DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

163rd Meeting of the

NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM

May 9, 2023

The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened its 163^rd meeting at 11:04 a.m. on Tuesday, May 9, 2023, in hybrid format, i.e., both in-person and via Zoom videoconference. The Council met in closed session from 10:00 a.m. to 10:45 a.m. to review grant applications and cooperative agreements. Dr. Philippe Marmillot, Acting Director of the Office of Extramural Activities, presided over the Council’s review session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. The closed session recessed at 10:45 a.m.

Council Members Present:

Nancy Barnett, Ph.D.
Andrew MacGregor Cameron, M.D., Ph.D.
Christopher S. Carpenter, Ph.D.
Christina Chambers, Ph.D.
H. Wesley Clark, M.D., J.D.
Beth Kane-Davidson, LCADC, LCPC
David Kareken, Ph.D.
Charles H. Lang, Ph.D.
Mary E. Larimer, Ph.D.
Michael J. Lewis, Ph.D.
Laura E. Nagy, Ph.D.
Laura O’Dell, Ph.D.
Katie Witkiewitz, Ph.D.

Ex-Officio Members

Col. Charles S. Milliken, M.D.

NIAAA Director and Chair: George F. Koob, Ph.D.

NIAAA Deputy Director: Patricia Powell, Ph.D.

Acting Executive Secretary: Ranga V. Srinivas, Ph.D.

Senior Staff: Vicki Buckley, M.B.A.; Ralph Hingson, Sc.D.; M. Katherine Jung, Ph.D.; Raye Litten, Ph.D.; David Lovinger, Ph.D.; Phillipe Marmillot, Ph.D.; Antonio Noronha, Ph.D.; and Bridget Williams-Simmons, Ph.D.

Other Attendees at the Open Session

Approximately 200 people observed the meeting, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

Call to Order

NIAAA Director Dr. George F. Koob called the open session of the Council meeting to order at 11:04 a.m. on Tuesday, May 9, 2023. Council members and NIAAA senior staff introduced themselves.

Director’s Report

Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.

In Memoriam. Dr. Koob announced the passing of three eminent leaders in the alcohol research field: George Fein, Ph.D., University of California San Francisco, the San Francisco VA Medical Center, and Neurobehavioral Research, Inc.; John Littleton, M.D., Ph.D., University of Kentucky; and Enoch Gordis, M.D., former Director of NIAAA (1986-2001).

NIAAA Budget. Since 2014, NIAAA’s annual budget has increased steadily. For Fiscal Year (FY) 2023, NIAAA received $596.6 million, including a $1.3 million AIDS transfer. This represents a $21.7 million increase (3.8 percent) over FY 2022. 

NIAAA Funding Opportunities. Dr. Koob announced two new Funding Opportunity Announcements (FOAs) from NIAAA:

• Advancing mHealth Interventions for Understanding and Preventing Alcohol-Related Domestic Violence (NOT-AA-23-003): This Notice seeks to advance the development, testing, and implementation of scalable, low resource, and remotely delivered interventions via mobile devices (mHealth) that rely on communication technologies for reducing and preventing alcohol consumption and domestic violence.
• HIV Prevention and Alcohol (NOT-AA-23-005 [R01 Clinical Trials Optional], NOT-AA-23-006 [R34 Clinical Trials Optional]): NIAAA intends to publish a new Notice of Funding Opportunity (NOFO) to solicit applications to expand the HIV/AIDS prevention toolkit among alcohol-impacted populations with a range of patterns of episodic and long-term use and associated behavioral and biological risks for HIV acquisition. The Notice of Funding Opportunity (NOFO) is expected to be published in Spring 2023.

A full list of FOAs and Notices of Special Interest (NOSIs) may be found in the NIAAA Director’s Report.

NIH Science and Technology Research Infrastructure for Discovery, Experimentation, and Sustainability (STRIDES). STRIDES is a new initiative to provide discounts and favorable pricing on computing, storage, and related services from Amazon Web Services, Google Cloud Platform, and Microsoft Azure, as well as consultation, technical support, training, and certification. The NIAAA Data Archive is supported by the STRIDES Initiative. NIAAA-supported researchers may contact NIAAA representatives Dr. Dan Falk and Dr. Elizabeth Powell with questions about the new service.

 Request for Information (RFI) on “Preaddiction.” The National Institute on Drug Abuse (NIDA) and NIAAA issued an RFI inviting input on the use of a term such as “preaddiction” for identifying and intervening in substance misuse and mild/early-stage substance use disorder within healthcare settings. The term “preaddiction” has been proposed to raise public awareness about potentially harmful patterns of substance use, spur greater utilization of screening and brief intervention, prevent overdose, and promote the development of new interventions. The RFI sought input both on the concept’s terminology and the concept itself. The RFI closed on April 27, 2023. Feedback is being analyzed. 

Recent NIAAA Scientific Meetings. Dr. Koob highlighted two recent scientific meetings sponsored by NIAAA: 1) The Annual Public Meeting of the Interagency Coordinating Committee on Fetal Alcohol Spectrum Disorders (ICCFASD) was held virtually on April 17, 2023. Participating federal agencies provided updates on their activities related to FASD; 2) The Interagency Work Group on Drinking and Drug Use in Women and Girls held a webinar on March 10, 2023, focused on research findings from epidemiological and neuroscience research, including developments in behavioral treatments and pharmacotherapies for women who drink at harmful levels.

Diversity, Equity, Inclusion, and Accessibility Efforts. Ongoing NIAAA efforts within this domain include recruitment of a Scientific Diversity Officer, expected to be completed in the next few weeks.  The funding opportunity Research Opportunities for New and "At-Risk" Investigators to Promote Workforce Diversity (PAR-22-181) will support R01 grant applications from New Investigators and At-Risk Investigators from diverse backgrounds, including those from groups underrepresented in the health-related sciences. NIAAA continues to participate in the “Maximizing Opportunities for Scientific and Academic Independent Careers” (MOSAIC) Program to increase diversity in the alcohol research field. In 2022, NIAAA announced its support for three new MOSAIC scholars: Josiah Hardesty, Ph.D., University of Louisville; Gabriela Lopez, Ph.D., Brown University; and Laura C. Ornelas, Ph.D., University of North Carolina Chapel Hill.

What’s Ahead? Dr. Koob reported that he and Dr. Noronha will attend the “Alcoholism and Stress: A Framework for Future Treatment Strategies” meeting on May 16 - 19, 2023, in Volterra, Italy. He also announced a National Institute on Aging (NIA)-NIAAA joint workshop on July 26 - 27, 2023 to identify research gaps and challenges related to the impact of alcohol misuse on the onset and progression of Alzheimer’s disease and related dementias.

 Communications Update. In recognition of Alcohol Awareness Month in April, NIAAA shared social media messages and engaged in a Twitter chat with the American Society of Addiction Medicine about alcohol myths and treatment. NIAAA launched a major update to Alcohol Facts and Statistics, a popular online resource which consistently ranks among the most viewed NIAAA webpages. The update includes recent alcohol statistics, expanded demographic information, and improved readability and navigability. 

