Welcome, all. My name is Vikas Gupta, I'm an adolescent and adult psychiatrist, I work at MGH. I'll be your moderator for this session. Really excited about our session titled Alcohol Use Disorder as the Elephant in the Room, the Changing Conversation around Alcohol in the United States. Before we get started, let's get a temperature of the room. How many of you are practicing psychiatrists? Show of hands, please. And how many of you are practicing addiction psychiatrists? Show of hands, please. And how many of you are trainees, residents, medical students? Thank you. So we got a fair share of different levels of training. Before we get started, I'm going to talk about our phenomenal speaker who is here with us today. So, Dr. George F. Koob is the Director of the National Institute on Alcohol Abuse and Alcoholism, NIAAA, and a senior investigator at the Intramural Research Program of the National Institute on Drug Abuse, where he directs the Neurobiology of Addiction Laboratory. He has published over 750 peer-reviewed papers, mentored 13 PhD students, 85 postdoctoral fellows, 11 K99s, and authored several books, including the Neurobiology of Addiction. Dr. Koob is a recipient of many honors, including membership in the National Academy of Medicine, an award of the Legend of Honor in France. Please give a warm welcome to Dr. Koob. Thank you. Thank you, Vikas. That was very nice. Well, it's a real pleasure to be with you today, this afternoon. We chose this title because we're beginning to see a sea change in the United States vis-a-vis the alcohol, and I'll try and explain that as we move through the talk today. So this is my deputy's favorite cartoon. We use it in multiple ways, but it basically says I'm right here in the room and no one even acknowledges me. I really believe that there's a dearth of understanding about alcohol and its pathological effects, and even I suspect that if I asked you all to define what a standard drink is, you might have a little bit of problem with that. You remember the New Yorker cartoon where they say I only have one glass of wine every day and it's the size of a liter bottle, the glass. So I'm the director of the National Institute on Alcohol Abuse and Alcoholism. We are one of 27 institutes and centers comprising the National Institutes of Health, and we are the largest funder of alcohol research in the world. Our mission is to generate and disseminate fundamental knowledge about the effects of alcohol on health and well-being, and apply that knowledge to improve the diagnosis, prevention, and treatment of alcohol-related problems, including alcohol use disorder, across the lifespan. We provide leadership in a national effort to reduce alcohol-related problems. We conduct and support a wide range of basic translational and clinical alcohol research. We coordinate and collaborate with other research institutes, agencies, and organizations engaged in alcohol-related work, and we translate and disseminate research findings to health care providers, researchers, policymakers, and the public. Now I have a very ambitious outline today, but I'm not going to dwell on any one of these in any super great detail. But I want to talk about raising the awareness of the scope of the problem. I want to talk about how we are embracing the changing culture around alcohol in our society, tracking drinking trends and consequences. This one's quite important to us at the institute, and hopefully you will participate in this at some point. Advancing alcohol screening, brief intervention, and referral to treatment, fondly known at NIAAA as SBIRT, as part of routine health care. Promoting widespread use of the health care professional core resource on alcohol, which I think was introduced here this morning in a symposium. Assessing and implementing the Addictions Neuroclinical Assessment Framework, which is a window on individualized etiology prevention and treatment. And enhancing recovery research, supporting research to integrate alcohol use disorder treatment with treatment of co-occurring conditions. And I'm going to argue that the hepatologists, yes, the liver people, are actually leading the way, combating stigma and disseminating NIAAA resources. So let's get started. I'm not going to spend a lot of time on this slide, but basically, according to NSDUH and DSM-5 criterion, which are currently used in the NSDUH survey, there are almost 30 million individuals with alcohol use disorder in the United States. And you can see that there are an enormous number of emergency department visits per year. If you list them as all alcohol-related, it's up there at 5 million. And 140,000 deaths associated with alcohol annually. And I stole this quote from John Kelly at the Recovery Institute in Boston, and he and Sarah Wakeman wrote this in 2019. The quote goes like this, most middle and high-income countries globally have become largely inured to the endemic premature mortalities related to more commonly used substances such as alcohol and tobacco. While these account for a much larger number of deaths and economic and social harms than opioids each year, the devastation wreaked by these substances, their casualties, and the associated blood and tears are all relatively willingly absorbed into the social fabric. So I used this word inured to the hepatologist a couple of weeks ago, and they told me I was wont to use large words. But I like inured. And you know, I'm not joking. Alcohol is involved in more than 200 diseases that are associated with the body. It ranges from everything from mental health, your specialties, to liver disease, obviously. And gastrointestinal problems, pancreatitis. But more recently, the National Cancer Institute has been partnering with us, or we've been partnering with them because they're very engaged in this, but apparently 5 to 6 percent of cancer is now attributable to alcohol. So it's, and it is something that is largely unknown in American society. So there have been trends in alcohol misuse and consequences. There's a piece of good news, which is the first bullet. I'll show you a slide on it in a second. But the rest of these are not such good news. Women and alcohol, I'll come to the details of that. Older adults and alcohol, and the effects of the COVID-19 pandemic on alcohol use and its consequences. The good news is that there's been a steady decline in underage drinking in the ages of 12 to 17 over the last 20 years. And I'd like to think that NIAAA contributed with its work significantly to this effort. But the bad news is when you look at the sex difference there, the gender difference, you see that men and women now in this age group are more or less drinking the same amount of alcohol. And in fact, we have numbers from college campuses indicating that women for the first time are past men in binge drinking and past 30-day drinking. So these are some of the trends. Alcohol use is decreasing in adolescents and young adults, but faster for males than for females. In young adults, alcohol use is increasing, but faster for females than males. For middle-aged adults, alcohol use is increasing for females, but not for males. And in older adults, alcohol use is increasing more in females than in males. And that you can see at the bottom right-hand graph, where again, this convergence that's been taking place over 20 years where males used to drink much more alcohol than females is basically disappearing. And why is this important? Well, one reason it's very important is the study suggests that women are more likely than men to experience a whole variety of alcohol-related harms at comparable doses. Everything from hangovers, blackouts, liver disease, cognitive deficits, certain cancers, and large increases in alcohol-related emergency department visits, hospitalizations, and death for women over men than men over the past 20 years. And women are less likely to receive alcohol use disorder treatment. And even in my field of neurobiology, yes, women have been included in imaging studies, but only about a quarter of those structural imaging studies did they actually analyze the gender sex difference. This is changing. Some of you know that preclinical work now at NIH requires both female and male studies. So hopefully