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National Advisory Council Meeting - February 3-4, 2010
Summary of the 123rd Meeting
February 3-4, 2010
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 123rd meeting at 3:00 p.m. on February 3, 2010, at the Fishers Lane Conference Center in Rockville, Maryland, in an open session. This session recessed at 4:15 p.m., and the Council reconvened in closed session from 4:30 to 6:30 p.m. Dr. Kenneth Warren, Acting Director, NIAAA, presided over the open session, and Dr. Abraham Bautista, Director, Office of Extramural Activities , presided over the closed review of grant applications and administration of the Enhancing Peer Review Initiative Survey. In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the closed session on February 3, 2010, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. Dr. Warren presided over a closed session of the National Advisory Council on February 4, 2010, from 8:00 to 8:45 a.m., for a report of the Board of Scientific Counselors. At 9:00 a.m. Dr. Warren once again convened the Council in open session. The closed session on February 4 excluded both the public and NIAAA extramural staff.
Council Members Present:
Michael E. Charness, M.D.
David W. Crabb, M.D.
Gen. Arthur T. Dean
Cindy L. Ehlers, Ph.D.
Scott L. Friedman, M.D.
R. Adron Harris, Ph.D.
Deborah S. Hasin, Ph.D.
Andrew C. Heath, D.Phil.
Vimal Kishore, Ph.D.
Lynell W. Klassen, M.D.
John H. Krystal, M.D.
Peter M. Monti, Ph.D.
Larry I. Palmer, LL.B.
Edward P. Riley, Ph.D.
Linda P. Spear, Ph.D.
Gyongyi Szabo, M.D., Ph.D. (ad hoc)
John P. Allen, Ph.D., M.P.A.
Jill Carty, Psy.D., M.S.P.H.
Chairperson: Kenneth R. Warren, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Vivian B. Faden, Ph.D., Ralph W. Hingson, Sc.D., M.P.H., George Kunos, M.D., Ph.D., Robert Huebner, Ph.D., Antonio Noronha, Ph.D., Howard B. Moss, M.D., Samir Zakhari, Ph.D.
Other Attendees at the Open Sessions
Approximately 75 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 Open Session, February 3, 2010
Dr. Kenneth Warren called the open session of the 123rd meeting of the Council to order at 3:00 p.m. on Wednesday, February 3, 2010, and welcomed participants. Council members and NIAAA senior staff introduced themselves.
Substance Use, Abuse, and Addiction Working Group Report
William Roper, M.D., M.P.H., Dean of the School of Medicine, Vice Chancellor for Medical Affairs, and Chief Executive Officer of the UNC Health Care System, University of North Carolina, described the work of the Substance Use, Abuse, and Addiction (SUAA) Working Group of the National Institutes of Health’s (NIH) Scientific Management Review Board (SMRB). Congress established the SMRB in 2006 to advise on NIH reorganization. The SUAA Working Group’s charge is to evaluate whether organizational change can optimize research into substance use, abuse, and addiction.
The SUAA Working Group has convened several times to consider whether NIAAA and the National Institute on Drug Abuse (NIDA) should be merged or whether another form of organizational change might be beneficial. The Working Group has been contemplating the scientific opportunities, current research, criteria to apply to the consideration of organizational change, strategies to implement such changes, and metrics to judge the success of a merger. Dr. Warren and NIDA Director Nora Volkow have provided input into the process, along with prevention specialists, treatment providers, patient advocates, policy specialists, scientists, and experts on alternative models for organizing SUAA research, including representatives of the judicial system, academia, and industry.
Advocates for reorganization assert that the high prevalence of drug users who also use alcohol suggests both scientific and policy justification for a merger, that the segregation of the disciplines creates public health gaps, and that reorganization (particularly merging) would create synergy for advancing the science of substance use, substance abuse, and addiction, as well as increase flexibility in cross-training. Advocates against reorganization assert that reorganization, especially a merger, would create research gaps in understanding the multiple organ targets of alcohol and the unique factors underlying abuse and addiction; contextual and socio-cultural differences warrant separate, focused research efforts (alcohol is legal, while most drugs are not); compelling evidence is lacking to suggest that reorganization would improve treatment, prevention, research, and/or training; the current organization mirrors the separation of professional and scientific associations; and reorganization, particularly a merger, would decrease emphasis on alcohol’s effects on multiple organ targets, jeopardize the priority and budget of alcohol-related research, and create organizational/administrative obstacles and reversals. Dr. Roper stated that the initial dialogue has focused on the status quo or merging the Institutes, but the universe of possibilities is broader; two separate Institutes with a single Council, clustered functions by two separate Institutes, new initiative as an outgrowth of the two Institutes, blueprint across multiple Institutes, merged Institute, or new Institute. Key data questions include how the science is, or is not, served by the current Institutes, and whether areas are neglected or gaps exist. The group also has undertaken an inventory of research on addiction across NIH and has considered other countries’ approaches.
Dr. Roper stated that the SUAA Working Group continues to assess the need for change. Next steps include evaluating options for change and offering recommendations to the SMRB for implementing and evaluating change in the future. The SMRB will submit a full report to the NIH Director.
Discussion. Dr. Michael Charness asserted that the fact that brain pathways that may be involved in motivated behaviors with some compulsive aspects are common among drugs of abuse and alcohol and other motivated behaviors, such as sex and eating, is not a compelling argument for or against a merger. He stated that the science would argue that compulsive use of alcohol is different from addiction to other drugs. Genetics support this statement, in that children born of alcoholic parents are at risk for alcohol, but not for becoming drug dependent. In addition, most NIAAA-sponsored research on medications that impact drinking shows that these have no effect on drug dependence. Therefore, both the genetics and the response to treatment argue that the pathophysiology is different, even if there are common pathways. Dr. Charness noted the importance of studying the two problems separately; the underlying disorders arise in different ways and have different biological and psychosocial underpinnings. He asserted that the public health burden of alcohol abuse justifies the separate study of alcohol. While most people who abuse drugs also drink, this group represents a small percentage of people who use alcohol, and the approximately 85% or more of people who abuse solely alcohol constitute the major public health problem. He further noted that a visible, integral, and separate institute on alcohol influences career choices among young people, who have concerns about where funding flows. He feared a cessation of people flowing into alcohol research, which is critically important to the nation’s public health response to alcohol abuse and use. Dr. Roper responded that the assertion regarding the attraction of young researchers to NIAAA exists in tension with the increasingly interdisciplinary nature of science.
Mr. Larry Palmer suggested soliciting input from science historians and political scientists with expertise in health policy and health benefits.
Dr. John Krystal noted alcohol’s complex pattern of comorbidity, including substance use and psychiatric disorders. He suggested the construct of a circuitry of motivated behavior and inquired how the National Institute of Mental Health might factor into the issue. Dr. Roper acknowledged that the sphere of influence extends beyond just two Institutes, but that incorporating the universe may become unwieldy.
To a question from Dr. Edward Riley, Dr. Roper responded that he envisioned “point” recommendations as opposed to a menu. He added that the massive reorganization experiences of the Health Care Financing Administration/Centers for Medicare and Medicaid Services and the Centers for Disease Prevention and Control will offer valuable lessons.