Research Highlights. Dr. Koob presented highlights of alcohol-related research suggested by NIAAA divisions and the intramural program that represent the breadth of NIAAA-supported research:

“Initiation of and Escalation to High-Intensity Drinking in Young Adults” was published in JAMA Pediatrics (2023 Mar 1;177(3):286-293. PMID: 36716022) by ME Patrick, RJ Evans-Polce, BJ Arterberry, and Y Terry-McElrath. High-intensity drinking (HID), defined as consuming 10 or more drinks in a row, is a particularly concerning drinking behavior. This study used a sample of 451 young adults who reported past 30–day drinking while in 12th grade and initiated HID by age 20. Initiating HID by grade 11 (vs later) was associated with higher average weekly alcohol consumption, HID frequency, and Alcohol Use Disorders Identification Test (AUDIT) score at age 20 years.

“Candida Albicans-specific Th17 Cell-mediated Response Contributes to Alcohol-associated Liver Disease” was published in Cell Host & Microbe (2023 Mar 8;31(3):389-404. PMID: 36893735) by S. Zeng, E Rosati, C Saggau, B Messner, H Chu, Y Duan, P Hartmann, Y Wang, S Ma, WJM Huang, J Lee, SM Lee, R Carvalho-Gontijo, V Zhang, JP Hoffmann, JK Kolls, E Raz, DA Brenner, T Kisseleva, S LeibundGut-Landmann, P Bacher, P Stärkel, and B Schnabl. Alcohol-associated liver disease (ALD) is accompanied by an imbalance of the intestinal fungal microbiome (mycobiome dysbiosis). Proinflammatory cytokines, such as IL-17, produced mainly by T helper 17 (Th17) lymphocytes, are a contributing factor to autoimmune and inflammatory conditions. This report found that T-helper 17 cells reactive to the yeast Candida albicans increase in the blood and liver of patients with ALD. In a mouse model, data showed that molecular activation of T-cells reactive to Candida developed more severe ethanol-induced liver disease and an antifungal agent decreased ethanol-induced liver disease. Results suggest that Candida albicans-reactive T helper 17 cells migrate from the intestine to the liver, where they contribute to the development of ALD.

“Preclinical and Clinical Evidence for Suppression of Alcohol Intake by Apremilast” was published in the Journal of Clinical Investigation (2023 Mar 15;133(6):e159103. PMID: 36656645) by KB Grigsby, RA Mangieri, AJ Roberts, MF Lopez, EJ Firsick, KG Townsley, A Beneze, J Bess, TK Eisenstein, JJ Meissler, JM Light, J Miller, S Quello, F Shadan, M Skinner, HC Aziz, P Metten, RA Morrisett, JC Crabbe, M Roberto, HC Becker, BJ Mason, and AR Ozburn. Phosphodiesterases are a superfamily of enzymes that hydrolyze the cyclic nucleotides cAMP and cGMP. Apremilast is a phosphodiesterase type 4 (PDE4) inhibitor and currently U.S. Food and Drug Administration (FDA)-approved for the treatment of psoriasis. Via PDE 4 inhibition, apremilast elevates intracellular cAMP levels, which is thought to decrease levels of some pro-inflammatory mediators and increase the production of certain anti-inflammatory mediators. Apremilast reduced excessive alcohol intake in preclinical animal models and in non-treatment-seeking humans with alcohol use disorder (AUD) in a double-blind, placebo-controlled Phase 2a study.

“Chemosensory Alterations and Impact on Quality of Life in Persistent Alcohol Drinkers” was published in Alcohol (2023 Jan 9;58(1):84-92. PMID: 36208183) by K Agarwal, JW Luk, P Manza, C McDuffie, L To, RB Jaime-Lara, BL Stangl, ML Schwandt, R Momenan, D Goldman, N Diazgranados, VA Ramchandani, and PV Joseph. In this study from NIAAA’s intramural research program, researchers observed a significant impairment in smell ability of heavy drinking individuals compared to non-drinking individuals, and the impairment was associated with a deterioration in physical, psychological, social, and environmental quality of life. Early assessment of smell function in individuals with AUD may help predict disease-associated comorbidities, especially in quality-of-life domains.

“Additive Effects of Stress and Alcohol Exposure on Accelerated Epigenetic Aging in Alcohol Use Disorder” was published in Biological Psychiatry (2023 Feb 15;93(4):331-341. PMID: 36182531) by J Jung, DL McCartney, J Wagner, J Yoo, AS Bell, LA Mavromatis, DB Rosoff, CA Hodgkinson, H Sun, M Schwandt, N Diazgranados, AK Smith, V Michopoulos, A Powers, J Stevens, B Bradley, N Fani, RM Walker, A Campbell, DJ Porteous, AM McIntosh, S Horvath, RE Marioni, KL Evans, D Goldman, and FW Lohoff. Stress contributes to premature aging and susceptibility to AUD; AUD itself is a factor in premature aging. To better understand the interrelationships between stress, AUD, and premature aging, this study used high density methylome arrays and telomere length assays in a deeply phenotyped sample of patients from the NIAAA intramural program. The present study showed that the combination of stress and heavy alcohol use additively accelerated epigenetic cellular age by about 4.5 years. The finding was replicated in external samples from the Grady Trauma project and Generation Scotland. Epigenetic age correlates highly with chronological age but accelerated epigenetic age due to factors such as combined stress and AUD likely increases the risks of morbidity and mortality.

“Neuroimaging-Derived Predicted Brain Age and Alcohol Use Among Community-Dwelling Older Adults” was published in the American Journal of Geriatric Psychiatry (2023 Feb 20:S1064-7481(23)00217-8. PMID: 36925380) by M Funk-White, D Wing, LT Eyler, AA Moore, ET Reas, and L McEvoy. Evidence indicates that alcohol misuse among older adults contributes to accelerated aging in certain brain regions and impaired cognitive function, learning, memory, and motor function. In this study, researchers found that heavier drinkers (defined here as >14 drinks per week) showed older brain predicted age differences (brain-PAD) than light drinkers (by about 6 years). Brain-PAD is the difference between the brain-predicted age and chronological age based on neuroimaging data. The brain-PAD among light and moderate drinking older adults did not differ from their nondrinking counterparts, suggesting no protective benefit of alcohol on brain aging. These results support the growing body of evidence that alcohol misuse contributes to accelerated neurodegeneration among older adults.

Council Discussion

Dr. Koob asked Dr. Lovinger to comment on increased stipends for intramural researchers. Dr. Lovinger explained that NIH Institute and Center (IC) directors agreed to increase stipends to the maximum amount by the end of the current fiscal year to help post-baccalaureate, pre-doctoral, and post-doctoral fellows meet the high cost of living in the metropolitan Washington, DC area. Dr. Powell noted that the increase is also a matter of equity; NIH does not want to marginalize those whose parents cannot afford to support them. Dr. Koob concurred that equity was a major consideration for NIAAA on this issue.