we'll see much more data coming in the near future. And I might tell you that, again, from my own field, there are vast differences in how female rodents and primates respond to alcohol, and probably there are vast differences in the circuitry and neurochemicals that mediate those changes. So more research is obviously needed to better understand sex differences and alcohol use and consequences. What about the older population? You're looking at one here. Alcohol affects behavior and health differently as we age. Health consequences of alcohol tend to shift from acute causes, injuries, to chronic causes, cancer, heart disease, pancreatitis, liver disease, as I mentioned. Older adults are more sensitive to the sedative effects of alcohol, as well as to the effects of alcohol on reaction time, balance, attention, and driving skills. I always say that men over 50 shouldn't climb ladders, but men over 50 should definitely not climb ladders after having a drink, right? Older adults experience reductions in body weight and body water, leading to higher blood alcohol levels. They take more medications that may interact with alcohol. And as many of you already know, any sedative, hypnotic, or opioid mixed with alcohol, two plus two equals five when it comes to respiratory depression and possible overdose. So both alcohol and aging involve widespread inflammation that can contribute to cardiovascular diseases and cancer. And one that's often missed is sleep is disrupted as you get older, and alcohol contributes mightily to sleep disruption. So the COVID pandemic really exposed, and I like to say, shined a light on a sub area of alcohol pathology that I've long been interested in from my own research perspective. So first of all, the isolation, physical distancing can lead to social isolation or loss of social support, which can lead to stress. Drinking to cope with stress of the pandemic can increase the risk of alcohol use disorder and other consequences. And when it comes to treatment, physical distancing obviously posed challenges. You all lived through that, but particularly for those with alcohol use disorder and emphasizes the need for telehealth and virtual meeting options for individuals seeking treatments in recovery from alcohol use disorder. Early on in the pandemic, we wrote up this schema that you see on the right hand side of this slide where social isolation and stress can contribute to alcohol misuse that can lead to behavioral disinhibition, impaired immune function, increased risk of viral infection that loops back and produces a ever more dysfunctional cycle. And what really did happen? Well, during the pandemic, a quarter of the population in the US increased drinking. For several measures, women were generally more likely to increase drinking than males. Greater increases in the quantity of alcohol consumption was observed among black and non-white participants, particularly in the United States. And there were multiple small studies, but you put them all together. Individuals who increased their drinking were more likely to drink to cope with stress. So the factors associated with increased drinking during the pandemic have been reviewed recently in a systematic review and meta-analysis. And they included the following, income and loss of financial stress, greater depression or anxiety, greater general psychological distress, greater drinking to cope with stress, home and work factors. The more children in the household associated with increases in drinking, working remotely associated with increased drinking, essential workers were more likely to increase drinking compared to others. So the overall picture was one of increased drinking in a subgroup of people in the United States, but drinking to cope with the stress of the pandemic. And this leads to the interaction of alcohol and social determinants of health. A variety of social determinants of health can impact the likelihood of alcohol misuse and alcohol use disorder. This sounds like obvious, but we often forget about it. The social environment, growing up in a home with a parent that has alcohol use disorder, discrimination, racism, social isolation, these are all stressors and allostatic loads on our brains, reward and stress systems. Physical environment, alcohol outlet density, exposure to violence, healthcare services, access to and quality of care, economic stability, job security and income, education access and quality. Adverse social determinants of health serve as allostatic loads on the body's stress systems. They increase the vulnerability to mental and physical health conditions and contribute to health disparities and inequities. What is an allostatic load? I'm assuming most of you have heard this before, but that is basically stability through change where the body tries to adapt to the challenge and basically meets the challenge, but it sets a load on the system such that the next challenge that comes along can ultimately possibly push the individual to pathology. Such stressors can drive alcohol misuse to cope, which in turn exacerbates the initial problems further fueling alcohol misuse. A good example of this is the increases in alcohol-related harms during the COVID-19 pandemic, increases in emergency department visits, increases in the incidence of alcohol withdrawal in hospitalized patients, increased deaths from alcohol-associated liver disease that was bigger than increases in prior years, 14% increase in alcohol-impaired driving fatalities. You can see the graph here, which shows increases in hospitalizations for alcohol-associated hepatitis between 2019 and 2020, particularly among women and people less than the age of 40. They're down doing transplants at the transplant centers for individuals in their 30s because of alcohol use disorder. And I think this slide really is one of the more dramatic, indicating the pathology associated with the pandemic vis-a-vis alcohol. There was actually a 25% increase in death certificates, actual death certificates listing alcohol as the cause in the first year of the pandemic, 2020. It went up another 10% in 2021, so you could call that a 35% increase over pre-COVID. And in 2022, it's come down slightly. If Hurricane Katrina, which was more localized, if 9-11, which was a little more widespread, are any indication, there's going to be a long tail in pathology associated with this pandemic, not only with alcohol use disorder, but of course in mental health in general. And speaking of mental health, the COVID-19 pandemic contributed to a global decline in mental health. The World Health Organization estimates the following global changes, about a 28% increase in cases of major depressive disorder, 26% increases in cases of anxiety disorders. The pandemic also worsened or declining mental health in the United States. And given the links between poor mental health and alcohol misuse, one might expect more drinking to cope during the pandemic. And I think that's exactly what we've seen. Alcohol and mental health are intertwined. There was a symposium on this earlier in the week. Alcohol is highly comorbid with mental health disorders. The prevalence of alcohol use disorder among people with anxiety and mood disorders can range from 20% to 40%. Between 30% to 60% of people who seek alcohol use disorder have PTSD. Alcohol misuse often precedes diagnoses of mental health conditions. Alcohol misuse is commonly used in an effort to cope with symptoms. In the end, alcohol misuse makes prognoses worse. And similarly, mental health conditions complicate treatment for AUD. Alcohol misuse is, and I'll speak to this more in a few minutes, but it's actually a window on possible other issues associated with patients. Sometimes they're physical, but many times they're mental health in a subject coming in to the office. And then alcohol, pain, and opioids are intertwined. The opioid crisis overlaps with other public health challenges such as untreated chronic pain, mental illness, and alcohol use disorder. Alcohol misuse contributes to both physical and emotional pain, and pain contributes to alcohol misuse through drinking to cope. I'll talk more about this when we talk about alcohol use disorder tomorrow in the symposium. There are overlapping