seven times more African Americans and three times more Hispanics than
whites. People with HIV/AIDS are susceptible to opportunistic infections
caused by viruses or bacteria that usually do not make healthy people
sick.   HIV-infected individuals may also suffer from depression,
dementia, various psychiatric conditions, and early neuropathology,
manifested as impaired cognition and motor function, and poor executive
function.

Studies estimate that more than 80 percent of HIV-infected individuals
drink alcohol and that between 30 and 60 percent of people with HIV also
have alcohol use disorders.  Research also indicates that chronic
alcohol consumption facilitates HIV infection in people who have been
exposed to the virus, and accelerates the disease process and death of
HIV-infected people who progress to AIDS.  The reasons for these effects
are unclear, but may involve basic biological actions of alcohol and its
metabolites on the virus and its tissue target.  Alcohol may also
interfere with the metabolism of anti-HIV medications, an effect that
could account for the increased frequency of adverse medical events from
treatment with antiretroviral regimens among HIV-infected individuals
who drink alcohol.

Social factors influence the interaction between HIV and chronic alcohol
consumption and may affect the progression to AIDS.  For example, people
with alcohol use disorders are less likely to be tested for HIV.  Such
individuals who do get tested and are found to be HIV-positive are less
likely to seek treatment, and less compliant with prescribed treatments
for HIV infection or related diseases, than individuals without alcohol
use disorders. Excessive alcohol consumption also is closely associated
with HIV/AIDS risk behaviors such as unprotected sexual intercourse and
intravenous experimental drug use.  Although HIV is most commonly
diagnosed at midlife, HIV infection usually is contracted earlier in
life, typically during the young adult stage, a period often
characterized by heavy alcohol consumption or binge drinking and
increased prevalence of high risk behaviors associated with HIV
transmission.

Effective treatment for both alcohol abuse and HIV/AIDS leads to
reductions in viral load, viral mutation, and subsequent infectivity.
The complex interactions between alcohol and HIV/AIDS, as well as the
broad range of co-morbidities experienced by HIV-infected individuals
who drink alcohol provides a rationale for longitudinal clinical studies
aimed at advancing our understanding of these complex issues.

**D. Treatment: Mechanisms of Behavior Change**

Most individuals who seek alcoholism treatment do so during the midlife
period. Currently available treatments, which include behavioral
therapies and those that employ behavioral treatment with newly
available medications, help many such individuals successfully recover
from alcohol dependence. With minor exceptions, therapeutic approaches
using different models yield similar results, and there is only minimal
interaction with a wide variety of demographic and clinical patient
characteristics.

Just as some young adults recover from alcoholism without the benefit of
treatment, some individuals' transition away from alcoholism during
midlife without the help of any specialty alcohol treatment, a
phenomenon sometimes referred to as "aging out." Indeed, the NESARC and
other studies reveal that a large majority of heavy drinkers (including
those with dependence) reduce or stop drinking without seeking help in a
specialty treatment program. However, many other individuals either do
not experience this aging out phenomenon at all, or achieve multiple
episodes of short-term success from their alcohol use disorder followed
by relapse back into alcohol dependence.

People who resolve heavy drinking and its related problems without
specialized treatment differ systematically from those who do. Recovery
outside of treatment is more likely in those with fewer symptoms of
dependence, less co-morbid psychiatric disorders, less pressure to quit
drinking, and more social capital. This group of individuals forms a
unique population for further study. Although these individuals resolve
their alcohol use disorder, a more comprehensive understanding of how
the natural recovery occurs would provide the research community with
the information required to develop interventions targeting those
individuals who would not normally seek treatments. One of the goals of
this area of research would be to reduce the amount of time these
individuals must endure the current and future range of consequences
related to their alcohol use disorder before they age out or recover
naturally. Progress has been made to delineate trajectories and their
statistical predictors among young people, where much non-treatment
change takes place.

Still, a better understanding of the characteristics, mediators, and
environmental factors that motivate individuals to try to change their
drinking behavior, either on their own or through professional
alcoholism treatment, will greatly aid the search for improved
prevention and treatment strategies. If specific psychotherapy
techniques are not primary change agents, how does change occur? Even if
"common factors" such as therapist empathy, expectancy, therapist
allegiance to the model, and the therapeutic alliance are change agents,
how, exactly, do they work? In addition, improving the efficacy of
alcoholism treatment will require greater knowledge of the factors and
mediators that underlie a transition from alcohol dependence in those
individuals who are successful in recovering, in both the absence and
presence of formal alcoholism treatment. Insofar as it appears that the
change processes begin well before treatment entry, it may be that
treatment is more a result of change rather than a cause of it. Even if
that were the case, though, treatment could still have important effects
such as prevention of relapse, or more rapid or profound or more
gratifying change.

