National Advisory Council on Alcohol Abuse and Alcoholism

Summary of the 107th  Meeting

September 8-9, 2004

The National Advisory Council on Alcohol Abuse and Alcoholism convened for its 107th meeting on September 8, 2004, at the Pooks Hill Marriott in Bethesda, Maryland, in a closed session, and again on September 9 in an open session in Building 31, National Institutes of Health (NIH), Bethesda. Dr. Ting-Kai Li, Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), presided.

In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the meeting on September 8 was closed to the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds.

Council Members Present:

Raul Caetano, M.D., Ph.D.
Gail A. Jensen, Ph.D.
George F. Koob, Ph.D.
Steven M. Mirin, M.D.
Hon. James W. Payne
Kenneth J. Sher, Ph.D.
Alan C. Swann, M.D.
Boris T. Tabakoff, Ph.D.

Ex-Officio Council Members Present:

Colonel Kenneth J. Hoffman, M.D., M.P.H.
Richard T. Suchinsky, M.D.

Chairperson: Ting-Kai Li, M.D.

Executive Secretary: Karen P. Peterson, Ph.D.

Council Assistants:

Faye Calhoun, D.P.A., M.S., Mark Goldman, Ph.D., Bob Huebner, Ph.D., Ralph Hingson, Ph.D., George Kunos, MD, Ph.D., Stephen Long, Antonio Noronha, Ph.D., Kenneth R. Warren, Ph.D., Mark Willenbring, M.D., Ricardo Brown, Ph.D.

Other Attendees on September 9, 2004:

Approximately 40 additional observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

Call to Order of the Closed Session

Dr. Ting-Kai Li, Director, NIAAA, called the closed session of the 107th meeting of the Council to order at 5:30 p.m. on September 8, 2004, for consideration of grant applications. Dr. Tina Vanderveen reviewed procedures for critiquing grant applications and reminded Council members of regulations pertaining to conflict of interest and confidentiality. Members absented themselves from the discussion and evaluation of applications from their own institutions and in situations involving any real, apparent, or potential conflict of interest. The closed session adjourned at 6:35 p.m.

Call to Order of the Open Session, Appreciation Ceremony, and Introductions

Dr. Li called the open session to order at 9:05 a.m. on September 9, 2004. He presented certificates of appreciation to departing Council members Drs. Brown, Caetano, Koob, Mirin, and Hingson. Members of the Council and the audience introduced themselves.

Director's Report

Referring to the published "Director's Report," Dr. Li highlighted the following Institute activities:

• Budget. Congress has not taken final action on the FY2005 budget. The House Appropriations Subcommittee sent a marked-up budget to the floor on July 14 for over $28 billion for NIH and $441,911,000 for NIAAA-identical to the President's budget request. The corresponding Senate subcommittee has not yet acted. Including AIDS funding, the President's budget for NIAAA calls for a 3.1 percent increase over FY2004 and an increase for grants and contracts of 2.7 percent.

• Scientific and advisory activities. Since the last Council meeting, Dr. Li presented a plenary lecture in Beijing. He reported that the U.S. will sign a larger bilateral agreement with China, plus an agreement of collaboration and research training with Peking University and the National Institute on Mental Health. Dr. Li also spoke at a conference on co-occurring disorders co-sponsored by several federal agencies and at meetings of the Research Society on Alcoholism (RSA), the Teratology Society, and the Robert Wood Johnson Foundation.

• Staff changes. Marcus Heilig, M.D., Ph.D., serves as NIAAA's new Clinical Director. Dr. Li noted that extramural staff changes reflect individuals' human resources and leadership development, and noted new positions for Gayle Boyd, Ph.D., Eugene Hayunga, Ph.D., Tina Vanderveen, Ph.D., Charlene LeFauvre, Ph.D., Kathy Salaita, Ph.D., and Vivian Faden, Ph.D. Ed Linehan and Elsie Taylor have retired. David W. Herion, M.D. has joined the Laboratory of Clinical Studies.