brain mechanisms in chronic pain, alcohol use disorder, and opioid use disorder. A detailed understanding of this relationship provides an opportunity for preventing and treating these problems, and it's something we're, at this moment, beginning to engage at NIH as part of the HEAL Initiative. Preventing alcohol misuse in individuals with chronic pain and opioid use disorder may help improve patient outcomes. And this is actually a picture of me fairly recently where I did a symposium at the Treatment Summit and Illicit Drug Summit in April with Larry Tabak, the acting director of NIH, and Nora Volkow, the director of the National Institute on Drug Abuse. So what about embracing the changing culture around alcohol? What do we mean by that? Well, drinking alcohol increases cancer risk, but very few Americans are aware of that link. Even a little alcohol can harm your health. It's estimated that for women, even one drink on average per day increases the likelihood of breast cancer. It's small, but it's there. There's really no healthy use of alcohol, is the way we like to put it now. There's also been a large interest in programs like Dry January, which came up like a wellspring in society, basically started in the UK in the United Kingdom. The arguments are pretty strong and pretty good evidence that Dry January actually has some health benefits. It helps us evaluate our relationship with alcohol. I often tell the press, and I did 18 press interviews on Dry January in January. I was getting to have a different form of Dry January. That is in my, probably was close to becoming hoarse from all the interviews, but it really caught on this year. That really was, in some sense, heartening that a lot of people have engaged in it. More recently, there was just a group of celebrities who were telling their own individualized stories about Dry January and how it helped them. What I often say to the press is, if you stop drinking in the month of January and you suddenly feel better, if you feel better when you're not drinking, then your body is trying to tell you something and you should listen to your body. Another area that is evolving is, the way I like to look at this as very, very important is having alternatives for people at parties and celebrations and gatherings other than alcohol. You can do this in multiple ways. In my day, when I had colleagues who were recovered from alcohol use disorder, I would go with them to the reception. We'd both get a glass of Pellegrino or Perrier or sparkling water. We'd put a lime in it, and we enjoyed the party just like everybody else. You can be more official about it and spend money on it, and that's called a mocktail. There are now dry bars in many major cities. I find this really useful for individuals who don't want to drink. There are even sections of football stadiums during football season now where you can go if you want to escape people sloshing beer over you and you're recovered from alcohol use disorder. Another area that we're really, really big on in the Institute, and there is very, very good evidence that SBIRT works, Screening, Brief Intervention, and Referral to Treatment, but we'd really like to have this as part of routine health care. The U.S. Preventive Task Force recommends alcohol screening and brief intervention or counseling in primary care settings for adults 18 or older. We've been promoting the use of screening and brief intervention with referral to treatment as part of routine health care for many years. Screening for alcohol misuse can also help clinicians spot other physical and mental health-related issues, like I mentioned earlier. Adults who binge drink are more likely than drinkers who do not binge to report past year suicidal ideation, episodes of major depression, and prescription pain medication misuse. But here's the part that's really compelling, and I understand Kerry Mintz gave a talk earlier this week here, but in this really nice study, what she showed is using NSDUH data that yes, physicians do screening, and that is wonderful. Your doctors are beginning to ask you how much you drink. You may lie, but at least they ask you, and at least you think about it. But the problem goes downhill from there because brief interventions are very, you know, it's only 11% as opposed to 80% for screening, and referral to treatment is even lower, 5%. So you know, in the U.S., women appear to have lower odds of receiving a brief intervention for unhealthy alcohol use across all age groups, particularly during middle age, and black women and Latina, Hispanic women appear to be less likely to receive brief intervention than women in other race, ethnicity groups. I'm going to mention this twice. Again, there was a symposium on this earlier today, but in this light, we launched, and Dr. Kwakow is in the back there, was one of the lead individuals with Maureen Gardner and Ray Litton in our institute of what we call the healthcare professional's core resource on alcohol. This was launched in May of last year, one year ago. It's an online educational resource, covers the basics of what every healthcare professional needs to know about alcohol, including the many ways that alcohol can impact a patient's health and provide strategies for alcohol screening and interventions. For healthcare providers who are not addiction specialists, it can help overcome barriers to care for patients with alcohol problems, including ways to counteract stigma in practice. It was developed by NIAAA with input from 70 contributors, including practicing physicians and clinical psychologists with busy clinicians in mind. Basically it's everything you ever wanted to know about alcohol. It's in there. And it's probably aimed, I mean it is aimed, mainly at primary care docs as kind of in the median, but it's useful for everyone from a pharmacist to a nurse practitioner to a clinical psychologist to a board certified addiction medicine specialist. Some of you are in the audience. This is a little more complicated, but it's in a sense a window on individualized etiology prevention and treatment. This is our way of looking at precision medicine. Again, I'll talk about this in more detail tomorrow when I talk about alcohol use disorder in particular, but just to remind you, there is a three stage cycle that we elaborated many years ago, binge intoxication, withdrawal, negative affect, and preoccupation anticipation stage. We argued that these three components, three stages. You know, mediated domains of dysfunction, incentive salience and pathological habits for the binge intoxication stage, negative emotionality or what I called reward deficit and stress surfer in the withdrawal negative affect stage and executive function deficits in the preoccupation anticipation stage. And for those of you neuroanatomically inclined, we can also superimpose circuits that mediate these domains of dysfunction, the basal ganglia in the blue there for the binge intoxication stage, the extended amygdala and other connections in the negative emotional domain of the withdrawal negative affect stage. You don't have to be a neuroanatomist to realize that the green is largely frontal cortex which mediates executive function. So I just want to be a little narcissistic and tell you where that came from because it leads to a little bit of a story. So I actually made up this cycle in 1997 teaching a course to undergraduates at the University of California, San Diego called Impulse Control Disorders and I put up there the actual part of the syllabus that I wrote for that course in April of 1997. In October of 1997, I published a paper in science with Michel Lemoine where we outlined the three stages as spiral as you can see here. I want to point out that I then went to the neuroscience meeting and somebody had mounted my spiral on the toilet. So Barbara Mason whose colleague and actually my wife as well is the first person who said, George, you got to lose the spiral and put it in a circle. So that's how that evolved. But on a serious note, Laura Kwaka when she was in the intramural program at NIAAA, she's now in charge of health services in our division of treatment and recovery, came up with a group of us including David Goldman, Ray Litton and a number of