Historically, research on professional psychosocial interventions
focused first on development of theoretical frameworks to explain change
and to direct intervention efforts. Examples of such frameworks include
cognitive-behavioral, twelve-step, and motivational enhancement.
Subsequent research in this area included studies to refine the internal
validity of studies of these frameworks using therapy manuals, training,
and monitoring; development and use of well-validated and reliable
instruments; and improved research designs such as randomized controlled
trials. The results were unexpected: treatments with very different
conceptual frameworks and intervention techniques have approximately
equivalent (and reasonably good) outcomes (e.g., abstinence or
significantly decreased drinking and consequences). Furthermore,
relatively brief, non-intensive treatments yield outcomes as good as
more intensive treatments. These results suggest that non-specific
factors such as a decision to seek help, installation of hope, empathy
and the therapeutic alliance may be more important that specific factors
hypothesized by treatment models. An alternative explanation is that the
mechanisms are specific to each technique but they lead to a common
outcome. One reason that the two alternatives have not been
differentiated is that research to date has primarily focused on simple
efficacy comparisons, and therefore has been silent on the question of
what the mediators and moderators of change in these treatments actually
are.

**E. Treatment: Medications Development**

While for many years, alcoholism treatment approaches relied almost
exclusively on behavioral therapy, efforts to develop medications for
alcohol use disorders have expanded rapidly in recent years. Three
agents \-- disulfiram, naltrexone, and acamprosate \-- are now approved
for use in the United States and many other countries. As is the case
with medications for other chronic diseases, these medications have been
found to be highly effective with some patients but others have failed
to respond to them. New medications, providing effective therapy to a
broader spectrum of alcoholic individuals, would be of value for the
treatment of alcohol dependence. Research findings revealing that
drinking and alcohol-seeking behavior are influenced by multiple
neurotransmitter systems, neuromodulators, hormones, and intracellular
networks provides evidence that there are a number of potential target
sites for which new pharmaceuticals may be developed. Potential target
sites include neurotransmitter systems related to opioids, serotonin,
dopamine, glutamate, gamma-aminobutyric acid (GABA), cannabinoids, the
hypothalamic-pituitary-adrenal (HPA) axis, adenosine, neuropeptide
systems (for example, neuropeptide Y, corticotrophin releasing factor),
signal transduction pathways (such as, protein kinase A and protein
kinase C); and gene transcription factors (delta fos B and cAMP response
element-binding protein \[CREB\]). Indeed, many such agents are under
test as shown in Table VI-3. Among these agents several promising
compounds are currently being considered as candidates (baclofen,
rimonabant, and memantine) for evaluation to determine their safety and
efficacy in the treatment of alcohol use disorders and it is likely that
additional agents will be identified as medications development efforts
for alcoholism proceed.

**Ta**ble VI-3. NIAAA Medication Development Lead Compounds

+------------------------+----------------------+---+----+----+-----+
| **Medication under     | **Mechanism**        | * | *  | *  | *   |
| development**          |                      | * | *P | *P | *Ph |
|                        |                      | P | h1 | h2 | 3** |
|                        |                      | r | ** | ** |     |
|                        |                      | e |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      |   |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | C |    |    |     |
|                        |                      | l |    |    |     |
|                        |                      | n |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| Naltrexone depot       | Opiate antagonist    |   |    |    | **  |
| formulation            |                      |   |    |    | X** |
| (Vivitrex^®)^          |                      |   |    |    |     |
| Alkermes)              |                      |   |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| Topiramate (Topamax™   | Facilitates GABA and |   |    | *  | **  |
| Ortho-McNeil)          | inhibits glutamate   |   |    | *X | X** |
|                        | activities           |   |    | ** |     |
+------------------------+----------------------+---+----+----+-----+
| Gabapentin (Neurontin™ | Facilitates GABA and |   |    | *  |     |
| Pfizer)                | inhibits glutamate   |   |    | *X |     |
|                        | activities           |   |    | ** |     |
+------------------------+----------------------+---+----+----+-----+
| Ondansetron(Zofran™    | 5-HT~3~ antagonist   |   |    | *  |     |
| GSK)                   |                      |   |    | *X |     |
|                        |                      |   |    | ** |     |
+------------------------+----------------------+---+----+----+-----+
| Baclofen (FDA          | GABA~B~ agonist      |   |    | *  |     |
| approved)              |                      |   |    | *X |     |
|                        |                      |   |    | ** |     |
+------------------------+----------------------+---+----+----+-----+
| rimonabant             | Cannabinoid CB~1~    |   |    | *  |     |
| (Acomplia^TM^          | antagonist           |   |    | *X |     |
| Sanofi-Synthelabo)     |                      |   |    | ** |     |
+------------------------+----------------------+---+----+----+-----+
| Memantine (Namenda ™   | glutamate NMDA       |   | *  |    |     |
| Forest Laboratories)   | antagonist           |   | *X |    |     |
|                        |                      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| antalarmin             | CRF~1~ antagonist    |   | *  |    |     |
|                        |                      |   | *X |    |     |
|                        |                      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| CRF1 antagonist        | CRF~1~ antagonist    |   | *  |    |     |
|                        |                      |   | *X |    |     |
|                        |                      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| Kudzu extract          | Unknown              |   | *  |    |     |
|                        |                      |   | *X |    |     |
|                        |                      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| Diphenylureido         | glutamate NMDA       |   | *  |    |     |
| compound, DCUKA        | antagonist, sodium   |   | *X |    |     |
|                        | channel blocker      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| Aripiprazole           | Dopamine partial     |   | *  |    |     |
|                        | agonist              |   | *X |    |     |
|                        |                      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| LY686017               | NK1 receptor         |   | *  |    |     |
|                        | antagonist           |   | *X |    |     |
|                        |                      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| Nociceptin agonist     | NOP agonist          |   | *  |    |     |
|                        |                      |   | *X |    |     |
|                        |                      |   | ** |    |     |
+------------------------+----------------------+---+----+----+-----+
| N,N                    | Glutamate NMDA       | * |    |    |     |
| \'-bis-(3-aminopropyl) | antagonist           | * |    |    |     |
| c                      |                      | X |    |    |     |
| yclohexane-1,4-diamine |                      | * |    |    |     |
| (DCD)                  |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| 2-Methyl-6-(p          | mGluR5 antagonist    | * |    |    |     |
| henylethynyl)-pyridine |                      | * |    |    |     |
| (MPEP)                 |                      | X |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| NPY                    | NPY                  | * |    |    |     |
| agonists/antagonists   | agonists/antagonists | * |    |    |     |
|                        |                      | X |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| CRF~2~ agonists        | CRF~2~ agonists      | * |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | X |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| Adenosine A~2~         | Adenosine A~2~       | * |    |    |     |
| antagonists            | antagonists          | * |    |    |     |
|                        |                      | X |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| betaCCt                | GABAAα1 mixed        | * |    |    |     |
|                        | agonist/antagonist   | * |    |    |     |
|                        |                      | X |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+
| RY 023                 | GABAAα5 inverse      | * |    |    |     |
|                        | agonist              | * |    |    |     |
|                        |                      | X |    |    |     |
|                        |                      | * |    |    |     |
|                        |                      | * |    |    |     |
+------------------------+----------------------+---+----+----+-----+