Dr. Kareken asked why NIAAA’s Research Program Grant (RPG) level is lower than the Institute’s 30 percent budget increase. Dr. Koob explained that the cost to conduct research is increasing due to inflation and that grants are generally larger than they were previously. Other factors, such as the increased cost to include both male and female animals in studies in compliance with NIH’s Sex as a Biological Variable (SABV) requirement, also have an impact. Dr. Jung suggested that another possible explanation is that R01 grants cover a five-year period and the number of R01s increases each year. Dr. Koob stated that another contributor may be that NIAAA seeks to fund early-stage investigators at the 25^th percentile and has been fully successful in achieving that goal. Dr. Noronha observed that his Division of Neuroscience and Behavior has experienced a tremendous increase in R21 grants and wondered if Dr. Kareken was only considering R01s. Ms. Buckley noted that NIAAA has increased support for K awards and that costs for insurance, overhead, and assessments from NIH for the Centralized Animal Procurement System (CAPS) have gone up significantly. Dr. Williams-Simmons interjected that the RPG pattern noted by Dr. Kareken was for R01 awards, noting that other expenses such as those cited by Ms. Buckley are also included in the NIAAA budget. Dr. Koob stated that NIAAA has not embarked on new large-scale ancillary programs but supports Centers that focus on specific areas such as epigenetics or the microbiome. The Centers program has been capped for many years.

Dr. Koob, noting that he has challenged Dr. O’Dell with tracking SABV efforts following the retirement of former Council member Dr. Jill Becker, asked for her comments on studies highlighted in the Director’s report. She noted that data in the animal studies had not been disaggregated by sex. Dr. Koob commented that NIAAA now includes both males and females in animal studies and uses the male/female symbol on data so that readers can identify differences. Dr. Clark asserted that research should deal with racial/ethnic differences in addition to sex differences. He noted that the brain-PAD study did not examine differences by race/ethnicity, nor did it find any protective or negative effects of light to moderate drinking. He observed that people are looking for simple solutions to complex behavior. Dr. Koob noted that the number of participants in a study is often too small to tease out the relative impacts of race and culture. More research into the cultural appropriateness of various metrics is needed to assure they are actually measuring concepts correctly. Dr. Koob also pointed out that controversy still swirls around any beneficial effects of alcohol at low doses. He asked Dr. Aaron White, Senior Scientific Advisor to Dr. Koob, to comment. Dr. White replied that it’s not moderate drinking that’s healthy, but moderate people. Those who can stop at one glass of wine tend to exercise more, eat more healthfully, and are more educated. When light drinkers are used as a control and adjustments are made for body mass index (BMI) and socio-economic status (SES), what appears to be the beneficial effects of low drinking disappear. The risks of harm from alcohol start at one drink or less per day. Dr. Clark responded that the issue of wealthier people being more moderate than non-wealthy people raises significant equity issues. It is easy to distort data based on SES, as people of color are often denied access to opportunities of society. Dr. Jinhui Zhao’s paper in JAMA Network (March 2023) indicated that there is a J curve for low to moderate drinking with cardiovascular problems. The article did not focus on those benefits, however, but on alcohol’s negative effects. The alcohol research field loses community because people see empirically that wealthier people have greater latitude with their social behaviors. That creates tension between those who have and those who have not. It also calls into question the legitimacy of the academy and its objectivity. Dr. White agreed, noting that there is often insufficient data to look at differences by race or sexual identity and that aggregated data often disguises more subtle trends. He noted that NIAAA’s revised Alcohol Facts page has data broken down on a more granular level than in the past. Dr. Williams-Simmons thanked Dr. Clark for giving the Institute new ideas about how to approach data and different questions to ask.

Dr. Witkiewitz, noting that the term “preaddiction” may be stigmatizing, asked for more information about the number of comments to the NIDA/NIAAA RFI and how the possibility of increasing stigma is being considered. Dr. Koob responded that there may be better terminology, but the goal is to capture early onset of addiction. Dr. Chambers interjected that preaddiction may be the wrong term and may be stigmatizing but it is important for targeting women of reproductive age who may experience unplanned pregnancies. Dr. Koob reported that there will be a work group at the scientific meeting of the College on Problems of Drug Dependence to discuss the concept. He asked Dr. Williams-Simmons to update Council on the RFI. She responded that about 80 responses had been received and will be analyzed by the NIAAA and NIDA policy branches.

Dr. Milliken said that military substance use treatment programs were originally designed to control substance use problems in the ranks rather than to help soldiers; individuals were reluctant to report a substance use problem to a commander who could order treatment because it might hurt the person’s career. Today, the military has implemented a successful voluntary treatment option that has been well-received, with approximately 40 percent of those in treatment using this pathway.

 Council Member Presentation: From Harm Reduction to Recovery

Dr. Koob introduced Council Member Dr. Katie Witkiewitz, University of New Mexico, who presented “From Harm Reduction to Recovery: Drinking Reductions and Precision Medicine as Part of a Broader Public Health Approach to Reducing Alcohol-Related Harm.” She noted that a 2018 Lancet article reported that even one standard drink has a negative effect on morbidity and mortality. It’s important to acknowledge as a starting point that when an individual drinks alcohol, he or she is knowingly putting a toxic substance into the body. Alcohol use is one health behavior choice, among many, that people make for themselves. Abstinence from alcohol is harm reduction and one successful pathway to recovery. However, few people achieve continuous abstinence and many individuals with AUD who seek treatment do not want to abstain or avoid treatment for this reason. Therefore, reductions in drinking may be a more desirable outcome for more people with greater public health benefit.

Drinking Reductions. Research by Dr. Witkiewitz and others has demonstrated empirically that drinking reductions—short of abstinence—are achievable, sustainable, and associated with improved health and function. These findings provide the basis for a positive motivational message to the public, i.e., one can reduce health risks by reducing drinking without quitting altogether, as well as offering a springboard for the development of treatments.

In 2000, the World Health Organization (WHO) published risk levels of drinking for males and females that categorize risk into low, medium, high, and very high risk based on the quantity of alcohol consumed daily and weekly. This provides a useful metric for patients and providers to determine the level of risk the individual is willing to assume. Researchers within the Alcohol Clinical Trials Initiative group have sought to validate this guidance, discovering that reductions in WHO drinking risk levels are associated with a reduced risk of AUD and AUD remission; fewer drinking consequences and better mental health; decreases in craving; improvements in quality of life, blood pressure, and liver function; reduced risk of liver disease, depression, and anxiety disorders; medication treatment effects; and reductions in health care costs. Reductions in drinking levels achieved have remained stable over time. AUD severity does not moderate these effects in health, functioning, and stability over time.

Recovery. Dr. Witkiewitz and Jalie Tucker, Ph.D., University of Florida, published Dynamic Pathways to Recovery from Alcohol Use Disorder (2022) that examined recovery more broadly than simply alcohol use. The book includes empirical work that examined latent levels of recovery 3-years-post treatment using data from the Project MATCH and COMBINE studies of both pharmacological and behavioral therapies. Over one-half (51 percent) of the two samples were functioning very well and either not drinking much or abstaining. About 15 percent were doing poorly. The middle two groups (low functioning/infrequent heavy drinking, and high functioning/heavy drinking)—both around 15-19 percent—continued some heavy drinking. Those who were high functioning at 3-year post-treatment, maintained function for at least a decade post-treatment, as indicated by significantly greater purpose in life, less depression, and lower anger (Project MATCH) and higher self-reported health and fewer hospital stays (COMBINE). These findings confirm that functioning is an important outcome for recovery. There is a group that can maintain high functioning and high-quality health, even while continuing to drink.

