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National Advisory Council Meeting-September 19-20, 2007
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
Summary of the 116th Meeting
September 19-20, 2007
The National Advisory Council on Alcohol Abuse and Alcoholism convened for its 116th meeting at 5:30 p.m. on September 19, 2007, at the Fishers Lane Conference Center in Rockville, Maryland , in a closed session. The Council convened in open session at 9:00 a.m. on September 20. Dr. Tina Vanderveen presided over the review of grant applications in the closed session on September 19. Dr. Ting-Kai Li, Director of the National Institute on Alcohol Abuse and Alcoholism, presided over the open session on September 20. In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the meeting on September 19, 2007, was closed to the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds.
Council Members Present:
Michael E. Charness, M.D.
Cheryl J. Stephens Cherpitel, M.P.H., Dr.P.H.
Gen. Arthur T. Dean
Cindy L. Ehlers, Ph.D.
R. Adron Harris, Ph.D.
Joannes B. Hoek, Ph.D.
Mack C. Mitchell, Jr., M.D.
Peter M. Monti, Ph.D.
James W. Payne, J.D.
Kenneth J. Sher, Ph.D.
Alan C. Swann, M.D.
Chairperson: Ting-Kai Li, M.D.
Executive Secretary: Abraham Bautista, Ph.D.
Vivian B. Faden, Ph.D., Ralph W. Hingson, Sc.D., M.P.H., Robin I. Kawazoe, Howard Moss, M.D., Antonio Noronha, Ph.D., Tina Vanderveen, Ph.D., Kenneth R. Warren, Ph.D., Mark Willenbring, M.D.
Other Attendees on September 20, 2007
Approximately 50 additional observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order of the Closed Session, September 19, 2007
Dr. Tina Vanderveen called the closed session of the 116th meeting of the Council to order at 5:30 p.m. on Wednesday, September 19, 2007, for consideration of grant applications. She reviewed 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 adjourned at 6:50 p.m.
Call to Order of the Open Session and Introductions, September 20, 2007
Dr. Li called the open session to order on September 20, 2007, at 9:02 a.m. and welcomed participants. Members of the Council, NIAAA staff, and audience introduced themselves.
Director’s Report/Special Announcements
Referring to the published “Director’s Report,” Dr. Li highlighted the following Institute activities:
§ Legislation, Budget, and Policy. In legislative action regarding name changes for NIAAA and the National Institute on Drug Abuse (NIDA), the Senate Committee on Health, Education, Labor, and Pensions reported a bill with an amendment to change the name of NIH’s National Institute of Child Health and Human Development to the Eunice Kennedy Shriver National Institute of Child Health and Development. An anonymous senator blocked consideration of the bill by the full Senate, and the House has taken no action on the companion bill. Dr. Li announced that the Senate passed a mental health and substance abuse parity bill on September 20; the House has taken no action. The House Appropriations Committee passed a bill that would increase the NIH and NIAAA budgets to $29.6 billion and nearly $443 million, respectively—a 1.6 percent increase for NIAAA. The full Senate passed a bill that would increase NIH funds by $800 million over the President’s request, with a 2.2 percent increase for NIAAA at nearly $446 million.
§ Director’s activities
§ Tomorrow’s Medicine Today , a television show produced by Medical Missions for Children, taped a program segment featuring Dr. Li to be broadcast over the Medical Broadcasting Channel and New Jersey public television.
§ Dr. Li presented an update on NIAAA’s budget and research initiatives at the Research Society of Alcoholism’s annual meeting. He noted that the Institute’s success rate for funding has remained flat at 30 percent, while most other Institutes’ rates have declined. NIAAA anticipates funding 27 young investigators in FY 2007.
§ Dr. Li mentioned that Lorraine Gunzerath, Ph.D., M.B.A., recently analyzed NIAAA trainees’ success rate; and he will present these findings at the upcoming training directors/trainee workshop in Indianapolis, IN. The percentage of NIAAA pre- and post-doctoral trainees and fellows who apply and succeed in obtaining R01 and R21 awards is good for all Institutes and Centers, and particularly for those who receive NIAAA R01 and R21 awards.
§ NIAAA staff and organizational changes. Dr. Li reported Dr. Moss’s appointment to the task force that will oversee development of the DSM-V. New NIAAA employees include Thomas Greenwell, Ph.D., at the Division of Neuroscience and Behavior; M. Katherine Jung, Ph.D., at the Division of Metabolism and Health Effects (DMHE); He (Joe) Wang, Ph.D., DMHE; and Bridget Williams-Simmons, Ph.D., Science Policy Branch, an alumna of the Emerging Leaders Program. Dr. Li also announced the retirement of Diane Lucas, Ph.D., and Marlene Sable, and the departure of Roger Sorensen, Ph.D., who has joined NIDA.