others with a hypothesis that we could maybe use these domains of dysfunction to better diagnose alcohol use disorder and addiction in general. And so we call this the Addictions Neuroclinical Assessment, a framework for improved diagnosis prevention and treatment. The goals were to identify how these three domains influence differences between people diagnosed with alcohol use disorder which can be then used to guide treatment decisions to better understand differences between individuals with and without alcohol use disorder. This is really a research domain approach like NIMH launched but it's restricted to one disorder which is alcohol use disorder. The dream we had, which is now partially realized, is that not only scales or self-report but also neuropsychological tests might predict individuals who enter the cycle from one or more of these domains. And I want to point out while I have this up that the way I've conceptualized the cycle is you don't start with binge intoxication, yeah many people do, but you can enter the cycle as we've seen with COVID-19 through the withdrawal negative affect stage. You can enter the cycle through the executive dysfunction stage, think attention deficit hyperactivity disorder. So we were having a meeting with Nora Volkow and we were discussing the protocol that Laura Kwako was writing and that protocol finally did get approved and is now being directed and coordinated by Vijay Ramachandran in our institute in the intramural program. But Nora came up with the idea that well you've already run patients through the clinical program, lots of them, why don't you utilize that data to see if you can validate the three stage model. And obviously I wouldn't be talking to you about this if it hadn't worked out that way. But measures of addiction, personality, cognition, behavior, and exposure to early life stress were collected in 454 patients. The study confirmed the relevance of the three neurofunctional domains to alcohol use disorder and then using multiple indicators, multiple causes approach, early life stress and social demographic factors were identified as predictors. And you can see them listed here and then you can see the indicators on the other side. But to a large extent it was these three domains that fell out. And I just want to emphasize that in the last three years, basically during the, largely during the time of the pandemic, there have been quite a few studies that have validated now these three neurofunctional domains. Among heavy drinkers, the same three factors fell out and they, you know, significant predictors in this study included a history of alcohol use disorder, positive family history of alcohol dependence, earlier age of first drink, and history of childhood emotional abuse and physical neglect. This is by Demartini et al. Among problem drinkers, they had four constructs that fell out, the same three that I mentioned, but also negative alcohol-related consequences. In non-treatment seekers, deep phenotyping combined with factor analytic techniques implicated the same three intercorrelated neurofunctional domains. This was with methamphetamine use, not alcohol, so it extended to another drug. And in non-treatment seekers who were undergoing functional MRI after exposure to alcohol cues and negative cues, functional changes in the nucleus accumbens and amygdala were associated with incentive salience and negative emotionality domains. Again, those are components of the basal ganglia and the extended amygdala. And then among treatment seekers with alcohol use disorder, the incentive salience domain showed construct validity and greater predictive validity in drinking outcomes. Work from Katie Wickerwitz's group and the negative emotionality domain showed construct validity and demonstrated concurrent associations with more frequent and heavier drinking and drinking to regulate negative affect. So you could well ask, well, what did NIAAA do during the pandemic? Well, first we did the healthcare core professional resource, which I've already alluded to, but we also, a team in treatment and recovery, worked on coming up with an operational research definition of recovery. So most people who need treatment receive no treatment of any kind in alcohol use disorder, and little is known about what sustains longer-term recovery. To enhance health, we are expanding our focus on long-term recovery, but we have to have a metric for recovery. So NIAAA defined recovery from alcohol use disorder based on qualitative feedback and key recovery stakeholders, in this case, researchers, clinicians, and recovery specialists. And we view recovery as both a process of behavioral change and an outcome that incorporates time periods for two key components, remission from DSM-5 criteria and cessation from heavy drinking, which is a non-abstinent recovery outcome. You could argue a harm reduction-like outcome. Our definition of recovery also emphasizes the importance of biopsychosocial functioning and quality of life in enhancing recovery outcomes. This is a research definition. I don't expect that you're necessarily going to use this in your private practice for somebody who's had five DUIs, okay? I think that's up to you as individuals and who you're diagnosing and what the situation is. But for us, to find out what works in different treatment programs and follow-up treatment programs and recovery programs, this will be invaluable if it's adopted in research protocols. And then to go back to the research domain criteria, in a very recent study, greater relief negative emotionality at baseline predicted greater drinking intensity and more frequent heavy drinking during recovery. And so in this particular study, they found that relief negative emotionality at baseline gave a predicted percent heavy drinking days in recovery. And the same study used patients from Project Match and Project Combine, which were huge NIAAA-supported studies looking at medications and other treatments, but it validated the three domains of the addiction cycle. But in one-year follow-up, relief negative emotion scores were associated with drinks per day and percent heavy drinking days. And the metric here is a beta value, which basically is the coefficient of the degree of change in the outcome variable for every unit change in the predictive variable. And the converse was also true. So lower relief negative emotionality predicted high-functioning, infrequently drinking during recovery. And you can see that in this box that's circled with orange, lower relief negative emotionality predicted membership in a high-functioning, infrequent drinking profile versus non-recovery profile. So, you know, this is a really nice study from the Kitty Witkiewicz and just published, and it really shows that, you know, utilizing these three domains in the addiction neuroclinical assessment, you know, there's hope that we can identify people who come to addiction for different reasons and more specific to each individual. Going back to changing the conversation about alcohol, what about alcohol and liver disease? Not something probably most of you think a lot about, but integrating treatment of alcohol use disorder and alcohol-associated liver disease is a big project at NIAAA. Alcohol misuse accounts for nearly half of liver deaths in the United States now each year, half. Alcohol-associated liver disease is the most common alcohol-related cause of death and the leading cause of liver transplantation now in the United States. And deaths associated with liver disease increased 47 percent between 2000 and 2019, and they increased faster for women and young adults, as I alluded to earlier. So we've been working with the liver docs, as we call them, in a paradigm shift of integrated treatment. We believe that integrated treatment of both alcohol-associated liver disease and alcohol use disorder can improve patient outcomes. Treating alcohol use disorder with medications reduces the chance of alcohol-associated liver disease and the progression of existing alcohol-associated liver disease. And behavioral or pharmacotherapy for alcohol use disorder after discharge from hospitalization for alcohol-associated liver disease reduces readmission and death. And this gets even more