alcohol use, abuse, and dependence
DESCRIPTION
Alcohol Use, Abuse, and Dependence. Ting-Kai Li, M.D. Director National Institute on Alcohol Abuse and Alcoholism National Institutes of Health U.S. Department of Health and Human Services. Ting-Kai Li, M.D. Director National Institute on Alcohol Abuse and Alcoholism. - PowerPoint PPT PresentationTRANSCRIPT
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Alcohol Use, Abuse, and Dependence
Ting-Kai Li, M.D.Director
National Institute on Alcohol Abuse and Alcoholism
National Institutes of HealthU.S. Department of Health and Human
Services
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http://www.niaaa.nih.gov/AboutNIAAA/DirectorsCorner/default.htm
Ting-Kai Li, M.D.
Director
National Institute on Alcohol Abuseand Alcoholism
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National Institute on Alcohol Abuse and Alcoholism Mission
● increase the understanding of how alcohol use impacts normal and abnormal biological functions and behavior across the lifespan
● improve the diagnosis, prevention, and treatment of alcoholism and other alcohol-related disorders
● enhance quality health care
http://pubs.niaaa.nih.gov/publications/StrategicPlan/NIAAASTRATEGICPLAN.htm
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Alcohol Use
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Alcohol: Our Most Primitive Intoxicant
Egypt (el-Guebaly N, el-Guebaly A, 1981, Int J Addict., 16:1207-21)
barley beer is probably the oldest drink in the world with its origin in Egypt prior to 4200 BC
China (McGovern et al., 2004, PNAS, 101:17593-17598)
7000 BC - the production of a prehistoric mixed fermented beverage of rice, honey and fruit (neolithic village of Jiahu in Henan province)
2000 BC- unique cereal beverages (Shang and Western Zhou Dynasties)
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Ancient Warnings About Alcohol and Harmful Use Through the Ages
1600-1050 BC - Downfall of Egyptian and Chinese Empires and Dynasties attributed to excessive alcohol use
460-320 BC- Grecian Scholars issued advisories on drunkenness and moderate drinking
Plato – No use under age 18, between 18-30 use in moderation, no restrictions for use by those older than 40
Aristotle and Hippocrates were both critical of drunkenness
11th Century AD - Simeon Seth, a physician in the Byzantine Court, wrote that drinking wine to excess caused inflammation of the liver, a condition he treated with pomegranate syrup
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Total Per Capita Consumption in Gallons of Ethanol by State - United States, 2003
■DC
■ 1.99 or below (10)■ 2.00-2.24 (15)■ 2.25-2.49 (16)■ 2.50 or over (10)
■DC
■ 1.99 or below (10)■ 2.00-2.24 (15)■ 2.25-2.49 (16)■ 2.50 or over (10)
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Cumulative Distribution of Alcohol Consumption in the United States
65% of the population are drinkers*
Males reported drinking 74% and females 26% of all alcohol consumed
73% of the alcohol is consumed by 10% of the population
* Individuals who reported drinking at least one drink in past 12-months
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90 100
Percentile Group (High to Low)
Per
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on
sum
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NIAAA National Epidemiological Survey on Alcohol and Related Conditions (NESARC) (2001-2002).
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Drinking Patterns: Rates and RisksModerate Drinking
Most people abstain or drink moderately placing them at low risk for alcohol use
disorders. In general, Moderate Drinking is up to 2 drinks/day for men; up to 1 drink/day for
women (USDA/HHS Dietary Guidelines, 2005)
One drink: one 12- ounce can or bottle of beer or wine cooler , one 5- ounce glass of wine , or 1.5 ounces of 80 - proof distilled
spirits .