• Research priority emphasis. NIAAA has established an Extramural Advisory Board, chaired by Dr. Fulton Crews, to assist with portfolio review, advise on strategies for the future, and provide scientific guidance and guidance on research priorities.

• Research programs. NIAAA has awarded funding to Boston University School of Public Health for a new Alcohol Research Center. NIAAA currently funds grants at several universities under the Rapid Response to College Drinking Problems program. The research team on Underage Drinking will draft an RFA for an upcoming program. NIAAA staff who participated in or co-chaired meetings include Drs. Calhoun, Goldman, Warren, Tom Gentry, Margaret Mattson, Bin Gao, Raye Litten, and Bridget Grant. Collaborative programs include a state grant program with the Department of Justice's Office of Juvenile Justice and Delinquency Prevention (OJJDP) to study underage drinking laws in rural communities and an outreach effort for social work research. A total of 328 new and competing continuation research grant applications were assigned to NIAAA.

• Grantee publications. NIAAA is beginning to track its awardees' publications related to research advances in the alcohol field, to identify key findings and science advances in areas of key discovery, to identify their impact on the field, and to guide research strategies for the future. Since May, grantees have published 236 peer reviewed articles. Several papers on NESARC have emerged on co-occurring alcohol and drug use. Several other papers focus on moderate drinking, stress responsiveness in women, liver injury, alcohol's role in causing cell death in the developing brain, and the role of adenosine as a neuromodulator in explaining alcohol's actions.

• Outreach efforts. Among other activities, NIAAA continues to work with the Leadership to Keep Children Alcohol Free in its efforts to introduce the first-ever childhood drinking semi-postal stamps, with monies to fund research in this area.

• NIAAA multimedia products. Several electronic media activities recently won awards, including an NIAAA publication, public service announcements, and website. Alcohol Research & Health explains various aspects of alcohol science; NIAAA is looking into transmitting information to other audiences and making Alcohol Alert more user friendly. NIAAA hosts websites for middle school students and others, and has developed a curriculum for social work educators.

• Future activities. Events include an international symposium on mechanisms of alcohol-associated cancers (October 2004) and the Keller Memorial Lecture (November 2004) at which Dr. Koob will present.

Enforcing Underage Drinking Laws Program

Judge Linda Chezem described NIAAA's collaboration with the Office of Juvenile Justice and Delinquency Prevention (OJJDP) in evaluating enforcement of underage drinking laws. Having worked together with NIAAA on an initiative involving larger communities, OJJDP has established a grant program for rural communities. Awards were made to Illinois, Pennsylvania, New Mexico, and Nevada, and NIAAA evaluators will work with the states on the evaluation design and then will conduct the evaluation. OJJDP has invited NIAAA to work on another round of grants in three states.

From Animal Modeling to Human Therapeutics in Alcohol Dependence

NIAAA Clinical Director Markus Heilig, M.D., Ph.D., discussed the process of trying to discover and validate potential treatment targets. He stated that his primary objectives for the Laboratory of Clinical Studies' treatment development program are relapse prevention and inhibition of the neuroadaptive process. The drug properties that drive the early initiation stages of developing dependence, which rely on positive reinforcing properties of drugs, are probably different from those that drive later maintenance stages, which are largely related to negative reinforcement. A variety of strategies must be used to discover and validate potential targets in animal models prior to clinical trials. At the Laboratory of Clinical Studies, it is possible to work through all stages of the process, particularly to filter out strategies not worth pursuing.

Research has shown that repeated cycles of intoxication and withdrawal can result in long-term changes in the phenotype of genetically nonselected rats. Persistent alcohol preference is induced at 4 to 7 weeks in these animals. At the same time, the amount of alcohol preferred undergoes a change as well, from approximately 20 percent to 75 percent, and this change remains constant for the lifetime of the animal.
This component of drinking is exquisitely sensitive to acamprosate, which eliminates the added component induced by the exposure procedure and does not touch baseline drinking in normal animals. This indicates two different types of motivation underlying ethanol drinking in experimental animals: one related to addictive properties of alcohol and the other to appetite or nutrition or to some other factor.