Dr. Cindy Ehlers noted, with reference to the construct of a common reward circuit, that creating dogma with little support in clinical studies can stifle the way science is approached and can dampen opportunities for funding and the benefits of innovation. She asserted that it is more important to view drug and alcohol dependence as a problem related to appetitive and consumptive behaviors; many more issues are related to the metabolic syndrome than to an addiction circuit. In the event of a merger, she urged attention avoiding narrowing of the science.
Dr. Gyongyi Szabo cautioned that loss of an alcohol institute might endanger needed public health and outcomes research on alcohol use (as distinct from abuse) in terms of intensive care unit usage, cardiovascular disease, gastrointestinal cancers, and pancreatic cancer. Dr. Lynell Klassen added that most current professional medical groups have little interest in alcohol-related organ diseases and expressed concern about consequences if the value of doing clinically oriented work were diminished.
To Dr. Adron Harris’s inquiry, Dr. Roper responded that work is underway on an analysis of other Institutes’ funding in nicotine, food, and alcohol addiction.
In response to a question from Dr. Scott Friedman, Dr. Roper stated that while the SUAA Working Group has not yet tried to articulate a particular vision, the sense is that a merger should not be a budget-cutting exercise and that any merger recommendation must accommodate research on the non-addictive aspects of alcohol. He added that he will return to speak to the Council when recommendations have been made.
Dr. Deborah Hasin asserted the need for a public health message more nuanced for alcohol than for drugs, including nicotine. In contrast with drugs, light drinking is not “bad.” If NIAAA and NIDA were aggregated, Dr. Hasin anticipated difficulty in maintaining the approach needed to inform the public about use of alcohol in lighter and heavier forms. Dr. Howard Moss called attention to the political relationships surrounding the potential for a merger, noting that NIDA is under regulatory control of the Office of National Drug Control Policy, while NIAAA is not. NIDA is unable to fund research that demonstrates the benefits of illicit drugs, while NIAAA can talk about potential benefits of moderate alcohol use. He noted that a merger might place constraints on future research; 17 states have medical marijuana laws on the books or under discussion, though NIH has funded no research on its benefits.
Dr. Andrew Heath noted that the science has steered alcohol researchers towards many Institutes. While NIDA is not the ideal partner, the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging (NIA), and National Cancer Institute are natural partners. He noted that merging NIAAA and NIDA would create inflexibility in following the science. Dr. Roper noted that many mechanisms can accomplish collaboration across organizational boundaries. Dr. Linda Spear, who stated that she has served on both NIDA and NIAAA External Advisory Boards and study sections, and is funded currently by both Institutes, endorsed breaking down silos.
Dr. Warren offered a historical perspective on NIAAA, which Congress created in 1970 to focus not on addiction, but on the medical consequences of alcohol use, which NIH Institutes at that time ignored. Dr. Roper pointed out that the Working Group has not focused on financial consequences of changing the status quo. He welcomed input from the Council as a whole or from individual members. Dr. Szabo inquired about the context of organizational change, and Dr. Roper explained that another SMRB Working Group focuses on that issue.
The open session recessed at 4:15 p.m.
Call to Order of the Closed Session, February 3, 2010
Dr. Abraham Bautista called the closed session of the 123rd meeting of the Council to order at 4:30 p.m. for consideration of grant applications and administration of the Enhancing Peer Review Initiative Survey. In the grant review, he described procedures 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 recessed at 6:30 p.m.
Call to Order of the Closed Session, February 4, 2010
Dr. Kenneth Warren reconvened the closed session of the 123rd meeting of the Council at 8:00 a.m. for the report of the Board of Scientific Counselors presented by Dr. George Michalopoulos.
Call to Order and Introductions, February 4, 2010
Dr. Kenneth Warren reconvened the open session on February 4, 2010, at 9:00 a.m. and welcomed participants. Council members and NIAAA senior staff introduced themselves.
Global Health in the 21st Century: Is There a Role for Research on Alcohol-Related Diseases?
Roger I. Glass, M.D., Ph.D., Director, Fogarty International Center, Associate Director for International Research, NIH, discussed the potential role of research on alcohol-related diseases in an environment of global research and as a priority endorsed in the United States by the Obama Administration, NIH, and academia, and by the G8 nations. Dr. Glass noted that in working to achieve its mission to promote research and training in global health, the Fogarty Center works with all NIH Institutes and Centers.
Life expectancy in the United States currently is more than 80 years, and throughout the developing world, with the exception of Sub-Saharan Africa, life expectancy also has been prolonged. It is necessary now to focus not only on tropical, parasitic, and infectious diseases in the developing world, but also on chronic diseases—some of which may be alcohol related, with implications for injuries, traffic accidents, homicide, and violence. Dr. Glass noted the value of research on alcohol-related diseases. Over the last 40 years, life expectancy in China has grown from 39 to 74 years, with great consequences for health research and global health; China’s agenda includes infectious diseases, child health and maternal mortality, and chronic disease. A future agenda must include environmental hazards, traffic accidents, obesity, climate change, and addictive behavior. Dr. Glass explained that cancer is a global disease that may have an alcohol component. Policy changes in the United Kingdom in light of research on smoking have led to a dramatic decline in lung cancer in that country—but not in France. Dr. Glass asserted that policy questions regarding smoking are similar to those for alcohol, particularly in terms of taxation as a means of prevention. He suggested the need to apply lessons learned in nicotine addiction to control alcoholism as an addictive behavior.
Dr. Glass noted that NIH has mounted a global effort to look at studies of the genetics of nearly every disease, including alcohol. Understanding the genetics of alleles responsible for alcohol-related diseases will be a research topic of great interest, and overseas populations may offer opportunities to study them. He added that studying environmental hazards—different types of drinking and different substances—will be critical in the alcohol research agenda.
The Fogarty International Center promotes collaborative research, training U.S. and foreign researchers, and developing partnerships. Fogarty’s investment in young researchers, as well as partnering them with U.S. resources, has been instrumental in developing and maintaining the competitiveness of U.S. research. The Fogarty International Clinical Research Scholars and Fellows Program offers fellowships to spend a year in the developing world to develop a research career. The Framework Program brings together behavioral scientists and biomedical researchers on U.S. campuses to address global health research and training. Dr. Glass suggested that a meeting on alcoholism research might be organized to include psychologists, economists, policy makers, and people in law, business, and taxation, in addition to biomedical researchers in medicine, public health, and nursing. Fogarty has taken up grand challenges for chronic disease initiatives where alcoholism would be a major player. Lessons remain to be learned about the genetics of fetal alcoholism during fetal alcohol syndrome that might prevent and find treatment in the United States. A challenge in implementing the science involves getting the message out to women to stop drinking.
Fogarty’s strategic plan focuses on both chronic and acute infectious disease agendas, bridging the implementation gap in research activities, developing young investigators at home and abroad, twinning U.S. and foreign institutions, and building partnerships with other institutes and donors. Dr. Glass noted that India, China, Brazil, and South Africa each offer partnership opportunities that require no U.S. funds; each country invests massive money in research and asks for validation of their research.
Dr. Glass described opportunities for NIAAA to engage in the global health agenda. For example, alcoholism is the most common cause of death, particularly among adult males, in Russia. Research has shown that the rate of alcohol-related deaths declined directly due to policies associated with the dissolution of the Soviet Union, new anti-alcoholism regulations, and the devaluation of the ruble. Alcoholism can be controlled by many interventions, including taxation.