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Nearly 3 in 10 U.S. adults engage in these high-risk drinking patterns1
Men: more than 14 drinks in a typical weekmore than 4 drinks on any day
Women: more than 7 drinks in a typical weekmore than 3 drinks on any day
1 Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
Drinking Patterns: Rates and RisksHigh-Risk Drinking
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Drinking Patterns: Rates and RisksBinge Drinking
The National Advisory Council on Alcohol Abuse and Alcoholism has recommended the following definition
of Binge Drinking
A “binge” is a pattern of drinking alcohol that brings blood alcohol concentration (BAC) to 0.08 gm% or above. For the typical adult, this pattern corresponds to consuming 5 or more drinks (male) or 4 or more drinks (female) in about 2 hours. Binge drinking is clearly dangerous for the drinker and for society
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U.S. Adult Drinking Patterns and Risks2001-2002: Odds Ratios
NIAAA National Survey on Alcohol and Related Conditions, (2001-2002)
Alcohol screening limits—number of drinks:In a typical WEEK—14 (men), 7 (women)
On any DAY— 4 (men), 3 (women)
The Odds of Having An Alcohol Use Disorder are
Increased by a Factor of. . .
Drinking PatternPercent of U.S. adults
aged 18 or older
Abusewithout
dependence
Dependence with or without
abuse
Never exceeds the weekly or daily screening limits
72 %Reference group
(1.0)
Reference group(1.0)
Exceeds only the weekly limit 2 % 7.8 12.4
Exceeds only the daily limit less than once a week
14 % 17.0 33.0
Exceeds only the daily limit once a week or more
2 % 31.1 82.0
Exceeds both weekly & daily limits once a week or more
10 % 31.1 219.4
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0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
12 13 14 15 16 17 18 19 20 21 22-23 24-25 26-29 30-34 35-49 50-64 65+
Age
Males
Females
Day
s
U.S. Substance Abuse and Mental Health Services Administration, 2003 National Survey on Drug Use and Health (NSDUH)
Harmful Drinking Pattern Across the Lifespan Number of Days in Past 30 Drank 5 or More Drinks
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Relative Risk of an Alcohol-Related Health Condition as a Function of Daily Alcohol Intake
0
5
10
15
20
25
30
Oral cavityand pharynx
Esophagus Breast Essentialhypertension
Coronaryheart disease
Ischemicstroke
Hemorrhagicstroke
Liver cirrhosis Chronicpancreatitis
Condition
Rel
ativ
e R
isk 50 g/day 100 g/day
Adapted from Corrao et al. (2004), Preventive Medicine, 38:613–619
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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
NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2004.
Odds of Co-Occurrence of Current (12-month)DSM-IV Alcohol Dependence and Selected Psychiatric
Conditions
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Burden of Disease Attributable to Alcohol Among the 10 Leading Risk Factors for Disease In Developed Countries
0% 2% 4% 6% 8% 10% 12% 14%
Iron deficiency
Unsafe sex
Illicit drugs
Physical inactivity
Low fruit and vegetable intake
Overweight
Cholesterol
Alcohol
Blood pressure
Tobacco
% Total Number of Health Years Lost to Death/Disability
The World Health Report 2002: http://www.who.int/whr/2002/en/whr2002_annex14_16.pdf
Nat
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titu
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n A
lcoh
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buse
and
Alc
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Nat
iona
l Ins
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n A
lcoh
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buse
and
Alc
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ism
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Alcohol Abuse
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DSM-IV Alcohol Abuse ICD-10 Harmful Use
A. A maladaptive pattern of alcohol use leading to clinically significant impairment or distress, as manifested by one or more of the following occurring within a 12-month period:
A. A pattern of alcohol use that is causing physical and/or mental damage to health.
recurrent drinking resulting in a failure to fulfill major role obligations
recurrent drinking in physically hazardous situations*
recurrent alcohol-related legal problems continued use despite having persistent or
recurrent alcohol-related social or interpersonal problems
B. The symptoms have never met the criteria for alcohol dependence
B. No concurrent diagnosis of the alcohol dependence syndrome
Definition and Diagnostic Criteria for Alcohol Abuse/Harmful Use of Alcohol
*Ninety percent of those diagnosed as having Alcohol Abuse endorse this criterion. Others are 20% or less (Dawson, DA. Unpublished NESARC Analysis, 2006)
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Do Alcohol Use Disorders Fall Along a Continuum of Severity?