The development of new medications for alcoholism is greatly aided
through the use of animal models for the screening of new agents that
can alter attributes associated with alcohol dependence. Several
laboratory paradigms which model facets of alcoholism are now used to
study the behavioral effects of alcohol in mice, rats and monkeys. These
include:

-   Models that involve self-administration of large amounts of alcohol
    sufficient to produce tolerance, withdrawal and high blood ethanol
    levels (i.e., \> 100 mg/dl). These behaviors are found in animals
    predisposed to prefer alcohol solutions (e.g., selectively bred
    strains), or after induction periods under certain conditions (e.g.,
    dependence-induced drinking).

-   Animals that are motivated to procure alcohol when no longer
    available, or in the face of impediments or negative consequences.
    Drinking attributes can be evaluated for these models using operant
    self-administration paradigms. These animals model
    obsessive-compulsive attributes of human alcohol dependence
    characterized by craving, and drinking despite adverse consequences.

-   Cycles of remission and relapse to drinking can be modeled using
    alcohol deprivation paradigms.

-   Environmental events triggering an episode of alcohol seeking
    following a remission period can be modeled in a reinstatement
    paradigm.

Therefore, while it is now possible to model some attributes of
dependence, craving, lapse, and relapse using a variety of current
animal laboratory paradigms, new models that more closely model the
endophenotypes and intermediate phenotypes (for definitions see Table
I-10) involved in the development and expression of alcoholism would
greatly benefit medication development efforts. For example, the
endophenotype of neural disinhibition may be modeled in different animal
models and prove useful as a tool for medication development research.

Another aid in the search for new medications is through human
laboratory testing. Testing of model therapeutics, in a human laboratory
environment with a relatively small subject population carefully
selected for their targeted drinking behavior can provide a significant
savings in the time and cost associated with clinical trials for the
development of new medications. These efforts are undertaken after
animal pre-clinical screening. Currently, there is no consensus on the
best way to evaluate drugs to treat alcoholism in the human laboratory
environment, although two models have been used: alcohol
self-administration and relief from the symptoms of alcohol protracted
abstinence. The continued study of these laboratory animal models, and
the development of new models is timely and required for rapid progress
to be made in the screening of targeted compounds shown to offer promise
from animal studies.

The identification of new biomarkers to provide an early indication of
treatment success would be a great asset in medications development.
During the past years, efforts have been made to develop and
characterize new as well as traditional biomarkers of alcohol
consumption and alcohol-induced tissue injury. Traditional biomarkers of
alcohol consumption include gamma-glutamyl transferase (GGT), aspartate
aminotransferase (AST), alanine aminotransferase (ALT), and corpuscular
volume (MCV). Newer markers include carbohydrate-deficient transferrin
(CDT), 5-hydroxytryptophol (5-HTOL), a serotonin metabolite, and ethyl
glucuronide (EtG), a metabolite of alcohol.

In addition to biomarkers of alcohol consumption, biomarkers of
alcohol-induced tissue injury are also of importance. Such potential
markers for alcoholic liver disease include alpha-smooth muscle actin
(SMA), fibronectin, collagen type I, serum hyaluronate, matrix
metalloproteinase (MMP)-2, and MMP-9.

However, current biomarkers, for the most part, lack specificity or
sensitivity, or have a very short half-life. Due to the limitations of
these biomarkers, it is vital to discover new biomarkers that are unique
to alcohol consumption and/or alcohol-related diseases. Recent advances
in high-throughput technologies for proteomics, genomics, and
metabolomics have been successfully used for studying complex biological
problems and show promise for the identification of individual
biomarkers and unique signatures. These high-throughput technologies
have created new exciting opportunities for discovering and developing
novel biomarkers that may be useful for alcohol-use disorders.