Harmful drinking is a global problem, with opportunities in a number of countries to study population genetics, unusual exposures to drinking, binge drinking, and alcohol containing other substances. In terms of the global burden of disease, alcoholism is a major determinant of disability-adjusted life years, which will increase as the population ages. Dr. Glass noted that fetal alcohol syndrome and fetal alcohol spectrum disorders are particularly troublesome worldwide. In Russia, for example, many children with these conditions in orphanages or boarding schools become adopted by Americans. The challenge remains to learn how to prevent fetal alcohol syndrome in Russia, in South Africa, and in the Alaska Native population; Fogarty and NIAAA collaborate on studies in Russia and Poland.
Potential areas of collaboration between Fogarty and NIAAA involve the international fellowship program to identify scholars interested in global health research on alcoholism, alcohol-related disease, or fetal alcohol syndrome, and to provide fellowships and scholarships for individuals to work with world-class researchers in the developing world to begin their research careers and to begin a twinning partnership in research that can last their entire careers. The Fogarty International Research Collaboration Award allows foreign researchers to partner with NIH researchers on R01 grants to extend the research beyond the U.S. and to have the collaboration of foreign researchers for a 3- or 6-year period. Larger programs twin U.S. academic centers and academic centers in the developing world, for example, in brain disorder research, trauma and injury research training, and clinical, operational, and health services research training. In addition, collaboration between Fogarty and NIAAA offers an opportunity to increase the research capacity at home and abroad to work on alcohol-related disease, and to extend the studies on populations with unusual genes, unusual exposures, or unusual patterns of drinking, which may lead to new methods of treatment or prevention.
Dr. Glass asserted that NIH’s investments in global health are good for science as the new frontier; for diplomacy; for humanity, to correct health disparities; for economic development and political stability for businesses overseas; for the war on terrorism; and to improve our own future.
Discussion. Dr. Friedman inquired how Fogarty helps individual investigators identify investigators and agencies overseas. Dr. Glass responded that Fogarty facilitates networking and individual institutions can identify potential researchers. Dr. Friedman suggested that Fogarty partners with professional societies or national or regional associations on global research. Dr. Charness remarked on the differing lung cancer rates in England and France. Dr. Glass stated that much can be done to prevent smoking where it has not yet been adopted, and that an epidemic of lung cancer in China is expected in 20 years. He suggested that the effectiveness of taxation in lowering smoking rates may have policy implications for drinking legislation and policy, and may be a good area for prevention research.
Dr. Warren highlighted key recent Institute activities, referring to the written report:
§ Legislation, budget, and policy. In FY 2009, NIAAA obligated $449.5 million for 191 new and competing R01 grants and 530 noncompeting grants. In addition, NIAAA received $113.8 million for FY 2009 and 2010 under the American Recovery and Reinvestment Act (ARRA), of which the Institute obligated $61.4 million in FY 2009 for 61 highly meritorious R01s and R21s. NIAAA also supported 14 competing supplements, 18 Challenge Awards, and 13 Grand Opportunities Awards.
§ Congress passed the Omnibus Appropriations Act, and the President signed it in December 2009 for FY 2010, under which NIH received $31 billion, an increase of $692 million or 2.2% over 2009 levels. NIAAA received $462.3 million, an increase of $12.3 million or 2.7% over 2009. The balance of the ARRA funds, $52.4 million, will support the second year of the grants made in 2009. In addition, targeted funds are to be invested in contracts for new drug development.
§ In 2009 NIH supported approximately 1,800 first-time R01-equivalent investigators, which surpassed the target of 1,650. The goals for 2010 are to award R01 grants to at least 34 first-time investigators and to achieve the same success rate for new investigators as for the overall portfolio. In 2009 NIAAA met the success rate and exceeded the target number. In 2009 and 2010 the new-investigator pay line was 5 points beyond the established-investigator pay line.
§ Released on February 1, 2010, the President’s FY 2011 budget request to Congress included a total of $32.1 billion for NIH, representing a $1 billion increase or 3.2% over 2010. The request for NIAAA amounts to $474.6 million, a $12.5 million increase or 2.7% over 2010. NIH’s scientific priorities include genomics and other high-throughput technology, translational medicine, global health, reinvigorating biomedical research, and ensuring a steady pipeline of talented, well-trained investigators. Dr. Warren noted that NIAAA must abide by specific parameters in implementing the budget, including limitations on fund shifts from one program to another. He stated that with $284 million in funding for research program grants, a $4.3 million increase, NIAAA anticipates supporting 726 grants, 22 fewer than in 2010. Research centers and intramural research would receive modest increases. Funding for research training would rise 5.9% to cover stipend increases to trainees and fellows. All NIH Institutes contribute funds to a new Basic Behavioral Sciences Operations Network, and 10% of NIAAA’s budget supports intramural research, similar to other Institutes.
§ NIAAA’s priorities include good stewardship of funds in making Type 5 awards, maintaining the highest possible success rate for new and competing grants, and stimulating new research in areas of high program priority. NIAAA’s success rate has been better than for NIH overall. A large increase in applications in 2011 is anticipated.
§ NIAAA staff and organization. Ms. Shuly Babitz has joined NIAAA’s Communications and Public Liaison Branch as a writer/editor. Dr. Warren reported that all members of the research team, data, and computers in NIAAA’s Haitian project were accounted for after the earthquake, and staff were locating study participants. Dr. Kendall Bryant stated that NIAAA will support bridge funding to help continue this project, a translational research grant that represents a new approach to broad-scale intervention in critical areas.
§ Multimedia products from NIAAA. NIAAA’s 2009 fact sheet describes physiological effects of excessive drinking and how many common abilities may be compromised due to drinking. More than 240 websites featured the fact sheet. In addition, NIAAA has improved the user interface to the Alcohol Policy Information System (APIS), which facilitates navigating the website and downloading state data. NIH, NIA, and the National Library of Medicine produced a new topic area for NIH’s Senior Health Website on older adults and alcohol. Dr. Warren noted that NIAAA receives weekly requests for an average of 3,000 copies of “Rethinking Drinking.” Notable requests have come from the Los Angeles VA Medical Center and from a Southern California labor union health plan, which ordered 8,000 copies for distribution and will track claims of substance use services to determine whether the brochure effects a change.
§ Outreach. NIAAA co-sponsored the annual meeting of the National Hispanic Science Network, where Dr. Judith Arroyo co-chaired a plenary session.
§ News Media Interactions. The NIH website highlighted a press release entitled “Molecule Repairs Alcohol Metabolism Enzyme.” This molecule corrects defects in an enzyme, found in 1 billion people in the world, that affects the ability to drink alcohol, is associated with a 100-fold risk for esophageal cancer, and is important in the functioning of certain drugs in treating ischemic heart disease. Also, NIAAA hosted a media event at the National Press Club on recent research on holiday drinking.
§ What’s Ahead. NIAAA is beginning its 40th year as independent Institute, a milestone to be marked throughout the year. Banners will be posted on the main NIH campus, and the NIH website will be redesigned and a branding effort launched to increase recognition of the Institute and its products.
§ NIH Neuroscience Blueprint. The NIH Neuroscience Blueprint announced a funding opportunity for development of new drugs for nervous system disorders. The Blueprint is establishing a complete pharmaceutical pipeline to develop promising hit compounds from chemical optimization through Phase 1 human testing. Successful applicants will receive funding for biological testing in their labs and unprecedented access to a full range of industry-style drug-development services and expertise. Applicants will retain ownership of the intellectual property for the compounds they develop.