§ Awards. Together with HBO, the Robert Wood Johnson Foundation, and NIDA, NIAAA received the American Academy of Television Arts and Sciences’ Board of Governors Award, the Emmy that represents the Academy’s highest honor, for The Addiction Project. NIAAA’s Ann Bradley facilitated the program, portions of which may be viewed at www.hbo.com/addiction. In addition, a record four postdoctoral fellows in the Division of Intramural Clinical and Biological Research received the Fellows Award for Research Excellence at NIH; Bridget Grant, Ph.D., received the 2007 Jellinek Award; Andrew Holmes, Ph.D., received the 2007 Senior Preclinical Wyeth Award of the British Association for Psychopharmacology; Bill Huang, Ph.D., received the Young Investigator Award from the American Society for Biochemistry and Molecular Biology; Antonio Noronha, Ph.D., was part of the group that received the NIH Director’s Award for his scientific leadership of the Molecular Libraries and Imaging Roadmap; and Ellen Witt, Ph.D., was part of the group that received the Blueprint for Neuroscience Research Director’s Award.
§ NIAAA research programs. Dr. Li emphasized the importance of collaborative international research. NIAAA engages in such research to learn about, for example, special genetic predispositions in certain populations that can inform research and care for the melting-pot populations of the U.S. , and also because of the global nature of alcohol problems. In the past several years, NIAAA has established relationships with individuals at INSERM, France ’s equivalent of the NIH. The agencies have begun joint projects and personnel exchanges, scheduled meetings in both countries, participated in joint workshops, and discussed common areas of interest. NIAAA also jointly helped establish an extramural program with INSERM at the Scripps Institute. In addition, NIAAA has hosted visitors from the Republic of Korea ’s NIH, which is interested in collaborating on alcohol research, and a letter of intent is expected to evolve. Similar agreements have been forged with Taiwan and Japan, and an agreement with Germany may ensue.
§ Research reports. Publication of journal articles on NIAAA research is increasing, including articles on the contributions emerging from NESARC and laboratory-based research. An important finding from Intramural research is the involvement of cannabinoid receptors in the development of fatty liver and fibrosis, in addition to brain reward functions.
§ Scientific meetings. Many NIAAA staff members participated in organizing and presenting at local and national scientific meetings, including the Research Society on Alcoholism among many others. Research topics of particular importance for the future were NIH’s Workshop on Immortalized Cell Lines for Gene Expression and the Blueprint Neuroplasticity Workshop.
§ Outreach activities. Dr. Li reported that the Surgeon General issued and is disseminating a “Call to Action to Prevent and Reduce Underage Drinking,.” the culmination of years of collaborative effort by Leadership to Keep Children Alcohol Free, NIAAA, the Substance Abuse and Mental Health Services Administration (SAMHSA), and others. Drs. Vivian Faden and Trish Powell and others wrote the underlying science. Three important companion guides have been issued, for families, educators, and communities. North Carolina First Lady Mary Easley announced a new evidence-based media literacy program, Media Ready, aimed at middle-school students to reduce harm and prevent underage drinking. In addition, NIAAA continues its outreach to campuses on college drinking. Dr. Li expressed anticipation that Community Anti‑Drug Coalitions of America (CADCA) will work with NIAAA to develop the evidence base, as well as prevention and treatment strategies at the local level.
§ Multimedia projects. NIAAA’s revised Clinician’s Guide and various dissemination materials have received considerable attention. The Communications and Public Liaison Branch continues its award-winning work, having received the World Wide Web Health Award for 2006 and other honors.
§ Announcements. Dr. Boris Tabakoff will deliver the Keller Lecture in October 2007, and the Society for Neuroscience will honor Dr. Henri Begleiter at a November symposium sponsored by NIDA and NIAAA. Upon the death of Dr. Jack Mendelson, first director of the national alcoholism research effort, Dr. Li asked the Council to concur in the establishment of a Jack Mendelson Memorial Lecture.
Research, Condition, and Disease Categorization
Timothy Hays, Ph.D., Project Director, Research, Condition, and Disease Categorization (RCDC), and Chief, Portfolio Analysis and Scientific Opportunities Branch, Office of Portfolio Analysis and Strategic Initiatives, NIH, discussed the process underway to categorize NIH funding. NIH reports annually on expenditures in research and disease areas in 260 categories. The aggregate amount equals 4.5 times the total budget, reflecting the fact that projects fall into multiple categories.
NIH is working to change the categorization process in order to provide consistent, comparable information in answer to questions from Congress and constituency groups on spending amounts, patterns, and priorities. In response to National Academy of Sciences reports, in 2003 NIH began to look at automated tools that would change its process to summarize R&D contracts. Lack of a central repository of electronic research descriptions for the projects NIH funds impedes the work, although grants.gov has improved the situation and Intramural projects provide summary reports. In 2004 NIH implemented text-matching software, and, with a prototype in place in 2006, Congress has mandated the use of an electronic system for all categorization at NIH.