Data from NIAAA’s two general population sample epidemiological studies* and others (e.g., Langenbucher et al., 2004; Krueger et al., 2004; Kahler and Strong, 2006; Saha et al., 2006; Proudfoot et al., 2006) agree that:
Alcohol Use Disorders are not bi-axial (abuse and dependence), but fall along a continuum of severity
Current criteria for alcohol abuse are not associated only with a milder form of alcohol use disorder; most tap into the more severe end of an alcohol use continuum
Current criteria for abuse and dependence contain redundancies
* NESARC and the 1991-1992 NIAAA National Longitudinal Alcohol Epidemiological Survey (NLAES)
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Alcohol Dependence(Alcoholism)
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Elements of Alcohol Dependence: DSM-IV and ICD-10(3 of 7 during one year required for diagnosis)
* elements of addiction
1. Tolerance2. Withdrawal: relief/avoidance
Pharmacological
3. Impaired control*
Maladaptive
larger/longer unsuccessful attempts to
quit/control
4. Compulsive Use* craving (ICD-10) only)
neglect activities time spent use despite negative
consequences
Severity of Addiction
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Prevalence of Past-year DSM-IV Alcohol Dependence by Age United States, 2001-2002
18 + yrs. - NIAAA NESARC ( Grant et al. (2004) Drug and Alcohol Dependence, 74:223-234)12-17 yrs - U.S. Substance Abuse and Mental Health Services Administration 2003 National Survey on
Drug Use and Health (NSDUH)
0%
2%
4%
6%
8%
10%
12%
14%
12-17 18-20 21-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69
Age
Most people seek
treatment at this ageO
ne
-Ye
ar
Pre
va
len
ce
Prevalence of DSM-IV Alcohol Dependence in 2001-2002 was
3.8%
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Etiology of Alcohol Use Disorders
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Alcohol use, abuse, and dependence are complex behavioral traits influenced by many factors:
genetic and biological responses
environmental influences
stages of development, from childhood to early adulthood
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Alcoholism: A Common Complex Disease
Genes:60%additive, both alcohol specific and non-specific
Environment: 40%both shared
and non-shared
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Extent of Influence
Initiation of Drinking
Progression Alcoholic Drinking
Environmental (familial and non familial)
Personality/Temperament (Endophenotype)
Pharmacological effects of ethanol (Intermediate Phenotypes)
Developmental Trajectory of AUDInitiation and Continuation of Drinking
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Gene-Environment Interactions in Alcohol Dependence
G1G1 G2G2 G3G3 G4G4 G5G5G1G1 G2G2 G3G3 G4G4 G5G5
E1E1 E2E2 E3E3 E4E4 E5E5
Alcohol Dependence
(Severe)
Alcohol Dependence
(Severe)
G1G1 G2G2G5G5
E1E1 E3E3E4E4
Alcohol Dependence
(Severe)
Alcohol Dependence
(Severe)
G1G1 G2G2G5G5
E1E1 E3E3E4E4
G2G2 G4G4
E2E2
Alcohol Dependence(Moderate)
Alcohol Dependence(Moderate)
G2G2 G4G4G2G2 G4G4
E2E2