interesting when you start thinking about what were the criterion for a liver transplant, historically. Currently, many U.S. transplant centers typically require a six-month period of alcohol abstinence prior to liver transplantation. So you would select patients who are more likely to abstain from alcohol after transplant and exclude patients from transplant who might improve and not require transplant. Yet it's not realistic in severe alcohol-associated hepatitis where a majority of the patient deaths occur within two months of diagnosis. So the data suggests now that patients who receive a liver transplant without the six-month waiting period, which are now called early liver transplant, have similar survival outcomes and alcohol relapse rates as patients who received a transplant after the six-month waiting period. To build on this research, NIAAA recently issued a request for applications to encourage studies on factors that influence the selection, management, and outcomes of patients who receive early liver transplantation. You know, I'd like to argue with you that we could do the same with mental health and actually join forces to help treat both. And I think something to think about for the future. Nora Volkow and Josh Gordon and I, you know Josh Gordon is the director of the National Institute of Mental Health, we wrote a paper for neuropsychopharmacology not too long ago about words matter. And we can help alleviate stigma associated with alcohol-related conditions by consistently using non-pejorative, non-stigmatizing language to describe these concerns and the people who are affected by them. So some words in our field that are most commonly used in society, such as alcoholic, alcohol abuse, or stigmatizing. Use alcohol use disorder instead of alcohol abuse, alcohol dependence, and alcoholism. Use alcohol misuse instead of alcohol abuse when referring broadly to drinking in a manner that could cause harm. Use first-person language to describe people with alcohol-related problems. Person with alcohol use disorder instead of alcoholic. Person in recovery instead of recovering alcoholic. Use alcohol-associated liver disease instead of alcoholic liver disease. We even purged everything that I could find on our website about alcoholic beverages. You can just say a beverage containing alcohol. It's pretty easy. Another area that we are engaged in at NIAAA that I'm really, really excited about, and the NIH in general is really excited about this, is advancing diversity, equity, inclusion, and accessibility in the alcohol field. We fully support and are committed to the NIH UNITE Initiative, which is a coordinated effort to address structural racism and promote racial equity and inclusion in NIH and within the larger biomedical enterprise. We are focusing on three primary areas to advance diversity, equity, and inclusion, workplace and culture, increasing diversity and equity in the scientific and administrative workforce, and enhancing the NIAAA scientific research portfolio. You know, it's become clear to me, I've been a researcher for 50 years, the more diverse the environment and the individuals working on a given topic, the more creative is the enterprise, the more spectacular the results that come out of it. And there are studies that actually support that feeling that I've had most of my life. I can't tell you how many times one of those undergraduates raised their hand and asked me a question that made me really stop and think, why am I doing this? Maybe I should be doing that. And, you know, you really learn from teaching. That's my personal view. I didn't have to teach. I was at Scripps, but I went over to UCSD to teach for that reason. We are hiring an NIAAA chief diversity officer, or we're trying, anyway. We're recruiting a chief diversity officer to coordinate our activities around diversity, equity, inclusion, and accessibility. I'm not going to spend a lot of time on this slide, but just to illustrate to you that we engage in every initiative at NIH that involves diversity. The BRAIN Initiative has been pushing the envelope. You can see it listed here in a number of places. Anything that involves diversity where we feel that it's going to advance our efforts in this area, we just join up. And it's proven to be really, really rewarding. So I would urge you at the bottom, join us in advancing diversity, equity, and inclusion in the alcohol research enterprise. We welcome your input, help, and partnership in this important endeavor. And I'm not going to spend – I'm going to go very quickly because I wanted to end in an hour, and I have three minutes left to do that. I've told you about the Healthcare Professional Core Resource. We're very proud of this. I already went through this slide, but I put it back in here to remind me to tell you about it. You know, it fills common gaps in training about addiction, including the neuroscience of addiction, evidence-based alcohol use disorder therapy and medications, and various paths to recovery. It provides how-to for alcohol screening and assessment tools that address time constraints but provide a definitive picture of drinking levels and alcohol use disorder symptoms. It tells you what is heavy drinking, alcohol severity levels, and recovery to build confidence in providing brief advice and collaborating on recovery plans. And, you know, I already talked about stigma, but there's a whole section of that in the HPCR as well. So the other resources we have that are quite popular are Rethinking Drinking, which I've already mentioned is a way of reevaluating your relationship with alcohol. It can get you started. There's a really nice diagram of what is a standard drink to get started, but many of the terms that we've been talking about are in there. The NIAAA Treatment Navigator tells individuals what is an alcohol use disorder, what is the spectrum of an alcohol use disorder, what is the spectrum of treatments used to treat alcohol use disorder. It's not just Alcoholics Anonymous. It's not just 28-day rehabilitation. And you can type in your zip code and use the SAMHSA locator or the Psychology Today locator and actually find a treatment facility in your area. We offer all kinds of information to the public. They're available in English and Spanish. We actually translated one pamphlet into Chinese at a special request. We'll do whatever anybody asks us, if we can, and we have the funds to do it. The NIAAA Spectrum is an online newsletter that features articles and news updates on NIAAA and the alcohol field. You can explore the newsletter and sign up for updates. All of this is on our website. We have a new improved website. It's a living website, so we can change it. So if you find errors, please let us know. And believe me, people do let us know. And for those of you in the academic realm, Alcohol Research Current Reviews is actually our own journal. We're one of two institutes at NIH that has their own journal. It has a reasonably robust impact factor of 7.7. It's now published online in a continuous rolling basis. We cover a whole variety of research topics and disciplines through invited reviews, which are very up-to-date when they're published. And it's very carefully screened. So I want to thank you very much for your attention. I want to give special thanks to a lot of people who helped me with these talks for APA. Fred Donadeo in our press office, Laura Kwakos in the back of the room who's coordinating all of our efforts for APA, and then Laura Brockway-Lunardi, Kathy Young, Svetlana Radeva, Gregory Roa, Bridget William-Simmons, who's head of science policy and assistant director for research, Aaron White, who's a special advisor to me, and Patricia Powell, my deputy director. So thank you very much. APPLAUSE Thank you, Dr Koop, for that excellent, excellent presentation. We are now open for the Q&A. So if you have a question, please stand up to the mic and state your question in 30 seconds or less. Thank you. I have a very quick question. I was intrigued by your statistic that 25% of adults increased their drinking during the pandemic. Did you take a look at any that may have decreased their drinking? The same number decreased drinking. So it had a bimodal effect. But the pathology