RCDC, an electronic reporting system, matches projects to definitions of research areas. NIH plans to implement this system for all Institutes and all types of research with 360 categories related to research and disease areas. Benefits include consistency, achieved by the application of definitions across all NIH Institutes; transparency, with every project listed in every appropriate category; efficiency in responding to inquiries; and new opportunities for portfolio analysis. RCDC combines a project’s title, abstract, and specific aims, and counts the number of mentions of specific concepts. The result is a weighted list of concepts for each project that forms the “fingerprint” for that project. The concepts are drawn from a thesaurus with 300,000 medical and scientific terms representing disorders, conditions, and research areas. The fingerprint is matched electronically against the 360 categories to see which categories might be relevant to the fingerprint. Some fingerprints may fall into multiple categories, but they reflect equal weight for each of the categories, and the full amount of funding is reported for each category.
In 2008 NIH plans to introduce RCDC to communities and investigators prior to rolling out the tool, explaining that most of the funding statistics previously reported will be revised—but solely due to the methodological change, not representative of revised priorities. NIH plans to launch RCDC in February 2009 with FY 2008 projects.
Discussion: To a question from Dr. Sher, Dr. Hays stated that RCDC will be used only for NIH-funded projects. Project staff is considering ways to use RCDC for comprehensive analysis, but many applications do not arrive electronically and resources are inadequate to extract information manually. When grants.gov handles all applications, NIH will have information to start to review for pre-award. Eventually the information will be posted on a redesigned Web site, accessible on the NIH Web site by searching “Funding and Diseases.” In addition, it may be possible to incorporate the data into an NIH-wide reporting website (under consideration) to search by keyword within a category. Dr. Hays replied to Dr. Warren that data obtained from applications submitted using PHS 398 and SF 424 forms, Intramural, and R&D contracts are captured electronically, but data from R&D contract summaries must be extracted manually. Dr. Hays responded to Dr. Harris that animal species probably will not be coded, unless the animal model appears in the abstract; methods sections will not be coded. All abstracts and titles currently are posted on the CRISP Web site. In response to a question from Dr. Chiapella, Dr. Hays stated that new categories will be incorporated in the future via a rapid scan to respond to a specific request for information and a more comprehensive process to develop the category for year-end reporting. NIH plans to finalize the tool’s functionality prior to adding new categories. Dr. Li raised the issue of consistency of categorization between NIH staff and investigators, and the relative importance of their interpretations. Dr. Hays replied that investigators have an opportunity to incorporate relevant concepts into their abstracts and thereby to influence outcomes.
Dr. Sher suggested that for automated submissions, a function might be added to RCDC to enable an applicant or grantee to respond with information on the degree to which they felt the categories accurately conveyed their intent. Dr. Hays expressed the need for caution regarding the political implications of a system that goes beyond its intended purpose. Dr. Sher acknowledged that applicants might try to seize advantages in the disposition of their applications. Dr. Hays stated that permitting investigators to provide additional information would be considered, but that he prefers the strategy of applicants working with a program administrator to adjust applications and abstracts, and entering a newly adapted abstract into the categorization process. To a question from Dr. Moss, Dr. Hays explained that RCDC would not be used to route applications for review, a process accomplished by means of cover letters and existing referral guidelines. Loading an abstract with concepts may result in placement in undesirable categories from the standpoint of the applicant, and Dr. Hays counseled writing applications and abstracts in a straightforward manner. Dr. Hays responded to Dr. Sher that NIH must report on the amount of funding for basic and applied science; basic science accounts for 55-60 percent of NIH research. Dr. Hays acknowledged the continuing need to communicate to the public on the fundamental importance of basic research.
NIAAA Strategic Plan 2008-2013: Update
Dr. Kenneth Warren presented the first update of NIAAA’s Strategic Plan. The plan aims to identify opportunities, including potential initiatives arising from the confluence of new concepts, new knowledge, and/or new technologies directed toward important problems related to alcohol disorders. These initiatives must be feasible within current fiscal realities. The plan is a dynamic document to be updated periodically based on new scientific developments.
Organized from a lifespan perspective across six periods—fetus, child, adolescent, young adult, middle age, and senior—the cross-cutting issues of genes and environment, alcohol metabolism, neurobiology, and diagnostic issues for alcohol disorders and dependence affect all phases. A new chapter, Birth to Age 10, appears in the update, and sidebars have been added to other chapters with specific reference to topics recently reviewed by the Extramural Advisory Board (EAB) and approved by Council.
The new chapter describes key contexts of the child development process, reciprocal interaction of individual characteristics/genetic endowment, and environment/context unfolding over time. It notes children’s vulnerability to internal and external forces that will shape their response to exposure to alcohol, which may affect their future willingness to experiment with alcohol and other drugs. In addition to directly influencing learning processes, attitudes, and behaviors, the potential exists for epigenetic processes that affect future gene function.
