National Advisory Council on Alcohol Abuse and Alcoholism

Summary of the 102nd Meeting

February 5-6, 2003

The National Advisory Council on Alcohol Abuse and Alcoholism (NACAAA) convened for its 102^nd meeting at 5:30 p.m., on February 5, 2003, at the Pook’s Hill Marriott Hotel in Bethesda, Maryland, and again at 8:30 a.m., on February 6, for a closed session before the 9:15 a.m., opening of the public policy session in Conference Room E1/E2 of the Natcher Conference Center, Building 45, at the National Institutes of Health (NIH), Bethesda, Maryland. Dr. Kenneth R. Warren, Executive Secretary and Director of the Office of Scientific Affairs, presided over the closed review of grant applications on February 5; Dr. George Kunos, Scientific Director of the Institute’s Intramural Program, presented a report for the Board of Scientific Counselors in the closed session on February 6; and Dr. Ting-Kai Li, Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), chaired the open session on February 6.

In accordance with the provisions of Sections 552b(C)(6), title 5, U.S.C. and 10(d) of Public Law 92-463, the February 5 meeting was closed to the public from 7:00 to 9:00 p.m. for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. The meeting of the NIAAA Board of Scientific Counselors beginning at 8:30 a.m. on February 6 was also closed to the public for the purpose of presentation of reports from the NIAAA Board of Scientific Counselors. The open session for discussion of program and policy issues began at 9:15 a.m., on February 6, and lasted until its 3:00 p.m. adjournment.

Alpha E. Brown, Ph.D., J.D., D.Min
Sandra A. Brown, Ph.D.
Raul Caetano, M.D., Ph.D.
Richard A. Deitrich, Ph.D.
Howard J. Edenberg, Ph.D.
Rueben A. Gonzales, Ph.D.
Ralph W. Hingson, Sc.D., M.P.H.
Gail Jensen, Ph.D.
George F. Koob, Ph.D.
Steven M. Mirin, M.D.
Stacia A. Murphy, M.S.
Stephanie S. O’Malley, Ph.D.
Sheryl Ramstad, J.D.
obert E. Taylor, M.D., Ph.D.

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

Executive Secretary: Kenneth R. Warren, Ph.D.

Council Assistants: Mrs. Ida Nestorio and Ms. M. Virginia Wills

Approximately 140 additional observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

Dr. Ting-Kai Li, Director, NIAAA, called the closed session of the 102^nd meeting of the NACAAA to order at 5:30 p.m., February 5, 2003, for consideration of grant applications.

Dr. Kenneth R. Warren, Director, Office of Scientific Affairs, reviewed procedures for the conduct of grant application reviews, 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.

Dr. Kenneth R. Warren, Director of the Office of Scientific Affairs, NIAAA, called a closed session of the Board of Scientific Advisors to order at 8:30 a.m., on February 6, 2003, to consider a report from Dr. George Kunos, Scientific Director of the NIAAA Intramural Program.

Dr. Ting-Kai Li, M.D., Director, NIAAA, called the open session of the 102^nd meeting of the National Advisory Council on Alcohol Abuse and Alcoholism to order at 9:15 a.m., on February 6, 2003. After thanking the dedicated staff at NIAAA for their assistance during his first months as Director and their continuing support during coming era of restrained budgetary growth,Dr. Li introduced four new Council members:

• Gail A. Jensen, Ph.D., Professor in the Institute of Gerontology at Wayne State University
• Ms. Stacia A. Murphy, President of the National Council on Alcoholism and Drug Dependence, Inc. (NCADD)
• Stephanie S. O'Malley, Ph.D., Professor of Psychiatry at the Yale University School of Medicine and President of the Research Society on Alcoholism
• Robert E. Taylor, M.D., Ph.D., Chairman and Professor in the Department of Pharmacology at Howard University College of Medicine

To thank Dr. Raynard Kington for his stewardship as Acting Director of NIAAA following the retirement of Dr. Enoch Gordis until last November, Dr. Li read an excerpt from a formal Proclamation of Appreciation that Council unanimously endorsed at its September session. This citation, copies of which were supplied to Council members, commended Dr. Kington’s administrative leadership, the trust he inspired in Council members, his commitment to bolstering NIAAA’s research efforts, and his substantial contributions to leading the Institute through a number of milestone initiatives. The Proclamation concluded that the association with Dr. Kington had made, "the Council and the NIAAA better able to serve the Nation."

In accepting the plaque, Dr. Kington said he was deeply honored and that the time spent at NIAAA was a joyful learning experience during which he developed great respect for the Council and the staff.

To begin his first report to Council, Dr. Li outlined NIAAA’s mission as leading national efforts to reduce alcohol-related problems by:

• Conducting and supporting research in a wide range of scientific areas;
• Coordinating and collaborating with other research institutes at the NIH and with other Federal programs on alcohol-related issues;
• Collaborating with international, national, state, and local institutions; organizations; agencies; and programs engaged in alcohol-related work; and
• Translating and disseminating research findings to health care providers, researchers, policymakers, and the public.

An accompanying vision statement for NIAAA detailed four explicit goals and social benefits that alcohol research and education are expected to achieve. These include:

• Removing the stigma associated with the common, but complex, disease of alcoholism
• Revealing the genetic, other biological, and sociocultural origins of variations in individual responses to alcohol and the consequent risks and benefits of alcohol to health
• Developing effective treatment and prevention strategies that address

-  The physical, behavioral, and social risks attributable to excessive and underage alcohol consumption.
-  The chronic relapsing nature of alcoholism and the mechanisms that underlie alcohol addiction.

• Improving the acceptance of—and access to—quality care.

Turning to the budget, Dr. Li noted that the FY 2004 request presented to Congress in late January anticipates that NIH’s research budget will grow by $550 million—an increase of 7.7 percent—largely dedicated to biodefense research. NIAAA’s budget request for FY 2004 is for $430.1 million—an increase of $14.8 million or 3.6 percent over the current FY 2003 level.

Among the highlights are:

• Support for approximately 192 competing research project grants (RPGs) with an average cost increase of 6.6 percent over the FY 2002 level.
• A modest increase in the budget for Alcohol Research Centers to support 15 Centers.
• $11.3 million for 85 research career awards and $13.4 million for cooperative agreements.
• Modest increases in monies for research training—mostly to increase stipends for NRSAs and post-doctoral trainees.
• Maintenance funding for the Intramural Research Program.