Therapeutic Potential of Peripheral CB 1 Receptor Blockade
George Kunos, M.D., Ph.D., Scientific Director, NIAAA Intramural Program, described the therapeutic potential of peripheral CB 1 receptor blockade. In recent years his laboratory has focused on the biology of the endocannabinoid system; endocannabinoids influence alcohol drinking behavior and alcohol-induced tissue pathology. In the mid-1980s two cannabinoid receptors were identified: CB 1 receptors are the most abundant of all receptors in the human brain, but are present also at much lower concentrations in many peripheral tissues; CB 2 receptors are expressed predominantly in cells of the immune and hematopoietic system. In the mid-1990s, a group of endogenous ligands was discovered. Within the last 15 years, endocannabinoids and their receptors were revealed to have physiological and pathological functions, including influences on relaxation, eating, drinking, resting, sleeping, saving/storing, and conserving energy—cardinal features of the thrifty phenotype that enabled mankind’s survival during periods of starvation. But in the last 50 years, with an abundance of food supply and sedentary lifestyle, cannabinoids have become the major culprit in the epidemic of obesity and related metabolic disorders.
Dr. Kunos noted that his group was the first to identify the endocannabinoid system in the hypothalamus as part of the leptin-regulated neural circuitry that regulates food intake. This discovery prompted the pharmaceutical industry to develop drugs that block the cannabinoid receptor as a potential treatment for obesity. The prototype compound rimonabant was found to be effective in reducing weight and in improving associated cardiovascular risk factors. Unexpectedly, in a large number of patients, rimonabant blocked the reward pathway and increased depression, anxiety, and suicidal ideation, which led to its withdrawal from the market.
Animal and human studies on cannabinoids and obesity found that while a reduction in food intake is transient, associated weight loss is maintained, suggesting effects independent of food intake most likely through effects on peripheral metabolism. In Dr. Kunos’ study of diet-induced obesity, C57 mice gained weight on a high-fat diet due to an increase in adipose tissue mass, but they also exhibited changes seen in humans with metabolic syndrome, including hepatic steatosis. CB 1-receptor-deficient animals were strikingly resistant, however, to these effects. Another mouse strain that lacks CB 1 receptors only in hepatocytes was almost as resistant to diet-induced steatosis as mice with the global knockout, which suggests that the hepatic CB 1 receptor may play an important role in the development of steatosis. Dr. Kunos’ group found that the liver has low, functionally relevant levels of expression of receptors in hepatocytes from animals on a normal diet. When placed on a high-fat diet, the animals exhibited a several-fold increase in receptors at the message and protein levels. Other researchers have found a similar induction of CB 1-receptor expression in other metabolically active tissues—skeletal, muscle, and adipose tissue—suggesting that the endocannabinoid system is upregulated and becomes activated in this condition. The tissue level of anandamide also increased about three-fold in the liver because of a decrease in activity of the enzyme that normally degrades anandamide. These findings suggest that the endocannabinoid system may be instrumental in the development of hepatic steatosis through activation of CB 1 receptors in the liver. The underlying mechanism is that cannabinoids, through activating CB 1 receptors in the liver, increase de novo lipogenesis and, at the same time, decrease fatty-acid oxidation, both resulting in the accumulation of fat in the liver. This was tested by treating animals on a normal diet with a single dose of a potent cannabinoid agonist and then monitoring the incorporation of a radiolabeled tritium from water into fatty acids. The agonist caused a significant increase, but not in CB 1 knockout or liver-specific CB 1 knockout animals, indicating that this effect is due to CB 1 stimulation in the liver. The same agonist caused a 50% reduction in the activity of the rate-limiting enzyme in fatty acid beta oxidation, whereas the CB 1 antagonist rimonabant increased the activity and interfered with the ability of the agonist to reduce the activity of the enzyme.
Similar mechanisms have been identified in alcohol-induced fatty liver. Evidence exists that alcohol leads to the development of fatty liver with an increase in de novo lipogenesis, increased expression of the transcription factor and enzymes involved, and decreased fatty-acid oxidation. Dr. Kunos’ group, as had others, found that wild-type mice on a 4-week alcohol diet developed steatosis, increased liver triglycerides, and increased ALT levels, but both the CB 1 knockout and liver-specific knockout animals are resistant to these changes. They found further that the expression of CB 1 receptors in hepatocytes was increased by alcohol using the endocannabinoid 2-arachydonoylglycerol (2AG). The alcohol-induced increase in liver 2AG could be localized exclusively to hepatic stellate cells while there was no change in hepatocytes.
This finding led Dr. Kunos to postulate that paracrine activation of CB 1 receptors and hepatocytes occurs by 2AG from adjacent stellate cells to induce to steatosis. The study found that receptors in the liver influence liver fat metabolism and that another component of the metabolic syndrome is insulin resistance. Animals on a high-fat diet do not exhibit a normal glucose tolerance curve; they exhibit resting hyperglycemia; the same glucose load leads to a much greater increase and slower return to normal; and they exhibit insulin resistance. CB 1 knockout animals were completely resistant, but the liver-specific knockouts were also largely resistant to the insulin-resistance-producing effect of the high-fat diet, suggesting that the CB 1 receptor plays an important role in insulin resistance. The great promise of the CB 1 antagonist, aside from its unwanted effects, led Dr. Kunos to consider the possibility of developing compounds with limited brain penetrants that could still affect metabolic parameters through actions on peripheral receptors—not just in the liver, but in CB 1 receptors on adipose sites. Skeletal, muscle, and pancreatic beta cells also are known to contribute to metabolic effects without causing central nervous system (CNS) effects.
Dr. Kunos noted that an analogue of rimonabant, AM6545, is much less lipid soluble but allows oral bioavailability. This new compound was shown to have identical high potency for CB 1 receptors and similar high selectivity for CB 1 over CB 2 receptors, but, unlike rimonabant, is a neutral antagonist. When AM and rimonabant are administered and tested an hour later, as well as administered over time, the brain-to-plasma ratio with the AM compound is lower than with rimonabant. The AM compound is less lipid soluble, which may explain some of the difference. Another mechanism that keeps drugs out of the brain is the specific transporter protein p-glycoprotein and its related analogues, the ABC transporters that are present in the endothelial cells of the blood-brain barrier that pump out compounds that may have penetrated the blood/brain barrier. Dr. Kunos tested the compound’s potential involvement in peripheral selectivity in mice that are knockouts for the major two p-glycoproteins or triple knockouts for those as well as an additional isoform of these proteins. Compared to wild-type mice, in which very little enters the brain, in the knockouts the compound becomes like rimonabant with high levels in both brain and plasma, but produces behavioral effects. Testing mice for central and peripheral effects vis-à-vis cannabinoids and rimonabant showed that rimonabant blocks catalepsy, while the compound in an equal dose has no blocking activity. The cannabinoid agonist causes a drastic reduction in the ambulatory activity of mice; while rimonabant blocks the effect, AM has no influence. Testing revealed that the hypothermic effects of cannabinoid have a peripheral component, but the central component is unaffected by the AM compound, a peripherally restricted antagonist.
