Minutes of the 156th Meeting of the NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
156th Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
February 4, 2021
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 156th meeting at 12:20 p.m. on Thursday, February 4, 2021, via Zoom videoconference and NIH Webcast. The Council met in two closed sessions from 11:00 a.m. to 11:35 a.m. to review the NIAAA Board of Scientific Counselors (AABSC) intramural review report, and from 11:35 a.m. to 12:20 p.m. to review grant applications and cooperative agreements. Dr. Abraham Bautista, Director, 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 12:20 pm.
Council Members Present:
Louis E. Baxter, M.D.
Jill B. Becker, Ph.D.
Daniel J. Calac, M.D.
Christopher S. Carpenter, Ph.D.
Alex M. Dopico, M.D., Ph.D.
Robert J. Hitzemann, Ph.D.
Constance M. Horgan, Sc.D.
Beth Kane-Davidson, LCADC, LCPC
Charles H. Lang, Ph.D.
Mary E. Larimer, Ph.D.
Laura E. Nagy, Ph.D.
Laura Elena O’Dell, Ph.D.
Scott J. Russo, Ph.D.
Vijay H. Shah, M.D.
Susan M. Smith, Ph.D.
Edith Vioni Sullivan, Ph.D.
Col. Charles S. Milliken, M.D.
NIAAA Director and Chair: George F. Koob, Ph.D.
NIAAA Deputy Director: Patricia Powell, Ph.D
Executive Secretary: Abraham P. Bautista, Ph.D.
Senior Staff: Vicki Buckley, M.B.A.; David Goldman, M.D.; Ralph Hingson, Sc.D.; M. Katherine Jung, Ph.D.; George Kunos, M.D., Ph.D.; Raye Litten, Ph.D.; Antonio Noronha, Ph.D.; and Bridget Williams-Simmons, Ph.D.
Other Attendees at the Open Session
Approximately 144 people viewed the NIH live webcast plus 66 who joined the meeting via Zoom, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order
NIAAA Director George Koob, Ph.D., called the open session of the Council meeting to order at 12:20 p.m. on Thursday, February 4, 2021. He thanked retiring Council members Louis E. Baxter, M.D.; Daniel J. Calac, M.D.; Alex M. Dopico, M.D., Ph.D.; Robert J. Hitzemann, Ph.D.; Vijay H. Shah, M.D.; and
Susan M. Smith, Ph.D., for their service. Council members and senior staff introduced themselves.
Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.
In Memoriam: Dr. Koob acknowledged the passing of multiple eminent members of the research community, recognized their contributions, and expressed condolences on behalf of NIAAA. Kathleen (Kathy) M. Carroll, Ph.D., the Albert E. Kent Professor of Psychiatry at Yale School of Medicine and the Director of the Psychosocial Research in the Division on Addictions, made seminal contributions to improving treatments for addiction. Samuel W. French, M.D., Distinguished Professor of Pathology at the University of California, Los Angeles and researcher at the Lundquist Institute for Biomedical Innovation, was a prolific researcher whose work focused on alcohol-associated liver disease (ALD). Linda P. Spear, Ph.D., Distinguished Professor Emerita of Psychology at Binghamton University and former NIAAA Advisory Council and Extramural Advisory Board member, was known for her work related to the behavioral effects of alcohol in adolescents and the effects of alcohol exposure on the developing brain that were foundational to advances in the field.
NIAAA Scientific Division Update: Dr. Koob announced the merging of two Divisions – the Division of Medications Development and the Division of Treatment and Recovery Research – into one, the Division of Treatment and Recovery (DTR) with two branches: Medications Development Branch and Treatment, Health Services, and Recovery Branch.
Staff Transitions: Dr. Koob welcomed the following new staff to NIAAA: Sukru Demiral, Ph.D., Division of Intramural Clinical and Biological Research (DICBR), Laboratory of Neuroimaging; Paule Joseph, Ph.D., Tenure Track Investigator and Chief of the Section of Sensory Science and Metabolism; Shailesh Kumar, Ph.D., Health Scientist Administrator, Division of Neuroscience and Behavior (DNB); and Yiming Shen, Ph.D., postdoctoral fellow, DICBR.
He announced the transitions within NIAAA of Megan Ryan, now a Senior Health Scientific Policy Analyst in the Office of the Director (OD); Mariela Shirley, Ph.D., who joined DTR from the Division of Epidemiology and Prevention Research (DEPR); and Bethany Stangl, Ph.D., now a Staff Scientist in the Section on Human Psychopharmacology.
Dr. Koob also noted the retirements of Deilia (Dee) Beard, Information Technology Specialist; Isabel Ellis, Public Health Analyst; and Klaus Gawrisch, Ph.D., Chief of the Laboratory of Membrane Biochemistry and Biophysics; as well as the departures of Thelma Fulton, former Extramural Support Assistant in the Extramural Project Review Branch, Office of Extramural Activities, and Aya Matsui, Ph.D. who completed her postdoctoral training.
Budget: NIAAA closed out the Fiscal Year (FY) 2020 budget of $545.4 million. This funding supported 750 research project grants (RPGs), 182 other research grants, 21 research centers, and 323 training positions. NIAAA funding for Research and Development contracts was $34.1 million and Intramural research support totaled $56.5 million. For FY 2021, NIH received a total of $42.9 billion, including: general increases to NIH institutes and Centers; coronavirus supplemental appropriations; allocations for the Helping to End Addiction Long-term (HEAL) Initiative, the 21st Century Cures Act, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and research on influenza; and continued support for the Gabriella Miller Kids First Act pediatric research initiative. NIAAA received a total of $554.9 million for 2021; the Institute anticipates supporting a total of 736 RPGs in FY 2021.
Extensions for Early Career Scientists Impacted by COVID-19: NIH plans to support early career scientists whose career trajectories have been significantly affected by the pandemic by providing an opportunity for recipients of NIH Fellowship (“F”) and NIH Career Development (“K”) awards who have been impacted by COVID-19 to request no-cost or funded extensions of awards. More information may be found in the Notice: Requesting Extensions for Early Career Scientists Whose Career Trajectories Have Been Significantly Impacted by COVID-19: NOT-OD-21-052.
NIAAA Funding Opportunities: New Funding Opportunity Announcements (FOAs) and Notices of Special Interest (NOSI) issued by NIAAA include:
- Integrative Neuroscience Initiative on Alcoholism (INIA) Consortia, RFA-AA-20-011; RFA-AA-20-012; RFA-AA-20-013;
- Improving Health Disparities in Alcohol Health Services, RFA-AA-21-001; NIAAA Resource-Related Research Projects, PAR-21-072;
- Prevention and Intervention Approaches for Fetal Alcohol Spectrum Disorders, PAR-21-097; and Prevention and Intervention Approaches for Fetal Alcohol Spectrum Disorders, PAR-21-098. New NIAAA
- Notices of Special Interest (NOSIs) include Advances in Research for the Treatment, Services, and Recovery of Alcohol Use Disorder, NOT-AA-20-022; and
- Alcohol-induced Tissue-specific and Organ System Diseases, NOT-AA-20-024.