Noting that nearly 86 percent of NIAAA’s expenditures go to extramural and intramural research, with an additional 3 percent for education and outreach and only 11 percent in indirect costs, Dr. Li announced 11 new research initiatives for the FY 2004 budget that were developed in conjunction with Council's Research Priorities Subcommittee and the Research Priorities Committee of the Research Society on Alcoholism. These priority research areas are:

1. Conducting basic research on medications development for alcohol use disorders.
2. Continuing genetic studies of vulnerability to alcohol.
3. Identifying mechanisms and markers of alcohol-induced organ damage and protection.
4. Identifying behavioral and genetic risk factors for alcoholism and their interactions.
5. Cataloguing long-term, community-based prevention and intervention studies of alcohol problems at specific life stages.
6. Identifying the neuroscientific basis of addiction and underlying neuroadaptive response mechanisms.
7. Initiating a multi-site, collaborative study of fetal alcohol syndrome (FAS).
8. Continuing collaborative studies with other NIH initiatives of women and HIV/AIDS.
9. Investigating disparities in the adverse and beneficial effects of alcohol.
10. Advancing behavioral therapies for alcoholism.
11. Training the next generation of investigators, using innovative and effective mechanisms.

From the written Report on Institute Activities that each Council member received and is accessible on the web page, Dr. Li called attention to several activities:

• The RFA entitled Research Partnership Awards for Rapid Response to College Drinking Problems, that NIAAA issued in December, will soon be followed by a similar Program Announcement. Both solicit collaborations between colleges and researchers on prevention and intervention strategies for students’ alcohol-related problems.

• The Governors' spouses who spearheaded the Leadership to Keep Children Alcohol Free initiative have been asked to serve as honorary chairs for the NCADD celebration of Alcohol Awareness Month in April.

• Testifying on behalf of the Leadership spouses in November, Ms. Teresa Racicot, former First Lady of Montana, urged the National Academy of Sciences’ Committee on Developing a Strategy to Prevent and Reduce Underage Drinking to focus serious attention on very early drinkers—children aged 9 to 15 years old.

• The Office of Collaborative Research (OCR) released an RFA in October entitled Collaborative Initiative on Fetal Alcohol Spectrum Disorders (FASD).

• In January, staff from OCR participated in a retreat with Directors of NIAAA Alcohol Research Centers to inform participants about available resources at the Centers and their particular emphasis on mentoring new career investigators.

• The Scientific Communications Branch, Office of Scientific Affairs (OSA), which publishes Alcohol Alert, printed an issue on Changing the Culture of Campus Drinking that will be followed by one on underage drinking.

• Council members received advance copies of a newly revised publication, Helping Patients with Alcohol Problems: A Health Practitioner's Guide. Two additional NIAAA publications, Make a Difference: Talk to Your Child About Alcohol and Alcohol: What You Don't Know Can Harm You, have also been revised and reprinted. The full text for each is available on the web site at http://pubs.niaaa.nih.gov/publications/brochures.htm.

• The new video, Alcohol: A Women's Health Issue, which Council viewed at its June meeting and was jointly produced by NIAAA and NIH's Office of Research on Women's Health, won a bronze World Medal in the New York Festival film and video competition.

• In conjunction with NIDA, NIAAA’s Division of Biometry and Epidemiology is co-funding a follow-up National Epidemiologic Study on Alcohol and Related Conditions.

• Upon the January retirement of Dr. Richard Fuller as Director of the Division of Clinical and Prevention Research (DCPR), Dr. Robert Huebner, the Deputy Director, became Acting Director. Dr. Raye Litten will assume Dr. Fuller’s role as Project Officer for COMBINE.

Finally, Dr. Li personally welcomed a dozen recently appointed staff members at NIAAA.

Dr. Kenneth Warren, Director of OSA, reported on two NIH planning approaches that impact how NIAAA sets priorities and monitors the achievement of research goals. The first model, stemming from the Government Performance and Results Act (GPRA) that was enacted in 1993, requires all Federal Government agencies to set goals for accomplishment that can be monitored by the Office of Management and Budget (OBM).

NIH was initially permitted to design its own GPRA monitoring program that focused on a qualitative assessment of science "advances." Each institute designated and described 15 to 25 successful research projects that were reviewed by a committee within the NIH Office of Planning, but no outcome objectives were required or applied. Following a change in the administration and new leadership at OMB, alterations in NIH’s GPRA monitoring system were mandated in 2002. The revised protocol requires each institute to define a set of 10 research-based target outcomes that are categorized on a risk-time matrix, ranking risk from low to high and by whether objectives are short- or long-term. The intent is to select a final set of 27 NIH outcome objectives for submission to HHS and OMB. Although limited in number, 27 target objectives were considered adequate for monitoring purposes.

Copies of the matrix listing 10 GPRA outcome objectives endorsed as priorities by NIAAA were provided to Council members. One or more of these is expected to be on the final NIH list that is under review by DHHS and OMB before acceptance and public dissemination. Progress toward fulfilling the outcomes will be reported annually, and the objectives may be redefined yearly.

A second strategic planning model, the NIH Roadmap, introduced by Dr. Zerhouni, NIH Director, outlines a vision for research as well as the scientific challenges, endpoints, and issues that NIH must address collectively. Roadmap was sparked by the existence of large-scale, unprecedented, and high-end technologies across the scientific domains of the NIH institutes as well as the emergence of many unifying and ubiquitous concepts (e.g., genomics, proteomics, metabolomics, cell signaling, apoptosis, cell trafficking, cell cycle control). The three goals of the NIH Roadmap exercise are to:

• Accelerate the pace of discoveries in the life sciences;
• Achieve a more rapid translation of basic research into application; and,
• Develop novel approaches in prevention and healthcare that are orders of magnitude more effective than current ones.

NIH scientists and institute directors have identified four major themes in this Roadmap effort and directed planning committees to:

• Use revolutionary research methods that include structural biology, molecular libraries, and tool kits for nanotechnology, bioinformatics, and computational biology.

• Find new discovery pathways (e.g., biological circuitry toolkits, integrative approaches to systems biology, quantitative analyses of dynamic genome-wide expression patterns, stem cell research, regenerative medicine) and address behavioral issues such as gene-environment interactions and stabilization of behavioral change.