Dr. Kunos explained that the ability of the cannabinoid antagonist rimonabant in rodents to cause long-lasting hyper-ambulatory activity is a tell-tale sign of neuropsychiatric side effects in humans, an effect due to CB 1 blockade that is not seen in CB 1 knockout animals. In wild-type animals the antagonist is inactive, indicating that it does not enter the brain. Mouse studies showed that rimonabant, but not AM6545, causes CB1 receptor–mediated, anxiety-like behavior and that AM6545 blocks anandamide-induced decrease in transit through the gastrointestinal system.
Metabolically important effects were seen in genetically obese mice, as well as in mice with diet-induced obesity. Dr. Kunos presented results related to pathologic genetic obesity due to lack of leptin. When treated daily for 4 weeks with rimonabant or AM6545, rimonabant causes a slight but significant reduction in body weight due in part to reduced food intake, but the compound has no significant effect on body weight or adiposity. But both hepatic triglyceride and plasma ALT levels are effectively reduced, with greater effect from the peripheral antagonist than rimonabant in doses that cause maximal CB 1 receptor blockade. The two compounds are equally effective in reducing hyperglycemia and hyperinsulinemia, and both cause a small but significant increase in HDL and significant reduction in LDL levels, resulting in similar increases in the HDL/LDL ratio, and significantly reduce elevated plasma triglyceride levels. The compounds’ effects on glycemic control seem weight independent after treatment. Significant glucose intolerance and insulin resistance are effectively reduced by both compounds.
In order to develop incontrovertible evidence that the antagonist acts at hepatic CB 1 receptors to produce these effects, Dr. Kunos developed a rescue model using different mouse strains. Put on a high-fat diet, wild-type mice (which have a very high level of CB 1 receptor in the brain and a low but significant level in the liver) become glucose intolerant; CB 1 knockout mice (which have no receptors in the brain or the liver) do not become glucose intolerant; and hepatocyte-specific knockout mice (which have the same high levels in the brain as the wild type, but none in the liver) are somewhat more glucose intolerant than the wild type. The investigators mimicked the effect of a chronic high-fat diet by an acute treatment with anandamide, which acutely induces glucose tolerance in wild-type mice, even more in transgenic mice, but not in the CB 1 knockout. When they put the transgenic mice on a high-fat diet, the animals developed glucose intolerance and insulin resistance. After daily treatment for a week with the peripheral antagonist, the glucose intolerance and insulin resistance completely reversed, and reduced the modestly elevated hepatic triglyceride levels in the transgenic mice. An emerging, interesting concept is that a major factor in diabetes is the endoplasmic reticulum (ER) stress in insulin-resistant tissues that could be monitored by the translation-initiation factor, eIF2alpha. A high-fat diet activates this factor involved in ER stress by increasing its phosphorylation status. Animals on a high-fat diet with the strong phosphorylated eIF2alpha treated with AM6545 reverses the marker of ER stress.
In summary, Dr. Kunos explained that the endocannabinoid CB 1 receptor system clearly regulates energy homeostasis. In the CNS, cannabinoid receptors control food intake as well as behavioral responses to cannabinoids. The metabolic syndrome is associated with activation of the peripheral endocannabinoid system, which may be a key pathogenic feature of the metabolic syndrome. Activation of hepatic CB 1 receptors contributes to diet-induced insulin resistance and steatosis, and alcohol-induced steatosis. Targeting peripheral CB 1 receptors has value in the treatment of the metabolic consequences of obesity or chronic alcohol use. The AM6545 compound CB 1 is already part of the NIH rate program for toxicology, with plans to test it in Phase 1 studies for both obesity and fatty liver disease.
Discussion. Dr. Kunos responded to a question from Dr. Harris that hepatocytes are the major glucose-producing cells where insulin effect in the liver is materialized and which accumulate fat in fatty liver. CB 1 receptors also are expressed on stellate cells and Kupffer cells.
In terms of the CNS exclusion, Dr. Friedman suggested that interaction with the p-glycoprotein receptor may have implications for competing out other drugs that might ordinarily need uptake, or vice versa: Drugs might prevent exclusion and inadvertently lead to increased CNS uptake of this compound. Dr. Kunos acknowledged the value of pursuing this idea.
Dr. Kunos responded to Dr. Crabb on whether ER stress might cause or result in steatosis. Dr. Kunos stated that a paper under consideration links ER stress response to the ability of cannabinoids to inhibit AKT phosphorylation, but he has not explored whether ER stress may develop secondary to fatty liver.
Dr. Kunos identified for Dr. Ehlers a study by Lotersztaijn and Mallat that generated epidemiological data on chronic marijuana use, or combined marijuana and alcohol use that may have effects on the liver. The study indicated that heavy marijuana use among HCV-infected individuals predisposed people to more rapid progression of steatosis. Dr. Kunos is collaborating with NIDA to study the relationship without the complicating factor of HCV.
Dr. Spear queried whether the AM compound’s lack of effect on body weight would be expected. Dr. Kunos stated that among pathologically obese ob/ob mice, rimonabant caused a longer lasting, more significant reduction in body weight, while AM caused only a transient early effect. The fact that the diet-induced obesity model produced a reduction in food intake, but not the leptin-deficient model, suggests that the reduction in food intake in the diet model reverses the leptin resistance. Leptin is known to have important peripheral effects, which means that the ability of leptin to be transported through the blood-brain barrier is inhibited.
Dr. Harris inquired whether rimonabant, as an inverse agonist, were important in its CNS pharmacology. Dr. Kunos stated that another neutral antagonist goes through the blood/brain barrier and causes similar weight loss in the obesity model, but does not induce nausea. Cannabinoids are known to be the most potent anti-nausea agents in the brain, and though some evidence exists that there may be some tonic activity, these results suggest that perhaps it is not tonic activity. A neutral antagonist that does not cause nausea indicates that there is no tonic activation of those receptors.
Dr. Kunos responded to Dr. Monti that no hard evidence exists for the notion of eating as an addiction in humans. To the extent that there is some important component of appetite reduction, rimonabant’s action may have an anti-addictive component. Eating addiction is a known important component of many forms of obesity.
Dr. Krystal inquired about the relationship of leptin to weight gain and diabetes caused by antipsychotic medications. Dr. Kunos stated that the Sanofi’s group treated mice with olanzapine and found that the CB 1 blockade effectively counteracted the weight-gain effect. Drug testing studies are underway in Europe.
Services for Treatment of Substance Use Disorder in the Veterans Health Administration
John Allen, Ph.D., M.P.A., Associate Chief Consultant, Addictive Disorders, Veterans Health Administration (VA), acknowledged NIAAA and NIDA’s involvement in research on delivery of treatment services. The VA has enjoyed increasing success in identifying the substance problems of veterans who seek health care; they currently represent 8.4% to the VA population, up from 6.5% in FY 2002. The VA now requires every patient to be given annually an abbreviated AUDIT. Amphetamines and opioid use have remained relatively steady since 2002, but cannabis and cocaine use have risen dramatically. Dr. Allen noted the need for analysis of marijuana use.
The VA is treating increasing numbers of patients with medications, but only 3–4% of persons with diagnoses of alcohol problems receive Naltrexone, a situation that deeply concerns the VA. A new performance monitor will look at whether health care providers discuss medications with patients with alcohol diagnoses, and considerable mentoring is under way to increase medication use system wide. The VA operates its own methadone maintenance programs and contracts for others; some programs also offer psychosocial services. The VA also administers buprenorphine in the form of suboxone. While the use of methadone has leveled, buprenorphine treatment is becoming more common. Methadone will continue to be made available for older patients uninterested in buprenorphine.