Alcohol Dependence(Moderate)
Alcohol Dependence(Moderate)
Alcohol Dependence
(Mild)
Alcohol Dependence
(Mild)
G3G3
E2E2 E5E5
Alcohol Dependence
(Severe)
Alcohol Dependence
(Severe)
G1G1 G2G2G5G5
E1E1 E3E3E4E4
Alcohol Dependence
(Severe)
Alcohol Dependence
(Severe)
G1G1 G2G2G5G5
E1E1 E3E3E4E4
G2G2 G4G4
E2E2
Alcohol Dependence(Moderate)
Alcohol Dependence(Moderate)
G2G2 G4G4G2G2 G4G4
E2E2
Alcohol Dependence(Moderate)
Alcohol Dependence(Moderate)
Alcohol Dependence
(Mild)
Alcohol Dependence
(Mild)
G3G3
E2E2 E5E5
Genes + Environment =different types of alcoholism with different
characteristics and levels of severity
Genes + Environment =different types of alcoholism with different
characteristics and levels of severity
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Pharmacokinetics: absorption, distribution, and metabolism of alcohol
3-4 fold Pharmacodynamics: subjective and objective
responses to alcohol
2-3 fold
About one-half of these differences is genetic
Between Individual Variations in Responses to Alcohol
(Why drink; Drink more; Drink despite)
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Metabolism of Ethanol and Acetaldehyde in Hepatocyte
TCATCA
ATP
CO2
H2O
NAD+NADH
NAD+NADH
NAD+
NADH
NAD+
NADH
electron transportelectron transport
Energy Yield: 7 Kcals/g
CH3CH2OH(mM)
ADHADH
CH3CHO(μM)
NAD+ NADHNAD+ NADH
ALDH1ALDH1
CH3CHOALDH2ALDH2
CH3COOH(mM)
CH3COOH
CH3COOH(mM)
CYTOSOL
NADH Shuttle
NAD+ NADH
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Age at Onset: DSM-IV Age of First Use of Alcohol, Nicotine, and Cannabis
0%
5%
10%
15%
20%
25%
30%
35%
5 10 15 20 25 30 35 40 45 50
Age
Age of First Alcohol Use
Age at first Nicotine Use
Age of First Cannabis Use
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o
beg
in u
sin
g a
lco
ho
l
0%
5%
10%
15%
20%
25%
30%
35%
5 10 15 20 25 30 35 40 45 50
Age
Age of First Alcohol Use
Age at first Nicotine Use
Age of First Cannabis Use
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o
beg
in u
sin
g a
lco
ho
l
Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
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2001-2002
0
10
20
30
40
50
60
<=13 14 15 16 17 18 19 20 >=21
Age at First Use of Alcohol%
Pre
vale
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Source: 2001-2002 National Epidemiologic Survey on Alcohol nad Related Conditions; Laboratory of Epidemiology and Biometry; DICBR, NIAAA, Bethesda, MD.
1991-1992
0
10
20
30
40
50
60
13 14 15 16 17 18 19 20 21
Age at First Use of Alcohol
% P
reva
lenc
e
Source: Grant and Dawson. (1988). J. Substance Abuse, 10(2):163-73
Prevalence of Lifetime Alcohol Dependence by Age of First Alcohol Use and Family History of Alcoholism
Parental History PositiveTotalParental History Negative
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mDaily Consumption by P and NP Rats Responding on a Two-Bar Operant Task for Water and Different Concentrations of
Ethanol
% ethanol
Wat
er(m
l/d
ay)
Eth
anol
( m
l/d
ay)
g/k
g/d
ay
2 5 10 15 20 25 4030
*p=<0.05
Murphy JM, Gatto GJ, McBride WJ, Lumeng L, Li TK ((1989). Alcohol. 6(2):127-31.