• Develop collaborative, multi-disciplinary research teams and leverage NIH resources to form public/private partnerships.

• Re-engineer the clinical research enterprise by incorporating innovative research designs (e.g., large-scale longitudinal cohort studies, partnerships to facilitate subject recruitment, improved research data structure, medical informatics, training new clinical scientists).

Responding to a Council member’s question, Dr. Li emphasized that interdisciplinary research applies to the entire spectrum from genes to whole animals. Clinical studies, for example, may include a broad variety of disciplines in a team approach to problem solving.

Mr. Darian LeBlanc, from the Real Estate Contracting Branch of the Office of Research Services, described the Fishers Place Project—a complex of six new buildings also known as the Twinbrook Cluster—that will house several NIH components, with substantial research and administrative space for NIAAA in 5625 and 5635 Fishers Lane.

NIAAA will be the largest tenant in 5635 Fishers Place, an 180,000 square-foot administrative building that will replace 6000 Executive Boulevard. Other likely NIH occupants are the National Eye Institute, the National Institute of Mental Health, and some components of the Human Genome Research Institute. The terrace level will contain about 6,500 square feet of state-of-the-art conference facilities, while the plaza level will have a sidewalk café and other retail stores. The site is also close to amenities on Rockville Pike, including the Mid-Pike Shopping Center.

The research facility, 5625 Fishers Place, is a 140,000 square-foot building directly across the pedestrian-scape from the administrative offices. It will be occupied solely by NIH components, including the National Eye Institute, the Human Genome Research Institute, and the Office of Research Services. Another research facility at 5615 Fishers Place is in the planning stage.

In response to queries from Council members, Mr. LeBlanc explained that:

• A seven-story parking garage will have space to accommodate 1,000 cars—more than sufficient for all the buildings’ tenants. Although a portion of this partially completed structure recently collapsed, the damaged part has been cleared and construction resumed.
• The National Institute of Allergy and Infectious Diseases will use the building currently under construction at 12735 Twinbrook Parkway as a research facility.

Dr. Lorraine Gunzerath, Planning and Evaluation Branch in OSA, explained the Congressional requirement, established by the 1993 NIH Revitalization Act, for a biennial report on each institute’s compliance with a mandate to include women and minority groups in clinical research studies and Phase III clinical trials in sufficient numbers to reflect their prevalence in the disease, disorder, or condition being studied and to conduct statistically valid analyses of subgroup differences in intervention effects. Since FY 1995, all NIH-funded programs, grants, cooperative agreements, and intramural research efforts have been required to adhere to these inclusion guidelines, reflecting the composition of the U.S. population, but targeting subject enrollment levels.

Compliance with this mandate is ensured through a multi-step process. NIAAA program officers may help grant applicants ascertain how many subjects in different subgroups must be enrolled; the initial review group determines whether or not women and minorities are adequately represented in specific applications; and the scientific review administrator summarizes any IRG concerns or comments and codes the summary statement to reflect these decisions. Any concerns or comments must be revised accordingly by the potential grantee. Even after an application is accepted, the Institute tracks whether the subject numbers reflect projected targets. Because of a reporting lag time, subjects enlisted in 2001 only appear in FY 2002 enrollment figures.

Institute staff is periodically trained regarding gender/minority subject inclusion requirements since rules change frequently. Most recently, the Census Bureau revised the way ethnic and racial categories are recorded. Hispanic/Latino is now an ethnicity instead of a race, and racial categories were modified to separate Pacific Islanders/Hawaiians from Asians. Each respondent has both a race and an ethnicity and can choose to be classified as having more than one race.

While all new projects must use the new Census categories, continuing research studies may choose either the old or new reporting format. As a result, the enrollment numbers for FY 2001 are not comparable to anything submitted previously. The only category that has remained the same across years is total numbers/percentages of males and females.

When aggregate subject enrollment percentages are compared, NIAAA has a much smaller percentage of female subjects than NIH whose figures reflect the very large, recently aborted Women's Health Initiative. Any comparison of subjects in NIAAA Phase III clinical trials with similar NIH initiatives can be misleading because NIAAA has only two Phase III projects plus the Project COMBINE sites; and 19 percent of NIH projects are female-only, while NIAAA has no gender-specific Phase III projects.

In response to Dr. Warren’s request that Council take a vote regarding whether the figures provided reflect Institute compliance with mandated procedures for recruiting and enlisting women and ethnic minority groups as subjects in clinical studies and achievement of appropriate enrollment targets, a motion to that effect was made, seconded, and unanimously approved.

Jeffrey W. Runge, M.D., Administrator of the National Highway Traffic Safety Administration (NHTSA), spoke about activities of particular interest to NIAAA and potential collaborative ventures. In a PowerPoint presentation that will be made available to Council, he stressed that:

• Accidents are the leading cause of death in Americans under age 35, motor vehicle crashes are the major cause of unintentional injury and death at every age, and alcohol is a leading contributor to vehicle crashes.

• Since the establishment of NHTSA in 1966, the fatality rate per 100 million vehicle miles traveled (VMT) has dropped from 5 to 1.52. While rates are improving, the increased numbers of cars on the road resulted in 42,116 highway deaths in 2001 and over 3 million injuries. The economic cost of motor vehicle crashes in the United States was $230.6 billion in 2000.

• The 17,448 alcohol-related motor vehicle fatalities in 2001 reflected a fatality rate of 0.63 per 100 million VMT. Nearly 15,000 of these fatalities had blood alcohol levels (BACs) at or above 0.08. NHTSA’s goal is to reduce the alcohol-related fatality rate to 0.53 per 100 million VMT by the end of 2004.

• Traffic crashes involving an alcohol-impaired driver or pedestrian are about 50 percent more likely to result in an injury or fatality than crashes in which no alcohol is involved. Moreover, there’s a clear linear relationship between BAC levels and crash risk: A driver with a 0.04 BAC is 18 percent more likely to be involved in a crash than a non-drinker; a driver with a 0.08 BAC level is 2.5 times more likely to have an accident; the driver with a 0.10 BAC is 5 times more likely to crash; and the driver with a 0.15 BAC is 22 times more likely to have a collision.

• A few geographic areas, population subgroups, and vehicle types contribute a disproportionate share of the alcohol-related motor vehicle fatality problem.