Precision Medicine. Precision medicine is tailoring approaches to the specific needs and individual characteristics of each patient. These may include genotypic approaches in which specific genotypes that respond to specific treatments are identified (e.g., OPRM1 and naltrexone, GRIK1 and topiramate, 5-HT(3) and ondansetron, and GABRA2 and 12-step facilitation) or phenotypic approaches in which specific patient characteristics that respond to specific treatments are identified. The latter approach needs more attention, as many clinics will not have the capacity to genotype patients.

Dr. Witkiewitz’s lab has been developing precision medicine approaches to AUD treatment using phenotypes grounded in the addiction cycle developed by Dr. Koob and his colleagues. Per the model, there appears to be different types of drinking based on different neuro-biological adaptations and dysfunction: For people in the cravings/reward seeking phase, drinking may be maintained by positive reinforcement; in the withdrawal/negative affect stage, drinking is based more on negative emotionality and seeking relief from negative experiences; in the preoccupation/anticipation phase, there are deficits in executive function and a loss of control over drinking. Dr. Witkiewitz and her colleagues adapted a 10-item measure based on the abstinence self-efficacy scale and--after some psychometrics and factor mixture modeling—successfully used it to identify reward and relief drinking phenotypes. Most recently, they have added executive function deficits, testing a 15-item measure that predicted the reward, relief, and loss of control domains of the addiction cycle.

Do these phenotypes work for precision medicine? Previous research suggested that individuals with alterations of the opioidergic system and who drink alcohol primarily in the context of positive reinforcement may benefit more from naltrexone. Working with Dr. Karl Mann, Dr. Witkiewitz and her colleagues have seen small effect sizes for the total sample across three separate naltrexone vs. placebo studies. Among reward drinkers, however, naltrexone was shown to have a large effect that is mediated by reductions in the desire to drink, i.e., it works to relieve cravings, as it is designed to do. The investigators have also looked at relief drinking. Earlier studies demonstrated that individuals with alteration of the glutamatergic system and who drink primarily in the context of negative reinforcement may benefit more from acamprosate. In the single acamprosate vs. placebo study conducted to date by Dr. Witkiewitz’s lab, no effect was found in the total sample, but a small effect was observed among the relief drinkers. Dr. Witkiewitz’s lab has also begun investigating behavioral therapies. In a new study about mindfulness-based relapse prevention, it developed a relief drinking scale at baseline and then looked at heavy drinking days at 12-month follow-up. In the treatment-as-usual condition, they found a strong positive correlation between relief drinking and heavy drinking. In the mindfulness-relapse prevention condition, there is an almost total attenuation of that effect.

Addiction Cycle Domains and Recovery. Research—based on a 15-item questionnaire administered at baseline--suggests these phenotypes based on the addiction cycle can successfully predict recovery three years later. In particular, those who are higher on the reward/incentive salience dimension (i.e., generally less severe AUD) have higher odds of achieving recovery at three-years post-treatment. Similarly, those with lower relief/negative affect also have a higher likelihood of success. There was little effect for those with loss of control/executive function deficits. What is important from a clinical/translational perspective is the fact that a 15-item questionnaire can predict recovery success. However, the social environment also plays an important role. For example, some studies have shown that those with high SES enjoy a higher likelihood of successful recovery, as do those who live in neighborhoods with higher levels of health insurance. It’s important to acknowledge that people drink and recover within an environmental context.

Future Studies. Dr. Witkiewitz expressed optimism about using the WHO drinking levels as endpoints for clinical trials. She and her colleagues are striving to develop patient-oriented measures for the addiction cycle domains that are consistent across demographic and sociodemographic groups. Noting that all research to date has used retrospective data, Dr. Witkiewitz’ lab has launched a new prospective study with naltrexone. Finally, further research is planned on the effectiveness of mindfulness-relapse prevention for those with impaired executive function who also drink for both relief and reward. Dr. Witkiewitz concluded by thanking NIAAA for leading the field with its new definition in recovery. She identified the need for empirical studies of the new definition, especially studies that target whole person health and attend to broader behavioral change. Finally, she recommended that investigators examine social determinants of health (SDOH) when studying individual-level outcomes and consider environmental factors when examining alcohol use behaviors in translational models.

Intramural Presentation: Alcohol, Aging, and Epigenetic Clocks

Dr. Koob introduced Dr. Falk W. Lohoff, Chief, Section on Clinical Genomics and Experimental Therapeutic (CGET), Division of Intramural Clinical and Biological Research, NIAAA, and Lasker Clinical Research Scholar. Dr. Lohoff introduced the topic by noting that alcohol is associated with premature aging. AUD has been associated with age-related morbidities and often leads to premature death. However, the underlying biological mechanisms of aging in AUD are largely unknown. Understanding more about alcohol’s impact on aging is important because aging poses major challenges to the health care system as people develop chronic diseases that are both expensive to treat. For example, delaying aging by only 20 percent is estimated to save the US $3 trillion in Medicare/Medicaid spending in the next 50 years, while a one-year slowdown in aging would create $38 trillion in economic benefits.

Aging and Alcohol. Key questions confronting the field about aging and alcohol include:

• What is the effect of a modifiable risk factor – alcohol – on aging?
• How can we measure alcohol’s effect on biological aging?
• What is a good biomarker that tracks aging?

DNA methylation (a methyl group addition to the cytosine carbon 5 in cytosine-phosphate-guanine [CpG]) is a biomarker of aging. Methylation can be measured in over 850,000 methylation sites across the genome at the same time. Epigenetics can be defined as changes in gene expression that do not arise from DNA sequence changes. Epigenetic age can be estimated by DNA methylation levels at certain CpG sites which are correlated with age. There are several iterations of different epigenetic clocks to predict aging using various CpG sites identified in tissue and/or blood samples. As they have evolved, these clocks have become more refined and accurate. Some can predict mortality risk, some lifespan, some health span, and some phenotypic age.

Dr. Lohoff and his colleagues used one of these epigenetic clocks, Horvath’s Pan Tissue Clock, in a small pilot study of individuals with AUD using blood and liver samples. Analysis of both samples found that DNA methylation age is accelerated in alcohol dependence. The researchers sought to confirm these findings with a sample five times larger (N=532) than in the pilot study, consisting of individuals with severe AUD (12+ drinks/day). Using the Levine Age Acceleration Clock, they found again that those with AUD had robust age acceleration compared to mild deceleration in the controls. After controlling for smoking and BMI, those with AUD were about 1.38 years older than their counterparts in the control condition. Next, the team examined those who already had organ damage or elevated liver enzymes. Those with the highest gamma-glutamyl transferase (GGT) level had about a 3-year age acceleration compared to those with the lowest GGT level.