The chapter highlights opportunities for research, including examining the onset of drinking in young children; parental beliefs and practices concerning childhood alcohol use to determine factors that function to increase or decrease risk; and ontogeny of attitudes, intentions, and expectancies. Additional opportunities exist to further characterize both externalizing and internalizing pathways for the development of problematic drinking in adolescents with regard to early initiation, alcohol use, and alcohol use disorders (AUD); further assess the role of modifying factors such as gender and ethnicity; and apply various data collection and analysis strategies with state-of-the-art technologies in genomics, imaging, and statistical modeling to determine the relative contribution of biology, environment, and genetics to the risk for alcohol dependence or abusive alcohol consumption in later life.
A major update to the HIV/AIDS section in the Midlife chapter was based on an EAB report and other insights from NIAAA’s AIDS program. The plan also updates the discussion of opportunities for research in the area of alcohol and HIV, including research on organ and tissue injury; brain injury and disease; anemia and bone marrow dysfunction; liver disease; cardiopulmonary disease targets; mitochondrial dysfunction as a common outcome of HIV and ethanol-related cellular injury; interactions of nutrition; alcohol, HIV, and HIV therapy; pharmaco-kinetic and -dynamic effects of alcohol; impact of alcohol use and treatment of alcohol disorders on biomedical approaches to HIV prevention; and others.
Discussion: Dr. Li stated that the Strategic Plan provides scientific direction and a time line, and also facilitates justifying the NIAAA budget to Congress.
Personality and Alcohol: Understanding a Complex Relationship
Council Member Kenneth J. Sher, Ph.D., Professor, University of Missouri–Columbia and the Midwest Alcoholism Research Center, described knowledge and research on the role of personality in alcohol-related behaviors. The link between personality and problematic alcohol involvement has been demonstrated, but not the existence of an addictive personality.
Evidence that personality is related to problematic use of alcohol and other drugs appears in the association of various traits to the tendency to experience negative affect and disinhibition, but research has failed to distinguish “pre-alcoholic” and “clinical alcoholic” traits (e.g., Barnes, 1978). Prospective associations consistently show future alcohol problems or dependence associated with disinhibition/impulsivity and, to a lesser degree, neuroticism (Sher et al., 1999). A genetic correlation was proposed by Cloninger but never demonstrated until Slutske and colleagues (2002) showed a genetic link between conduct disorder (CD) and alcoholism. Dr. Sher noted the proportion of variance attributable to the additive genetic effects for positive emotionality, negative emotionality, and behavioral undercontrol (all around 50 percent), and CD and alcohol dependence (also very high). High genetic correlation between alcohol dependence and behavioral undercontrol appears to account for the comorbidity with CD.
Dr. Sher discussed theories of the relationship between personality and pathological alcohol use: individual differences in sensitivity to the rewarding or disinhibiting effects of alcohol, substrate for motivations for use, and environment selection. In 1929 McDougall theorized the susceptibility of people with “extroverted personality” with “little inhibitory control to the influence of alcohol.” Cleckley (1941) defined “fantastic and uninviting behavior after drink” as a criterion for psychopathic behavior. The notion that temperament might be related to individual differences in sensitivity to the rewarding or disinhibiting effects of alcohol (Sher and Levenson, 1982) was popular for a while. People rated high in impulsivity were more sensitive to the negatively reinforcing effect of alcohol when stressed, a finding replicated with stricter definitions, but this outcome may have alternative explanations. Dr. Sher stated that inconsistency in the literature has occurred because of under-dosing.
Giancola’s (2003) work on the effects of alcohol, empathic concern, and provocation on aggression shows an alcohol effect when people low, but not high, in empathy are stressed—a conditional effect upon a basic personality dimension. Dr. Sher asserted that at least some variation in alcohol sensitivity is related to temperament. Cooper’s work on alcohol motivations shows a link between sensation seeking and drinking to enhance (to get high). She found that the drinking-to-enhance pathway is mediated totally through alcohol use, but she also found a residual path of consequences related to motivation that is not purely mediated by the amount of alcohol consumed. Dr. Sher noted that a recent review of studies by Cunch determined this to be a replicable finding. Dr. Sher suggested that persons with an anxiety disorder or depression may use alcohol as a self-regulation strategy away from social situations.
Dr. Sher shared his recent work on personality traits, drinking motives, and AUDs. His study looked at neuroticism and behavioral undercontrol, and coping motives and enhancement motives for emerging adults at age 18 and at ages 25, 29, and 34. Dr. Sher found neuroticism to be related to coping, which in turn is related to AUDs, and at age 18 predicts strongly for ages 25 and above. With behavioral undercontrol, an unmediated direct effect and an unmediated longitudinal extension are seen. Similar results have been shown for borderline personality disorder.
Dr. Sher explained that individuals self-select into different environments, an important consideration in the gene/environment interplay, in part because of personality traits. Some environments may impose risk for alcohol problems; some selection may relate to drinking aspects of the environment. Selection may not be tied to drinking per se, however, but may be related to other attractive characteristics of the environment. Different types of personality/environment co-variation may exist.