Dr. Koob also presented examples of NIH-wide FOAs and NOSI’s with NIAAA’s participation as follows:
- Providing Research Education Experiences to Enhance Diversity in the Next Generation of Substance Use and Addiction Scientists, PAR-20-236;
- Health Services Research on Minority Health and Health Disparities, PAR-20-310; BRAIN Initiative (Pilot Resources for Brain Cell Type-Specific Access and Manipulation Across Vertebrate Species RFA-MH-20-556;
- BRAIN Initiative Cell Census Network (BICCN) Scalable Technologies and Tools for Brain Cell Census RFA-MH-21-140;
- New Concepts and Early-Stage Research for Recording and Modulation in the Nervous System RFA-EY-21-001);
- HEAL Initiative (Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain, RFA-NS-21-010;
- HEAL Initiative - HEALthy Brain and Child Development Study, RFA-DA-21-020, RFA-DA-21-021, RFA-DA-21-022);
- Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR), RFA-DA-21-029, RFA-DA-21-030).
A full list of FOAs and NOSI’s are listed in the NIAAA Director’s Report.
Alcohol and the COVID-19 Pandemic: Dr. Koob reported on how alcohol has interfaced with the COVID-19 pandemic. Analysis of on- and off-premises sales of alcohol suggest there has been a general increase in sales. Dr. Koob described a bi-directional relationship between the pandemic and alcohol misuse: Isolation and stress could lead to increased alcohol misuse, i.e., physical distancing can lead to social isolation or loss of social support, which can lead to stress or precipitate relapse for those in recovery. Physical distancing also poses challenges for treatment and recovery though telehealth and virtual meetings can be helpful options for individuals seeking treatment or in recovery from alcohol use disorder (AUD) to mitigate such challenges. Biological and behavioral effects of alcohol misuse could also exacerbate the pandemic: Alcohol produces behavioral disinhibition that may promote risky behavior and less compliance with guidelines to reduce the spread of the virus. Alcohol compromises immune function, increasing the risk and severity of lung infections. This combination of behavioral disinhibition (e.g., not wearing mask, shouting) and impaired immune function may increase the risk of viral infection.
Limited data to date do support the hypothesis of a role of stress as a contributing factor in alcohol use during the pandemic: Alcohol use increased among college students in March, particularly among those reporting higher levels of stress and anxiety. People who said their psychological well-being was impacted negatively by the pandemic also reported more drinking days and more drinks per occasion. An Australian survey found that 20 percent of people reported drinking more during the pandemic and about half endorsed stress, anxiety, boredom, or worry about COVID-19 as reasons for drinking more. To illustrate the role alcohol plays as a coping mechanism during the pandemic, Dr. Koob presented a conceptual framework for a three-stage cycle of binge/intoxication, withdrawal/negative affect, and preoccupation or anticipation. The negative emotional state of drug withdrawal, termed hyperkatifeia, drives negative reinforcement that leads to compulsive alcohol seeking and using, as well as impulsivity and the discomfort of abstinence, factors associated with relapse. Pandemic-related stress may increase hyperkatifeia associated with alcohol use and thus contribute to deaths of despair.
Research Highlights: Dr. Koob presented highlights of NIAAA-funded studies with a focus at this Council on alcohol and negative affect. Studies included the following.
“Chronic Alcohol-Induced Neuroinflammation Involves CCR2/5-Dependent Peripheral Macrophage Infiltration and Microglia Alterations” was published in the Journal of Neuroinflammation (2020 Oct 9; 17(1):296) by PP Lowe, C Morel, A Ambade, A Iracheta-Vellve, E Kwiatkowski, A Satishchandran, I Furi, Y Cho, B Gyongyosi, D Catalano, E Lefebvre, L Fischer, S Seyedkazemi, DP Schafer, and G Szabo. This report provided evidence that chronic alcohol use can induce peripheral macrophage infiltration to the central nervous system (CNS). Further, blockade of CCR2/5 signaling with cenicriviroc (CVC) successfully limited the alcohol-induced infiltration of peripheral macrophages into the CNS. CVC treatment also reduced alcohol-induced markers of inflammation in the hippocampus and reversed some alcohol-induced alterations in CCR2/5 axis gene expression. These results support further exploration of the CCR2/5 axis as a therapeutic target for the treatment of alcohol-associated neuro-inflammation.
“Bioinformatics Identification and Pharmacological Validation of Kcnn3/K Ca 2 Channels as a Mediator of Negative Affective Behaviors and Excessive Alcohol Drinking in Mice” was published in Translational Psychiatry (2020 Nov 27; 10(1):414) by AE Padula, JA Rinker, MF Lopez, MK Mulligan, RW Williams, HC Becker, and PJ Mulholland. Investigators used a bioinformatics discovery tool to identify K+ channel genes in the amygdala that correlated with both anxiety-like and high alcohol drinking phenotypes in genetically diverse mice. The top candidate gene, Kcnn3 (which encodes a small-conductance calcium-activated potassium channel, KCa2.3), was then pharmacologically validated in behavioral testing. By identifying a role for Kcnn3 in regulating excessive drinking and negative affective behaviors in stressed, alcohol-dependent mice, these results demonstrated that KCa2 channels may be a potential pharmacogenetic target for the therapeutic treatment of alcohol use disorder and comorbid mood disorders.
“TSPAN5 Influences Serotonin and Kynurenine: Pharmacogenomic Mechanisms Related to Alcohol Use Disorder and Acamprosate Treatment Response” was published in Molecular Psychiatry (2020 Aug 4. doi: 10.1038/s41380-020-0855-9) by MF Ho, C Zhang, L Zhang, L Wei, Y Zhou, I Moon, JR Geske, DS Choi, J Biernacka, M Frye, Z Wen, VM Karpyak, H Li, and R Weinshilboum. Previous studies have shown that genetic variants near the TSPAN5 gene were associated with both plasma serotonin concentration and risk for alcohol use disorder (AUD). As part of a study designed to explore the biological function of TSPAN5, investigators assessed the relationship between genetic variants near TSPAN5 and the length of abstinence during three months of acamprosate treatment in patients with AUD. Results demonstrated that several TSPAN5 genetic variants might be biomarkers for abstinence length in patients with AUD treated with acamprosate, suggesting that TSPAN5 might contribute to individualized acamprosate treatment outcomes through a novel pharmacogenomic mechanism.
“A Multimodal, Longitudinal Investigation of Alcohol’s Emotional Rewards and Drinking Over Time in Young Adults” was published in Psychology of Addictive Behaviors (2020 Aug; 34(5):601-612) by WJ Venerable and CE Fairbairn. In a laboratory study, researchers assessed real-time emotional responses to alcohol in a laboratory study of 60 young adult heavy social drinkers. A subset also participated in an ambulatory (real-world) assessment. A follow-up was conducted 18 months later to determine the impact of alcohol- related positive mood enhancement and alcohol-related reduction in negative moods at baseline on drinking behavior and problems over time. Results indicated that alcohol-related positive mood enhancement at baseline predicted drinking problems and binge drinking status at the 18-month follow-up. Similarly, alcohol-related reduction in negative mood in the lab predicted drinking problems at follow-up. In the ambulatory study, use of alcohol to reduce negative mood in everyday contexts also significantly predicted drinking problems at follow-up. Results suggest that emotional rewards produced by alcohol may be a factor contributing to problematic drinking.
“Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders: A Multivariable Mendelian Randomization Analysis” was published in JAMA Psychiatry (2020 Nov 11: e203554) by DB Rosoff, GD Smith, and FW Lohoff. To investigate the potential relationship between genetic liability for prescription opioid and other non-opioid pain medication use and both major depressive disorder and anxiety and stress-related disorders, investigators performed 2-sample Mendelian randomization using summary statistics from genome-wide association studies (GWAS). Analysis indicated that the genetic liability for prescription opioid use, but not other non-opioid pain analgesics, may increase the risk for major depression and anxiety disorders – even after accounting for chronic pain conditions. These results suggest a link between prescription opioid use and mood disorders, which may inform future intervention and prevention strategies.