Stress, Alcohol, and Aging. Since both stress and alcohol are known to accelerate aging, the research team turned its attention to the question: Is there an interaction between alcohol and stress or even an additive effect? The researchers designed a study in which they used a discovery cohort to develop a composite score of stress (epigenetic age acceleration) based on a factor analysis of 13 factors (e.g., anxiety, depression, and abuse) that correlated with accelerated aging, and then an epigenetic cohort to develop a methylation score of stress that tracks 211 CpGs that accurately capture stress exposure but do not correlate with aging related CpGs. They found that the higher the methylation score, the higher the epigenetic age acceleration. This was even more true among those with AUD, accounting for an almost four-year age acceleration. A comparison of methylation scores for stress and methylation scores of alcohol consumption, revealed that that the effect of alcohol and stress on aging is additive.

Next, the investigators asked: Are there additional markers of cellular aging? To answer the question, they looked at telomeres, tandem repetitive nucleotide sequences at the end of chromosomes. They protect genomic DNA against double-strand breaks and DNA end-joining and recombination. Telomeres shorten with every cell division, ultimately contributing to irreversible cell cycle arrest; thus, telomere shortening is a biomarker frequently used to indicate cell senescence. Previous research found that there are 140 CpG sites that can be used as a proxy measure of telomere length. To examine the role of telomeres, the NIAAA team evaluated whether alcohol use affected cellular aging as indicated by telomere length among one of its cohorts. The researchers discovered that telomere length was indeed shorter among those with AUD, thus confirming what is seen in the epigenetic clocks. Finally, looking at their phenotypes, the researchers found that those with the most severe AUD and those with elevated liver enzymes also had the shortest telomeres.

Mechanisms of Alcohol-associated Epigenetic Age Acceleration. What are the underlying mechanisms of alcohol-associated aging? To address this question, the NIAAA lab used a multi-omics approach, integrating genomic, epigenomic, transcriptomic, proteomic, and metabolomic data. The availability of large “omic” datasets and single cell datasets coupled with analytic tools such as genomic-wide association studies (GWAS) have made these new approaches possible. For example, Dr. Lohoff and his colleagues used FUSION, cross-tissue expression quantitative trait locus (eQTL) weights, and GWAS summary statistics to impute gene expression signatures associated with epigenetic age acceleration (EAA) and multivariate longevity. They identified 22 high confidence genetic associations with EAA. Among these, FLOT1, KPNA4, and TMX2 are novel high confidence EAA-associated genes. They also identified seven high confidence genetic associations with multivariate longevity. In general, the genes identified are involved in insulin/nutrient signaling, mitochondrial function, cellular response to stress, and metabolism. The investigators also conducted a metabolome-wide Mendelian randomization (MR) analysis of 249 circulating metabolites drawing on data from the Nightingale Health-UK Biobank metabolomic GWAS partnership’s first release (N = 115,078) to characterize the influence of circulating metabolites on EAA and multivariate longevity. The most significant effects on multivariate longevity involved non-high-density lipoprotein (non-HDL) particles and associated apolipoproteins in the pathogenesis of cardiovascular diseases^. However, no significant effects of circulating metabolites on EAA were identified.

In summary, Dr. Lohoff emphasized these key points: 1) Alcohol accelerates cellular aging and shortens longevity. The most severe phenotypes have over 4 years of age acceleration. 2) Multi-omic strategies offer new insights into the underlying biology of aging, including identification of novel genetic targets involved in immune regulation, oxidative stress, and nutrients signaling for EAA. LDL/non-HDL lipids play major roles in longevity. Finally, future studies are needed to understand the molecular mechanisms underlying alcohol’s role in aging.

Discussion. Dr. Koob kicked off the discussion with this question to Dr. Witkiewitz: Is there a need to change the scales and tests in the domain criteria models to accommodate differences in race, culture, and/or gender? Dr. Witkiewitz responded that she and her colleagues have definitely found that items do not function the same across all groups. That’s why the prospective work (including cognitive interviewing and computerized adaptive testing) that her colleague at the University of New Mexico, Cassandra Boness, Ph.D., is conducting is designed to develop measures that are as universal as possible. She believes this can be accomplished within the next five years. Dr. Koob asked Dr. Lohoff if diet affects aging. Dr. Lohoff stated that diet is a big factor, as is weight/BMI. Heavy drinkers consume a lot of unhealthy calories each day. He noted that there are probably some underlying metabolomic effects; these are currently being studied. Dr. Chambers asked Dr. Lohoff if his laboratory is looking at telomere length linearly, noting a recent report showing that long telomere length is linked to cancer. Dr. Lohoff responded that doing so is a good suggestion. Dr. Litten asked Dr. Lohoff if his group had discovered connections between their epigenetic and metabolitic findings in the multi-omics study that would suggest pathways. Dr. Lohoff said that studies are in progress to overlay these findings functionally from transcriptomics to the proteome to the metabolome. One issue is the availability of tissue; better data sets are needed. Dr. Litton observed that some epigenetic impacts may be related to dementia; Dr. Lohoff concurred.

Dr. Koob asked Dr. Witkiewitz if she has tapped into the work that Richard Weinshilboum, M.D., at the Mayo Clinic has been conducting on acamprosate and glutamatergic metabolomics. She replied that he may have data that would help them replicate their acamprosate-related phenotype studies. Dr. Williams-Simmons asked Dr. Witkiewitz if there are specific SDOH that appear to play a role among the lower-functioning individuals from the Project MATCH and COMBINE studies. Dr. Witkiewitz responded that they are working with limited SDOH data so she’s not able to fully answer that question. Income inequality was one of the biggest predictors. Other valuable predictors might include the density of alcohol outlets and amount of green space. She believes that the impact of SDOH is something the alcohol study field has missed.

Yousef Tizabi, Ph.D., a professor at Howard University, inquired if AUD can exist without stress. Dr. Lohoff, noting that this is an important question, responded that his group’s research has identified people with AUD who have low levels of stress as well as low levels of accelerated aging. Dr. Clark asked Dr. Lohoff if he had looked at methylation in low-risk drinkers. Dr. Lohoff responded that his group has only looked at extremes, but that many studies have looked at methylation at various alcohol drinking levels. As methylation increases, problems increase. If drinking is reduced, methylation’s impact on aging is most likely also reduced.

Dr. Koob asked Dr. Witkiewitz what she would say to the FDA about using a reduction in drinking as a level of success in alcohol drug treatment, e.g., is a move from high drinking to just binge drinking an inadequate measure of success? Dr. Witkiewitz responded that she would point them to data that shows convincingly that people are functioning almost as well when drinking to binge levels as are those who abstain altogether. She observed that addiction is the only disease for which the FDA requires a binary no-symptom definition. Improvement in symptoms in other diseases would get a medication approved. That’s been a disservice to medication development in the alcohol field. Dr. Litten commented that NIAAA has been working with the FDA for a long time. He observed that its goal is to evaluate drug interventions to determine if they improve outcomes, not to set policy. Dr. Clark noted that he is a proponent of contingency management which may require abstinence. However, low risk drinking in a society that still embraces some alcohol consumption is better than high-risk drinking. Dr. Witkiewitz concurred. Dr. Koob inquired if there has been a change in reimbursement for contingency management plans by the FDA. Dr. Clark replied that the decision is at the FDA Office of the Inspector General.