Another important direction for medications development research lies in
pharmacogenetic research, that is, the identification of genetic
subtypes of alcohol dependence that respond to specific pharmacologic
agents. Research in recent years has discovered specific genetic
variants that may contribute to the risk for alcoholism, and which may
define specific sub-sets of alcohol dependent individuals who respond to
specific therapeutic agent. Among the genetic variants are the GABA~A~
receptor genes *GABRA2* and *GABRG3* that have recently been associated
with alcoholism. Other promising sites include the short versus the long
allele of the serotonin transporter, the presence or absence of the A1
allele of the dopamine D~2~ receptor gene, catechol-O-methyltransferase
(COMT) Val158Met allele, and the NPY gene variant Leu7Pro. Also included
here, as discussed in the context of protection versus susceptibility
for alcoholism, are the polymorphisms in the alcohol dehydrogenase gene
*ADH1B* and the aldehyde dehydrogenase gene *ALDH2.* Consideration of an
individual patient's unique genetic profile and phenotypic
characteristics may help in the future for selecting the most effective
anti-alcohol medication. Although research is in early stages, some
advances have been made. A polymorphism in the gene that codes the
opioid *mu* receptor (A118G, which causes an Asn40Asp substitution in
the protein) has recently been associated with the response to
naltrexone in alcohol dependent patients and to a family history of
alcoholism, alcohol intoxication, and alcohol-induced stimulation and
sedation. In a preliminary study, alcoholic patients treated with the
drug olanzapine who possess the dopamine *DRD4 L* allele (7 or longer
repeat allele of the tandem repeats \[VNTR\]) experienced reduced
craving for alcohol, while olanzapine did not reduce craving in those
with the *DRD4 S* allele.

Progress has also been made with respect to defining new medication
targets for organ pathologies. In particular, cytokines, reactive oxygen
species (ROS), and other primary factors in the onset and progression of
alcoholic liver disease may prove fruitful as medication targets. For
example, it has been found that the severity of alcohol-induced liver
injury in rats could be reduced through the administration of antibodies
against tumor necrosis factor α (TNF-α), a molecule that promotes
inflammation. Antioxidants such as Vitamin E, glutathione, or its methyl
donor, S-adenosyl-L-methionine (SAMe) also have shown potential for
treating alcoholic liver disease. These compounds can quickly inactivate
ROS, by-products of alcohol metabolism that can damage the liver.
Research suggests that cannabinoid CB~1~ antagonists and CB~2~ agonists
may be a potential therapeutic target for alcohol treatment given their
close association with the reward centers of the brain (nucleus
accumbens) and their modification by ethanol intake in animal studies.
Furthermore, metformin, an insulin-sensitizing agent, also warrants
further study as a potential medication for alcoholic liver disease.

**F. Opportunities**

*Metabolism and Organ Injury*

-   The mechanisms by which alcohol may elicit altered metabolic and
    physiological states in disease development common to multiple
    organs within the body can be more comprehensively pursued including
    the exploration of how alcohol and its metabolic intermediates, such
    as reactive aldehydes, ROS and alterations in the redox state of the
    cell change following alcohol consumption. Research on the
    consequences of such changes may be approached by examining the
    direct and indirect actions of alcohol in altering transcription
    factors, cytokines and other agents altering communication networks
    within the body.

-   Continued research on the effects of alcohol at low and moderate
    dose levels may be feasibly approached to further uncover the
    mechanism underlying both pathologic and potential beneficial
    outcomes of these levels of alcohol exposure. Longitudinal research
    may be entered into collaboratively with other institutes of the NIH
    in the overall study of a range of alcohol and non-alcohol related
    diseases.

-   Investigate how alcohol influences the disease course of various
    pathogens, such as Hepatitis C and Hepatitis B.

*Alcohol and HIV/AIDS*

-   Examine whether alcohol's effect on HIV infection and AIDS
    progression varies with age of infection, and how co-infections (TB,
    HepC) alter disease progression.

-   Identify the alcohol-related factors associated with increased HIV
    infectivity, such as viral shedding, the alteration of HIV variants
    through such processes as epigenetics, and the potential effect of
    alcohol on metabolism of anti-HIV medications, including highly
    HAART medications.

-   As AIDs patients' life expectancy has increased since the
    introduction of HAART medications, the causes of AIDs mortality has
    changed with liver disease becoming more prominent. As alcohol is
    also a toxic agent for liver and other organs, identify how alcohol
    further contributes to organ and tissue damage in HIV-infected
    individuals. Follow infected individuals longitudinally using
    various tests for organ damage (e.g., neuropathology using MRI) to
    determine the relative role of alcohol consumption pattern (and
    amount) and anti-retroviral drugs on disease progression, and
    morbidity/mortality from opportunistic diseases

-   Determine the implications of alcohol and AIDS basic science
    discoveries for prevention and treatment research.

*Treatment and Behavioral Change*

-   Behavioral research should be further pursued to identify biological
    factors and contextual social factors that contribute in the
    decisional process to change drinking behavior involved in the
    transitional process out of alcohol dependence, and the factors that
    are the underpinning of sustained recovery among those individuals
    who succeed in both the presence and absence of professional
    treatment. Measures reflective of these factors might include those
    of implicit cognition, hedonics, arousal, or emotion, and these
    measures might be suggestive of the decisional process to inflect
    change or the sustained recovery from alcoholism. Naturalistic,
    qualitative and longitudinal studies can identify factors
    influencing natural history and disease course, in order to inform
    more explanatory studies.