Research has demonstrated that release of glutamate escalates over progressive cycles of withdrawal. Parallels exist with gene expression data, leading Dr. Heilig to believe that long-term adaptation involves progressive recruitment of a hyperglutamatergic state. Neuroprocesses are started with a prolonged presence of alcohol in the system, and each withdrawal produces a hyperglutamatergic drive that probably is an important component of the craving state preceding relapse. Several possible targets for imminent research may modulate this kind of hyperglutamatergic state. The ability to suppress elevated CNS glutamate might be used as a biomarker to screen for clinical efficacy. Candidates on Dr. Heilig's "wish list" include neuropeptide Y, which, in animals that had undergone a neuroadaptive process and had high levels of consumption, normalized alcohol intake levels.

Other targets include the CB1 cannabinoid receptor and the MAP kinase pathway. In the AA rat, dysregulation of the endocannabinoid system is an important mechanism to drive increased alcohol self-administration. Early data with the MEK inhibitor U0126 show that neuroadaptive effects of alcohol exposure can be mediated in part through the MAP kinase pathway, though research is just beginning to tease apart the spatial organization of the pathways that employ the MAP kinase signaling in order to produce long-term effects.

From a translational perspective, it is necessary to develop a paradigm to look at humans in terms of anti-neuroadaptive interventions. Cycles of withdrawal are critical for the neuroadaptive process; the hyperglutamatergic state is a key mediator and marker; and central glutamate/GABA balance can be measured in humans using MR spectroscopy. Dr. Heilig suggested a 4-week withdrawal study of the important known clinical manifestations, including biochemical and neuroendocrine aspects. MR spectroscopy is important, as is using acamprosate as a pharmacological probe to validate the paradigm. Dr. Heilig stated his hope to use this paradigm with sufficient speed to validate using acamprosate and then test other compounds to understand the commonalities between the animal models and the human situation.

Discussion. Dr. Tabakoff questioned whether a core system might be the most opportunistic target. Dr. Heilig responded that the ability to do the expression analysis and to develop upstream factors that drive changes of pattern is important, but declined to identify a target. Dr. Tabakoff stated that his approach is to look at regulatory regions of the changed genes to identify common transcription sites. To Dr. Koob's question on primate research, Dr. Heilig stated that primates will be useful to study cognitive function and early life experiences, such as bonding and the effects of separation. Dr. Li suggested comparing highly vulnerable animals to those that are not, to see if the number of cycles of exposure is an important indicator, using biomarkers as trait or state markers. Dr. Heilig noted that one way to probe the interaction between susceptibility and neuroadaptation is to look at the course of neuroadaptation in genetically selected animals. However, exposure to cycles of intoxication and withdrawal does not modify alcohol intake in genetically selected preferring rats. Another approach is to look at heterogeneous outbred populations that achieve neuroadaptation faster, later, or not at all, and controlling for the effects of the ethanol. Dr. Koob suggested looking at animals that resist becoming dependent using gene array analysis.

Extramural Advisory Board Process

Fulton T. Crews, Ph.D., Director of the Bowles Center for Alcohol Studies, University of North Carolina-Chapel Hill, identified the board's diverse members and staff, and then described the proceedings of the new, experimental Extramural Advisory Board in its first meeting on "Etiology of Risk: Genes and Environment." Dr. Li charged the board to review NIAAA's gene and environment portfolio to ensure responsiveness to emerging trends and to examine interactions between genes and environments. Members reviewed scientific models and worked to define a 5-year vision for the portfolio. They heard presentations on animal and human genetics portfolios, and environmental factors such as behavioral genetics, family environment, and other social and physical environments. Dr. Crews noted that the genes researched in animal genetics do not overlap with genes in ongoing human research. The board discussed proof of principles, reviewed staff guidance on objectives and recommendations, and identified infrastructure and training issues. Dr. Crews cited examples of topics under review for recommendations, including mechanisms to promote basic animal studies linking to human studies to better integrate gene-environment interaction (about which there is not yet consensus) and human longitudinal studies to develop methods for existing studies to better define "environment." Near consensus is a recommendation for NIAAA to convene scientists who are studying human alcoholism and animal studies to educate research communities better and to create product opportunities for synergy.