presumably is being driven by the individuals who drank more. Mike Dawes, VA Boston and Boston Medical Center. Particularly for the screening brief intervention type of work, I'm just wondering how NIH and just different organizations can get what the findings are into translational work that actually applies to patient care. And what are some of your thoughts about that? Could you say that last part one more time? The findings, well, from all of the clinical studies, not just AAA, but NIDA, NIMH, there's a lot of findings out there, but it always takes, you know, 5, 10, 15 years to translate it into practice. And I'm just wondering how you would think about maybe improving that translation and speed that process up. Well, that's the billion-dollar question. I mean, that's the question I struggle with on a daily basis. I call it scaling up. I think one of my colleagues called it a meta-analytic approach. But, you know, it's a real challenge in the face of the healthcare system that we have. So one of the things we're doing is working with Kaiser Permanente. Well, they're working with us because we're funding them in a competitive grant. But, I mean, you know, the fact is that's one effort. I'll be honest with you. I'm theoretically going to be meeting the new director of ARPA-H, and I'm going to raise this question with her exactly the way you raised it. It is really a challenge. How do we scale up this and many other things that we know the information about? And so, you know, what we really did during the pandemic was try and get a lot of this information in a place where we could possibly scale it up, and the Healthcare Professional Core Resources is one example of that. Yes, thank you for the talk. Alcohol has gained a general social acceptance in our society, and many will even say that their cardiologist has told them that they can drink one glass or two glasses of wine. But I heard you say that there's no real good use of alcohol at the safe level. So what can we tell these ones that will always want to argue about what their cardiologists have said? So our analyses, and I think my senior advisor, Aaron White, is probably going to put together a paper on this eventually, or at least a review. But our analyses are indicating that the J-shaped curve, which you kind of were referring to, which means that at one drink or two drinks a day, you supposedly had health benefits, disappears if you run the appropriate control groups. So a non-drinker is not an appropriate control for these kind of analyses because they could be not drinking because they're actually ill. And so most of the analyses where you use a low level of drinking as the control group, there's no improvement in virtually any metric with low levels of alcohol. So the way we put it is sometimes I say there's no safe amount of alcohol, but I think a better way to put it is there's no healthy level of alcohol. And I think each individual has to decide for themselves how much they want to drink. And like I said, my personal view is if you don't feel good and you're not sleeping well when you're drinking a certain amount, I don't care if it's one drink a day, half a drink a day, or six drinks a day, you should think about it. And I think that's the message that we're trying to get across. But it's a very good point. I'd like to follow up on the last question. A lot of people say, yeah, when I go out with friends, I have a drink beforehand because it's social lubricant, and I don't know what to tell them. It makes sort of sense to me. You know, like a positive use of alcohol to increase socialization. No, it is a social lubricant. It's used by 70% of Americans. I don't know of any society, with the possible exception of ASAM, that does not serve alcohol at the opening reception, including the Research Society on Alcoholism. They serve alcohol at the opening reception, but it gets two tickets. I know. Because I never go to the reception. Well, we won't go there. But nevertheless. And you could consider that a value of alcohol. I can only imagine the billions of contracts and grants in our fields where people have interacted. But at the same token, it's not required. There's famous studies. It may have been Alan Marlatt who actually did some of these. But there's some famous studies that show that if you actually have people go to a party where they have a non-alcohol containing beverage and an alcohol containing beverage, they can't tell the difference. They have just as good a time and just as much social interaction as the people with the alcohol. I don't think we're going to ever return to prohibition. So those of you that like your Pinot Noirs, I'm not out there to put a damper on your Pinot Noir drinking. But I'm just saying that I think when you get past a standard drink, there's a much higher likelihood of pathology. And for some people, they shouldn't even have a standard drink. If you have the mutation in the ALHD2 gene, you're going to get a terrible flush reaction. It's going to be very uncomfortable. One of my colleagues says, I can't drink, George, not because I'm intoxicated, because of the acid aldehyde surge makes me dizzy. I don't want to get behind the wheel of a car when I'm dizzy. So he doesn't drink. If everybody in your family is riddled with alcohol use disorder, I've had colleagues who joined Al-Anon, never drank, simply because of the history in their family. And you can go on from there. There are a lot of individual reasons why people may not want to drink. And we need to have them have the option of doing that in social situations. So you should tell APA, if they're having receptions, they should have some Perrier there. Deidre. Well, there's one more back there. Thank you. So this session is also being live-streamed, and we have a few live-streamed questions. I'm supposed to be kind of back and forth between the two. We'll get to you two in a minute. So the first question we have here is, can diasulfiram cause neuropathy or liver damage? I believe it can. I'm not the world's expert on disulfiram, but if you take large amounts of it beyond what's approved, and or you drink on top of it, I think there are indications on the warning label. Definitely. And I've read some case reports of it causing neuropathy, and it is a known cause of liver damage. Yeah, I mean, the idea with disulfiram is you're not supposed to drink. Okay, it's a deterrent, a punisher. Thank you. The next question is, is it advised to have the spouse or family members involved in the treatment of AUD? It's part of, you know, what they used to call a community reinforcement approach is to involve families, yes, for multiple reasons. And it certainly helps in many cases. I don't know, Laura, do you want to add to that? Yes or no, but, I mean, I'm assuming that family therapy can be an added benefit and help in treatment. This is Dr. Kwakow. Can you repeat the question? Sorry. Is it advised to have the spouse or family members involved in the treatment of alcohol use disorder? Yeah, so, George, you're absolutely right. There are multiple modalities of family therapy and also couples therapy that have evidence, in particular alcohol behavioral couples therapy. But, you know, it can be beneficial for the family as well. It really just depends on the individual circumstance. And we often recommend it as an adjunct to individual psychotherapy, psychopharmacology with the three FDA-approved medications, mutual support. So it is something that's, you know, in the arsenal of treatments for AUD that have robust evidence. Thank you. There's another question. Is there a role for a camperol in the prevention of cravings? Yes. Camprosate, which is camperol, is calcium homotaurine. It was developed by a French drug company, and it is an effective treatment for alcohol use disorder. But, again, it's one that you have to take to make it be effective. It's generally recommended after at least a short period of abstinence, and it does seem to, you know, decrease that irritability, you know, negative emotional state that's associated with protracted abstinence that can lead people to relapse. And in that sense, you know, relief craving is alleviated by a camprosate. It has the same effect size as naltrexone in meta-analyses and