The NIAAA-funded IMPACTS Study looks comprehensively at adjustment to college life and predicts the nature of alcohol problems over the college years. Assessed by a paper-and-pencil survey at freshman welcome and subsequent semesters via a Web-based instrument, 88 percent of first-time freshman participated at baseline screening and 90 percent participated in at least two waves. Thirty-six percent participated in all assessments and 60 percent participated at the final wave. As the investigators’ experience with a Web-based survey increased, they shortened the questionnaire and paid more money with resulting improvement in responses. A composite measure of heavy drinking shows between one and two heavy drinking occasions per month on average, including the 20 percent who abstain, on a campus with higher-than-average drinking as determined by the Wechsler survey. Dr. Sher modeled the change using a standard multivariate growth analysis over the ensuing 3 years. The amount a student drinks prior to entering college predicts selection into the Greek system, producing a strong selection effect in addition to a later socialization effect.
Dr. Sher highlighted the novel aspect of the research: Individuals select into fraternities and sororities for personality traits both strongly related to alcohol seeking and incidental to drinking, for example, extroversion. When extroverts enter the high-risk environment of a Greek society and become subject to the socialization effect, the heavy-drinking environment can be a social trap. To understand personality-based environment selection, one must understand the fit between the trait and the needs the environment will satisfy.
Dr. Sher discussed the dramatic implications of personality changes in the course of alcohol-related problems. Personality traits show normative age-related changes over the course of development; during same period of time, considerable “maturing out” of alcohol problems also occurs. Roberts et al. (2006) show that emotional stability and conscientiousness rises a great deal during the lifespan, at a rapid rate in late adolescence and emerging adulthood, with close to a standard deviation difference from approximately age 10 to late life.
Dr. Sher highlighted the 78 percent retention rate over 17 years and 7 waves of the AHB study. The effects were so strong on the course of drinking, using DSM-III criteria for AUD prevalence, that he encountered problems in publishing the data. Although half the subjects had a positive family history, reviewers considered the rates excessively high. NESARC has since shown that college-age individuals have the highest rates, which eventually decline, but at the time of the study, clinical stereotypes predominated. Rates decline dramatically by the late 20s, then may creep up. Graphing the mean alcohol consequences, observed versus estimated, demonstrates the strong fit of the growth model with raw data. Personality was assessed at every wave, along with alcohol, at ages 18, 25, 29, and 34. Data show a moderate association between change in impulsivity over this period of time and change in the consequences people experience. Adding marriage and/or children into the equation reduces consequences, in measures of both psychoticism and neuroticism, both strong associations that are not artifacts of environmental change. Dr. Sher stated that maturing out accounts for more effect than social role transitions, but noted that no researchers appear to be exploiting knowledge about personality change to understand life course of drinking. He asserted that maturing out is related to normative personality change that must be viewed in a developmental context.
In summary, Dr. Sher stated that personality relates to multiple pathways for risk for heavy alcohol use, problems, and dependence. Pathways appear to include alcohol sensitivity, alcohol motivation, and environment selection. In addition, personality changes as a function of development, and these changes are associated with change in risk for problematic alcohol use. The AHB study has implications across domains, including gene hunting, studying personality by situation effects on drinking, identifying treatment moderators, tracking risk developmentally, and potential subtyping. Although personality is not an endophenotype, Dr. Sher considers the MAOA interaction probably to be related to broad personality traits. Although Project MATCH did not live up to expectations, some personality data show strong situational effects on drinking, and some recent data (Conrad and Stewart) on personality-based targeted approaches are strong. Dr. Sher suggested the value of looking at treatment that addresses underlying personality dispositions and creating environments that meet basic personality-related needs incompatible with heavy drinking.
Discussion: Dr. Ehlers inquired about effects on people with CD who did not develop antisocial personality disorder (ASPD). Dr. Sher responded that little full-blown ASPD appears in college settings, but noted that his study used CD symptom counts; grading norm-violating behavior before age 15 predicts severity of course and persistence. The categorical nature of CD might obscure what is a graded phenomenon, but the study has good variability in CD symptom counts. To a question from Gen. Dean, Dr. Sher responded that his study has a large enough sample to stratify personality on the basis of gender; men and women are more similar than not when looking at covariance, but differences occur. The study population is largely people of European descent, with samples too small to do informative sub-analyses on ethnicity. Nevertheless, Dr. Sher pointed out, different cultural norms are associated with different ethnic groups, and the relative importance of different processes might vary as a function of one or another demographic stratum.
Dr. Sher responded to a question from Dr. Li about diagnosis. Approaches to the architecture of personality differ, and the most established approach is lexical: how many traits, what they are, and how they relate to each other. The Big Five Theory considers five dimensions: neuroticism (negative affectivity), extroversion or sociability, agreeableness, conscientiousness, and openness to experience (intellect); the Big Three Theory is similar. The number of traits is robust, about 50 percent heritable, and it is known that personality can moderate and change in trajectory over the lifespan. Dr. Sher will send Dr. Li a paper by Troll on the genetics of borderline personality. Noting that persons with borderline personality often have comorbid substance abuse, eating disorders, and self harm, Dr. Sher stated that the most effective treatment is dialectical behavior therapy, which emphasizes self-control and creates coping strategies, but does not change underlying personality. Dr. Willenbring observed that a maturing-out process occurs for borderline personality.