Intramural Research Presentation: The Peripheral Endocannabinoid/CB1 Receptor System as an Emerging Therapeutic Target for Metabolic and Addictive Disorders, George Kunos, M.D., Ph.D. Director NIAAA DICBR and Director of the Laboratory of Physiologic Studies, DICBR
The Laboratory of Physiologic Studies led by Dr. Kunos focuses on the potential involvement of endocannabinoids (ECs) in human disease. ECs are lipid mediators that regulate a broad range of biological functions both in the central nervous system (CNS) and the periphery. In the early 2000s, the first-in-class CB1 receptor antagonist rimonabant initially held great promise in the treatment of metabolic syndrome but was withdrawn from the market due to CNS side effects. Dr. Kunos’ Laboratory has focused since then on the hypothesis that selective targeting of peripheral CB1R may retain most of the metabolic benefit of rimonabant without its neuropsychiatric liability. A key question is: How does blockade of peripheral CB1R influence functions regulated by neural circuits in the brain, such as appetite or alcohol seeking behavior?
NIAAA researchers, led by Dr. Joseph Tam and collaborators Drs. R Cinar, J Liu, G Godlewski, D Wesley, T Jourdan, G Szanda, B Mukhopadhyay, L Chedester, JS Liow, RB Innis, K Chen, JS Deschamps JR, RF Chorvat, JF McElroy, G Kunos (Cell Metabolism 16:167-79, 2012) reported previously that in mice with high fat diet (HFD)-induced obesity, the peripheral CB1 antagonist JD5037 (JD) was equally effective with its brain penetrant parent compound ibipinabant (SLV319, BMS-646,256) in reversing weight gain and insulin resistance even though, unlike ibipinabant, the JD compound did not occupy CB1R in the brain. Surprisingly, JD5037 and ibipinabant were also equally effective in reducing food intake, a centrally regulated function. Obesity is associated with leptin resistance maintained by the high circulating levels of leptin. The researchers found that JD5037 treatment of diet-induced obese (DIO) mice rapidly reversed their hyperleptinemia by blocking CB1 on adipocytes, resulting in decreased leptin production and blocking CB1R in proximal tubular kidney cells, resulting in increased leptin clearance. As a result, sensitivity to endogenous leptin was restored.
In a more recent study, Drs J Tam. G, Szanda, A Drori, Z Liu, R Cinar R, Y Kashiwaya, ML Reitman ML, and G Kunos, (Molec Metabolism 6:113-25, 2017) provided additional evidence for the obligatory role of leptin in the weight-and appetite-reducing effects of peripheral CB1R blockade. They tested the effects of JD treatment in three mouse models of obesity. In wild type (WT) mice with HFD-induced obesity, JD treatment robustly reduced body weight and food intake as well as hyperleptinemia. In contrast, in leptin-deficient obese (ob/ob) mice, which are morbidly obese on a normal diet, JD treatment had no effect on weight and food intake, supporting the role of leptin in these effects. The third group was ob/ob mice chronically infused with leptin via a minipump at a rate restoring physiological plasma levels of leptin, which rapidly normalized their body weight and appetite. The mice were then placed on HFD resulting in DIO indistinguishable from that in WT mice, except that plasma leptin was clamped at normal levels. These mice were also resistant to the effects of JD, indicating that those effects are contingent on hyperleptinemia and its drug-induced reversal.
Next, Tam and his collaborators listed above (Mol Metab 6:1113-1125), tested leptin signaling by the leptin-induced phosphorylation of STAT3 in the leptin receptor-rich arcuate nucleus. In lean mice, daily injection of 3 μg/g leptin for 4 days caused robust STAT3 phosphorylation. Basal pSTAT3 levels were increased in DIO mice with no further change caused by leptin treatment. After only one week of JD treatment, leptin again caused a robust increase in pSTAT3. A similar pattern was evident when instead of treating mice with pharmacologic doses of exogenous leptin, they elicited an increase in endogenous leptin by using a fasting/refeeding paradigm. Similar to exogenous leptin, the increase in endogenous leptin resulted in increased pSTAT3 in lean and JD-treated DIO mice but not in vehicle-treated DIO mice. In the arcuate nucleus, leptin inhibits orexigenic NPY/AgRP neurons and stimulates anorexigenic POMC/CART neurons. Leptin treatment induced pSTAT3 in about one third of NPY/AgRP+ neurons, as quantified by double immunohistochemistry (IHC). This proportion was reduced in DIO mice and the reduction partially reversed in JD-treated DIO mice. In contrast, a much higher percentage of POMC/CART neurons were activated by leptin in lean control as well as DIO mice treated with JD, whereas pSTAT3 levels remained unchanged at a low level in vehicle-treated DIO mice. Activation of POMC neurons by leptin resulted in the release of the POMC-derived peptide aMSH, which, in turn activated MC4R to reduce food intake. In agreement with POMC neurons being the primary target of leptin, JD lost its anti-obesity efficacy in naturally obese MC4R KNOCK OUT ko mice (top) or HFD-fed wild-type mice chronically infused with an MC4R antagonist. Thus, the researchers drew the following conclusions: 1) Once DIO mice are re-sensitized to endogenous leptin by JD5037 treatment, leptin exerts its effects primarily through activation of anorectic POMC/CART neurons and the subsequent release of the POMC-derived peptide αMSH which acts via MC4R to reduce body weight and food intake. 2) In this paradigm, the peripherally generated but centrally acting hormone leptin is a humoral link between peripheral CB1 receptors and the central neural pathways controlling appetite and body weight.
Another study by NIAAA Intramural scientist, Dr. Grzegorz Godlewski in collaboration with Drs. R Cinar, NJ Coffey, J Liu, T Jourdan, B Mukhopadhyay, L Chedester, Z Liu, D Osei-Hyiaman, M Iyer, JK Park, RG Smith, H Iwakura and G Kunos (Cell Metab 29: 1320-33, 2019) used C57Bl6 mice, known to display hedonic traits such as preferring diets high in fats and drinking alcohol. Both these preferences are driven by ECs activating CB1R, as indicated by the well documented ability of rimonabant to inhibit both. The researchers’ previous observations on food intake and body weight made them wonder whether selective blockade of peripheral CB1R may also inhibit voluntary alcohol drinking. Staff Scientist Greg Godlewski, Ph.D., decided to test this, using a two-bottle, free choice as well as a restricted access, drinking in the dark paradigm. Using the first paradigm, mice with access to water or a 15 percent ethanol solution displayed high preference for the ethanol solution, with an average daily intake of 11.5 mg ethanol per g body weight, which remained unchanged by vehicle treatment but was sharply and similarly reduced during 5 days of daily oral treatment with either rimonabant or JD5037. CB1 involvement in these effects was further supported by findings that CB1R knockout mice displayed significantly lower ethanol preference and intake, which were not further reduced by CB1 blockade. CB1 blockade had no effect on total fluid intake. In wild-type mice, alcohol intake was also significantly suppressed by JD5037 in a restricted access/drinking in the dark paradigm that resulted in inebriating blood ethanol concentrations. By reducing alcohol intake, JD lowered blood alcohol levels without affecting ethanol metabolism, as indicated by the lack of effect of JD on blood alcohol levels following the injection of a fixed dose of ethanol.