The VA provides substance use services in a specialty care system of about 3,000 providers. Two thirds of patients are treated in integrated care settings that offer behavioral health support either within primary care or mental health services, including care for substance use disorders in PTSD units. Each hospital has a PTSD team, supplemented in 2009 with an established position for a substance use disorder specialist who is a clinical or counseling psychologist. This enables veterans to obtain care under one roof, while at the same time dispelling the stigma of substance use. An expert panel reviewed the scientific literature and recommended how these specialists might function; the panel will reconvene in 2011 to examine new research and assess performance. VA practice supports treatment for substance use and PTSD in a coordinated and concurrent fashion.
In 2005 the VA significantly cut resources for substance use treatment, a situation that substantially has been ameliorated. Since 2008 the VA has established 405 new positions for specialists in substance use disorder treatment. Numbers of licensed independent providers in community programs have increased at the VA, and many individuals with Ph.D and M.D. degrees work full time in the program. People in the field at the VA’s 153 medical centers are changing their practice based on the science.
When VA patients join treatment, typically they meet with a professional three times a week for at least 3 hours per session. The VA has two inpatient programs and 140 intensive outpatient programs. The VA has added substance use disorder specialists in community-based outpatient clinics. The VA’s residential rehabilitation treatment program (RRTP) serves veterans with multiple problems who are unable to live in the community without considerable assistance. Although several RRTPs are designated for veterans with substance abuse, approximately 80% of patients at non-substance-abuse RRTPs have a previous history of substance abuse. Substance use disorder specialists who work at non-substance-abuse RRTPs arrange community supports.
Among veterans returning from Iraq and Afghanistan, a higher percentage experience alcohol problems than drug problems 1 or 2 years after their return. The VA has great concern for these veterans as they attempt to readjust to the community. Often they are uncomfortable on wards with a larger percentage of Vietnam veterans, and they do not readily identify with the treatment program. The VA emphasizes working with the veterans early, before problems become resistant to change. Despite media indications of a rampant epidemic of substance problems, Dr. Allen stated that this is not the case. Rather, returning veterans have unique problems that the VA is working to address.
The VA is nearing completion of a regulation (known as a handbook) that specifies mandatory services for substance use disorder and how the services must be provided. The VA has published the summary for Clinical Practice Guidelines for the Treatment of Substance Use Disorder, an online publication prepared in conjunction with the Department of Defense. The VA conducted a series of Webinars in 2009 for physicians on medical interventions, particularly medications, for substance use disorder. The VA issued a memorandum on a requirement for safe and effective detoxification, linked with a referral to a substance use disorder treatment program. Guidance is about to be finalized for substance use disorder specialists assigned to PTSD teams. The VA has assigned substance use disorder experts in each region to consult with VA programs, provide professional training, and serve as a sounding board for the VA on the impact of changes on the field. A patient flyer to encourage drug treatment is in draft form, and materials are available on the Internet.
Public Law 110-387 mandates treatment for substance use disorders. Dominant themes of the Uniform Mental Health Services Handbook for Substance Use Disorder include access to care, continuum of care, substance use disorder care provided in both specialty programs and other services, and use of evidence-based interventions and clinical practices.
The VA provides universal screening for alcohol misuse in new patient encounters and provides follow-up for positive screens with a multidimensional evaluation. Interventions include emergency departments with the capacity to do 23-hour observations, medically managed withdrawal, brief interventions in primary care or mental health systems, or referral to specialty care. The VA program features integration of mental health with primary care services. Patients have a right to intensive outpatient services, and coordination of services is required in cases of dual diagnoses. The VA offers patients a choice of two evidence-based practices, opiate agonist therapy and evidence-based pharmacotherapy. If a patient refuses care, the VA continues to follow up with telephone calls, and, at the next visit to primary care, another follow-up attempt is made.
Discussion. Dr. Moss noted that NIAAA has collaborated extensively with the VA and has invested heavily in large-scale projects such as the Veterans Aging Cohort Study, for which NIAAA’s investigators and interested scientists continue to have difficulty accessing the data. Dr. Allen explained that the VA system exerts strict division between the research and treatment sides. Dr. Krystal added that there are many examples of collaboration and that persistence is needed. Dr. Allen suggested dealing directly and establishing collaboration with a VA research group. Dr. Moss raised the larger question of future NIAAA collaboration with the VA if data are not forthcoming. Dr. Krystal suggested that Dr. Warren meet with the head of the VA’s medical research department to build bridges. Dr. Heath noted that colleagues have taken uncompensated appointments at the VA in order to work with its data. Gen. Arthur Dean inquired about the percentage of young returning veterans with alcohol and drug issues, PTSD, and suicides, and Dr. Allen stated that he will provide him with the data.
Consideration of the September 16–17, 2009, Minutes and Future Meeting Dates
Council members voted unanimously to approve the minutes of the Council meeting of September 16–17, 2009. Upcoming Council meetings will take place on June 9–10, 2010, September 22–23, 2010; February 16–17, 2011, June 8–9, 2011, and September 14–15, 2011; February 8–9, 2012, June 6–7, 2012, and September 19–20, 2012. In addition, an Extramural Advisory Board meeting on alcohol and cancer will be held on June 8–9, 2010.
Evidence-Based Air Force Substance Abuse Prevention Programs
Culture of Responsible Choices (CoRC)
Milton Cambridge, Ph.D., U.S. Air Force, Demand Reduction Prevention and Outreach Manager, Office of the Surgeon General Mental Health Division, stated that the Department of Defense (DOD) Survey of Health Related Behaviors Among Military Personnel shows a pattern in the Air Force and other armed services of heavy alcohol abuse that occasionally results in behavioral problems. In 2005 approximately 11% of Air Force personnel experienced alcohol abuse, compared with 14% in 1980. Consequences of alcohol abuse include lost productivity, in addition to assaults, assault and battery, and traffic accidents.
Dr. Cambridge stated that despite significant increases in illicit drug use across U.S. armed services from 2002 through 2005, the Air Force recorded fewer than 1% positive drug tests through 2005. He noted that the definition of alcohol-related incidents differs by service, but under its new Culture of Responsible Choices (CoRC) approach, the Air Force focuses on alcohol-related misconduct in violation of the Uniform Code of Military Justice. In the Air Force, 9% of personnel are under age 21, a population that accounts for a large proportion of incidents of alcohol-related misconduct. The Air Force has adopted an evidence-based population-health model (in part based on NIAAA’s Call to Action and an IOM report), which incorporates strong leadership, environmental strategies, a range of strategies, early identification and intervention, anonymous screening, and prevention.
The Air Force had conducted a successful drinking campaign named 0-0-1-3, referring to 0 underage drinking, 0 driving under the influence, 1 drink per hour, and 3 drinks per night (for a typical 170-pound airman), a construct designed and adaptable to keep airmen’s blood alcohol concentration levels below 0.05 and to help inexperienced drinkers make responsible decisions. The 0-0-1-3 program served as a conceptual framework for the current CoRC approach, which integrates leadership, the individual, the base community, and the local community. This multilevel prevention program has engaged primary care physicians to look for teachable moments; initiated popular base activities such as late-night basketball, paintball, and other diversions from drinking; created a media campaign developed by airmen on base; developed implementation guidance and rolled out the program service wide; and established community coalitions to help address the problem. CoRC relies on standardized elements with tailored implementation and no funding. The first year of the program generated significant reductions in alcohol-related misconduct, but the numbers rose the second year, possibly due to better reporting. The Air Force currently is developing program metrics.