-   Increase understanding of the role of social context in promoting or
    retarding positive change in drinking behavior. Included within the
    context of social factors are marital or other partners, friendship
    and kin networks, employment environments, legal and economic
    environment (availability and price of alcoholic beverages,
    proximity to outlets, DWI laws), religious groups, mutual help
    groups, and similar activities. This research needs to be approached
    over a time dimension to aid in defining the mediators and
    moderators underlying successful transitions and include an
    identification of the time course of the various stages of change.

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-   Develop animal models that more closely reflect the human endo- and
    intermediate phenotype underlying the clinical syndrome phenotype.

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-   Apply new technologies in neuroscience research to further
    understand how acute as well as chronic alcohol use affects neural
    circuits (rather than gross morphological brain areas), and how
    neural circuits are modified by treatment and recovery. In terms of
    neural circuits, use objective measures of brain function such as
    EEG and specific brain imaging techniques (e.g., diffusion tensor
    imaging) to identify potential intermediate phenotypes, or
    endophenotypes (see Table I-10), associated with alcoholism and the
    effects of treatment. Furthermore, measures of implicit cognition,
    and neurofunctional changes associated with cognitive/emotional
    deficits in alcoholic subtypes and recovering alcoholics would be a
    novel focus. This research could best be accomplished by
    transdisciplinary collaborations among behavior, social and
    neuroscience researchers.

-   Apply insights and methods \-- such as model development using
    sophisticated statistical techniques \-- developed in neuroscience,
    immunology, oncology, sociology, genomics, metabolomics and other
    fields to study change in drinking behavior.

*Medications Development*

Increase the number of medications available for the treatment of
alcoholism to reach a broader spectrum of individuals with alcoholism.
To accomplish this goal, the following initiatives are currently timely
and feasible:

-   Identify new target sites in the brain for which lead compounds
    could be developed. Identification of new target sites requires an
    expansion of basic neuroscience research to uncover the
    neurocircuits underlying relevant behaviors including: biological
    reward; alcohol-seeking behavior, protracted withdrawal symptoms,
    craving, and the psychological and social dynamic attributes of
    drinking. The NIH Roadmap Molecular Library which has been
    established provides a repository for many potential test compounds
    to accelerate progress in identifying both the molecular sites and
    lead compounds.

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-   To facilitate the testing of lead compounds, develop animal models
    that more closely reflect the human endo- and intermediate phenotype
    underlying the clinical syndrome phenotype. It is anticipated that
    multiple models will be required as no single animal model can fully
    model the clinical syndrome phenotype of human alcoholism. Given the
    diversity of models, pharmaceuticals targeted to different aspects
    of alcohol dependence may be pursued and effective pharmacotherapy
    for some individuals may require multiple therapeutic agents.
    Positive outcome from evaluations of test compounds with animal
    laboratory paradigms will guide decisions about whether lengthier,
    more expensive, clinical tests in human alcoholics are warranted.

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-   Develop human laboratory paradigms modeling surrogate outcomes for
    alcoholism treatment. This requires an understanding of expressed
    behavioral or physiological traits (endophenotypes and intermediate
    phenotypes) associated with the risk for, or expression of
    alcoholism. Potential new markers include cue sensitivity, neural
    inhibition, and other electrophysiological indicators to add to
    those already available.

-   Expand efforts in pharmacogenetic research to identify genotypic and
    phenotypic characteristics of patients that predict efficacy and
    safety of different medications. Such research will help delineate
    alcohol dependence subtypes and offers the clinician the potential
    to prescribe medication regimens tailored to the individual. In
    recognition that pharmacogenetic variants do exist, it is important
    to formulate methodological and statistical strategies to select the
    most appropriate outcome measures for detecting moderate-sized
    effects in alcohol pharmacotherapy trials.

-   Identify and develop novel biomarkers and other surrogate endpoints
    to measure success objectively in pharmacotherapy trials. As well,
    apply the technology of the non-invasive, continuous monitoring
    biosensor for the measurement of alcohol, and other appropriate
    analytes, to monitoring of pharmaco- and other treatment
    effectiveness and in particular, to study dynamics of relapse.

-   Continue research targeted to the prevention and treatment of
    alcohol-related organ pathologies involving anti-oxidant agents, and
    cannabinoid related agents.

-   Develop collaborative networks among government, academia, and
    industry in order to overcome the many challenges in development of
    medications to treat alcohol problems. Establishing these
    partnerships will allow for a more comprehensive effort to discover
    and develop safe, effective medications, and for the application of
    the resources of the NIH Roadmap such as molecular libraries, and
    infrastructures for clinical protocol testing.

**G. Outreach**

-   NIAAA has developed working relationships with many outside
    organizations with missions and goals that extend the ability to
    move research results to practice and to the public. Jointly, the
    NIAAA seeks to assure informed and research based policy and program
    decisions by these organizations and to provide support to assist in
    the distribution of alcohol research knowledge. The NIAAA
    collaborates with these organizations by providing symposia,
    workshops and meetings in which alcohol researchers or staff present
    relevant study results.