Activating Effects of Alcohol: Mechanisms and Consequences
Council member Alan C. Swann, M.D., Professor and Vice Chair for Research, University of Texas Medical School, discussed research findings on issues related to ethanol as stimulant. Severe problems related to episodic heavy drinking without dependence include alcohol-related vehicle accidents, strongly associated with binge drinking; violence, with alcohol use within 2 hours prior to a violent act; risky sexual behavior in adolescents linked to excitement seeking and perhaps connected to HIV infection; and trauma. Dr. Swann’s research shows an association, independent of AUD, between binge drinking and both self-inflicted gunshot injury and medically severe suicide attempts. People experience these problems early in the course of alcoholism. A study of binge drinking in an emergency surgery population showed much higher incidence of binge drinking among younger people and women. A number of factors predict early trouble with alcohol before onset of alcohol use. In 11 year olds who were not drinking, for example, behavioral disinhibition predicted the onset of alcohol use at age 14 (McGue et al., 2001).
Dr. Swann discussed alcohol’s biphasic effects, which differ by ascending or descending limb of the blood alcohol concentration curve. The relative sensitivity of individuals and animals that experience these effects varies. Martin and colleagues (1993) developed the Biphasic Ethanol Effect Scale, which shows the stimulant-like effects of alcohol in the ascending phase, for example, feeling energized and excited, by adjusting the dosage of alcohol challenges. On the descending limb, these behaviors become less prominent and others, for example, feeling down and sluggish, appear. Dr. Swann expressed interest in understanding the ascending limb, in which impulsivity plays a role.
In discussing impulsivity, Dr. Swann explained that all animals with a measurable brain have a balance between potential generation and potential inhibition of action, regulated by different brain areas; an animal can think and decide on an action. When something disrupts the opportunity to reflect, impulsivity, entirely a relationship between behavior and its context comes into play; contrary to poor judgment, impulsivity is no judgment. Impulsivity involves the initiation of action unmatched to its context and an inability to modify action according to changes in context. Aspects of impulsivity may be measured by assessing the ability to withhold response, predisposition to impulsive behavior, and adaptation to an impulsive brain.
Impulsivity decreases through childhood and adolescence and into young adulthood, as the brain’s behavioral inhibitory systems develop and moderate reflexes and drive-related behavior. Children’s impulsivity correlates with the impulsivity of their parents. People with severe early onset impulsivity of any type generally have major disruptions in contact with parents; impulsivity increases with early trauma or abuse; and impulsivity also may be increased by prenatal drug exposure, but a genetic component is present. A correlation exists in impulsivity measured in teenagers and their parents due to genetics, developmental considerations, and adolescents’ erratic behaviors.
Dr. Swann discussed reasons for impulsivity at some times and not at others. In state-related impulsivity, a failed serotonin balance may relate to survival-related brain mechanisms. In response to extreme stressors, excessive norepinephrine (NE) stimulation of alpha-1b receptors inhibits prefrontal cortex and amygdale function (Armsten et al., 2001; Braga et al., 2005), thus short-circuiting the prefrontal cortex and enabling immediate action in an emergency. Stimuli other than stress can activate this process by anything that pathologically increases NE release, including being manic, substance abuse intoxication, and withdrawal from some drugs, especially after behavioral sensitization. This system appears to be related to state-related impulsivity: Yohimbine was associated with a dose-dependent increase in subjective activation, demonstrating the possibility of recognizing potentially risky internal states (Swann et al., 2005). Therapeutic approaches for impulsivity include measuring potentially risky internal states.
The mechanism by which alcohol works as a stimulant is unknown. Alcohol increases indices of NE turnover in some animals and humans. Several studies (McDougle et al., 1995, 2006) showed that plasma NE and MHPG correlate with subjective activation, systolic blood pressure, and anxiety. Alcohol to yohimbine achieved similar additive effects. The mechanism appears to be related, mostly in animal studies, to rewarding effects from alcohol. Dr. Swann stated that various aspects of impulsivity seem to be related to the likelihood of drinking alcohol or to be induced by alcohol. In genetic models, mice that lack 5HT-1b serotonergic receptors or protein kinase C have more behavioral impulsivity and voluntary alcohol consumption, apparently an effect of removing an inhibitory effect of alcohol and leaving any excitatory effects alone. Human populations with various abnormalities in genetic regulation of protein kinase C have increased impulsivity. Alcohol increases impulsivity in animals and humans at the right dose and at the right time, crucial variables in looking at this aspect of how alcohol works. Both major models of impulsivity used for the delay-discounting and rapid-response behavioral tests can be increased by alcohol. In populations with considerable variability, animals with a greater impulsivity response to alcohol self-administer more alcohol.
