4th Joint Meeting of the National Advisory Council On Alcohol Abuse
and Alcoholism, National Cancer Advisory Board, and National Advisory
Council on Drug Abuse
February 11, 2016
George F. Koob, Ph.D.Director
National Institute on Alcohol Abuse and AlcoholismNational Institutes of Health
NIAAA - Where We Want to Be 1. FDA approval of more medications for alcohol use disorder (AUD)2. Implementation of effective behavioral treatments for AUD3. Implementation of effective prevention strategies for adolescent
drinking4. Implementation of effective prevention strategies for drinking
during pregnancy5. Development of effective treatments for fetal alcohol spectrum
disorders (FASD)6. Elimination of alcohol-related HIV pathology7. Development of effective treatments for alcoholic liver disease8. Appropriate treatment of co-morbidities associated with AUD9. Successful recruitment of young investigators to the alcohol field;
elimination of disparities in the alcohol field; equal pay for women and minorities in the alcohol field
NIAAA Strategic Plan: 2016-2020Strategic Priorities
• Identify the Basic Mechanisms of Alcohol Action and Alcohol-Related Pathology
• Track, Prevent, and Diagnose Alcohol Misuse, Alcohol Use Disorder (AUD), and Alcohol-Related Consequences
• Develop and Improve Treatments for AUD, Co-occurring Disorders, and Alcohol-Related Consequences
• Strengthen the Public Health Impact of NIAAA-Supported Research
NIAAA Strategic Plan: 2016-2020Cross-cutting Themes
• Addressing alcohol misuse across the lifespan
• Addressing co-occurring disorders
• Advancing precision medicine
• Reducing health disparities
Alcohol Effects Across the Lifespan
NIAAA supports research to study how
alcohol can affect health and well-being
at various stages of life.
Alcohol
PrenatalAlcohol
Exposure
Underage / BingeDrinking Organ
Damage
MedicationInteractions
Alcohol Use DisorderAlcoholic
FamilyEnvironment
Lifespan Transcending Themes:• Neurobiology• Metabolism• Genetics • Epigenetics • Epidemiology• Health Services Research
Key NIAAA Initiatives and Programs-A Consortia Framework
1. FetalAlcoholSpectrumDisorders– Prevention&EarlyDiagnosis
2. UnderageandBingeDrinking– N-CANDA,ABCD,CollegeAIM
3. NeurobiologyofAlcoholism
4. GeneticsofAlcoholism
5. Treatment– MedicationsDevelopment
6. AlcoholicLiverDisease
7. AlcoholandHIV/AIDS
8. AlcoholBiosensors
9. CollegeAIM
The Collaborative Initiative on FASD (CIFASD)
A multidisciplinary consortium of clinical and basic science projects
GOALS: to improve capabilities in FASD clinical case recognition, interventions and prevention
THEMES:• structural & functional brain imaging• neurobehavioral phenotypes• 3D facial imaging• nutritional therapeutics (e.g., choline)
MORE INFORMATION AT:http://cifasd.org
Collaboration on FASD Prevalence (CoFASP)• Goal: to determine a prevalence rate for FASD (FAS, pFAS,
ARND) among young children within defined geographical areas of the US
• employs case ascertainment methodology
• PIs: Drs. Tina Chambers and Phil May
Goal: To gain insight into the effects of alcohol exposure in adolescence on brain circuitry
NADIANeurobiology of Adolescent Drinking in Adulthood
• Assess neurocircuitry and structural changes as a consequence of adolescent alcohol exposure in rat models relevant to human alcohol consumption.
• Study the effects of early vs late adolescent alcohol exposure and the individual differences of high drinkers vs low drinkers on adult brain morphology and function.
• Test the hypothesis that EtOH exposure during adolescence promotes the retention of adolescent-typical excitatory/inhibitory balances in specific brain regions.
• Evaluate the effects of adolescent ethanol exposure by assessing cortical thickness and DTI tractography of myelin tracks.
• Based on target genes, develop experiments to prevent/ reverse the effects of adolescent alcohol exposure (e.g. HDAC inhibitors, dietary choline or cholinergic drugs etc.)
Preclinical findings on the lasting consequences of adolescent binge drinking in adulthood
Administrative Center U01, Data Analysis Center U01, and five Research Project Site U01s
Accomplishments to date:• The NCANDA consortium met their enrollment goal of 831
adolescent participants• Completed the baseline assessment of all 831 participants in the
accelerated longitudinal design• Participants are now beginning their 3rd follow-up longitudinal
assessment • Five foundational manuscripts published describing study goals,
methods, and baseline findings
Very early results are showing that participants in the Exceeds-Criteria for alcohol consumption group are already demonstrating untoward effects on
brain structural development. More to come . . .