Discussion. Dr. Sher stated that the board has made a good start, but that much literature remains to be absorbed, particularly regarding the debate on the adequacy of animals and the fact that the alcohol field has no models for environmental effects. Dr. Goldman found striking the interactions among people working in different domains and suggested carrying forward the model of diverse panel membership. Dr. Crews stated that the board's goal is to provide advice to the Council, and board members are engaging in an iterative process with staff to develop recommendations. Dr. Li explained that staff are providing input into the portfolio assessment, identifying new opportunities and gaps, and asking the board to offer their judgments. Members of the board have agreed to serve for a fixed number of years, with rotating membership; other Council members are invited to participate. Board members focus on future research on gene/environment interplay, not gene environment interaction. Dr. Li cited the need to focus on training and recruitment into the field. He stated that NIAAA has established a stable multidisciplinary committee to review a variety of topics and research emphases. Within 12 to 18 months, NIAAA hopes to review all categories, plus infrastructure. Results will be posted on the NIAAA website, presented at RSA meetings, and possibly described in journals.

NIH Loan Repayment Programs

Dr. Kenneth Warren, Director, Office of Scientific Affairs, NIAAA, described the NIH Loan Repayment Program (LRP), established by Congress to counter economic disincentives for well-qualified, newly trained investigators to embark on biomedical and behavioral research careers. The program also serves as an incentive to attract investigators into specific areas of research defined by Congress. NIAAA participates in the Clinical Research and the Pediatric Research LRPs. Other LRPs, in which NIAAA is not directly involved, relate to researchers from disadvantaged backgrounds and to research on health disparities and infertility.

The programs repay awardees for two years up to $35,000 per year towards outstanding eligible educational debt. In return, participants commit to conduct research in the same area for at least two years. Applicants may apply for extensions. Debt must be greater than 20 percent of current salary and compensation, and the amount of repayment is determined with a sliding-scale formula. The program offers a maximum four years of eligibility, for a maximum repayment of $140,000. NIH also contributes an additional 39 percent to the Internal Revenue Service to cover taxes. Institutions must commit to support the awardee's research for the duration of the contract.

Recent program changes include lifting the requirement for grant support from NIH, and the requirement that an applicant must be supported by a domestic nonprofit entity or state or federal government. Most eligible candidates work within universities, and they must devote at least half their time to research within the qualifying area. At NIAAA the AA-3 committee (clinical committee) reviews each application, with emphasis on the applicant's potential to become a contributing scientist. NIH sets funding levels annually based on the size of an institute's clinical research portfolio. In FY2004 NIAAA funded 39 contracts for a total of $1.575 million, including 35 clinical and 4 pediatric contracts. Eight applicants received renewals and 31 contracts were new. The mean multiyear cost is $32,122, ranging from $5,778 to $106,057. NIAAA's success rate is high. Dr. Warren stated that qualified applicants should be encouraged to apply. Qualifications include status as a U.S. citizen, U.S. national, or permanent resident, with a doctoral-level degree in a health-related field. Typically fewer individuals have applied for the pediatric LRP than the clinical. Individuals must specify in their applications to which program they are applying. The FY2005 receipt date is December 15, 2004. For information, contact Carmen Richardson, or visit http://www.lrp.nih.gov.

Discussion. Dr. Warren stated that an individual who wished to do research on health disparities and alcoholism could apply either to NIAAA or to the health disparities program-but NIAAA's high success rate could be an incentive to submit applications to NIAAA. He stated that a two-year contract carries a two-year obligation, irrespective of the amount of the repayment. Dr. Caetano commented that in his experience with junior faculty members, the program generates great relief for the successful candidates and that the electronic system works well. Dr. Tabakoff suggested compiling a tracking report on awardees and their current status in the research field. Dr. Sher questioned whether an evaluation has been done on the degree to which the program deflects individuals from clinical careers to research. Dr. Warren agreed with the need for evaluation.