• States with the highest numbers of alcohol-related motor vehicle deaths as well as the highest rates for miles driven by their populations are Florida, Texas, Louisiana, Tennessee, South Carolina, Arizona, and Missouri.

• Heavy drinkers/alcoholics in fatal crashes have mean/median BACs of 0.16 grams of alcohol per deciliter of blood. They have a serious disease, not a social problem.

• Persons with at least one prior DWI conviction accounted for 8.4 percent of all alcohol-related traffic deaths in 2001—or 1,400 fatalities.

• A majority of alcohol-impaired drivers in fatal crashes are under 35 years old, 82 percent are male, 65 percent are not wearing seat belts, and 80 percent are beer drinkers.

• Most persons (55 percent) killed in alcohol-related crashes are drinking drivers, 23 percent are passengers, 15 percent are non-occupants, and 7 percent are sober drivers.

• The 2001 fatality rate for alcohol-related motorcycle crashes was 14.00 per 100 million VMT — about 28 times that of passenger cars (0.51) and light trucks (0.52).

• Adult pedestrians who have been drinking are more likely than those who are sober to be fatally injured by motor vehicles—accounting for 40 percent of 2001 pedestrian fatalities.

After an analysis found that a 33 percent reduction in impaired driving would save 30 percent of lost lives; increasing seat-belt use to 90 percent would save another 34 percent of lost lives; and all other safety countermeasures combined would save 36 percent of total lives lost, NHTSA decided to focus fatality-reduction countermeasures on impaired driving and safety belt use.

NHTSA’s 2003 goals for impaired drivers are: 1) to increase highly-visible and publicized enforcement; 2) to create the expectation of real consequences (e.g., detection, arrest, prosecution); and 3) to elevate public concern about this serious public health problem.

Among NHTSA’s short- and long-term priorities are the following:

• Better data and reporting of vehicle fatalities.

• Improved collection of alcohol blood and breath levels through uniform State systems.

• Better and more uniform impaired driving laws. Although administrative license revocation (ALR) for persons who refuse the test or have a specified BAC has a deterrent value, 10 States do not have this law. Similarly, clear scientific evidence supports a maximum BAC level of 0.08 for DWI, but 15 States have not enacted this law.

• Improved training for prosecutors and judges regarding sentencing alternatives for alcohol-involved juveniles and adults with DWI charges.

• More screening and early intervention tools, especially for convicted offenders.

• Available treatment for persons who screen positive, with some pressure—like that imposed by judges—to accept a referral.

• More training for physicians and other healthcare workers regarding early recognition and screening for alcohol impairment, conducting brief interventions, and making referrals.

Impaired drivers are not only a policy problem and public health emergency, but also a treatment issue requiring a science-based resolution. Although NHTSA is committed to increasing high-visibility enforcement in the near future, this is not a long-term solution and advice is needed from Council and NIAAA regarding alternative strategies. NHTSA is co-sponsoring a March meeting with NIAAA on the treatment of DWI offenders, and the two agencies are collaborating to identify randomized sanctions that reduce recidivism. For the future, NHTSA would welcome NIAAA’s help in evaluating the efficacy of impaired driving programs.

In response to questions from Council members, Dr. Runge clarified that:

• Health economists at NHTSA have not studied whether making DWI a felony offense is a cost-effective deterrent. NHTSA did fund a very successful DWI court in Maricopa County in 1997 that cost only $100,000 for two case workers and was easily justified by reductions in incarceration expenses as a result of using sentencing alternatives.

• It is unclear how the inclusion of marijuana/THC intoxication might affect the numbers and rates of traffic fatalities. While NHTSA and ONDCP have used drug recognition officers to observe clinical signs in roadside driver stops, little research exists on the driving effects of marijuana by itself since it is often combined with alcohol and other drugs. Even if roadside saliva tests for THC are reliable, a positive response does not necessarily explain a driver's current behavior since marijuana may be found in the systems of chronic users for days to weeks after they have smoked.

• With respect to tracking drivers’ use of other substances that potentially affect driving such as antihistamines, other medications, and over-the-counter drugs, any known drug use is entered into NHTSA data systems from police reports and hospital records. Little information, however, is recorded because few drivers voluntarily report drug use. In fact, fatigued drivers who drink a little alcohol are worse performers than wide-awake drivers who consume more alcohol. Impaired driving is not strictly a quantitative process.

• The NHTSA budget request for FY 2004 contains $50 million for States with high rates and numbers of alcohol-related vehicle deaths that are willing to increase high-visibility enforcement, establish special prosecutors for DWI or DWI courts, and expand treatment.

• Dr. Hingson added several relevant comments to the discussion. Namely:

• Since nearly a quarter of vehicle passengers in alcohol-related crashes are killed, and young drinking drivers are more likely to have more passengers in their cars, a higher percentage of these riders are likely to be at-risk of death.

• Because vehicle crashes are the leading cause of alcohol-related death among college students, college administrators, students, alumni, and parents should be enlisted as advocates for greater enforcement of drinking and driving laws.

• Collaborations between NHTSA and NIAAA are needed, not only for the college drinking initiative, but to incorporate alcohol-related traffic issues in treatment studies and data systems. College identifiers, for example, could be added to the FARS system.

Dr. David Lovinger, Chief of the Laboratory for Integrative Neuroscience in the Intramural Research Program, reported on his research being conducted in the Section on Synaptic Pharmacology (SSP). This work focuses on the ways in which alcohol and other drugs of abuse induce long-lasting changes in synaptic communications between nerve cells in the brain that seem to be related not only to learning and memory but to neuronal adaptations leading to addiction. The following are highlights of this presentation.

Using such approaches as electrophysiologic examinations of neurons isolated from rodents’ central nervous systems or slices of brain tissue, DNA engineering to alter protein structures, and rodent models developed from traditional laboratory rats or genetically-engineered mice, investigators in the SSP laboratory conduct studies of the synapse—or communication point between two neurons— that is the target for many drugs of abuse, especially alcohol. When activated, presynaptic nerve terminals release vesicle-stored neurotransmitter molecules that cross the synaptic cleft and bind to protein molecule receptors on postsynaptic elements. Some receptors not only bind the transmitter but have ligand-gated ion ports through which ions cross the membrane. Other receptors activate GTP-binding proteins that produce biochemical signals.