As an offshoot of CoRC, the Department of Justice offered the Air Force a Military Discretionary Grant to replicate the success of 0-0-1-3 at other bases. The Air Force signed a memorandum of understanding with the Department of Justice and NIAAA and began a demonstration project in 2006 using environmental strategies to combat underage drinking.
Enforcing Underage Drinking Laws
Christopher Spera, Ph.D., Vice President and Senior Scientist, ICF International, presented findings on alcohol use and misuse in Air Force; NIAAA and the Departments of Justice and Defense fund much of the research. In the context of more than 1.6 million U.S. troops deployed since 2001, the study examined how deployment is a risk factor for alcohol use, and, if so, how to prevent or treat it. Fresh data on the impact of deployment on substance abuse from the Defense Manpower Data Center show that 52% of Air Force members have been deployed in Iraq and Afghanistan for periods of 5 to 14 months. Research shows binge drinking to be common and at higher rates among Air Force members than civilians. Almost all the studies of deployment and substance use in the last 20 years looked at deployment in a dichotomous way, a problematical construct because of the many variables associated with occupational specialties, health or mental health issues, military spouses, and access to substances.
The research explored aspects of deployment that may affect likelihood of drinking, based on self-report data from a large, anonymous, Air Force database. Data was available on alcohol use and other risk behaviors. The AUDIT was used as an indicator of potential problem drinking. Data also were available on deployment in the last 24 months, number of times deployed, and direct or indirect exposure to combat. The study found that frequency and duration of deployment were predictive of problem drinking: Every additional year that a member was deployed increased the odds of problem drinking by 27%.
Dr. Spera described the EUDL program, which may contribute to reducing drinking among military members. The program, whose prototype was created by an Air Force commander who found a high rate of underage drinking upon his arrival at a Wyoming airbase, featured an initial letter to nearby bars thanking them for being part of community and for not serving underage airmen, and added that if it were found that if the bar did serve underage airmen, it would become off limits to all airmen. The commander offered popular alternatives to drinking. These activities brought alcohol-related incidents down 74%, and there were 81% fewer cases of underage drinking and 45% fewer cases of drunk driving.
The Department of Justice funded a replication study to reduce underage drinking among airman in five diverse communities and engaged NIAAA to sponsor an evaluation of the program. The program uses an environmental strategies approach that looks at demand reduction, examines policy influences, and focuses on establishments in the community that serve alcohol. The intervention’s core components included enforcing or reducing the social availability of alcohol, a compliance check program, increased DUI checks strategically where airmen congregated, local policy developments, media campaign using websites and marketing materials on the dangers of underage drinking by airmen, and encouragement of alternative activities to drinking.
Data is now under analysis in terms of prevalence of drinking, DUI arrests, alcohol-related traffic accidents, alcohol-related emergency room visits, and crimes against people. Three communities show evidence of reduced drinking activities. In one community, the percentage of establishments failing covert underage buying checks dropped a significant 13%, and incidents of alcohol possession by a minor also declined. Rates were higher for alcohol-related emergency room visits and for off-base accidents, possibly an artifact of more diligent reporting. Dr. Spera stated that the investigators are finding some evidence for the success of this program, which has potential to impact underage drinking, and are continuing to analyze the data.
Discussion. Dr. Ehlers inquired about imposing strict consequences on DUI arrests similar to those for positive drug screens or implemented random alcohol checks. Dr. Cambridge stated that the Air Force is educating commanders to look at alcohol similarly to the way they look at drugs, and the military is considering implementing a urine test among underage members to detect small amounts of alcohol. He acknowledged the difficulty in getting young people to take alcohol use more seriously.
Dr. Ralph Hingson commented on a nationwide secular increase in the behaviors that the investigators studied. He referred to a special supplement to the Journal of Studies on Alcohol and Drugs in July 2009 that summarizes NIAAA’s Rapid Response to College-Age Problem Drinking Initiative. He commended the Air Force study’s comprehensive approach and noted its importance for future research, especially as programs are brought to scale on a population level. Dr. Spera responded that some study data will be published in the Journal of Substance Abuse Treatment in May 2010. Gen. Dean endorsed the importance of combining research with environmental practices and procedures.
Council Award Discussion
Dr. Warren welcomed the Council’s perspectives in order to build a policy on training and mentoring K grant mechanisms and requested Council members to submit recommendations and suggestions.
Council Resolution to SUAA Working Group of the SMRB
Council members voted to finalize a resolution and rationale advising against any NIH reorganization that would eliminate NIAAA as an independent Institute. Following additions, review, and concurrence by Council members to an initial draft prepared and presented by Dr. Charness, the resolution was to be directed to the Council’s Executive Secretary for forwarding to Dr. Roper, with a copy to the chair of the SMRB. The resolution is attached as appendix 1.
Time was allocated for public comment, but no one came forward to speak.
Dr. Warren adjourned the meeting at 1:15 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Kenneth R. Warren, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
National Advisory Council on Alcohol Abuse and Alcoholism
Abraham P. Bautista, Ph.D.
Office of Extramural Activities
National Advisory Council on Alcohol Abuse and Alcoholism
Resolution of Council passed on February 4, 2010: 14 in favor; 0 opposed; 1 abstention.
The NIAAA Council strongly advises against an NIH reorganization that eliminates NIAAA as an independent Institute. We encourage increased collaboration across NIH Institutes and Centers to strengthen research on the use, abuse, and addiction to alcohol, tobacco, drugs of abuse, and high-fat and high-sugar foods. We also advocate increased collaboration to improve the diagnosis and treatment of the co-morbid mental health disorders associated with addiction.
We wish to emphasize the following points in support of our position:
1. Alcohol is the only legal, socially acceptable, recreational drug; research on alcohol requires a different approach than research on drugs of abuse.
Alcohol use disorders (AUDs) arise in the context of widespread, healthy, social drinking. More than 120 million Americans use alcohol recreationally with clear social and health benefits, including a reduced risk for heart disease and stroke. In contrast, the recreational use of inhalants, nicotine, prescription drugs or illegal drugs is never socially acceptable or medically advisable. An important goal of alcohol research is to inform public policy and education to help limit drinking to safe levels in healthy adults and to encourage abstinence during pregnancy and before the age of 21. Abstinence or prohibition, the fundamental model of prevention for most drugs of abuse, is a proven, failed policy for the prevention of AUDs in adults, precisely because the healthy use of alcohol is ubiquitous in society. Thus, research in areas of prevention and social policy differs markedly for alcohol versus illicit drugs. The merger of NIDA and NIAAA would blur the clear and distinct public health message of each Institute, and weaken crucial alcohol-related public policy research.
2. Alcohol use disorders are different than drug addiction.
The genetics of alcoholism differs from the genetics of drug addiction. Prospective studies have shown that the sons of alcoholics are at greater risk for alcoholism than for drug dependence. Furthermore, a number of medications effective in the treatment of AUDs are not useful for the treatment of drug dependence and vice versa, suggesting that divergent pathways of medications development must be followed to address fundamental differences in the underlying pathophysiology of these disorders.