 Concept Clearance: Alcohol Epidemiologic Data System (AEDS) Contract Proposals

Dr. Koob introduced Dr. Brad Kerridge, Program Officer, Division of Epidemiology and Prevention Research, who presented a concept clearance for the re-competition of the current Alcohol Epidemiologic Data System (AEDS) contract with CSR, Inc. which ends on September 26, 2023. This “R&D Support” acquisition requires peer review of concept and technical proposals in accordance with 42 CFR 52h and NIH Manual Chapter 6315-1.

Background. The Alcohol Epidemiologic Data System (AEDS) is a contract-funded effort in support of the NIAAA mission to provide in-house statistical analysis and programming support for use by NIAAA staff who are conducting alcohol-related epidemiologic research to facilitate publication of secondary analyses of epidemiologic surveys and other data reports and scientific journals. The contract supports alcohol-related epidemiologic research in numerous scientific areas including but not limited to alcohol-related morbidity and mortality, alcohol-related unintentional and intentional injuries, alcohol screening and brief interventions, alcohol-related health disparities, and interactions between alcohol and lifestyle risk factors including diet, exercise, and smoking.

Surveillance Reports and Data Depository. AEDS Reports are well-established mechanisms by which researchers, policy makers, and other interested individuals track alcohol-related information over time. Surveillance reports on three topics are produced: apparent per capita consumption of alcoholic beverages, liver cirrhosis mortality, and trends in underage drinking in the United States. Sample data sets are provided for each report. The Alcohol Epidemiologic Data Directory is a report that provides a current listing of surveys and other relevant data suitable for epidemiologic research on alcohol. The contractor also warehouses hard copies of publications such as County Alcohol Problem Indicators, State Trends in Alcohol-Related Mortality, US Apparent Consumption of Alcoholic Beverages, and others.

Technical Support for Epidemiological Research. Technical support in the form of statistical analyses and programming and scientific writing are performed under the contract to support NIAAA staff in in-house research projects that result in data-related products, including data tables, and in scientific manuscripts which may be published in peer-reviewed journals. Examples of data sources frequently used by NIAAA staff include but are not limited to: US population surveys and vital statistics; US traffic data; US Census Data; local, state or regional surveys of alcohol; WHO data; and NIAAA Alcohol Policy Information System data (APIS).

Discussion. Dr. Kareken inquired if the datasets are available to extramural researchers. Dr. Williams-Simmons responded affirmatively, noting that many AEDS reports and datasets are available on the NIAAA website. Dr. Kareken followed up by asking if there are formal procedures for gaining access to the dataset. Dr. Kerridge responded that questions about access could be directed to him privately.

 Action. Drs. Barnett and Lewis endorsed the AEDS concept.

Concept Clearance: FY24 HEAL Initiative Concept, Developing an Evidence Base for Co-Occurring OUD-AUD Interventions

Dr. Koob introduced Dr. Mark Egli, Deputy Director, Division of Neuroscience and Behavior, who began his presentation with an overview of the Helping to End Addiction Long-Term (HEAL) initiative at NIH.

Highly intervention-oriented, HEAL’s focus is on safe and non-addictive pain treatment options; new, repurposed, and reformulated therapeutics across the opioid addiction cycle; reduced risk for addiction, chronic pain, and suicide; effective and sustainable prevention and treatment strategies; evidence-based interventions at work in communities; and healthy developmental paths for babies exposed to opioids. NIAAA’s interests are closely aligned with HEAL. Firstly, opioids and alcohol are a potentially lethal mix: The number of opioid overdose death to which alcohol contributed has increases. Opioid agonist therapies (OAT) are contraindicated for people actively drinking alcohol and standard AUD medications (benzodiazepines, naltrexone) have potentially negative interactions with opioids. Secondly, alcohol causes pain which can motivate drinking. Approximately 50 percent of individuals with AUD report chronic pain conditions. Binge-level alcohol doses alleviate pain. However, long-term alcohol use increases pain and negatively affects severity.

Developing an Evidence Base for OUD-AUD Interventions. The proposed concept is premised on the observation that about one-third of people with opioid use disorder (OUD) also have AUD, yet projects dedicated to OUD interventions seldom recruit subjects with co-occurring AUD. The goal is to discover:

• What treatments are these individuals receiving?
• To what extent does alcohol use get worse in OUD treatment settings?
• Could drinking problems be a bellwether for conditions associated with opioid relapse (such as negative affect, untreated pain) and hence overdose risk given that OUD relapse rates are high?

 Concept Goal and Strategy. Co-occurring OUD-AUD is understudied, if at all, in OUD therapeutics research. Therefore, the concept goal is to develop an evidence base for a safe and effective arsenal of medication-assisted, psychosocial, and complementary interventions targeting distinct issues for people with OUD and AUD while considering frequently co-occurring conditions such as chronic pain and trauma exposure. The concept strategy is to expand OUD studies for greater representation of individuals with AUD, i.e., collecting comprehensive data relevant to AUD in the context of ongoing OUD intervention studies; initiating new studies complementary to ongoing studies; and performing secondary analysis of data from their studies or from archived data. The concept does not propose to develop novel treatment approaches. It proposes to develop an evidence base from existing treatment practices for the safest and most effective intervention strategies. It is best viewed as an initial step to allow investigators to expand investigations to include questions relevant to co-occurring OUD-AUD. Future efforts would build upon the outcome of these studies.

Concept Implementation. Multiple support mechanisms appropriate to distinct research strategies will be offered, such as secondary analysis of data from relevant projects and archives and exploratory, hypothesis-clarifying studies targeting OUD-AUD (R01s); revisions to funded projects to support ancillary research projects (competitive revisions); and piloting novel research protocols, subject recruitment, and data collection directed toward future grant applications (R34 planning grants).

The proposed concept fits within and complements existing HEAL initiative programs, such as the Health Data Ecosystem; Pilot and Feasibility Trials to Improve Prevention and Treatment Service Delivery for Polysubstance Use; Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR); Optimizing Multi-Component Service Delivery Interventions for People with Opioid Use Disorder and/or Suicide Risk; and Data and Methods to Address Urgent Needs to Stem the Opioid Epidemic.

Status. The concept has been reviewed by the HEAL executive committee and multidisciplinary working group. It was deemed a high priority for the program. The next step is development of a FY 2024 Funding Opportunity by the HEAL Translation of Research to Practice for the Treatment of Opioid Addiction Team.

Action. Dr. Clark endorsed the Developing an Evidence Base for Co-Occurring OUD-AUD Interventions concept.

CSR’s Initiatives to Strengthen Peer Review

Dr. Koob introduced Dr. Noni Byrnes, Director, NIH Center for Scientific Review (CSR), who reviewed CSR’s mission to ensure that NIH grant applications receive fair, independent, expert, and timely scientific reviews – free from inappropriate influences - so NIH can fund the most promising research. With approximately 275 scientific review officers (SROs), 19,000 reviewers, and 1200 meetings annually, CSR reviews over three-quarters (76 percent) of the approximately 79,000 applications received by NIH each year, or approximately 60,000 applications annually.