Connections between parts of the midbrain and the basal ganglia (i.e., caudate nucleus and putamen (CPU)—or striatum—and the nucleus accumbens) that are apparently involved in movement control and habitual behaviors are affected by drugs of abuse. The corticostriatal synapse, of special concern for addiction, connects the cerebral cortex with the striatum. When activated, this synapse releases the neurotransmitter glutamate that binds with AMPAR-type glutamate receptors that are ion ports. Positively charged ions flowing into the post-synaptic cell produce a measurable excitatory post-synaptic current. Striatal neurons also contain receptors for dopamine—a key neurotransmitter for addiction. Some G protein-coupled neurotransmitter receptors on the pre-synaptic elements can inhibit the release of neurotransmitters.

Transmission at the corticostriatal synapse is also subject to long-term synaptic depression (LTD)—or persisting decreases in the strength of glutamatergic synaptic connections between the cortex and the striatum following high frequency neuronal activity. LTD, which is implicated in habit learning and the development of proper movement patterns, may also contribute to the development of addiction.

The LTD process can be studied in rat or mouse preparations by using a micropipette to record the amplitude of the excitatory post-synaptic current generated when synapses coming onto striatal neurons are activated by either high-frequency electrical stimulation or drugs of abuse such as alcohol or delta 9-THC, the active ingredient of marijuana. Any decrease in transmission shows that the synapses aren't functioning normally.

Recently, Drs. Daniele Piomelli and Rafael Mechoulam discovered that endogenous cannabinoids—or endocannabinoid compounds—exist in everyone’s brains and activate the same receptors as delta 9-THC. These CB1 cannabinoid G protein-coupled receptors, which are particularly prevalent in the striatum, produce a biochemical signal inside the cell. Stimulation of the endocannabinoids also promotes LTD or a decrease in transmission that, as noted, appears to be a substrate of the learning process involved in addiction. This response is documented in genetically-engineered mice that lack CB1 cannabinoid receptors and don't exhibit striatal LTD when stimulated to release endocannabinoids.

Studies by Dr. George Kunos, NIAAA’s Intramural Scientific Director, have found that CB1 receptor antagonists decrease alcohol drinking and that alcohol drinking is reduced in mice that lack CB1 receptors. Future work, building on the efforts of Drs. Kunos and Hundgund, will hopefully determine the cellular and molecular interactions between endocannabinoids and alcohol.

It appears that all drugs of abuse affect striatal glutamatergic transmission—cortex to striatum transmission—and also affect interactions with dopamine. More specifically,

• Alcohol inhibits glutamate receptors and synaptic transmission in the striatum.

• Amphetamine and cocaine stimulate dopamine release and inhibit glutamatergic transmission which may alter synaptic plasticity.

• Nicotine stimulates dopamine release that appears to be a crucial step for LTD.

• Opioids, like cannabinoids, inhibit corticostriatal transmission.

The action of alcohol on the synapse that releases serotonin—5-HT (5-hydroxytryptamine)— is another addiction-related interest. The 5-HT₃ receptor—a ligand-gated ion channel neuroreceptor —has been strongly implicated in alcohol abuse. Direct application of alcohol enhances the function of these receptors and may be one mechanism underlying alcohol-induced dopamine release in the striatum. Other studies are exploring the relationship between the receptors’ protein structure and alcohol sensitivity. Because 5-HT₃ antagonists reduce alcohol drinking in rodents and subtypes of alcoholic humans, these 5-HT₃ receptors may be a target for future alcohol-related pharmacotherapies.

The following model posits how abused drugs produce long-term synaptic changes that progress to addiction:

• Alcohol and other drugs of abuse act directly at the synapse to alter either release of neurotransmitters from the pre-synaptic site or the function of receptors at the post-synaptic site and impact normal transmission patterns involved in learning and memory.

• This plasticity during early stages of addiction and dependence appears to "rewire" the strength of circuitry in key brain regions (e.g., nucleus accumbens, A10, dopaminergic neurons).

• Long-term drug abuse may contribute to the development of habitual, almost unconscious drug-taking behaviors that stem from plasticity in the striatum or the spread of synaptic modifications within the brain. Endocannabinoids may have an important role in setting up this change.

In response to a question from Dr. Koob, Dr. Lovinger explained that he had not looked at mu knockout mice in the cellular model to see how they correspond to cannabinoid 1 knockout mice because the mu is much less effective than the CB1 receptor in inhibiting transmission, although it may have a more prominent role in long-lasting transmission changes. However, the experiment is worth pursuing, particularly since there is evidence that drugs such as naltrexone and naloxone which prevent activation of the mu opioid receptor also prevent synaptic plasticity in other brain regions such as the hippocampal formation.

Steven M. Mirin, M.D., Council member, former Medical Director of the American Psychiatric Association (APA), and currently Senior Consultant to the Alcohol and Drug Abuse Research Center at McLean Hospital in Belmont, Massachusetts, spoke about the APA’s role in shaping the Nation's mental health agenda. Among the key points of this presentation are the following:

Major trends in the mental health field that are shaping the public policy agenda include national and international epidemiologic studies which underscore the prevalence and societal burden of mental illness—a leading cause of disability; advances in neurobiology, molecular genetics, and neuroimaging that are improving diagnoses, treatment, and prevention services; and new knowledge that is reshaping the diagnostic nosology and classification of mental disorders.

Positive and negative trends in the financing and delivery of mental health care that simultaneously influence policy decisions include an increased demand for services kindled by treatment advances, destigmatization, and spiraling public need; rising costs that have resulted in tighter controls over access to, intensity, and duration of services; and demands for improved accountability for clinical outcomes and fiscal costs by policymakers, payers, and patients.

Federal budget deficits are producing economic pressures on services delivered by academic health centers, particularly in high-touch, low revenue fields such as psychiatry, family practice, and pediatrics. Support for training psychiatrists, psychologists, and social workers is also more tenuous. Large educational debts incurred by most graduating medical students influence not only specialty selection but also pursuit of research careers. In the near future, adult and child psychiatry will remain shortage specialties and psychiatrist researchers will be even rarer.