To identify a possible hormonal signal that influences alcohol intake in a CB1R-dependent manner, Dr. Godlewski measured the plasma level of several appetitive and stress-related hormones in mice drinking alcohol or water. Plasma levels of leptin, ACTH, corticosterone or neuropeptide Y were unaffected by alcohol drinking. However, plasma ghrelin was significantly higher in the presence than in the absence of alcohol, in agreement with a population-based study in human drinkers, and this increase was attenuated by JD5037 treatment. Since ghrelin, a stomach-derived, appetite promoting hormone is also known to promote alcohol drinking, the investigators decided to explore its role as a possible link between peripheral ECs and the central structures regulating drinking behavior. They analyzed alcohol preference and its modulation by peripheral CB1 blockade in mice lacking ghrelin or its receptor, the growth hormone secretagogue receptor 1A (GHSR1A). Both ghrelin knockout and GHSR1A knockout mice had significantly lower ethanol preference than their respective wild-type littermates, and daily oral treatment with JD5037 significantly reduced ethanol preference in the controls but not in the two knockout strains. Food intake was unaffected by JD treatment in either wild-type mice or the knockout strains, in agreement with published data about the lack of effect of CB1 blockade on food intake in non-obese, lean mice. These findings suggest that ECs acting via peripheral CB1 receptors promote alcohol drinking by inducing the production, post-translational modification and/or release of ghrelin by ghrelin-producing cells of the stomach. Any of these mechanisms are predicated on the expression of CB1R by ghrelin producing cells. Using RNAscope, Nathan Coffey, then a post-baccalaureate fellow in the Lab and currently an M.D./Ph.D. student at the University of Pennsylvania, was able to confirm earlier findings of low-level expression of CB1R in ghrelin-producing cells, as indicated by co-expression of CB1 and ghrelin mRNA in cells in the stomach mucosa. Dr. Godlewski et al., also found that the mouse stomach contains very high levels of endocannabinoids (ECs), particularly anandamide, which were further increased in ethanol-drinking mice; no such increase was detectable in the brain or plasma. ECs and the associated enzymatic machinery are also present in MGN3-1 mouse gastric ghrelinoma cells, in which blocking EC metabolism unmasked a dramatic increase in the release of ECs into the medium. These cells were selected for further studies because they are known to express CB1 receptors as do primary stomach mucosal cells and because they can take up and metabolize long-chain fatty acids to generate octanoic acid for ghrelin acylation, unlike other ghrelin-producing cell lines that require octanoic acid supplementation to produce octanoyl-ghrelin. (Godlewski et al., Cell Metab 29:1320-33, 2019).
To become biologically active, ghrelin is octanoylated by the enzyme ghrelin O-acyl transferase (GOAT). Alcohol-drinking wild-type mice exhibited elevated plasma levels of both octanoyl-ghrelin and its precursor desacyl-ghrelin and JD treatment reversed the increase in octanoyl-ghrelin without affecting desacyl-ghrelin levels. The reduction of acyl-ghrelin by JD was absent in CB1 knockout mice, confirming the CB1 specificity of this effect. As for the alcohol-induced increases of both octanoyl- and desacyl-ghrelin, alcohol intake is known to increase sympathetic tone, and sympathetic stimulation increases ghrelin secretion via β1-adrenergic receptors on ghrelin-producing cells. Accordingly, treatment of alcohol-drinking mice with the β-adrenergic antagonist propranolol reversed the alcohol-induced increases of the plasma levels of both octanoyl- and desacyl-ghrelin and, in agreement with observations by Gilpin and Koob, also reduced alcohol preference and intake.
Given the abundance of ECs in the stomach and their increase by alcohol intake, the selective decrease in octanoyl-ghrelin by JD likely reflects the reversal of a CB1-mediated increase in ghrelin acylation. To test this hypothesis, Dr Godlewski and colleagues generated mice with a germline knockout of membrane bound O-acyltransferase (MBOAT) mRNA, the gene encoding ghrelin O-acyltransferase (GOAT). As expected, the knockout mice were unable to generate octanoyl-ghrelin and displayed lower ethanol preference than their wild-type littermates. Furthermore, JD reduced alcohol preference in wild type but not in MBOAT mRNA knockout mice. (Godlewski et al., Cell Metab 29:1320-33, 2019)
How does JD reduce octanoyl-ghrelin? Possibilities include reduced MBOAT gene expression, reduced enzyme activity of GOAT or reduced availability of the GOAT substrate octanoyl-CoA. Although Dr. Godlewski et al. detected a modest 16 percent decline in MBOAT mRNA in stomach tissue from alcohol-drinking mice, a much larger 50 percent decrease was earlier reported not to affect plasma levels of octanoyl-ghrelin, so this is an unlikely mechanism. CB1 blockade is also unlikely to inhibit GOAT enzyme activity directly: JD at a concentration resulting in maximal CB1 occupancy selectively reduced octanoyl-ghrelin but not desacyl-ghrelin production by MGN3-1 cells supplemented with 10 μM, but not 50 or 250 μM octanoic acid. In contrast, selective inhibition of octanoyl-ghrelin production by a GOAT enzyme inhibitor was similar at low and high substrate concentrations. Therefore, JD likely inhibits ghrelin acylation by depleting octanoic acid, and the inhibition can be overcome by excess octanoic acid. This mechanism is plausible, as CB1 blockade is known to increase energy expenditure by increasing fatty acid (FA) oxidation in different tissues including white and brown fat, liver and kidney. Dr. Godlewski et al. therefore tested if a similar mechanism operates in ghrelin producing cells. Mammals do not generate medium-chain fatty acids by lipogenesis, so octanoic acid could either be obtained from the diet or derived from long-chain fatty acids via their metabolism by β-oxidation. The former mechanism is unlikely as octanoic acid was undetectable either in the mouse chow or mouse plasma. Long chain fatty acids, predominantly palmitic acid, are taken up by cells and are conjugated with CoA in the cytosol. The acyl group of acyl-CoA is then transferred to carnitine by carnitine-palmitoyl transferase-1 (CPT1) in the outer mitochondrial membrane. Palmitoyl-carnitine translocates through the inner mitochondrial membrane where it is reconverted by CPT-2 to palmitoyl-CoA. Palmitoyl-CoA enters the β-oxidation cycle that sequentially shortens the acyl chain by 2 carbons ultimately resulting in acetyl-CoA which then enters the TCA cycle to generate ATP. (Godlewski et al., Cell Metab 29:1320-33, 2019)
NIAAA Intramural Staff Scientist Resat Cinar, Pharm.D., Ph.D., tested this hypothesis by incubating MGN3-1 cells with deuterated palmitic acid in the absence or presence of 100 nM JD5037 and followed its metabolic fate. The presence of JD did not affect the cellular level of deuterated palmitic acid thus its uptake is not modulated by CB1R. On the other hand, the conversion of palmitate to palmitoyl-carnitine, catalyzed by CPT-1, the rate limiting enzyme in fatty acid β-oxidation, was significantly increased by JD, indicating increased CPT-1 activity. Furthermore, JD induced a progressive reduction in the ratios of deuterated myristoyl-, lauroyl- and octanoyl-carnitine, resulting in a 50% decrease in deuterated octanoyl-carnitine generated. That this was due to increased oxidative degradation rather than decreased production of octanoyl-carnitine, was indicated by 3 lines of evidence: 1) In MGN3-1 cells preincubated with either deuterated palmitic acid or carbon-13 labeled octanoic acid, JD similarly decreased the amount of labeled octanoyl-carnitine generated, whereas its immediate degradation product, hexanoyl-carnitine, was less reduced. The resulting increase in hexanoyl:octanoyl ratio indicates increased metabolism of octanoic acid, which resulted in a decrease in ghrelin acylation. 2) Incubation of MGN3-1 cells with 10-100 nM JD5037 robustly increased the rate of oleic acid oxidation, as measured by the activity of a fluorescent extracellular O2 consumption reagent and reflected in an increase in the initial slope. This effect of JD was abolished by shRNA-mediated knockdown of Cnr1 in MGN3-1 cells. 3) Exposure of MGN3-1 cells to selective inhibitors of three different enzymes in the fatty acid β-oxidation pathway, including oxfenicine for CPT-1, triacsin C for long-chain acylCoA synthase, and 4-bromocrotonic acid for β-ketoacyl CoA thiolase, reduced octanoyl-ghrelin production and occluded the similar effect of JD5037. (Godlewski et al., Cell Metab 29:1320-33, 2019)