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Treatment of Alcohol Use Disorders
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m Many recover, or remit, without professional interventions
Early interventions are successful in reducing chronicity and severity
Treatment success rates are 30%-60% depending on outcome measure (e.g., abstinence, heavy drinking, social functioning)
Interventions include:
Brief intervention
Behavioral therapies (e.g., motivational enhancement, cognitive behavioral, 12-steps)
Pharmacological therapies
% P
PY
Pop
ulat
ion
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<5 5 to 9 10 to 19 20+
Interval (Years)
Abstainer
Low-risk drinker
Asymptomatic riskdrinker (subclinicaldependence)
Partial Remission
Still Dependent
% P
PY
Pop
ulat
ion
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<5 5 to 9 10 to 19 20+
Interval (Years)
Abstainer
Low-risk drinker
Asymptomatic riskdrinker (subclinicaldependence)
Partial Remission
Still Dependent0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<5 5 to 9 10 to 19 20+
Interval (Years)
Abstainer
Low-risk drinker
Asymptomatic riskdrinker (subclinicaldependence)
Partial Remission
Still Dependent
n=4,422Past-year Status by Interval Since Onset of Dependence
Dawson et al., (2005). Addiction. 2005 Mar;100(3):296-8. NIAAA National Epidemiological Survey on Alcohol and Related Conditions, 2001-2002
Treatment of, and Recovery from, Alcohol Dependence
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Heterogeneity of Treatment Populations: Severity
* >4 drinks/day, 14 drinks/week (men)>3 drinks/day, 7 drinks/week (women)
Disease management
None Harmful useDependence
(Early)Dependence
(Chronic)At-risk*
Prevention Facilitated self-changeBrief counseling
Behavioral and Medication Therapy
* >4 drinks/day, 14 drinks/week (men)>3 drinks/day, 7 drinks/week (women)
Disease management
Disease management
None Harmful useDependence
(Early)Dependence
(Chronic)At-risk*
Prevention Facilitated self-changeBrief counseling
Behavioral and Medication Therapy
Screening
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Clinical Trials in the Last Fifteen Years Have Shown:
Different kinds of behavioral therapies work equally well (e.g., motivational enhancement, cognitive behavioral, 12-steps)
Naltrexone with Disease Management works and potentially can be used in primary care settings
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Treatment Intervention
Primary Target Population(s)
High-risk drinkers
Alcohol abusers
Alcohol- dependent
Brief intervention
Motivational enhancement therapy
Cognitive behavioral therapy
Couples (marital) and family therapies
Community reinforcement
Behavioral Therapies
Selected References: Moyer et al. (2002) Addiction, 97: 279-292; Miller et al. (2002) Addiction, 97: 265-277; O’Farrell et al. (2000) J. Sub.Abuse Treat., 18: 51-54
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Medication Target Year Approved
Disulfiram Aldehyde Dehydrogenase
1949
Research from animal models over the past 25 years has provided promising targets for pharmacotherapy
Naltrexone Mu Opioid Receptor 1994
Acamprosate Glutamate and GABA-Related
2004
Naltrexone Depot Mu Opioid Receptor 2006
FDA Approved Medications for Treating Alcohol Dependence
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Medication Target
Topiramate GABA/Glutamate
Valproate GABA/Glutamate
Ondansetron 5-HT3 Receptor
Nalmefene Mu Opioid Receptor
Baclofen GABAB Receptor
Antalarmin CRF1 Receptor
Rimonabant CB1 Receptor
Medications for Treating Alcohol Dependence – Under Investigation
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Examples of NIAAA-Supported Clinical Pharmacotherapy Trials for AUDs and Co-morbid
Psychiatric Conditions
Co-morbidities Medication(s)
AD/Depression naltrexone; sertraline
AD/Bipolar valproate; naltrexone
AUD/anxiety disorders venlafaxine (Effexor)
AD/schizophrenia clozapine (Clozaril)
AD/tobacco dependence bupropion (Zyban)
AD/cocaine dependence topiramate (Topamax)
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NIAAA Clinician’s Guide Helping Patients Who Drink Too Much
Based on the AUDIT-C:
1. How often do you have a drink containing alcohol?
2. How many drinks containing alcohol do you have on a typical day when you are drinking?
3. How often do you have 6 or more drinks on an occasion?
The third question alone is:
sensitive for heavy drinking (79%) and alcohol abuse/ dependence (81%)
specific (83%) for heavy drinking, abuse and dependence1 1Bush et al, Arch Intern Med. 1998;158:1789-1795
Information and training materials for the NIAAA Clinician’s guide are available at: http://pubs.niaaa.nih.gov/publications/practitioner/CliniciansGuide2005/Guide_Slideshow.htm
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Conclusion: Alcohol Research Strengths and Opportunities
Alcohol pharmacogenetics human and animal models
Animal models genes, pathways and networks, and GxE
interactions Epidemiology
longitudinal general population and high-risk studies
Treatment behavioral pharmacological