Individuals with early onset of alcoholism and more likely to have binge drinking also are more impulsive by several behavioral tests than people who have later onset of alcohol problems; acute alcohol increases impulsivity by several models; and increased impulsivity correlates with other consequences of alcohol. Aggressive past behavior and impulsivity both predict alcohol-induced aggression. Binge drinking may represent a cycle of drinking for its stimulant-like effect, which results in impulsivity and increases the desire for more alcohol.
It remains to be learned whether behavioral sensitization occurs to these effects. Repeated exposure to classical stimulant drugs leads to increased motor and rewarding response. Cross-sensitization occurs across stimulants and between stimulants and severe stressors, which has implications for the effects of PTSD on later development of psychiatric symptoms. Sensitization and motor effects are measured, but rewarding effects also become sensitized. Both dopamine and NE are required for behavioral sensitization, along with excitatory amino acid receptors. Considerable inter-individual variation occurs.
Behavioral sensitization by ethanol has been reported, but the mechanism remains elusive. Sensitivity in some strains of mice is predicted by behavioral impulsivity, prior to alcohol administration, and responses to novelty. Rats sensitized to stimulants have increased drinking. Rats with larger behavioral responses to novelty also may be sensitized to alcohol, whereas rats that have smaller responses are not. Motor sensitivity also is associated with increased alcohol-induced aggression; mu-opioid antagonists inhibit sensitization to ethanol; and cross-sensitization occurs with cocaine, stressors, and nicotine, possibly related to development of more addictive patterns of drug use. Catecholamine sensitization to stimulants and ethanol require the same neurotransmitters and have the types of interactions described.
Dr. Swann stated that susceptibility to the stimulant and sedative effects of alcohol varies widely in terms of genetics, developmental stage, and personality characteristics. Sensitivity to the activating versus sedating effects of alcohol may change at different rates at different developmental stages. The mu-opioid receptor and the protein kinase C systems have been studied. Sensitization by a previous stressor, stimulant, or alcohol sensitizes to the others. Pharmacological treatment can differentially affect the activating and sedating responses to alcohol.
To address the problem of early consequences of alcohol, it is necessary to develop treatments for binge drinking, both pharmacological and nonpharmacological, that target some of the mechanisms described. In addition, it would be helpful to be able to identify at-risk individuals to determine who might make the transition to hazardous drinking and to identify prodromal signs of risk in individuals who would benefit from prevention interventions.
Dr. Swann summarized his presentation: Acute alcohol has stimulant-like effects in humans and other animals, although they are variable. Alcohol has a biphasic stimulating and sedating effect in part related to NE. The stimulant-like effects of alcohol appear to undergo behavioral sensitivity. Although relatively difficult to measure, it is fairly robust under certain circumstances. Stimulant‑like effects may be involved in binge drinking and in the early development of severe alcohol‑related problems.
Discussion: To a question from Dr. Mitchell, Dr. Swann commented on the potential role of caffeine when added to alcohol, noting the irony that people who are intoxicated and drink caffeine to sober up may sober up the wrong aspects of alcohol’s effects. Stimulants and caffeine in high enough doses cross-sensitize with other stimulants and with alcohol in certain strains of mice. Caffeine does nothing for sedation, because inhibitory and stimulatory effects have different mechanisms, but is likely to increase activation and impulsivity associated with alcohol, and alcohol prolongs the duration of caffeine’s action.
Consideration of the May 2007 Minutes and Future Meeting Dates
Council members voted unanimously to approve the minutes of the Council meeting of May 23-24, 2007. Dr. Abraham Bautista announced that upcoming Council meetings will take place on February 6-7, 2008; June 4-5, 2008; September 17-18, 2008; February 4-5, 2009, June 10-11, 2009, September 16-17, 2009; and February 3-4, 2010, June 9-10, 2010, September 15-16, 2010.
Judge James W. Payne offered his observations to the Council as his 4-year term ended. After 20 years on a juvenile court bench, he now manages a large State child protection agency that struggles annually with funding to improve the system under increasingly difficult and complex circumstances. His agency is examining new ways to improve the system.
Judge Payne pointed out the connection between his State system and NIAAA: 75 percent of abuse and neglect of children is linked to alcohol and drugs; close to 70 percent of abused children are under age 5; and most neglect fatalities are children under age 1. He asserted that the issue of research links critically to protecting young children, inasmuch as alcohol and drugs are associated with about 15,000 confirmed cases annually of abuse and neglect in Indiana . He encouraged his colleagues in their efforts to make an impact, particularly on judicial and child protection systems. He emphasized the fact that many people in responsible positions are unaware of the research and raised the issue of trying to return children to parents unlikely to resolve their problems. He urged Council members to share data and other information with State officials and to participate in conferences with judges and others in authority. Council members may under-estimate the impact they can have.
Dr. Li responded that Council includes members from diverse backgrounds who are not scientists, an arrangement that is mutually beneficial. Many of the populations NIAAA serves by its research are in the criminal justice system. The problems that alcohol causes in terms of family and children’s services are very large. He emphasized that NIAAA must engage community collaboration in conducting research in criminal justice settings. Services research translates basic to clinical science and clinical science to the community. Without engaging the community as partners, services research does not work.