GHS-R1A is expressed in brain regions associated with appetite or regulation of the drive to drink where it may be activated by blood-borne octanoyl-ghrelin. However, this may not occur in mice which lack a functional blood to brain transport mechanism for octanoyl-ghrelin. Alternatively, octanoyl-ghrelin released by ghrelin-producing cells of the stomach may act on GHS-R1A expressed on vagal afferents, which are in close apposition to the ghrelin cells with which they form true synapses. To test this, Dr. Greg Godlewski selectively inactivated vagal afferent signaling by neonatal capsaicin treatment, verified by the complete and irreversible loss of cholecystokinin-induced anorexia. In control, CCK-sensitive mice, both rimonabant and JD5037 reduced ethanol preference and intake. In contrast, capsaicin-treated, CCK-unresponsive mice displayed a significant increase in ethanol preference and intake, which remained unaffected by either global or peripheral CB1 blockade. Similarly, ethanol intake and preference in control mice were reduced by blockade of GHS-R1A using either a brain penetrant or a peripherally restricted GHS-R1A antagonist whereas both antagonists lost their effectiveness in capsaicin-treated, CCK-unresponsive mice. (Godlewski et al., Cell Metab 29:1320-33, 2019)
The research described above allowed the scientists to formulate the following conclusions: 1) Endocannabinoids acting via CB1R in ghrelin-producing cells in the stomach mucosa promote the octanoylation of ghrelin, which facilitates voluntary ethanol intake via activation of GHS-R1A located on afferent vagal terminals. 2) This effect is counteracted by CB1R blockade which reduces the cellular pool of octanoic acid due to its increased oxidative breakdown in ghrelin cells. 3). Thus, in this paradigm a neural signal triggered by ghrelin and conveyed via the afferent vagus is the link between peripheral ECs and the CNS. 4). Finally, peripheral CB1R blockade affecting the gut-brain axis has therapeutic potential in the treatment of alcoholism. This will be tested in coming years.
Discussion: Dr. O’Dell asked Dr. Kunos to comment on the role of insulin. He responded that his team has not analyzed the role of insulin in the alcohol drinking paradigm. Jill Becker, Ph.D., inquired if there are sex differences in response to JC5037. Dr. Kunos replied that previous studies used only male mice to reduce variation, but females appear to drink more in this paradigm. Hence, his Laboratory would like to explore that issue in the future. Dr. Becker commented that there are extensive sex differences in CB1 receptors and distributions as well as effects of estradiol on mitochondrial function. Thus, examining females should be very important in the paradigm, affecting not just the drinking but also the side effects. Dr. Kunos agreed. Dr. Shah asked about the status of the NIAAA’s hybrid iNOS/CB1R inhibitor on liver fibrosis that is undergoing commercial development. Dr. Kunos responded that it has been licensed by Inversago Pharma, a Montreal-based company. The compound entered Phase I clinical trial last September, which is expected to be completed sometime later this spring. The first target for Phase 2 studies will be Prader-Willi syndrome because, when rimonabant was previously tested, it caused neuro-psychiatric side effects in 2 percent of the general population, but 50 percent of those with Prader-Willi. Therefore, this is a useful model to test if a peripheral compound can reduce this liability. If successful, it will be available for testing in fibrotic disorders. Dr. Smith asked about the fraction of circulating ghrelin that is octanoylated and if it could be a contribution of microbial-derived oct-FA, as they are a good source of short-chain FAs. Dr. Kunos responded that in mice, it is normally about 20-25 percent. There is good evidence in the literature that all known biological activity of ghrelin is mediated by the octanoylated form. In terms of the FA issue, he does not believe NIAAA’s mouse model would be a good means to test this because, with the sensitivity of their assay, they were not able to detect any octanoic acid either in the mouse plasma or in the mouse chow used in this study. That may not, however, be true in humans. Dr. Smith suggested that the lack of detection may be dependent on diet. Dr. Kunos agreed that in humans, diet may be a possible source of octanoic acid. Dr. Koob asked Dr. Kunos if he thought a ghrelin antagonist might have a synergistic effect with a CB1R antagonist. Dr. Kunos responded affirmatively but noted that the effect of one might pre-empt the other.
Council Member Presentation: Science as a Platform for Promoting Diversity and Understanding Nicotine Use in Vulnerable Populations, Dr. Laura O’Dell, Ph. D.
Dr. Koob introduced Council member Laura O’Dell, Ph.D., a Professor at the University of Texas in El Paso (UTEP) who addressed the topic of science as a platform for promoting diversity, nicotine use in vulnerable populations, and the implications of her research for the alcohol field.
Science as a platform to promote diversity: Dr. O’Dell began by tracing her own path from her undergraduate years (1987-1989) at the University of Texas at El Paso (UTEP) to joining the faculty there in 2005. Dr. O’Dell’s personal mission is to promote young people from underrepresented groups working in science. She thinks about her efforts to promote diversity at three levels: the individual, the institutional, and the science community at large. Individually, she advises and mentors graduate students. Institutionally, she works with two training programs funded by the National Institute on Drug Abuse (NIDA): SMART:MIND (Summer Mentoring and Research Training: Methods in Neuroscience of Drug Abuse) for undergraduates and high school teachers, and VIDA:CARTT (Vulnerability Issues in Drug Abuse: Transdisciplinary Training Program) for post-doctoral students. To engage the scientific community, Dr. O’Dell is active in the National Hispanic Science Network on Drug Abuse and serves on the National Advisory Council on Alcohol Abuse and Alcoholism (NCAA) Working Group on Diversity and Health Disparity in the Biomedical Workforce.
Dr. O’Dell highlighted recent evidence about disparities in funding to underscore the challenges to greater diversity in the scientific workforce. There is clearly a leaking pipeline: The number of minorities engaged in neuroscience education declines precipitously from the undergraduate to tenured assistant professor levels. A 2011 study revealed that African American/Black investigators are less likely to be funded by NIH than white investigators, a pattern that had not changed in a subsequent 2019 analysis. Lack of funding discourages minority careers in science; there is a need to increase minority training programs and consider ways to explore authentic mentoring approaches.
Research on nicotine use in vulnerable populations: Dr. O’Dell described her research program which addresses why different populations have greater susceptibility to using nicotine. Focusing on those with diabetes, adolescents, and females, her laboratory examines this research question through the lens of short-term effects (rewards) and long-term ones (withdrawal responses during abstinence).
Her laboratory primarily uses models of rodent behavior and then looks for biomarkers that can be correlated with behavioral changes.