CSR has been implementing a Strategic Framework for Optimizing Peer Review since 2019 that addresses reviewers, study sections, and review processes. The goal is to achieve transparency, data-driven decision-making, stakeholder and staff engagement, training, and development. Dr. Byrnes focused her presentation on strengthening the review process via simplifying review of RPGs and improving review of National Research Service Award (NRSA) fellowships, as well as promoting fairness and diversifying panels within the reviewer domain.

Study Section Evaluation through ENQUIRE. ENQUIRE is a systematic, data-driven process by which CSR evaluates its study sections; about 20% of CSR’s study sections are evaluated each year, with every study section undergoing ENQUIRE every 5 years. ENQUIRE proceeds through two stages. First, an external panel comprising scientifically broad, senior scientists is convened. They are provided with relevant data such as publication data, ESI outcomes data, and sample abstracts and aims. The external panel is charged with evaluating the scientific currency of study sections to optimize identification of high impact research, with attention paid to emerging areas. In the second stage, a panel of NIH extramural staff with broad perspective is provided with relevant data and the recommendations of the external panel and asked to evaluate study section function. The process is overseen by directors of CSR’s scientific divisions and involves multiple steps after recommendations are issued such as mock referral, refinement of study section guidelines, and transfer of existing study section members to newly formed panels. ENQUIRE often results in substantive changes such as the elimination or merging of small, boutique panels and creation of new study sections to incorporate emerging areas of science.

Simplifying Review of RPGs. The two main goals of the plan to simplify review of RPGs (including R01s and R21s) have been to 1) refocus first-level peer review on its singular role of providing advice to the agency regarding the scientific/technical merit of grant applications, relieving reviewers of responsibility for administrative/policy compliance items, reducing burden, and incentivizing participation in review, and 2) mitigate reputational bias in the peer review process – specifically, refocusing the evaluation of the investigator and environment in the context of the proposed research project. Two CSR Advisory Council working groups with overlapping membership were convened to consider non-clinical trials (about 90 percent of NIH applications) and clinical trials RPGs. CSR reviews must adhere to legal and regulatory guardrails that mandate five review criteria: significance, investigators, innovation, approach, and environment as defined by PHS C.F.R. 52.h.8. NIH has discretion, however, about how to interpret or group them, and on all matters of scoring. Between January 2020 – March 2021, input was gathered through blog posts (Open Mike, Review Matters). Analyses of this input was provided to the two working groups and 11 virtual meetings were convened to develop a framework and recommendations. In April 2021, the full CSR Advisory Council approved the working groups’ recommendations, and the working group report was published. During July 2021 – September 2022, there were internal NIH input/modifications to the framework and approval by IC and NIH leadership. Between December 2022 – March 2023, public input was sought through an NIH RFI.

The review criteria have now been grouped in three Main Factors (all affect Overall Impact Score 1-9):

• Factor 1: Importance of the Research [individually scored 1-9] (Significance, Innovation)
• Factor 2: Rigor and Feasibility [individually scored 1-9] (Approach)
• Factor 3: Expertise and Resources [not scored à either “appropriate” or “gaps identified” (Investigators, Environment)

Most “Additional Review Criteria,” which may affect Overall Impact Score (e.g., Human Subjects/Vertebrate Animals) remain unchanged, while most “Additional Review Considerations,” which have no bearing on Overall Impact Score, have been removed from first-level peer review.

The RFI, which closed on March 10, 2023, received over 800 responses. The majority of respondents were very supportive; a minority felt that Factor 3 should be scored, while a still smaller minority suggested blinded reviews. Most respondents recommended that CSR develop strong training resources to communicate the change for reviewers, study section chairs, and SROs. A trans-NIH implementation committee with deep, multidimensional domain expertise in peer review, reviewer training, staff training, eRA systems, communications, policy, etc., will consider RFI input and develop roll-out strategy.

Implementation is tentatively set for October 2024 receipt dates (February/March 2025 review, May 2025 Council).

Improving Review of NRSA Fellowship Applications. A CSR Advisory Council Working Group was convened in 2022 to address a concern that NIH is potentially leaving out highly promising scientists because of a fellowship review process that too heavily favors elite institutions, well-known sponsors, and an overly narrow emphasis on traditional markers of early academic success. The Working Group

gathered data that substantiated the concern, i.e., that fellowship applications are concentrated in a small number of institutions and review outcomes for fellowships improve as the rank of the sponsor increases. The Working Group held 14 virtual meetings to develop two recommendations that CSR should adopt to ameliorate the process: 1) Revise the fellowship application to present the candidate’s accomplishments in the context of the opportunities they’ve had, consider the characteristics that lead to success in research (e.g., tenacity, persistence), and require a training plan that is targeted to the candidate’s specific training needs; and 2) Revise the review criteria to better focus on the potential of the applicant, strength of the science, and quality of the training plan, without inappropriate influence of the sponsor’s/institution’s reputation.

Recommended revisions to the fellowship application (i.e., information provided to reviewers) included ͏eliminating grades; revising the Fellowship Applicant section to better align with review criteria and allow applicants to present their scientific thinking, their needs, qualifications, and goals; revising the Sponsors, Collaborators and Consultants section to align with review criteria; placing greater emphasis on the sponsor’s training/mentorship approach and plan for this particular student and eliminating peer review of financial support (sponsor funding); revising letters of support to address targeted, trainee-specific questions in structured fields to discourages boilerplate language; and allowing an optional statement of special circumstances to address situations that might have hindered the trainee’s progress such as harassment, the COVID-19 pandemic, or other personal or professional circumstances. ͏No changes were recommended to the Research Training Plan.

Recommended changes to the fellowship review criteria increased focus on the scientific potential, fellowship goals, and preparedness of the applicant; science and scientific resources; and the training plan and training resources.

In 2022, CSR Advisory Council Working Group recommendations for NRSA fellowship application reviews were approved by the full CSR Advisory Council and endorsed by NIH leadership. Next steps included publication of a Request for Information (RFI) on Recommendations for Improving NRSA Fellowship Review that was published in March and remains open through June 23, 2023.

Promoting Fairness in Review. CSR conducts annual summer Chair Orientation Sessions for the approximately 90 incoming study section chairs each year. These two-hour online training sessions use a vignette-based framework to foster discussion, including what chairs can do to promote fairness in the review process. Since August 2021, CSR has been conducting 30-minute bias awareness training for reviewers about 4 weeks prior to the review meeting that is specifically targeted toward mitigating the most common biases in the peer review process. To date, over 19,000 reviewers have completed the training which has been very well-received by the scientific community--survey results indicate increased ability of reviewers to identify bias and increased comfort in intervening. This training will be required for all NIH reviewers beginning with May 2024 Council review meetings.

CSR has also developed a Review Integrity Training Module that is a 30-minute interactive, scenario-based training on the reviewer’s role in protecting confidentiality and integrity of the NIH review process. Its content is based on actual cases and input from the 2019 CSR Advisory Council Working Group on Review Integrity. Over 12,000 CSR reviewers have completed the training since its launch in Fall 2022. It will be required for all NIH reviewers beginning with the February/March 2024 review meetings.