The APA is a 501(c)(6) organization with three subsidiaries: the American Psychiatric Foundation (APF) that raises funds, awards grants, and directs public education; American Psychiatric Publishing, Inc (APPI); and the American Psychiatric Institute for Research and Education (APIRE) that conducts in-house research through a network of 150 psychiatrists and 130 fellows. The APA’s advocacy agenda encompasses numerous activities such as convincing the public and influential listeners in the public and private sectors that mental disorders are real, widespread, and treatable by disseminating credible data on the prevalence and societal impact of mental illness, demonstrating the efficacy and effectiveness of mental health treatments, and affirming the link between basic clinical and services research and subsequent advances in clinical care.

Additionally, the APA initiates and lobbies Congress to support legislative and regulatory initiatives that enhance access to quality care; advocates increased Federal support for basic clinical and services research; develops and disseminates evidence-based practice guidelines and other quality indicators; and defines/refines an evidence-based classification system for mental disorders—the Diagnostic and Statistical Manual (DSM). With a target publication date of 2008-10, work is already underway on the DSM-V in collaboration with the World Health and World Psychiatric Organizations to assure compatibility with the ICD-11.

The APA also helps supply psychiatric clinicians, teachers, and researchers by maintaining continued Federal support for graduate medical education; supporting the survival of academic health centers; and assisting psychiatrists to launch and sustain careers through Federal grants. The APA encourages caregivers’ continuing education by sponsoring special learning opportunities at the annual May meeting; publishing books and journals; supporting certification (e.g., Web-based CME credits); and conducting other collaborative efforts.

In 2003-4, the APA will focus on the following health and mental health policy issues:

• An improved public health response to terrorism, particularly bioterrorism.
• Reducing the rising costs of health insurance.
• Initiating drug benefits under Medicare.
• Patients rights in organized healthcare systems.
• Access to quality care for the growing number of uninsured children and elderly persons.
• Parity for insurance coverage.
• Reversing the adverse impact of declining State budgets on the public sector service. system, including Medicaid funding for treatment of people with alcoholism and other substance use disorders.
• Eliminating the continuing criminalization of the mentally ill.

To clarify questions by Council members, Dr. Mirin made the following points:

• A total of 37 States have parity insurance laws requiring the provision of mental health care at essentially the same level as general health care. However, only a dozen States include treatment for alcohol and drug abuse in this parity.

• With respect to using tobacco settlements to support mental health and substance abuse services, some States mandate that a portion of the funds go toward health care.

• Since substance use disorders are highly comorbid with other mental illnesses, it is ineffective to treat one while neglecting the other. Also, substance use disorders are medical illnesses that need to be insured on the same basis.

• Although a nationalized mental health insurance system may be needed, given the multitude of public and private insurers and variety of available treatments, resolution of this issue may not be achieved soon.

Ralph Hingson, Sc.D., M.P.H., Council member and Associate Dean for Research in the Boston University School of Public Health, reported on a recent meeting of the NESARC advisory committee that was formed after the September 2002 presentation to Council about the National Epidemiologic Survey on Alcohol and Related Conditions by its Director, Dr. Bridget Grant, Chief of NIAAA’s Biometry Branch in the Division of Biometry and Epidemiology.

NESARC is a continuation of the 1992 National Longitudinal Alcohol Epidemiology Study (NLAES) that attempted to identify how many people had DSM-IV-diagnosable alcohol abuse or dependence, needed treatment, and received some type of care. The first wave of NESARC, conducted by the U.S. Bureau of the Census between September 2001 and May 2002, had a remarkable 85 percent response rate from a representative sample of more than 43,000 randomly-selected U.S. adults, 18-years and older, who lived in households or other communal dwellings. Both the NLAES and the NESARC study over-sampled Blacks, Hispanics, and young persons to estimate those groups’ alcohol abuse and dependence.

Numerous publications using NLAES data have focused on the proportion of respondents with diagnosable alcohol abuse or dependence, rates of treatment, barriers encountered in treatment seeking, and motivations for pursuing help. A landmark article by Dr. Grant documented the increased likelihood that persons who start drinking at younger ages will become alcohol dependent at some point in their lives.

Because many NLAES items were retained in the initial NESARC, changes between 1992 and 2001 in the proportions of alcohol-abusing or dependent people or rates of treatment can be studied. Among new items added to the NESARC were family history of drug or alcohol abuse and depression; questions about mood disorders, general anxiety, specific phobias; gambling and its treatment; and additional questions about age of drinking onset, first drug use, and so on.

The NESARC Committee was formed to advise researchers about the content of a follow-up survey that expects to re-interview all of the initial NESARC respondents in 2004 and 2005. Input is being sought about important items that should be added, with the caveat that lengthening the survey interview will likely decrease the participation rate at a time when non-response is a growing problem. The interview currently takes an average of an hour to administer.

Among potential additions are items pertaining to sexual orientation, discrimination, social network support, acculturation, and social stress. Other Committee members want to collect biologic markers from which to extract DNA information and to create better linkages of survey data with death certificate information, medical records, and driver files. Some members agreed that questions from the original NLAES about motor vehicle crash involvement and injuries after drinking—that were eliminated in the NESARC—should be reinstated with related questions about the blood alcohol concentration (BAC) of people charged with impaired driving or involved in vehicle crashes.

Additionally, NESARC contains no questions about the relationship between drinking and risky sexual behavior, unplanned or unprotected sex, number of sexual partners, history of sexually transmitted diseases, HIV testing, or unplanned pregnancy. Some felt the survey should also document the problems that excessive drinkers pose to innocents that society should protect. No items currently pertain to the adverse effects of drinking by others such as criminal or sexual assault, domestic violence, child abuse, and other forms of victimization. If all of these questions are added, others will have to be removed. Dr. Grant is considering deleting items on mood states, phobias, and family history—which won’t change radically in 2-years. No final decisions were made at the meeting, and recommendations are still being accepted.

In response to Council members’ questions, Drs. Hingson and Mary Dufour, Deputy Director of NIAAA, clarified several aspects of NESARC:

• Although the NESARC Committee did not consider how data analyses might address respondents’ efforts to stop drinking and reduce alcohol consumption, rather than their escalating patterns of alcohol involvement and related problems, NESARC, as a longitudinal survey, has the capacity to examine such questions as how many persons spontaneously remit, whether those who receive treatment get better, and a range of similar queries that cannot be addressed in a cross-sectional survey.