Gen. Dean noted that neither the people of the U.S. nor government at any level have acknowledged the extent of alcohol and drug problems in the country sufficiently to allocate adequate resources to address them. Dr. Li responded that before he became NIAAA director, he focused on that issue as part of the Alcohol Center Outreach Program, working to disseminate knowledge to the Justice Department and providers in the judiciary and correctional systems. He acknowledged the difficulty of the task, recognizing that, as a research Institute, NIAAA must disseminate its findings to the public. NIAAA has established working relationships with the Justice and Defense Departments, but tangible results will take a long time.
Liaison Representative Reports and Public Comment
Judy Galloway, National Association of Children of Alcoholics (NACA), described selected products and activities. In collaboration with NAADAC, NACA recently developed a curriculum program for spiritual care giving based on a larger curriculum and toolkit. NACA now trains in the curriculum Celebrating Families and has worked with SAMHSA on the publication “Help is Down the Hall,” about children getting help through schools. She stated the importance of student assistance programs in schools. Another NACA project developed with SAMHSA is a handbook for clergy on addiction. Ms. Diane Miller stated that NIAAA’s and NACA’s Web sites are linked.
Mary Dargan, Alcoholics Anonymous, offered her services as a resource.
Dan Vincent, M.D., American Academy of Family Physicians, identified the need for additional research to make alcohol problems easier to identify and manage, and to learn how to fit attention to alcohol problems into primary care practice. He stated his hope that his colleagues in medicine will continue to submit research proposals. Dr. Li concurred with the need for refinement of best approaches to screening and noted the need for physicians’ offices to adopt best practices. He stated that brief interventions may be conducted by nonphysicians under physicians’ auspices. Dr. Li invited additional conversation with Dr. Vincent, particularly about updating the curriculum for primary care physicians.
Brandon Busteed, founder and CEO of Outside the Classroom, an organization that focuses on college binge drinking prevention, stated that his organization and its partners—American Council on Education, Association of Governing Boards, National Association of Student Personnel Administrators, United Educators, and the Gordy Foundation—plan to launch the first-ever Presidential Leadership Award for addressing college binge drinking. A $50,000 cash prize will be donated to a college or university. Dr. Li offered to collaborate in a public awareness effort.
Amy Pollack, Association for Psychological Science expressed appreciation for NIAAA’s continued commitment to psychological and behavioral research.
Nicolette Stephens, Al-Anon Family Groups, stated that the group’s recent membership survey appears at www.alanon.org. The survey covers the range of effects of alcoholism on friends and family of alcoholics. Ms. Stephens expressed interest in attaching a survey about the usefulness of the instrument and solicited input about future questions for the survey. Dr. Li stated that the Branch of Communications and Liaison at NIAAA would work with her on this project.
Mimi Fleury, president and co-founder of Community of Concern, which educates parents and builds parent partnerships to keep youth free of alcohol and other drugs, expressed appreciation to Dr Ralph Hingson, Dr. Vivian Faden, Dr. Patricia Powell, and Fred Donodeo for their leadership on underage drinking, and to Dr. Li for his support of outreach initiatives and encouragement of scientists to translate research into lay terms for parents to help their children.
Kim Crump, Alcohol Policies Project, Center for Science in the Public Interest, raised questions related to underage drinking. Dr. Li responded that although NIAAA supports research on alcohol advertising issues, the nature of NIH-supported projects depends on proposals initiated by investigators and by peer review. Recent publications have indicated results in this area, including a complex longitudinal study. NIAAA cannot address brand preferences, a marketing issue irrelevant to the science or effects of alcohol. Ms. Crump noted that the American Association for the Advancement of Science has a project with NIAAA to educate middle-school children on the benefits of moderate drinking, which could contradict evidence-based prevention messages. Dr. Li responded that the goal of the grant to the well-respected association is to teach about alcohol metabolism, the excitatory and inhibitory effects of alcohol, and how alcohol affects the brain. He emphasized the importance of presenting a balanced picture—not just that alcohol is harmful—to enable young people to make choices based on risk assessment and the science. Dr. Mitchell explained that science should be taught in a factual manner and does not imply encouragement to engage in certain behaviors. Ms. Crump suggested monitoring the grant to ensure best practices are used. Dr. Willenbring added that risk analysis and decision making are consistent with evidence-based practices in middle-school education. Ms. Crump urged NIAAA to ensure that the curriculum conforms to prevention goals. Dr. Li stated that NIH ensures that grantees do what they promise throughout the grant cycle—peer review, annual reports, and final report. Grantees demonstrate outcomes, and requests for continuation funding are reviewed by peers.
Dr. Li adjourned the meeting at 2:08 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Ting-Kai Li, M.D.
National Institute on
National Advisory Council on
Abraham Bautista, Ph.D.
Extramural Project Review Branch
National Advisory Council on
Prepared: February 21, 2008