-   A Memorandum of Understanding (MOU) between the NIAAA Division of
    Intramural and Clinical and Biological Research and the School of
    Medicine at Howard University will provide for the co-mentoring of
    pre-doctoral students including participation in research, seminars,
    examinations and short-term rotations. This partnership provides
    NIAAA opportunities to: explore mechanisms and develop hypotheses
    that may alleviate health disparities in alcohol related problems;
    provide education and information to the community and to health
    care providers which will aid in the prevention and treatment of
    alcoholism and alcohol abuse; increase the participation of
    minorities in research studies at NIAAA and Howard University.

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-   Use state-of-the-art communication strategies and techniques to
    increase awareness of critical alcohol and health messages,
    including that: research-based treatments improve the health and
    well-being of individuals with alcohol problems; research promises
    to further elucidate mechanisms of alcohol damage and lead to
    targeted interventions.

-   Partnering with the Office of AIDS Research to continue
    identification of the most prevalent research areas involving an
    interaction between HIV/AIDS and alcohol consumption.

-   Helping Patients Who Drink Too Much: A Clinician's Guide. This
    practical guide to aid physicians and other health care providers in
    the care of patients with alcohol use disorders, the *Guide*
    presents a user-friendly, research-based approach to screening,
    diagnosing, and managing patients with heavy drinking and alcohol
    use disorders. The 2005 version of the *Guide* was updated in 2007
    and offers the following new resources: CME/CE credits for
    physicians and nurses available through Medscape; support for
    medication-based therapy in non-specialty settings; a new handout
    with strategies to help patients cut down on drinking or quit; a new
    dedicated Web page devoted to the *Guide* and supporting resources
    for clinicians and patients
    ([[www.niaaa.nih.gov/guide]{.underline}](../www.niaaa.nih.gov/guide));
    and an updated PowerPoint presentation for educators and
    instructors. NIAAA has worked closely with several organizations to
    disseminate the *Guide* to their memberships including the American
    Medical Association, the American Society of Addiction Medicine, the
    Association for Medical Education and Research in Substance Abuse,
    and the American Academy of Addiction Professionals. In addition,
    copies were sent to the deans of schools of medicine and schools of
    nursing. The *Guide* and related products are also available in
    Spanish. Copies of the Guide are available from NIAAA, and responses
    to the *Guide* have been highly favorable. Of note, thousands of
    physicians and nurses have completed the online CME course.

-   ADDICTION, an HBO documentary: NIAAA along with the National
    Institute on Drug Abuse (NIDA) collaborated with HBO to create a
    90-minute documentary, ADDICTION, which aired on March 15, 2007. One
    of NIAAA\'s key scientific staff, Mark Willenbring, M.D., was one of
    several principal spokespersons for the documentary and was featured
    in a supplementary broadcast on treatment advances. Several NIAAA
    grantees appeared in the documentary. A general-audience HBO book
    accompanied the video.

-   *A Social Work Education Model for the Prevention and Treatment of
    Alcohol Use Disorders.* This comprehensive curriculum is directed
    towards social work educators who prepare professional to practice
    in a variety of settings where they have the opportunity to improve
    outcomes for their clients who either have an alcohol disorder
    diagnosis or are at risk for developing one. Lecture ready modules
    developed by NIAAA-funded alcohol investigators, social work
    researchers, and social work educators support MSW education.
    Materials include Powerpoint presentations, handout materials,
    classroom activities, and accompanying case examples and can be
    found at <http://pubs.niaaa.nih.gov/publications/Social/main.html>
    Modules can be used individually or as a series, and modified to fit
    specific teaching objectives. The curriculum covers current alcohol
    research in epidemiology etiology, prevention, screening,
    assessment, intervention, motivational interviewing, legal and
    ethical issues, coordinated care systems, intimate partner violence,
    adolescence, women, older adults, homelessness, comorbidity, sexual
    orientation, refugees and immigrants, ethnicity, disability, and
    fetal exposure to alcohol. An evaluation of the curriculum, using a
    random sample drawn from every MSW program in the country is
    currently underway and will be completed in 2008. Preliminary
    results have been presented at the Council for Social Work Education
    annual meeting, the Society for Social Work Research, and the
    Research Society on Alcoholism.

-   *Curriculum for BSW Nursing Education.* A curriculum is currently
    under development that is aimed at undergraduate nursing faculty.
    Similar to the Social Work curriculum, it will contain modules that
    can be used as a series or individually, in order to fit specific
    teaching objectives throughout the nursing curriculum. It is being
    written and edited by nursing researchers, nursing educators, and
    experts in addiction nursing. The goal of the curriculum is to
    educate practitioners who will work in a broad array of nursing
    settings, [not]{.underline} addiction specialists. Modules include
    topics in alcohol genetics, prevention and health promotion, the
    neurobiology of addictions, alcohol screening, treatment of high
    risk alcohol use, management of intoxication and withdrawal,
    assessment and treatment of DSM-IV alcohol use disorders, health
    consequences of alcohol use, and legal and ethical issues. In
    addition to the full curriculum which will be available on the NIAAA
    website, an interactive distance learning course is planned. A pilot
    test of the curriculum is scheduled to take place at Howard
    University School of Nursing September 10-11, 2007. An evaluation of
    the curriculum is planned for 2008-2010.