Consideration of the May 2004 Minutes

The Council accepted the minutes of the May 2004 Council meeting as submitted.

Epidemiology of Drinking Among Childbearing Women in the U.S. and Approaches to Prevention

Council member Raul Caetano, M.D., Ph.D., presented to the Council the first analysis of the NESARC (National Epidemiologic Survey on Alcohol and Related Conditions) database by an extramural researcher. He discussed census-based information about women of childbearing age, births, and pregnancies in the U.S. In June 2002, 61.4 million women were of childbearing age (15-44) in the U.S., of whom about 40 percent were members of ethnic minority groups and 47 percent were age 15 to 29. The overall fertility rate was 61.4/1000 (much greater for Hispanic women). Of the approximately 4 million births in the U.S., 36 percent were babies born to unmarried women, and between 1996 and 1999, 45 percent of pregnancies were unintended. Risk factors for drinking include unmarried and younger age. Unintended pregnancies are more common among younger, unmarried women, Blacks, women with less than high school education, and women on Medicaid. Among Whites, unintended pregnancies are associated with binge drinking. Using epidemiological data on alcohol consumption among pregnant and nonpregnant women, it is possible to identify subgroups of women at different risk levels for FAS/FASD. Earlier CDC data extrapolated by Dr. Caetano to 2003 show that pregnant women drink overall.

Questions within NESARC about pregnancy provide researchers an opportunity to examine differences between pregnant and nonpregnant women. Drinking rates are similar for both groups in the NESARC study, with about 12 percent at high risk for drinking during pregnancy. In terms of age, 25 percent of underage women are drinking at levels that would endanger a pregnancy, and about a third of women age 21-29 are in a high risk category for drinking. One fifth of pregnant women report that they either drink four or more drinks (four-plus) on an occasion or that they are abusers. Abuse/dependence among nonpregnant Native Americans and Hawaiians, Alaskan natives, and Pacific Islanders approaches 10 percent. Among pregnant women, whites are more at risk than Blacks or Hispanics in the four-plus and abuse/dependence categories.

Using a multivariate approach with pregnant women, age 21-29 and never married are the only risk factors for heavy drinking. For nonpregnant women, risk factors include unattached women, women living with someone, and age 21-29. Protective factors include being Black, Hispanic, and Asian; income of $100,000 or more; and homemakers and retired women compared to employed women.

In a discussion of a structured approach to prevention, Dr. Caetano described surveillance, for which good tools are available, such as NESARC and others; risk factor identification; and intervention evaluation and implementation, for which good information is not available. Different levels of prevention-universal (directed at all members of a population); selective (subgroups at high risk); and Indicated (highest risk and dependent)-call for different interventions. Universal interventions are directed at larger populations (e.g., supporting abstention, FAS risk awareness, physicians discussing drinking in routine health care); selective interventions include screening to identify individuals at risk; and indicated interventions (such as treatment) are more intense and directed to individuals at highest risk.

Dr. Caetano matched levels of alcohol consumption (abstainers, low-risk drinkers, four-plus drinkers, abusers, dependent drinkers) to a series of levels of intervention based on the public health approach and suggested by the Institute of Medicine. For low-risk drinkers, a selective intervention involving screening and counseling would be appropriate, but not necessarily for four-plus, abusers, and dependent drinkers, for whom an indicated intervention (such as treatment) would be appropriate. Universal interventions should reduce availability as a barrier to stop women from drinking who want to get pregnant, are about to become pregnant, are of childbearing age, or to impede progression to higher levels of risk. Experts' ratings of universal interventions show alcohol taxes to be highly effective in reducing availability; limits on hours and days and on outlets, differential availability/strength, and community mobility show moderate effectiveness; and advertising bans show limited effects. Evidence is lacking on public messages and warning labels. Education and persuasive interventions play a role in prevention to offer a rationale for alcohol policies and to generate community support to influence policy. Dr. Caetano asserted that a pragmatic, comprehensive approach is necessary to reach women at all levels of risk. Universal interventions must be part of an integrated strategy.