• Although molecular geneticists on the Committee unanimously agreed that biological samples from buckle swabs and/or mouthwashes should be collected as part of NESARC, Dr. Grant was not certain that the current technology warrants the additional costs. It may be more practical to defer the collection of DNA samples to a later iteration of the survey.

• With respect to issues and hypotheses that might be examined with the information collected by over-sampling ethnic groups in both NESARC waves, most attention at this meeting was given to measuring the acculturation construct and how to parcel out economic disadvantage from other ethnic and cultural issues.

Dr. Joanne Fertig, Program Director for NIAAA's Alcohol and Tobacco Research Program, reported on a collaborative NIH project involving the National Cancer Institute and the National Institute on Drug Abuse that NIAAA will join in coming months—the Transdisciplinary/Tobacco Use Research Center (TTURC) initiative. NIAAA collaboration is encouraged because alcohol and tobacco share common behavioral, sociocultural, and genetic determinants, and comorbidity of alcohol abuse/alcoholism and smoking is extremely high. The greatest cause of death among alcoholic persons is tobacco use. Dr. Fertig also introduced Dr. Alison Chausmer from NIDA's Translational Research Branch and Dr. Scott Leischow from NCI’s Tobacco Control Research Branch.

Dr. Glen Morgan, NCI Program Director for the TTURC Initiative, remarked that this effort had its genesis in late 1997, when a Tobacco Research Implementation Group at NIH gave priority to establishing transdisciplinary tobacco use research centers that would encourage scientists to share conceptual models. Following release of an RFA for the 5-year initiative in 1998, seven Centers were funded at a cost of about $14 million per year. These TTURCs are located at Brown University, Georgetown University (with an offshoot at the University of Pennsylvania), the University of Minnesota, the University of Wisconsin, Yale University, the University of California at Irvine, and the University of Southern California.

In 1998, tobacco use accounted for about 400,000 deaths annually and rates of new smoking had risen nearly 70 percent over the previous 3- to 4-year period. Over the last four years, tobacco-related death rates have increased by another 10 percent if smokeless tobacco use and environmental tobacco smoke are included. When the TTURCs were established, research on tobacco use etiology, epidemiology, treatment, and policy were not advancing at an acceptable pace; the number of young investigators entering the field was decreasing; and most tobacco-related research was uni-disciplinary rather than collaborative and integrative.

The TTURCs provide a critical mass of investigators and transdisciplinary collaboration within and across centers and offer a unique context for training both new and seasoned investigators. They also provide funding for exploratory pilot projects and share core resources for greater efficiency. Cross-Center workgroups are developing common measures and looking at phenotypes for tobacco use. Recipients of the P50 TTURC awards must have a minimum of three—and a maximum of five—major projects. Other cross-Center collaborations are focusing on gene and culture-environmental interactions in tobacco use (particularly among Chinese youth and adults), use of bupropion for smoking cessation, measures of dependence development, and neurobehavioral regulation of smoking and affect. The TTURCs have collaborated on a special issue of Nicotine and Tobacco Research that will be published in late spring. This initiative is being evaluated through a researcher survey, peer evaluations, and a bibliometric analysis of citations from the 61 articles published by TTURC investigators through June 2002 which has found that the work of the these researchers has been heavily cited. Their productivity is increasing and compares favorably to authors published in the same journals.

Council member Dr. Stephanie O’Malley described the TTURC at Yale University, which she directs. The goal of this Center is to improve the treatment of tobacco dependence by studying the underlying factors associated with treatment failure and developing novel behavioral and pharmacological treatments to address these factors. The focus is on smokers who are most resistant to current treatments—those who use/abuse alcohol, have depressive symptoms, or are female.

Tobacco use strongly determines how alcohol is used. Persons who have ever smoked have a 5- to 10-fold increased risk for alcoholism; genetic vulnerability to both alcohol and nicotine is shared; and the health risks of combined smoking and alcohol use are 50 percent higher than the sum of the individual risks.

Among the major questions being examined at the Yale TTURC are:

• How is reinforcement or withdrawal from nicotine changed by co-administering alcohol?

• What molecular neurochemical changes are associated with concurrent use versus single substance use?

• Can understanding the interactive effects of nicotine and alcohol lead to new pharmacological interventions for smoking cessation or more tailored treatments?

The several cores affiliated with the Center focus on policy, career development, laboratory activities, data collection, science, and sex-specific factors. The funded projects pertain to policy issues, animal models, early tobacco abstinence in high-risk groups; imaging techniques; the use of naltrexone to augment nicotine patch and smoking cessation techniques, particularly for drinkers who smoke; and messages that encourage treatment with bupropion. The Robert Wood Johnson Foundation is funding a communications core to consider how and to whom findings will be disseminated and how best to get them adopted. The Center is a very integrated effort, with many cross-disciplinary collaborations.

Mr. Don Saber from the American Medical Association remarked on the opportunities for transdisciplinary policy discussions between researchers in the fields of tobacco and alcohol treatment and prevention who address similar issues of promotion, pricing, and advertising, and noted that a declining economy justifies raising the price of tobacco and alcohol.

After noting that the minutes of the September 19^th Council meeting did not list one member who was present, Dr. Warren called for a motion to approve and accept the corrected version. Such a motion was duly made, seconded, and unanimously approved without further discussion. Future meeting dates are June 4-5 and September 17-18 of 2003 and February 4-5 of 2004. The May 26-27, 2004 Council meeting will be held at the new Fisher Lane facility.

Dr. Eugene Hayunga, Chief, Extramural Project Review Branch, Office of Scientific Affairs, briefly reviewed the NIH policy and procedures for appealing peer review decisions. He noted that Council members who participate in second-level reviews of grant applications at closed sessions of each meeting may also be asked to take part in the appeals process.

An appeal is a formal communication contesting some aspect of the review process that triggers a process to resolve stated issues. A formal appeal, once initiated, must be resolved before any funding decision can be made. Appeals are distinguished from requests to applicants for additional information that program staff need before issuing an award. Funding decisions per se cannot be appealed.

Referral issues that may be appealed include the assignment to an Institute for potential funding and to a scientific review group for initial review. Issues in the initial review that may be appealed include the composition and expertise of the scientific review committee, a conflict of interest, or some bias or prejudice that may affects the review outcome. Applicants may also appeal the findings and recommendations of review groups as well as scientific errors. Differences of scientific opinion expressed by reviewers may not be appealed and neither may disagreements about the importance or merit of the proposed work.