Adolescent nicotine use is a major problem. E-cigarettes have produced an unintentional increase in new users and dual use, particularly in young persons. Adolescents are more likely to continue to use tobacco products as adults. As a result, adolescents are at greater risk of smoking-related diseases caused by long-term nicotine use. The mechanisms that promote nicotine use during adolescence, however, are unclear. To address this issue, research in Dr. O’Dell’s laboratory has demonstrated that adolescent rats display strong rewarding effects of nicotine, but reduced withdrawal from this drug (behavior). Adult rats display a reduction in dopamine in brain reward pathways during withdrawal. Adolescents are insensitive to this effect (neurochemistry). The rewarding effects of nicotine are enhanced, and the aversive effects of withdrawal are reduced in adolescent versus adult rats. The possible clinical implications of these findings: The strong rewarding effects of nicotine are likely to drive use during adolescence. This may also facilitate use of other drugs, social interaction, and/or risk-taking behavior. From a clinical perspective, effective avenues might involve avoidance strategies. Insensitivity to withdrawal suggests that the field needs to re-evaluate the diagnostic criteria for nicotine dependence that are based largely on adults. Also, treatments that enhance dopamine may be less effective in adolescents who display fewer deficits in dopamine during withdrawal.
Diabetes is a major public health problem. Nicotine use enhances the health consequences of diabetes. Many factors may promote nicotine use in this population, including the appetite suppressant effects of nicotine. As compared to smokers without diabetes, diabetic persons report greater pleasurable effects of smoking, are less likely to quit smoking, are more concerned about weight gain if they quit, and display more anxiety during abstinence. The mechanisms that promote nicotine use in persons with diabetes are unclear. Findings from Dr. O’Dell’s laboratory indicate that diabetic rats display both stronger rewarding effects of nicotine and withdrawal versus healthy controls (behavior). Diabetic rats display deficits in dopamine transmission in brain reward systems (neurochemistry). These results are similar in Type 1 and Type 2 models, and the effects are normalized following insulin supplementation. The rewarding effects of nicotine and aversive effects of withdrawal are enhanced in rodent models of diabetes. Possible clinical implications of these findings include both the strong rewarding effects of nicotine and intense withdrawal contributing to promotion of nicotine use in persons with diabetes. Also, proper insulin regulation is an important aspect to consider when developing smoking cessation interventions for persons that have metabolic disorders, such as diabetes.
Females are particularly vulnerable to nicotine use. Women display lower cessation rates and less likely to benefit from nicotine replacement therapy (NRT). During nicotine abstinence, females experience higher levels of depression and anxiety. Women report that the anxiety-reducing effects of smoking is the main reason for continued use. Although smoking rates have declined in the general population, they have steadily increased in young females. The mechanism by which stress enhances withdrawal in females is unclear. Dr. O’Dell’s work has revealed that females display strong rewarding effects of nicotine and more intense anxiety-like behaviors during withdrawal from this drug than males (behavior). Females display greater release of stress hormones and changes in the expression of stress-associated genes during withdrawal then males (biomarker analyses). In females, these effects are mediated by ovarian hormones. The rewarding effects of nicotine and the aversive effects of withdrawal are enhanced in females versus males. The possible clinical implications of these findings are that the strong rewarding effects of nicotine likely promote the initiation, continued use, and relapse behavior in women. During abstinence, intense stress may also promote high relapse rates in women. Thus, stress is an important factor to consider when attempting to develop more effective cessation treatments for women.
The overall conclusion of Dr. O’Dell’s work is that nicotine reward and withdrawal differentially contribute to nicotine use in vulnerable populations, such as adolescents, women, and those with diabetes. The primary clinical implication is that the field needs to think about these groups differently, as well as the specialized medications that need to be developed to meet their needs.
Implications of her work for the Alcohol Field: Prior work in other laboratories has revealed that adolescent rodents are more sensitive to alcohol reward, social facilitation, and play behavior, while simultaneously less sensitive to cues that limit alcohol intake, which may promote binge drinking. They are also less anxious during hangover from alcohol exposure. Female rodents are more sensitive to alcohol reward, and this effect is dependent on age and ovarian hormone.
Alcohol and nicotine appear to disproportionately impact vulnerable populations. The best example of this is the addition of menthol to cigarettes to improve their palatability and make them more appealing to certain groups of people. Indeed, some studies have found that those who smoke menthol cigarettes have a harder time quitting smoking. This example documents strong interactions from both biological and socio-economic perspectives.
Discussion: Dr. Koob asked Dr. O’Dell if she thinks there is a link between some of the peripheral hormones, e.g., ghrelin and leptin, and nicotine, as there is for alcohol and food. Dr. O’Dell responded affirmatively. Her laboratory has largely focused on insulin resistance. Part of the interaction is that nicotine is an appetite depressant, but the diabetic animals eat more due to a lack of insulin signaling. Dr. Becker inquired about Dr. O’Dell’s new self-administration model for delivering nicotine to animals, particularly how she is determining the dose of nicotine delivered and calibrating it for males and females. Dr. O’Dell responded that her laboratory has begun to make its own cartridges for delivering nicotine because the doses in clinically used cartridges are variable. This allows them to control additives and examine issues such as potential sex differences in response to flavorings. Christopher Carpenter, Ph.D., asked about the best ways that other educators, institutions or organizations can support efforts to promote diversity in science. Dr. O’Dell responded that the burden should not be borne by those impacted by the issues, but that everyone has a role to play.
DEPR Concept Clearance: Public Policy Effects on Alcohol- and Substance-Related Behaviors and Outcomes
Dr. Koob introduced Gregory Bloss, Program Officer in DEPR, who presented a Concept Clearance for a proposed NOSI addressing Public Policy Effects on Alcohol-, Cannabis-, Tobacco-, and Other Drug-Related Behaviors and Outcomes. The purpose of the NOSI is to support research on the effects of public policies on health-related behaviors and outcomes associated with alcohol and other substances, and to support innovative research to examine policy effects that have the potential to lead to meaningful changes in public health. This funding opportunity replaces PA-17-132/134/135, soliciting R01, R03, and R21 applications, which expired in September 2020. NIDA and the National Cancer Institute (NCI) participated and are expected to continue to do so.
PA-17-132/134/135 was a follow-on to PA-07-427/428/429 and PA-11-087/088/089. To date, there have been 169 total applications (131 base projects) to the most recent set of announcements, resulting in 20 awards [15.3% success]. NIAAA received 32 applications (15 R01, 4 R03, 13 R21) and made 5 awards (4 R01, 1 R21) [22.7% success]. NCI received 13 applications (9 R01, 2 R03, 2 R21), resulting in 0 awards [0%]. NIDA received 124 applications (75 R01, 14 R03, 35, R21) and made 15 awards (8 R01, 2 R03, 5 R21) [15.8%]. The five NIAAA-funded projects included The Effects of Changes in Local Alcohol Policies and Enforcement on Alcohol Use and Impaired Driving; Assessing the Effects of State Alcohol Exclusion Laws on Alcohol-Related Behaviors and Outcomes; Evaluation of the Impact of Alcohol Control Policies on Morbidity and Mortality in Lithuania and other Baltic States; A Microsimulation of Alcohol Control Interventions to Advance Health Equity and Reverse the Current Decrease in Life Expectancy in the U.S.; and The Legacy Effects of Discriminatory Housing Policies on Community Availability of Alcohol.