National Consortium on Alcohol And NeuroDevelopment in Adolescence
Goal: to study the impact of alcohol drinking on brain structure and function during adolescence and into early adulthood
Adolescent Brain Cognitive Development (ABCD) Study
• In September 2015, NIH launched the ABCD Study.
• ABCD is the largest long-term study of cognitive and brain development in children in the U.S. to date.
• ABCD is recruiting 10,000 healthy children ages 9-10 and following them over 10 years into early adulthood.
• ABCD investigators will measure brain maturation in the context of social, emotional, and cognitive development at a level of precision that has only recently become possible. Investigators will look at multiple health outcomes including weight, growth, sleep quality, injury, mental health and substance use, and other life experiences such as driving a car, academic success, and physical activity.
• Findings from ABCD are expected to increase our ability to distinguish environmental, sociocultural, and genetic factors relevant to brain and cognitive development, in order to inform prevention and treatment intervention and public health strategies.
Goal: To elucidate adaptations to chronic alcohol in corticolimbic and corticostriatal brain circuitry and synaptic mechanisms that underlie altered response to stress (allostasis), which in turn can facilitate the transition from moderate/controlled drinking to excessive and habitual drinking.
Cutting-edge approaches in mice, monkeys & humans:
• Circuitry dissection with optogenetics & chemogenetics
• Behavioral, endocrine, & autonomic readouts of stress-ethanol interactions
• Adaptations in neural &synaptic plasticity
• Neuroimaging (fMRI)• Medications evaluation for
stress-related excessive drinking
Koob and Volkow (2010) Neuropsychopharm35:217-238
INIA Stress
Goal: Through a multidisciplinary & collaborative approach identify the genomic, cellular, and behavioral neuroadaptations related to excessive alcohol consumption, which focuses on the importance of neuroimmune and inflammatory signaling systems in promoting and maintaining excessive drinking.
Use this information to determine & test medication(s) in the treatment of an Alcohol Use Disorder.
Bing
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toxi
catio
nINIA-Neuroimmune
Sequencingnowongoing,newgenediscovery
Linkage/CandidatesCHRNA5-CHRNA3-CHRNB4,ADH1B,CHRNA6-CHRNB3
GWAS/LinkageAAGWASnowongoingGABRA2,CHRM2,ADH4,c15orf53,GRM8,KCNJ6
Rare/novelUncommon Common
EffectonRisk
VariantFrequency
Collaborative Study on the Genetics of Alcoholism (COGA)Goal: To identify genes and understand mechanisms underlying risk for the development of alcoholism and related disorders
• Family study: Recruit and follow large families densely affected with alcoholism.
• Extensive Phenotyping: Assess multiple domains: clinical, behavioral, neuropsychological, neurophysiological.
• Genetics: Identify rare and common variants contributing to disease risk and model their effects using expression studies and iPSC.
• Prospective Study: Follow every 2 years the adolescent & young adult offspring from COGA densely affected families with extensive age-appropriate assessments in multiple domains, including frontal lobe development to examine developmental trajectories and test for G x E interactions with newly identified risk variants.
NIAAA Medications Development ProgramDivision of Medications Development – est. 2015 to coordinate efforts to identify, screen, and evaluate compounds for treating AUD.• Human laboratory screening studies to bridge the gap between
preclinical and clinical trials
• SBIR/STTR program to bridge the “valley of death” between basic and clinical research by facilitating studies leading to the development of an IND application
• NIAAA Clinical Investigations Group (NCIG) to streamline the AUD medications development process by conducting “fast success/fast fail” phase II clinical trials, with a turn-around time of 18 months
• recently completed a trial of a vasopressin antagonist• launched a clinical trial of gabapentin in June 2015
NIAAA’s intramural program also conducts clinical studies on novel compounds with AUD treatment potential.
NIAAA also focuses on disseminating information about treatment options including medications to health professionals and the general public.
Wearable Alcohol Biosensors
Goal: the design and production of a wearable device to monitor blood alcohol levels in real time that could be used in research, clinical, and treatment settings and for individual health monitoring.