very close to the same effect side as serotonin selective reuptake inhibitors for the treatment of major depressive episodes. People don't realize that. The treatments for alcohol use disorder, first, aren't known by a lot of people, and secondly, they don't realize that they actually work. You have to take them, and they have to be prescribed. Thank you. Yeah, please go ahead. All right. I just want to say thank you for the core resource. Definitely going to be looking at that later on. And just a brief question. Does the core resource involve some of the brief interventions that you were talking about as well? Yes. Yes, it does. And, yes, I urge all of you to check it out. You don't have to go through the whole thing, although you can get CME credit for it, but just check it out. You know, it's on one level encyclopedic, but not in a boring encyclopedic, but in an effective encyclopedia. I don't think there's much in there that you would ask about alcohol that you can't find in the HPCR. Deidre had a question. Did you want to make a comment or a question, Deidre? Pregnant women. Yes, thank you, Deidre. So, Deidre is guiding a program at NIAAA on multiple ways of helping women of childbearing age get comprehensive care with a focus on alcohol use disorder, but also integrating with other mental health issues. And her point is that another group that should never drink are pregnant women, and I emphasize that. So, I wanted to ask just one more depth question about the brief interventions. Is there any study of brief interventions for organizations or organizational leadership? So, I'm Dr. Hart. I work with, I'm an Army psychiatrist, and definitely, you know, I interact with leadership teams and with individual clients who both either have a culture of alcohol use or a personal problem of alcohol use. I'm just wondering if you have any comments on that, on brief interventions when you're addressing leadership of an organization. Thank you. I believe the VA is utilizing brief interventions, referral to treatment. Is that correct, Laura? And I believe DOD is starting to look at this because they're, they actually are trying to do interventions earlier than later. They don't want to have the soldiers in, you know, meeting four and five criteria or six criteria for alcohol use disorder, and then they're going to get tossed out of the service because they've had a DUI. They're trying to catch them before it moves into that domain. Is that a pretty reasonable answer, Laura? Thanks. Other questions? Please go ahead. Thank you. I wanted to hear more about your thoughts on the J-shaped relationship. So specifically, you know, is there a way to better disaggregate the data when it comes to people who report no alcohol use whatsoever? And then also, alternatively, is there, like, a better approach that's more appropriate for, you know, kind of using, as opposed to referencing, sorry, using the reference group as, like, people who report low levels of alcohol use? Yeah, so, I mean, you've kind of asked and answered to some extent the way I would answer, which is, that's one of the factors. But there's another factor, which is diet. The amount of reversitrol in red wine that you would need to actually have, you know, a beneficial effect would probably kill you from the alcohol part. And one of the major hypotheses, and again, these are still hypotheses, but one of the major hypotheses as to why, you know, red wine drinkers do better in some of these measures is simply because they have a better diet, and they can afford a better diet of fresh vegetables, olive oil, fresh foods in general. So, you know, that's our take on it from multiple studies. You know, Aaron White can regale you when, you know, regale you with with the actual details and numbers, but I think there's something on our website about this at this point. Okay, thank you. Thank you for your presentation. I'm Caridad Ponsam, an addiction psychiatrist at UMass Medical School, and I have an interesting question because I was approached recently by our transplant team, who has reduced their indications in terms of six months of variety for transplantation. They've been very active in being able to transplant patients that present with alcohol-related acute hepatitis, and what they described to me is that those patients actually do really well after the transplantation. They tend to remain abstinent. Where they're really struggling is with patients with more chronic alcohol use disorder who remain abstinent until they get the transplant, and then relapse following the transplant. And there, I think what was interesting to me in what they described as a problem is that our definition from an addiction psychiatry in terms of a harm reduction doesn't work for them because even smaller amounts of alcohol can really have a severe impact on the liver function of these patients, who then would not be eligible for a second transplant. So any thoughts on that and anything that you know in terms of research in that arena? Yeah, no, I agree. That's why I said that from a research perspective, if we're looking globally at recovery for average patients in different programs, our definition is going to be useful. But there's going to be subgroups where you definitely are going to have to require full abstinence. Someone, you know, I've met with judges in my career in California and other places. You know, they asked me, what do I do after the person has three DUIs? They probably should never, they should probably try to remain abstinent or have some, you know, have an interlock on their car so they can't get in the car and start it. And some of these things are probably on their way eventually. I don't know the latest on the National Transportation Agency and interlocks and what the future is, but we've been working on trying to find a way to measure blood alcohol effectively by having what looks like an Apple watch on your wrist. And it's coming along. It's been five years, but it's coming along. It's called Backtrack and they're working on this and there are a number of other enterprises and we support a number of small business innovative research grants in this area. I'm moving away from your question, but I do think that there are going to be subgroups of patients where abstinence is required, period. Thank you. To answer your question though, so I'm a transplant addiction psychiatrist at Mayo Clinic. I do not think there is any evidence that alcohol hepatitis pathway patients, we call the exception pathway, would actually do better than patients who have had longer sobriety before the transplant. What we do at Mayo Clinic is that if we find the patient is the first episode of acute alcohol hepatitis and no prior episodes and we have good family support, patient is lucid when we're making the treatment. We cannot really make a decision when the patient is encephalopathy. We have to make sure the patient do understand that they have to go to a program and the family has to be on board with that. Then we can only pursue transplant. So it's not that we would just pursue transplant because we have responsibility toward justice about the person who is donating the organs and organs are scarce. So we cannot just give to our organ to someone thinking the patient's gonna die and very right that we are seeing a lot of younger patients in mid-20s, mid-30s, they're coming with the, you know, acute liver failure and they will die if you don't do the transplant. So it's more complicated than that. The research so far has shown that longer the sobriety and the family support, those two have the best way to predict the outcome. But I agree that we need more research about predicting outcome and how we can incorporate, you know, liver team with that. The only thing that I don't hear much is how we monitor patients. This is the biomarker. We don't talk much about biomarker in any transplant centers. The serum PET, phosphatidylethanol, has become a gold standard for biomarkers. This is more like a hemoglobin A1C in diabetes. So you can actually get a sense of their alcohol use over the past three to four weeks. So even if you have patients you have concern and they are saying they are drinking socially, if you do a serum PET, you can get