New research priorities under this NOSI include: interactions of alcohol and cannabis policies on health-related behaviors and outcomes; policy effects over the life course; effects of public policies on harms to others from use of alcohol and other drugs; effects of COVID-related policies affecting alcohol availability (Alcohol Policy Information System [APIS] data); and differential or disparate impacts of policies on vulnerable groups and disparity populations.
Positive comments on the proposed NOSI were received from Edith Sullivan, PhD., and Dr. O’Dell. Dr. O’Dell suggested adding research related to the disproportionate impact of public policies on special populations, including youth, women, and ethnic minorities. In response, NIAAA added a bullet to the research priorities reflecting this suggestion, as well as a previously omitted “harms to others” bullet.
Action: Dr. Carpenter strongly endorsed this concept. He suggested adding sexually diverse populations, in addition to those suggested by Dr. O’Dell.
DMHE Concept Clearance: RFAs for the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)
Dr. Koob introduced Joe Wang, Ph.D., Program Director, Division of Metabolism and Health Effects (DMHE), who presented a Concept Clearance to reissue Requests for Application (RFAs) for CIFASD. He provided a brief overview of Fetal Alcohol Spectrum Disorder (FASD), noting that it is an umbrella term describing a wide range of lifelong, debilitating consequences affecting individuals due to prenatal alcohol exposure. The wide range of clinical presentations in those with FASD are at the root of major challenges in the field, including diagnosis and intervention.
CIFASD is a multidisciplinary consortium of 12 research projects—leveraging multiple cohorts (U.S., Ukraine, United Kingdom, Canada) with goals to enhance diagnoses of FASD across the lifespan based on biological, physical, and behavioral assessment, and to improve outcomes in individuals with FASD. CIFASD4 research spans a wide array of topics, including imaging (facial, brain, fetal), risk and resiliency, an adult health survey, biomarker discovery, and translational ones, such as telemedicine, online and mHealth screening tools, and mHealth interventions.
CIFASD’s accomplishments since 2017 include over 70 publications, a majority involving collaborative research on large cohorts of subjects; advances in basic/clinical understanding, i.e., impact of co-exposure with cannabinoids, or tobacco, and miRNA and cytokine profiles to predict FASD outcomes; advances in translation and addressing healthcare disparities, such as an online screen tool using neurobehavioral profiling, a smart phone app for automated facial analysis, and an mHealth intervention for caregivers; and training of the next generation of researchers through K99 and K01 awards, F32 awards, and diversity supplements.
Research priorities for the new RFAs may address unmet challenges in the FASD field. These include identifying FASD cases early and accurately; improving interventions to mitigate FASD outcomes; expanding and translating basic and mechanistic understandings of prenatal alcohol exposure; and reducing prenatal alcohol exposure and the incidence of FASD. The re-issued RFPs will be an open competition using the mechanism of cooperative agreements: U01, UH2 (pilot) research projects, U24 for admin and resource cores. Responsive applications should address the urgent and high impact questions of the FASD research in diverse populations and across the lifespan. As a reflection of NIAAA’s Health Disparity and Diversity Commitment, NIAAA-funded consortia are expected to engage diverse group of scientists in biomedical research.
The Program recommends that NIAAA continue to support the CIFASD initiative by re-issuing RFAs.
Such support will provide the opportunity and momentum for researchers, through collaborative and multi-disciplinary approaches and leveraging numerous subjects, to address urgent and high impact challenges of the FASD field.
Discussion: Dr. Sullivan commented that she read this concept with great enthusiasm, noting that FASD remains a leading cause of preventable cognitive disability and that there is a high prevalence of minorities affected by FASD. It is a challenge to address both the alcohol issue and getting information about FASD to the minority community. She also appreciated the inclusion of aging in the concept, as there may be different types of alcohol-age interactions. Dr. Becker commented that it is important to be able to accurately diagnose FASD in both sexes, as there are sex differences in the effects of FASD. Dr. Koob concurred. Dr. Becker noted that inserting sex differences into the RFA clarifies that it is a priority.
Action: Dr. Sullivan strongly endorsed the CIFASD concept.
Concept Clearance: The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA)
Dr. Koob introduced Ben Xu, Ph.D., Program Officer, DNB, who reminded Council that the primary goal of NCANDA, founded in 2012, is to investigate effects of alcohol exposure during adolescence on the development of brain and behavior, and to identify psychobiological predictors for alcohol use disorder (AUD). It supports a multisite cross-sectional longitudinal study (baseline starting age 12-21). NCANDA’s objectives support research addressing the knowledge gap(s) related to the following questions: 1) What are the effects of both long and shorter-term adolescent alcohol exposure on the developing human brain? 2) What is the effect of timing, dose, and duration of alcohol exposure on brain development? 3) To what extent do these effects resolve or persist? 4) How to factor key covariates into alcohol's effects on the brain development? 5) How to identify early neural, cognitive, and affective markers that may predict alcohol misuse and onset or worsening of mental illness during adolescence and into adulthood?
Organizationally, NCANDA includes: 1) an Administrative Resource Core that provides the scientific leadership, coordination, and consortium-wide oversight including research development, tracking, and performance report across research project sites as well as managing the Scientific Advisory Board and the research Steering Committee; 2) a Data Analysis Resource Core that is responsible for the standardization, harmonization, storage, and analysis of the data acquired by the research project sites. It manages databases and coordinates data and resource sharing activities including long-term data archiving and public distribution of datasets and resources developed by the NCANDA consortium; and 3) Research Sites that are responsible for the acquisition of data according to the standard protocol of the consortium and for the development of site-specific research projects related to their expertise and interests that complement and support the overall objectives of the consortium. Currently, NCANDA has five research sites. The organizational structure under the new announcement will remain the same. The Administrative Resource Core and Data Analysis Core will fall under the U24 mechanism, while Research Sites will use the U01 mechanism.
NCANDA’s achievements to date include: 1) a demographically representative sample, specifically a unique cohort of 831 participants that is demographically representative of diverse racial and ethnic backgrounds and with a retention rate of > 94 percent; 2) data reproducibility and sharing, including new methods and techniques in neuroimaging data harmonization across multiple research sites and MRI scanner types to provide consistent data quality for data sharing, as well as the creation of data sharing resources and archives, and release of longitudinal data (e.g., structural and functional MRI, neuropsychological assessments, and clinical and demographic information) for use by investigators within and outside NCANDA; 3) research tool and techniques development, e.g., new integrated techniques combining NCANDA mobile apps (mNCANDA) with a wearable device (FitBit) for repeated online data collection for Ecological Momentary Assessments (EMA), along with development and testing of a novel non-invasive wearable nano-biosensing system for real-time measurements of alcohol oxidase concentration from interstitial fluid (ISF) with Bluetooth technology; and 4) publications and trainees, including over 40 peer-reviewed research articles.
NCANDA remains an important initiative for the following reasons: 1) The NCANDA study provides extensive and unique longitudinal data sets with detailed information on alcohol use during adolescence as well as on the impact of alcohol exposure on the maturation and brain development trajectories from adolescence into early adulthood in humans. 2) There continues to be significant knowledge and data gaps in understanding the progression and impact of adolescent drinking on the neurobehavioral development from adolescence into early adulthood. 3) Innovative investigative strategies, methods, tools, and research paradigms emerging from the NCANDA consortium provide invaluable empirical and scientific resources and opportunities to researchers in a wide range of fields to generate targeted intervention strategies, predictors, and hypothesis-based research questions pertaining to the etiology and neurobehavioral effects of heavy drinking and AUD in adulthood. 4) The continuing support of NCANDA will be based on the existing and unique NCANDA cohort of participants (N = 831; current age 18-29) and allow continuing data collection to capture a full range of the developmental trajectory and age-related changes in alcohol use behavior and its impact on AUD from adolescence to early adulthood (until age 30). 5) Finally, the continuing support will encourage the examination of COVID-19 pandemic impact on alcohol use behavior and the inclusion of underrepresented, ethnic minority, women, and early-stage investigators, as well as relevant experts outside the alcohol field.