Discussion. Dr. Calhoun reported that September 9 was FAS Day, when the new Congressional FAS Caucus was to meet for the first time. Dr. Warren cited the importance of emphasis on selective and indicated prevention, in addition to universal prevention, because risk increases with heavier drinking levels. Dr. Caetano concurred, stating that most FAS babies are born to women who drink more heavily. An advantage of universal prevention is that other problems are prevented in addition to FAS. He acknowledged tension in the field in achieving the right strategic balance. Col. Hoffman questioned what percentage of women are identified and given interventions. Dr. Caetano responded that an important concern is that health care providers typically do not ask questions about alcohol use. Dr. Mark Willenbring stated that some laws take a punitive approach toward substance abuse during pregnancy, making women fear mandatory reporting and criminal penalties. Dr. Warren pointed out that the highest risk group for FAS is women who have had a child with FAS or FASD; two research grants target this population. This connection suggests a link between pediatrics and obstetrics in an interventional approach.

MERIT Awards Procedures

Karen P. Peterson, Ph.D., Executive Secretary, NIAAA National Advisory Council, reviewed procedures for MERIT (Method to Extend Research in Time) awards (R37). The awards recognize outstanding scientific achievement among principal investigators by extending their original awards by 3 to 5 years without the need for competitive review.

Approximately half of NIH's Institutes and Centers (ICs) participated in the MERIT program in 2003. NCI and NIDDK made the most awards, while NIAAA made one in 2003 and has others on-going. Dr. Peterson reviewed other IC procedures, including NIAID, whose program staff nominate outstanding investigators, and then rank the nominations, which Council approves (about 15 annually). NIDDK procedures are similar, but also include 5-year extensions, based on expedited review. Some ICs have specific score and ranking criteria. NINDS has a 7-year award limit, with candidates selected by staff on the recommendations of Council. NHLBI's constraints are stricter, with a focus on the project rather than the person, one award per person, and a score below the 5th percentile for a new application or under the 10th and unamended for Type 2 applications. NIGMS makes only one award per person, considers only Type 2 applications and only after 10 years, and focuses on the project rather than the person. NIAAA (procedures on the website) identifies meritorious applications in the Office of Scientific Affairs from the previous three Council rounds, and program staff nominates candidates for consideration by Council. Nominating committee members prepare written critiques for applications deemed qualified to move forward and discuss and vote on the recommendations. The Financial Management Branch determines how many MERITs can be awarded, and NIAAA's Director makes final selections. Potential changes include consideration only of Type 2 applications; broadening the committee that makes MERIT selections; and disallowing extensions or minimizing length of extensions. A formal analysis of activities following the second extension of R37s is planned.

Discussion. Dr. Caetano acknowledged the helpfulness of the MERIT award and suggested considering MERIT awards for cross-sectional as well as longitudinal studies. Dr. Tabakoff noted that in different fields renewals are granted for ongoing studies. He questioned how to retain the best individuals available to alcoholism research in the MERIT track. Dr. Li tabled the discussion until the next Council meeting.

Next Meeting

Dr. Peterson stated that Council's next open meeting, Thursday, February 3, 2005 (and possibly the prior closed meeting), will be held at NIAAA's new facility at 5635 Fishers Place, Rockville, Maryland.

Reports from Ex-officio Members of Council and Liaison Representatives, and Public Comment

Col. Hoffman noted that the Department of Defense is considering new ways to deal with the high incidence of binge drinking and tobacco use. Progress is being made to firm up policies and personnel actions to deglamorize and diminish these behaviors. He suggested electronic solutions for greater outreach. Dr. Calhoun stated that NIAAA is interested in working with DOD on that strategy.

Although time was set aside for public comment, no one chose to speak.

Adjournment

Dr. Li adjourned the meeting at 2:15 p.m.

CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.

Posted: February 2005