> **CHAPTER VII. Senior Adult**

**A. Background**

Aging is associated with a variety of changes that place senior adults
at special risk for alcohol-related health problems.  As people live
longer, the absolute number of senior adults who continue to drink as
they age will increase. Since the percentage of aging individuals in the
general population is steadily increasing, the number of senior adults
with problem drinking habits will become a national healthcare issue.
Senior adults are known to differ in their physiological and behavioral
responses to alcohol in a variety of social contexts, and their ability
to respond to alcohol tolerance is greatly altered during the senior
years. Drinking can aggravate a variety of pathological conditions in
the senior adult including stroke, hypertension, neurodegeneration,
memory loss, mood disorders, and cognitive or emotional dysfunction.  On
the other hand, moderate drinking in the senior population has been
shown to have some effect on reducing the risk of death; both women and
men consuming alcohol daily had a 15% reduction in risk of death, and
the stable consumption of alcohol across the senior lifespan (measured
over two decades) appeared to be a significant factor. Notwithstanding
the obvious problems associated with diagnosing problem drinking in the
senior adult population, including the similarities in alcohol-related
and age-related manifestations, the results of studies may be influenced
by the location of the subjects at the time of measurement (e.g.,
nursing home or assisted care facility, independent living in retirement
community, hospital, primary care setting).

**B. Epidemiology**

Although senior adults drink less than other adults, their pattern of
alcohol consumption has changed over time; more recent birth cohorts of
seniors tend to drink more than less recent birth cohorts, which
represents generational shifts in attitudes about alcohol consumption
over time. Therefore, more aging individuals will be drinking more and
the health related issues resulting from this fact will change the need
for better surveillance of the problems faced by the future generations.

**Table VII-1. Percentage of U.S. Adults 18 and Over with Past-year
Alcohol Abuse or Dependence and Percentage of Those with Past-year Abuse
or Dependence Who Received Alcohol Treatment, by Type of Treatment**

+----------------+------+----------+---------+-------+------+---------+
| **Age group**  | **P  |          | **Type  |       |      |         |
|                | ast- |          | of      |       |      |         |
|                | year |          | trea    |       |      |         |
|                | di   |          | tment** |       |      |         |
|                | sord |          |         |       |      |         |
|                | er** |          |         |       |      |         |
+----------------+------+----------+---------+-------+------+---------+
|                | *    | **Depe   | **Any** | *     | *    | **12    |
|                | *Abu | ndence** |         | *12-S | *Oth | -Step** |
|                | se** |          | **trea  | tep** | er** |         |
|                |      |          | tment** |       |      | **and   |
|                |      |          |         | **o   | **on | Other** |
|                |      |          |         | nly** | ly** |         |
+----------------+------+----------+---------+-------+------+---------+
| Senior (60+)   | 1.4  | 0.5      | 3.4     | 1.9   | 0.8  | 0.6     |
+----------------+------+----------+---------+-------+------+---------+

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**Source: Adapted from Table I-8 in the overview.**

As shown in the table above (Table VII-1), only 0.5 percent of
individuals over 60 met criteria for a diagnosis of alcohol dependence
during the previous year. Only 1.4 percent met a diagnosis of alcohol
abuse. Despite this, only 3.4 percent of those meeting a diagnosis of
either alcohol dependence or alcohol abuse had, at some point in their
lives, treatment for their alcohol-use disorder.

In a large sample of seniors aged 65-103 years in primary care, heavy
alcohol consumption and binge drinking were associated with depression,
anxiety and perceived poor health compared with moderate drinkers, and
in another study, moderate alcohol consumption was associated with
better cognitive health and subjective feelings of well-being than
non-drinkers. In addition, moderate alcohol consumption was related to
lower Medicare costs in patients with cardiovascular disease (CVD) than
in non-drinking patients with CVD.

Longitudinal studies indicate the majority of those individuals who
drink heavily as seniors were also heavy consumers over the course of
their adult years before entering the senior adult years. Consumption of
alcohol has declined more slowly among the more recent cohorts of older
individuals as subsequent generations of senior adults are influenced by
generational attitudes towards drinking. This has significant
implications for healthcare of future senior adult populations. An
important distinction is made between individuals with an early onset
versus late onset of problem drinking: those with a late onset (the
majority are female) have a better chance at recovery and fewer
alcohol-health related problems than those with an early onset of
problem drinking, although little research on this specific topic has
been performed. However, alcohol misuse in the senior adult population
remains an important public health issue since older individuals are
more likely to have additional health problems that may confound
accurate diagnoses of wholly organic versus wholly alcohol problems.

One of the major issues with respect to estimating the prevalence of
alcohol abuse in senior adults involves survey location, e.g., estimates
are lowest from community-based surveys (those that sample from senior
adults living in independent settings), increased from health care
settings (hospital admissions from emergency room and psychiatric
wards), and the highest estimates were derived from studies within
nursing and critical care facilities, and the diagnostic criteria with
which senior adults are compared for the purpose of diagnosis (many of
the criteria are not relevant for the senior adult with drinking
problems).