CSR has also instituted a direct bias reporting mechanism headed by Dr. Gabriel Fosu, CSR Associate Director for Diversity and Workforce Development [Chief Diversity Officer]. Every allegation of bias is carefully investigated by CSR senior management. If CSR agrees a review was biased/flawed, it will re-review application in the same council round. If CSR disagrees, the official NIH appeals process through IC council remains available to all investigators. There is also follow-up with reviewers and actions, as necessary, by the CSR Scientific Division Director to foster culture change in the review community.

Diversifying Review Panels. CSR is seeking to broaden its pool of reviewers through its CSR Reviewer Finder Tool which helps SROs find “lesser known” qualified reviewers, drawing on input from multiple sources, such as ICs, early-stage career reviewers, and the applicant pool, among others. It employs a variety of strategies to diversify its review panels, including emphasizing the critical need for NIH to hear diverse perspectives to fulfill peer review’s mission of identifying the best, most disruptive, novel science. The most effective, highest-quality review committees are broadly diverse in multiple dimensions, including 1) scientific background and perspective; 2) demographic/geographic; 3) career stage and 4) peer review experience. The membership process for standing study section membership process is thorough with multiple levels of oversight and approval. Currently, CSR is focusing on enhancing diversity on special emphasis panels and raising collective awareness, setting expectations, and sharing panel-level data with management/staff. Finally, CSR is focusing on SRO training, especially SRO-to-SRO sharing of best practices in broader recruitment strategies.

Women now constitute 45 percent of standing members and underrepresented minority individuals, 18 percent. These levels are higher than among the NIH applicant pool (34% women, 9% underrepresented minorities among CSR contact PIs).

Discussion. Dr. Lovinger said he appreciates CSR’s efforts to bring early-stage investigators to study sections to learn how the review process works. He asked if the average age or level of experience of reviewers has changed, observing that he has served on review panels many times. Dr. Byrnes, noting that she does not have age data, responded that CSR has made substantial efforts to broaden the experience level within the reviewer pool so that more assistant and associate-level professors are included. She explained that CSR is also evaluating the review service of its reviewers to ensure a broader range of reviewers is included. Dr. Barnett asked for clarification about the report that the service of women and underrepresented minorities as reviewers is higher than their representation among funded grantees. Dr. Byrnes responded that the benchmark line shown on the relevant slide was for the percentage of applicants, not for awardees. Dr. Barnett commented that this represents a problem in the applicant pool because women and minorities are serving more than they are benefiting. It reflects a pattern in academic institutions in which women and underrepresented minorities are over-solicited for service and under-represented in resources relative to majority white men. Dr. Barnett clarified that she was not suggesting lowering the level of service but pointing out reality. She also reported anecdotally that the early-stage faculty that she has worked with who have undergone CSR’s reviewer training have found it helpful. Dr. Byrnes responded that CSR continues its early investigator reviewer training program and has been able to increase the number of early-stage reviewers to two on every study section, up from one. Dr. Byrnes commented that while she is aware of a minority-tax in terms of increased requests for service, there are really strong, qualified women and minority scientists who haven’t been asked to serve as peer reviewers. CSR is working to broaden the pool to include such people and beyond NIH applicants and grantees. Dr. Barnett commented that she always encourages her mentees to serve on a review group because it makes them better grant writers.

Dr. O’Dell thanked CSR for its attention to diversity, including small vs. large institutions, noting many Hispanic-serving institutions fail to access information about CSR’s approach. She also inquired about Dr. Byrnes’ perception of the empowerment of SROs to set the tone in review sections. Dr. Byrnes responded that CSR plans to strengthen its outreach this year. If there are groups of institutions meeting together, CSR will send a representative to talk about its efforts to end bias. She stated that Dr. O’Dell’s point about empowering SROs is well-taken. CSR established an Office of Training and Development last year focused on both reviewer and SRO training. The main goal of the SRO training is to empower SROs to be owners of the review meetings. The training includes mock study sections where SROs are encouraged to jump in and make comments, as appropriate. Dr. Kareken proposed a source of bias that may not have been considered and that could be enhanced on review forms and in training: In the review sections in which he has participated, there is a lot of commentary along the lines of “this research is not going to improve a diagnosis or treatment.” However, his understanding is that NIH is interested in basic mechanisms, even when there is not an immediate clinical application for that knowledge. Sometimes SROs address it and sometimes they don’t. Dr. Byrnes concurred, commenting that she thinks CSR has been very clear about this issue, which is addressed in both basic reviewer training and SRO training. She encouraged reviewers to report instances in which this issue occurs because specific cases help CSR make its points more clearly.

Open Discussion/Public Comments

Dr. Milliken--stating that he was reporting his own views and not those of the Army nor Department of Defense (DoD)--announced that a new DoD/Veterans Affairs (VA) clinical practice guideline on substance use was issued in 2022 that is comprehensive and publicly available. However, only newer research published within the past five years was included and older recommendations that have not been addressed in recent years or that failed to meet the quality bar set by the guideline developers were either not included or were downgraded, e.g., use of benzodiazepine to treat alcohol withdrawal. He also commented that the Army, Navy, and Air Force health services are currently being consolidated into a single health service within DoD. His view is that the effort is proving to be very bureaucratic. Funding is tight and the process appears to be moving a lot of services previously provided directly at hospitals or clinics on military bases out to civilian communities, some of which are under-resourced. The substance use community within the Army has not yet been impacted by this trend and it hopes that there will be recognition that substance use treatment will be retained within the current structure. Research support from NIAAA or Council members may be needed in the future.

Dr. Koob attended an Rx and Illicit Drug Summit in April as part of a panel discussion on the HEAL initiative that focused on the concept clearance on alcohol-opioid interactions presented in today’s meeting. At the meeting, he met a woman who claimed to have evidence that Wernicke–Korsakoff syndrome—a condition that is usually, but not exclusively, associated with chronic alcohol misuse and severe AUD--is grossly under-diagnosed and not being treated properly in emergency rooms where the use of thiamine has become routine but at insufficient levels for those with Wernicke-Korsakoff. Noting that it was difficult to get information about the syndrome for NIAAA’s fact sheet on the disease, he encouraged Council members with information on the condition to share it with NIAAA. Dr. Milliken interjected that this is a good example of the type of issue he was alluding to in his earlier comments on the new DoD/VA substance use guideline. Some of the research that supports these issues will never be replicated because of safety concerns. Dr. Koob encouraged Dr. Milliken to share NIAAA’s Healthcare Professional’s Core Resource on Alcohol with others in the military community.

Consideration of February 9, 2023, Council Meeting Minutes and Future Meeting Dates

The February 9, 2023, Council minutes were approved unanimously. Dr. Srinivas announced upcoming Council meeting dates for 2023. The next Council meeting is scheduled for September 7, 2023; it is expected to be a fully in-person meeting. In 2024, Council will meet on February 8, May 14-15, and September 12. Dr. Koob announced that NIAAA will continue to maintain a hybrid option for Council meetings. He also confirmed with Dr. Marmillot that one of the NIAAA study sections will be fully in-person.

Adjournment

 Dr. Powell thanked Council members for their contributions. Dr. Koob agreed, stating that NIAAA strives to be responsive to Council input. He adjourned the meeting at 4:06 p.m.

CERTIFICATION

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