3. Alcohol misuse disorders produce enormous medical, economic, and social costs.
Even if most individuals recover spontaneously from AUDs, their misuse of alcohol results in enormous medical, economic, and societal costs. AUDs cost the nation $235 billion annually, nearly 80% more than the costs related to all other addictive drugs. AUDs result annually in more than 80,000 deaths, approximately 1/3 of all fatal car crashes, 1/2 of all homicides, 1/3 of all suicides, and 1/3 of all hospital admissions. Alcohol damages virtually every organ system. Fetal alcohol spectrum disorders are the most common non-genetic cause of mental and cognitive impairment, affecting up to 1 in 100 live births. Alcoholic liver disease, alone or in combination with viral hepatitis, is the most prevalent form of chronic liver disease in the Western world. Most research on fetal alcohol spectrum disorders, alcoholic liver disease, and alcohol-related organ toxicity is funded by NIAAA.
4. Much of the public health burden of alcohol use disorders is caused by the non-addictive use of alcohol.
The non-addictive use of alcohol accounts for much of the public health burden related to AUDs, including that related to fetal alcohol spectrum disorders, fatal car crashes, accidents, and homicides. On college campuses alone, alcohol use results annually in almost 2000 deaths, 100,000 sexual assaults, 600,000 injuries, and 700,000 assaults. For most college students, problematic drinking and its associated morbidity will not be solved by novel pharmacotherapies. Rather, psychosocial and public policy research championed by NIAAA is critical in the effort to reduce harmful college drinking.
5. The existence of certain commonalities in the brain pathways that mediate the rewarding effects of alcohol and other drugs of abuse does not justify the merger of NIAAA and NIDA.
Reward systems in the brain govern many motivated behaviors, including eating, drinking, romantic courtship, sex, music appreciation, and diverse positive social interactions. The fact that these neural circuits also contribute to the rewarding effects of alcohol and drugs of abuse does not justify merging NIAAA and NIDA. Likewise, the fact that dopamine is an important neurotransmitter in signaling reward associated with myriad motivational stimuli does not provide a strong rationale for merging Institutes. Dopamine systems are perturbed in Parkinson disease, schizophrenia, and childhood dystonia, yet no mega-merger is proposed for NINDS, NICHD, NIMH, NIAAA, and NIDA. In the same way, we do not advocate the merger of NIDDK, NIAAA and NIDA to study those elements of food addictions, alcoholism, and drug addiction that share similar brain pathways, or the merger of NIDA or NIAAA with NIMH to study psychiatric co-morbidity. However, we do advocate enhanced collaboration among these Institutes to better understand how these disorders interact and overlap.
6. Most individuals with alcohol use disorders do not abuse other drugs.
NIAAA’s study of more than 43,000 subjects demonstrated that most individuals with AUDs do not have mental health disorders and do not abuse other drugs. Although most individuals who abuse drugs also have AUDs, this subgroup comprises a minority of individuals with AUDs and contributes to a small share of the public health burden associated with AUDs. The large size of the population with AUDs who don’t abuse other drugs and the enormous public health burden of their illness justify NIAAA’s focused approach to research on AUDs, separate from drug dependence. The combined abuse of alcohol and drugs can be addressed through enhanced collaboration between NIAAA and NIDA. Likewise, the subgroup of individuals with AUDs and mental health disorders can be studied through enhanced collaboration between NIAAA and NIMH.
7. Alcohol differs from other drugs of abuse in the degree to which heavy use damages the brain and other organs.
Alcohol is particularly toxic to the brain and myriad organ systems, as well as to the developing fetus. The neurological disorders that result from alcohol neurotoxicity and concomitant malnutrition constitute a large and important public health problem. Alcohol damages multiple organ systems through common mechanisms of toxicity, including oxidative stress, the disruption of critical cell signaling systems, and the generation of toxic metabolites, cytokines, and chemokines. The coordinated study of these multiple organ toxicities is best suited to a single alcohol Institute.
8. A systems approach is essential to the study of alcohol’s beneficial and adverse effects.
Alcohol affects the entire body, enhancing cardiovascular health with moderate use, and damaging multiple organs with heavy use. Alcohol-induced injury in one organ system, such as the gut, liver, or immune system, is inexorably linked to alterations in the structure and function of others, such as the brain. NIAAA recognizes that a systems biology approach is essential to study the universe of alcohol’s beneficial and harmful interconnected effects on the brain and other organ systems. The merger of NIAAA with NIDA to form a new Institute focused on addiction would orphan and dissociate critical programs focused on alcohol and cardiovascular health, liver disease, pancreatitis, fetal alcohol spectrum disorders, immune disorders, myopathy, neuropathy, and brain disorders. Alcohol research clearly benefits greatly from the organizational integrity of a single Institute that focuses on all aspects of alcohol.
9. A merger will sacrifice the diverse approaches of two Institutes to addiction research.
The cornerstone of health research in the United States is the investigator initiated grant and the thousands of ideas generated by independent investigators. Even at the level of NIH Institutes, there are advantages to diversity in the evolution of scientific ideas. NIAAA has fostered an agile approach to medications development that benefits from its focus on a single drug, alcohol, and an integration of basic science research, translational research, and clinical trials using patients at an early stage of disease development. The product of this research is more than a dozen medications approved or under investigation for the treatment of AUDs. NIDA utilizes a clinical trials network that tests medications for diverse drugs of abuse in individuals with more advanced disease who are often recruited from the criminal justice system. The creation of a single, large Institute under the direction of a single director risks losing the diversity of approaches to the development of treatments for these conditions and the agility of NIAAA, as a small Institute, to adapt quickly in response to scientific opportunities.
10. The loss of an independent NIAAA will damage NIH's initiative on improving global health.
NIAAA is a leader among NIH Institutes in conducting global health initiatives. Foreign countries that cannot afford an alcohol Institute have looked to NIAAA for guidance in setting policy on the use and abuse of alcohol. A decision to abolish NIAAA would send a message to the global community that the United States devalues the effort to coordinate research and policy related to alcohol, the fifth leading cause of global death and disability.
11. The loss of an independent NIH Institute dedicated to alcohol research will discourage young scientists from entering the field.
NIAAA’s emergence as an Institute brought the importance of alcohol-related health problems to national attention and signaled to researchers that alcohol research is an important public health endeavor and area of scientific inquiry. NIAAA has attracted some of the best and brightest investigators to the field. The loss of an independent Institute devoted to research on alcohol abuse and alcoholism will deter the recruitment of new researchers to the field.
12. What we stand to lose through the merger of NIAAA and NIDA is far more than what we stand to gain. What we stand to gain through merger can be accomplished through alternative approaches, including enhanced collaboration between NIAAA and NIDA.
Mergers of large organizations are traumatic, destabilizing, time-consuming, and costly; therefore, we stand to lose time, personnel, resources, and mission focus. Mergers often result in organizations that are too large, inflexible, and unwieldy to respond quickly to changing opportunities and sacrifice the diversity of their parent organizations. Dissolving NIAAA into an Institute on addiction or drug use and abuse will compromise the integrated study of genetics, cell biology, organ systems, psychology, social systems, and public policy that characterizes NIAAA’s coordinated approach to one of America’s most important public health burdens. On the other hand, it is not clear what we stand to gain, either scientifically or organizationally, through a merger of NIDA and NIAAA that could not be accomplished through enhanced collaborations between the two Institutes and across NIH.