Discussion: Dr. Xu shared two pre-meeting comments from Council members about the concept. Robert Hitzemann, Ph.D., asked why NCANDA should not be incorporated into the ABCD study. Dr. Xu commented that the data from the two studies cannot be merged because they use different research designs with participants of different ages. Dr. Becker commented that she would like to see some reference to the importance of looking at the effect of sex differences because it sends a message that considering the sex of subjects is important. Dr. Xu stated that NIAAA completely agrees with this comment. The NCANDA sample is approximately half male and half female, and several NCANDA publications have reported on sex differences. NIAAA will consider adding the importance of sex differences to the summary.
Dr. Koob responded to Dr. Hitzemann’s comment by noting that many investigators participate in both NCANDA and ABCD, so they cross-fertilize their research. It would be a bureaucratic and design nightmare to merge the two studies. Dr. Becker stated that it’s important to highlight the near-equal number of males and females because the study was designed before the Sex as a Biological Variable (SABV) guidelines were issued. Dr. Koob commented that many imaging studies include equal or large numbers of females, but don’t always analyze the data by sex. It’s important that NCANDA data be analyzed in terms of sex differences.
Action: Drs. Becker and O’Dell endorsed the NCANDA concept.
Response to the COVID-19 Pandemic Update on Funding Opportunities
Dr. Koob introduced Katherine Jung, Ph.D., who is the NIAAA Lead on COVID-related efforts She reported that NIAAA is participating on seven NIH-wide COVID Working Groups. Of particular impact, NIAAA continues to participate in NIH-wide research initiatives, including Rapid Acceleration of Diagnostics (RADx). NIAAA Deputy Director Patricia Powell, Ph.D. serves as Co-chair of the NIH-wide RADx Radical Working Group which has overseen 49 awards administered by 11 NIH Institutes totaling $107 million. DNB Program Officer Changhai Cui, Ph.D., serves as the Lead NIAAA contact for Automatic Detection and Tracing which has resulted in six awards totaling $5,701,930 (RFA OD 20 014). On the RADx-Under-represented Populations Initiative, Minority Health and Health Disparities Coordinator Judith Arroyo, Ph.D., is NIAAA’s representative. RADx-UP has resulted in 32 awards developed by all NIH Institutes totaling $234 million, including one NIAAA award.
NOT-AA-20-011, Notice of Special Interest (NOSI) Administrative and Competitive Revision Supplements on COVID-19 within NIAAA Mission, is ongoing from April 15, 2020 through April 16, 2021. In FY 2020, NIAAA awarded 36 COVID-19-related supplements totaling $5,363,094 (this includes responses to NOSIs from other ICs). In FY 2021 to date, six NIAAA awards totaling $576,815 have been made. Topics include the impact of alcohol misuse on incidence and severity of COVID-19 disease (physiological focus) and the effect of the COVID-19 disease and pandemic-induced restrictions on alcohol use and AUD (social, behavioral, and economic focus).
NIAAA is now soliciting applications to three RFAs that address urgent, time-sensitive research questions on SARS-CoV-2, COVID-19 and consequences of alcohol use that can inform the Nation’s response to COVID. These include NOT-AA-21-001 for three-year R01s with an annual direct cost cap of $250,000; NOT-AA-21-002 for R03s with an annual direct cost cap of $50,000; and NOT-AA-21-003 for R21s with an annual direct cost cap of $150,000. Up to three awards are expected to be made under each RFA; clinical trials are not permitted. Areas of interest that span all NIAAA Divisions include but are not limited to the following:
- conducting secondary analyses of COVID-19- and alcohol-related datasets;
- determining the influence of alcohol consumption on susceptibility to SARS-CoV-2 infection and COVID-19 outcomes, including post-acute sequelae;
- determining how alcohol misuse and AUD may contribute to neurological and psychiatric manifestations of COVID-19;
- characterizing changes in alcohol consumption during the pandemic and investigating pandemic-related causes;
- identifying best practices in service delivery and barriers to service delivery during the pandemic.
Action: Mary Larimer, Ph.D., endorsed the concept. Dr. Koob commented that NIAAA would like to expand the RFAs if more funds become available.
DoD Report and Council Discussion
Dr. Koob introduced Col. Charles Milliken, M.D., who shared new information about the upcoming consolidation of health services for each branch of the military into a single organization, the Defense Health Agency. The Army is proud of the mental health and addiction system of care it has developed to effectively serve its mostly young service members. One concern is that the Army has developed four residential treatment facilities and the Navy has three; one of these seven is up for closure.
Discussion: Dr. Koob inquired if there have been any studies conducted by the Department of Defense (DoD) on the impact of physical isolation during the pandemic. Dr. Milliken responded that up to 50 percent of the Army’s care is happening remotely. He hopes this policy change will remain in place because it helps young soldiers to have more senior military members directly involved with them and allows them to remain connected with others in treatment when they return to their previous location or are reassigned elsewhere. He noted that telemedicine has been a boon for Army careerists. Dr. O’Dell asked Dr. Milliken about his thoughts on encouraging members of the military to come forward to get help with an AUD. He reported that the Army piloted a voluntary care track where someone can come forward for help without career consequences. This approach has been so successful that it is now being reviewed at the DoD level for broader implementation.
Dr. Koob noted virtual meetings have been a silver lining to the pandemic, e.g., women have been more likely to participate in study sections because they don’t have to commit the time that travel to Washington, DC requires. NIH virtual seminars have also been well-attended. Policy changes have allowed therapy via telemedicine across state lines. NIAAA should consider eventually disseminate information about validated virtual approaches to the provision of care. Dr. Koob also noted that NIAAA is currently working on its next strategic plan which will be shared with Council after it’s been reviewed by the Divisions. He asked Dr. Arroyo about upcoming initiatives in diversity. She reported that some are still in development and cannot be shared publicly. She is working closely with senior leadership at NIAAA to see how the Institute can expand the involvement of everyone in diversity initiatives, e.g., including diversity in all out outgoing announcements and designating a diversity representative in each Division.
Consideration of Council September 10, 2020 Minutes/Future Meeting Dates
Council members voted unanimously to approve the minutes of the NIAAA Advisory Council meeting held on September 10, 2020.
Dr. Bautista announced upcoming meeting dates for 2021-2024. In 2021, the Council will meet on February 4, May 11, and September 9; the CRAN Council will meet on May 12, 2021. In 2022, Council will meet on February 10, May 10 and September 8; the CRAN meeting will be on May 11. In 2023, Council will meet on February 9, May 9, and September 7; the CRAN Council will meet on May 10. In 2024, Council will meet on February 8, May 14, and September 12; the CRAN Council meeting will meet on May 15.
Dr. Koob adjourned the meeting at 4:22 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
George F. Koob, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
National Advisory Council on Alcohol Abuse and Alcoholism
Abraham P. Bautista, Ph.D.
Office of Extramural Activities
National Advisory Council on Alcohol Abuse and Alcoholism