**C. Etiology**

The etiology of problem drinking by older persons is not well studied.
Obviously, senior adults differ from non-senior adults in physiology,
biology and social aspects, all of which may contribute to higher
alcohol consumption on average in the senior adults. In terms of
biological effects, senior adults have a smaller body mass and lower
water content than non-senior adults, thus the blood alcohol
concentration attained for like-amounts of alcohol consumed will differ
between these groups of individuals independent of their inherent
metabolism. Senior adults are more likely to have intrinsic problems
with health issues related to blood pressure, sleep patterns and bone
metabolism, for example, which may prompt an increase in alcohol
consumption to offset the perceived effects of such medical conditions.
Senior adults take more medications than non-senior adults, therefore
causing a potential reduction in the effectiveness of medications taken
to alleviate specific medical conditions or a significant interaction
between prescription drugs and alcohol resulting in additional potential
for harmful side effects of either drug on the individual.

There are various social factors that may result in increased alcohol
consumption in senior adults, such as loss of a spouse, lack of or
reduced family support, and the availability of disposable income to
engage in drinking. Furthermore, the period of retirement may be a risk
factor in the development of increased alcohol consumption since senior
adults have more unstructured free time and no longer have job-related
ramifications of heavy alcohol consumption. Individuals in any age range
may misinterpret the information regarding the benefits of alcohol
consumption on general health (including misinterpretation of amount and
frequency that may produce the benefit). For senior adults, the
consequences of inappropriately weighing the relative risk versus
benefit of alcohol consumption for their age group may have particular
negative consequences with regard to their personal medical conditions.

**D. Treatment and Prevention**

There is some evidence that senior adults will respond positively to
treatments especially if they are treated within groups consisting of
similar-aged individuals. Senior adults with late onset problem drinking
(more typical of female than male) and shorter history of problem
drinking tend to respond more positively to treatment efforts than those
with early onset problem drinking. The most efficacious therapies seem
to involve cognitive-behavioral therapy and group and family therapy,
which tend to involve familial support mechanisms that may have been an
exacerbating factor for the increase in late-life alcohol abuse. There
is some indication that medications developed to promote abstinence may
not work as well in senior adults given that the mechanism of benefit
may be altered due to age-related issues (more so than to
alcohol-related issues), although this area is not well studied in the
clinical population.

Similarly, based on the current literature, the most beneficial
prevention of senior adult alcohol abuse is education, since some
reports indicate that lack of knowledge about alcohol abuse rather than
a disregard for the information was at the root of some problems
associated with relapse in senior adult problem drinkers. Since there is
no definitive phenotype for the senior adult problem drinker, the
development of current prevention efforts must be geared towards
generalized personality or situational characteristics that have led to
problem drinking in like-age groups of individuals.

**E. Opportunities**

Although the fundamental processes responsible for normal chronological
aging clearly can influence individuals' responses to alcohol, the basic
biological mechanisms underlying this relationship have remained largely
unexplored.  Recent studies have yielded exciting new information about
how chronological aging affects brain function, cardiovascular function,
endocrine function, and immune function.  Likewise, there has been
dramatic progress in alcohol research from genetic to behavioral and
cognitive levels.  These advances, together with recently developed
technologies and experimental models, provide important new
opportunities to examine how mechanisms affected by alcohol exposure and
aging interact with one another. Some of these mechanisms may mediate
altered physiological functions in different tissues, while others may
participate in degenerative processes leading to tissue damage.

-   Current understanding the metabolic changes that occur with the
    progression of age is very limited. Technologies introduced in the
    last decade that permit a more detailed understanding of alcohol
    metabolic pharmacokinetics including alcohol clamping, and the
    examination of differential expression of genetic (genomic) protein
    (proteomic) and metabolic (metabolomic) profiles that have either
    been recently developed, or that will emerge from initiatives within
    the NIH Roadmap, can provide important information pertinent to
    individuals across the senior adult age ranges. These same
    technologies can be applied to important metabolic consequences
    associated with the range of pharmaceuticals taken by individuals in
    the senior age range given the common use of medications in the age
    group.

-   As efforts continue in the development of new medications for the
    treatment of alcohol dependence, a focus on the effectiveness of
    these emerging pharmaceuticals in the senior adult population, given
    the differences in physiology and potential interactions with other
    medications taken by this group will be an important adjunct to such
    research.

-   The changing demographics in the age of the U.S. population may
    translate into significant changes in the contexts of alcohol use in
    the senior adult population, as well as, the social consequences of
    that use. The continued monitoring of these changes will be
    important given the impact that alcohol may have on this population.
    Longitudinal assessments of the use, impact, and consequences of
    alcohol use, coupled into other longitudinal assessments jointly
    undertaken by multiple institutes of the NIH, will offer a cost
    effective approach for obtaining this important information. Such
    efforts also provide a cost effective means to determine the
    relationship of alcohol in the development of such disorders as
    Alzheimer's disease, Type II diabetes, and others that increase with
    age.

-   Animal models of alcohol abuse and aging can be used to examine
    specific contributions of alcohol to aging organ pathology (e.g.,
    brain, liver, heart).

**F. Outreach**

-   Working with the NIA, Association for the Advancement of Retired
    Persons (AARP), and Medicare, NIAAA will increase the transfer of
    information to practice for seniors through publications and
    assuring that health care providers have appropriate information.
    Co-sponsorship of meetings and conferences will be used to foster
    working relationships.