National Challenge CompetitionEight entries – different form factors
Judging in progress
Small Business Funding Six SBIR grants awarded in 2015
Translational Research and Evolving Alcoholic Hepatitis Treatment (TREAT): Crabb, Chalasani, Sanyal, ShahSevere AH1. Emricasan (caspase inhibitor – discount
due to toxicity concerns)2. IMM 124-E (anti-LPS) Moderate AH 1. Obeticholic Acid (Bile Acid Rec. agonist)
red. ox. stress.2. F-652 (IL-22 – hepatocyte survival factor)
Defeat Alcoholic SteatoHepatitis (DASH): Szabo, McCullough, Mitchell, McClain, NagySevere AH1. Anakinra (IL-1 rec. antagonist),
Pentoxifylline (anti-inflamm.) and Zinc (gut-barrier) (DASH )
Moderate AH1. Probiotics – to restore normal microbiome
(DASH)
Southern California Alcoholic Hepatitis Consortium (SCAHC): Morgan, Liu, French, Garner, CampSevere AH1. Prednisolone + Rilonacept (IL-1 Trap)
Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTeam): Bataller, Mathurin, Schnabl, Brenner, Schwabe, MehalMultinational observational and preclinical studies
GOALS: 1) To advance the understanding and treatment of Alcoholic Hepatitis; and 2) to use human trials to identify and test new mechanisms and strategies for the treatment of AH
Alcoholic Hepatitis ConsortiaRFA-AA-1207
Yale University: PI: Amy JusticeConsortium to improve OutcoMes in HIV/AIDS, Alcohol, Aging, and Multi-Substance Use (COMpAAS) & Veterans Aging Cohort Study (VACS)• VACS is one of the largest ongoing observational
studies of HIV• examines impact of aging and alcohol use among those
with and without chronic HIV infection
Boston University: PI: Jeffrey SametUganda Russia Boston Alcohol Network for
Alcohol Research Collaborations on HIV/AIDS (URBAN ARCH)
• interdisciplinary research on understanding how alcohol use impacts HIV+ individuals
• develops interventions to reduce alcohol use and HIV-related consequences in populations
The Johns Hopkins University: PI: Mary (Betsy) MCCaulAlcohol Research Consortium in HIV (ARCH)
• addresses clinical epidemiology of hazardous alcohol use in HIV-infection and
• determine best treatment interventionsGOALS: To advance operations or implementation research in the context of alcohol and HIV/AIDS in order to: 1) continue to develop a broader systems approach for monitoring complex HIV and alcohol-related morbidity and mortality; and 2) intervene to reduce the impact of alcohol and HIV disease progression and transmission.
Meeting the High Priority AIDS Research Areas as set forth by the NIH Office of AIDS Research
Consortia for HIV/AIDS and Alcohol-Related Research Trials (CHAART)
RFA-AA-16-001 Project Collaborative U01RFA-AA-16-002 Administrative Resource Core U24
RFA-AA-16-003 U24 Resource Core
Alcohol and HIV Don’t Mix
Brown University: PI: Peter MontiAlcohol Research Center on HIV (ARCH)
• reducing the impact of alcohol on the breadth and depth of the HIV epidemic
• interventions in HIV+ populations
The NIAAA CHAART Consortia:Meeting the Highest Priority Areas of HIV/AIDS Research
as outlined by the NIH Office of AIDS Research
The University of Florida: PI: Robert CookSouthern HIV and Alcohol Research Consortium
(SHARC)• research to improve health outcomes and • reduce HIV transmission among diverse populations
Insula
VTA
IncentiveSalience
Binge-Intoxication
Withdrawal-Negative affect
Preoccupation-Anticipation
NegativeEmotionality
ExecutiveFunction
Cue ReactivityTask
Facial EmotionMatching Task
Delay Discounting
Stages of the Addiction Cycle: Associations with Neurocircuits & Addictions Neurochemical Assessment
mPFC(AC)
Hippo
OFC
DS GP
Thal
VSVTA
Adapted from George Koob . Curr Top Behav Neurosci. 2011 Jul 10.
VS
Modifiedfrom:Kwako LEetal.(2015)
• CollegeAIM is a new resource from NIAAA that guides colleges to evidence-based strategies to help them address harmful and underage student drinking.
• Using CollegeAIM’s matrix based tool, school officials can easily compare a broad range of individual and environmental college drinking interventions.
• CollegeAIM is based on an extensive review of the literature conducted by a team of research experts in the college drinking field.
• CollegeAIM rates the relative effectiveness and other characteristics (e.g. cost, barriers to implementation) of nearly 60 strategies.
• Regional workshops that will review CollegeAIM and how to use it are being planned for 2016.
Surgeon General’s Report on Substance Use, Addiction, and Health
• NIAAA and NIDA have played major roles in the development of the first ever Surgeon General’s Report on Substance Use, Addiction, and Health.
• The report will present the state-of-the science on alcohol and other substance misuse from the perspectives of neurobiology, prevention, treatment, recovery, and delivery of care.
• It will provide a comprehensive review of the research literature on alcohol, drugs, and health; outline potential future directions; and educate, encourage, and call upon all Americans to take action.
• The report is expected to be released in 2016.
NIAAA: The Source for Credible Science Information on Alcohol Across the Lifespan
George F. Koob, Ph.D.Director
National Institute on Alcohol Abuse and AlcoholismNational Institutes of Health
Thank You!