The standard for resolving an appeal is whether or not the review process was "substantially flawed." The significance of errors or other contestable issues should be judged in the context of the entire review and the priority score. Operationally, this means that, if the error or other issue had not occurred, the application would have a reasonable probability of being in the competitive range for award consideration. If, for example, an application received a very poor priority score, contesting one of several issues leading to the score might have little impact on the outcome. In contrast, if there were a significant error when the priority score bordered on the funding cutoff, this could have made the difference between in the likelihood of an award. Other decisions about filing an appeal pertain to whether an error was minor or substantial or whether there were numerous errors that might infer bias or a lack of expertise among reviewers.

Levels of responsibility for administering the appeals process begin with the appropriate program administrator and the scientific review administrator at either the Institute or the NIH Center for Scientific Review, and extend to the Institute Appeals Officer, the Council, and the Institute Director.

Appeals have various outcomes. One option, administrative resolution, happens when the program administrator and the scientific review administrator responsible for the review agree that the application warrants re-review. The program administrator simply notifies the investigator and the appeals officer of this resolution, and the scientific review administrator proceeds with a re-review. Since a re-review must be of the identical application with all of its original weaknesses, the priority score may not improve. Also, a re-review delays any award decision. Another option is that the investigator withdraws the appeal after some consideration and concurrence with the program and scientific review staff that the review was not substantially flawed. Revising and resubmitting the application in response to the uncontested criticisms is often a more tenable solution.

If, however, the program and review staff do not agree about the merits of the review—or if the program and review staff agree that the review was appropriate, but the applicant disagrees—then the appeals officer must review and resolve the case, if possible. If there is no resolution at this level, then the case is forwarded to Council where individual members are assigned to review the appeal on the basis of their scientific expertise regarding the contested issues. These Council members are provided all necessary documents, including the application, summary statement, letter requesting an appeal, and any other relevant materials. During appeals to Council, both the program administrator and the scientific review administrator should be available for the discussion. Council may decide to: 1) recommend the application for re-review if there is agreement with the applicant about an error in the process; or 2) reject the appeal if there is concurrence with the initial scientific review.

Drs. Hayunga and Warren clarified Council members’ questions with the following explanations:

• NIAAA seldom receives more that a couple of appeals for each round of applications, and most are resolved before presentation to Council. The appeals that Council sees are only those that cannot be resolved internally. In those cases, Council’s judgment is required regarding whether the review was "substantially flawed."

• It was never the intent that any error found in a review should trigger an automatic appeal and re-review. An error in a summary statement needs to be evaluated in the context of the entire review process, to include scientific competency of the review, the fairness of the review, the magnitude of such an error, and the likelihood that it may have affected the funding outcome.

• Although summary statements now contain the raw critiques of individual reviewers prepared before the meeting, each individual reviewer is asked to amend and correct his/her critique following committee discussions to eliminate errors. Each SRA should take notes about committee discussions and explain any significant disagreement among reviewers in the "resume and summary of discussion" section of the summary statement.

Commending NIAAA’s newly revised Health Practitioner’s Guide as a useful tool for treatment providers, Dr. Alpha Brown noted that many persons don't have health insurance and can’t afford to enter the healthcare system. He wondered whether NIAAA had considered developing and measuring the effectiveness of simple interventions conducted by clergy, family members, teachers, or other community leaders that attempt to structure a compelling environment and encourage alcohol-involved relatives or friends to change drinking patterns before addiction occurs. It would be helpful to evaluate which models work for different populations groups.

In response, Dr. Li made the following points:

• Although NIAAA produces outstanding publications, some fail to address the populations that could most benefit from particular messages. NIAAA solicits reactions from users about appropriate publications for special populations in order to make relevant revisions.

• Intervention outcomes are a challenge to measure, but feedback from those who conduct this type of assistance would be useful with respect to what does and doesn’t work.

• Many NIAAA publications refer to standard drinks without clarifying the wide variation that exists in the way any particular individual absorbs and metabolizes alcohol and how it affects on the brain. This is an important message for young people and the public.

Ex-officio Council member, Colonel Hoffman, M.D., reported on the Department of Defense’s Prevention, Safety, and Health Promotion Council and the special Alcohol Abuse and Tobacco Use Reduction Committee. DOD is currently focusing on applied research and, in conjunction with the VA, is adapting clinical practice guidelines to the military environment. Evidence-based guidelines for military personnel and their dependents are needed after dramatic 1992 shifts in military health insurance for 8.7 million beneficiaries.

Mr. Steven Wing, Associate Administrator for Alcohol Policy at SAMHSA, called attention to a well-received kit addressing underage drinking that was developed last year for 5th graders and their teachers and will be disseminated again to public and private elementary schools in time for Alcohol Awareness Month. Also, SAMHSA and NHTSA are convening a March meeting to examine treatment interventions for alcohol-impaired drivers who have been arrested.

Ms. Susan Rook from Faces and Voices of Recovery commended Council and NIAAA’s emphasis on recovery.

Ms. Alice Murphy, representing the Council on Substance Abuse in Montgomery, Alabama, thanked NIAAA for participating in the recent International Conference on Addictions, which drew 400 attendees. She remarked that lawyers and healthcare providers should be required by States and professional Boards to pursue continuing substance abuse education credits on an annual basis because they do not get sufficient training of this type in their regular curriculums.

Ms. Sis Wenger, Executive Director of the National Association for Children of Alcoholics (NACA), underscored the need voiced by Dr. Alpha Brown for practical interventions that helpers from various communities can use to assist persons affected by alcoholism and other drug abuse. NACA has developed a set of core competencies for primary care practitioners and a more recent companion kit offering practical information about their encounters with children. NACA is now working with the Johnson Institute and CSAT to develop core competencies that clergy need to address alcoholism and its impact on the family.

Mr. Kevin Wang, University of Florida, Gainesville, spoke about recent advances in proteomics that many NIH institutes are using and noted that the technology could be relevant for assessing both vulnerability to alcohol abuse and biomarkers of organ damage. Dr. Li assured him that proteomics is already a growing, active part of the NIAAA portfolio.

Dr. Li adjourned the open Council meeting at approximately 3:00 p.m., on February 6, 2003.

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

Prepared: May 1, 2003