an estimate and that estimate tells you how much they could be drinking. And this is very objective evidence of their drinking than a subjective report. So we should be using more biomarker in our assessment even for social drinking and high-risk drinking. Thank you. No, I agree with you. That's why I dallyed into the area of the actual blood alcohol measures. And some of these now can measure for two weeks people's, whether they're actually drinking or not. We're not quite at the point where we can tell you that it's 0.06 versus 0.08. But we can tell you, they can tell you with some of these devices that are being used in research programs now, whether someone was drinking or not drinking. And the scram device has always been out there. That's that big thing that goes on your ankle. But we're talking about things that are on your wrist or actual little small devices that are like velcro that can go on your skin. And some of them actually would last for about two weeks. So, you know, there's some hope I think with some of this technology. I mean, in the really high security government, places like where they, you know, the people that control nuclear weapons and things like that, they have a box that's about this big. And if you put this part of your finger on a pad on that box, it measures your blood alcohol with an infrared detection device. So, you know, my dream was that we would miniaturize that box. Hasn't happened yet, but that's what got us started about five years ago. A few online questions again. Any comments of the negative synergy between alcohol and marijuana use? Does this combination pose an increased risk for mental illness development? Well, we don't know the answer to that. We are supporting work of combination of alcohol and marijuana for that exact reason, to find out the answer to that question. I mean, I don't think it's a good idea to be driving on, we're in California now, so I can say Highway 5 with a 0.08 blood alcohol level. I don't think it's a good idea to be driving on Highway 5 with a couple of joints under your belt. And I certainly don't think it's a good idea to be driving on Highway 5 with both, all right? So, you know, I think some of these things are obvious, but when it comes to, you know, the long-term effects, even the prenatal effects, that's one of the emphasis for the, Nora Volkow is taking the lead on this with NIDA of the Healthy Brain Cognitive Development Study, but also the ABCD study that we're doing, the Adolescent Brain Cognitive Development Study, so hopefully some of these kind of questions will start to fall out. Some of you know the ABCD study has 10,000 kids that we've been following since the ages of 9 to 10, and with imaging every other year, and neuropsychological tests on a regular basis, so we should be able to get some of this information, and it's a very important question. Thank you. Next question, how successful are patients with a history of alcohol use disorder at controlled or lessened use of alcohol instead of abstinence? So there's a burgeoning interest in what's called harm reduction, which would be where you would reduce your alcohol to a healthier level, and we believe that this is an outcome that we would like to pursue, particularly with the FDA, and we are pursuing with the FDA. Ray Litton, who is the director of our Division of Treatment and Recovery Research, works with the FDA on a regular basis to use the two-level, or even maybe the one-level decrease in drinking that the WHO argues can be beneficial, because the pathology associated with alcohol is dose-dependent, so the lower, the more you lower your drinking, the less the pathology. So, you know, but as I said before, what I typically say is, you know, you can start with abstinence, but we'll take whatever we can get, but for severe alcohol use disorder with repeated pathology that just does not seem to remit, I mean, abstinence may have to be the goal. I think we have to look at, you know, both sides, but what about a what about a 17-year-old that meets the criterion for alcohol use disorder because he was binge drinking with his friends? Is he going to be banned from drinking alcohol for the rest of his life? You know, I think, I think we have to look at both sides. Please go ahead. Yes, I just wanted to comment about the path that was mentioned as a biomarker. I'm in Houston at a transplant center, and we use that path, that phosphatidyl ethanol marker, a lot. I've seen it used in women too. I think oftentimes women, the questions about alcohol are minimized or missed, or someone may be with a NASH cirrhosis, but when you do a path, you realize you're really looking at an alcoholic cirrhosis. So I think that's really a valuable biomarker that people need to be aware of and was recommended. It can really give you some insight into what you're really dealing with. And I believe there have been some efforts made to make it easier to run the path as well. Is that not correct? Yeah, so I think it's, I think it's a very good point, both of you made this point, that it's more accommodating than it used to be as a measure. A couple of additional online questions, the next one is can you combine naltrexone and disulfiram? You can answer that for me. There have actually been some studies that show that. I have patients that I have used as combinations, so given this example, so an executive patient who usually drinks alcohol when he's out of state on a trip in the airport, so he's maintaining abstinence with naltrexone, but for extra caution when he's traveling he would use disulfiram on the top of naltrexone just to make sure that he doesn't drink. So you make treatment selection based on your patient reliability, their liver function test, medical comorbidity, and their motivation. As such, disulfiram works the best in supervised administration situation. But so I've used depending on the situations. And they could probably be used sequentially, too. So you get them to stop drinking with the disulfiram and then, you know, keep them. Yeah. Next question. I would just add to that, it probably would be helpful to fund studies where you're using actual combinations in RCTs where you actually could get, does it change effect size and that sort of thing? Because, you know, case series only give you so much information. Well, there have been naltrexone acamprosate studies and some of them are positive. And next online question. Please comment on alcohol and marijuana use or withdrawal and sleep issues. Well, both marijuana and alcohol produce pretty severe disturbances of sleep during withdrawal. I'm not as familiar with the marijuana literature because it's a while since I've been teaching marijuana, like 10 years. But with alcohol, sleep becomes a major marker of what I would call the negative emotional part of craving and protracted withdrawal. You know, you get into this loop where you're drinking to fall asleep, and alcohol does produce a slightly faster latency to fall asleep. You wake up in the middle of the night because you have to go to the bathroom, number one. And then you can't get back to sleep because your brain's hotwired because you have the rebound hyperexcitability. And the next night, you do two drinks instead of the first drink. And then you get into this vicious cycle where you're drinking to fix the problem that the drinking has caused. And some people drink because of insomnia. Some people get insomnia because of drinking. And I'm just using insomnia as a generic term here. I should probably say sleep problem. But it's a big issue, and we are funding research at NIAAA to look at whether some of these sleep medications, the newer ones, may actually help some patients with their alcohol use disorder because maybe that's part of the driving force for reengaging. It's an important issue. But marijuana combined with alcohol, these are all good questions, but there's not very many studies. I don't know. Laura, correct me if I'm wrong, but we don't have that many studies. We have a few. Another comment online, this is from Naveen Dayal. He says, brilliant presentation covering so much of data and looking forward to your presentation tomorrow. Okay. Well, tomorrow we get some biology in there. I had a question, Dr. Koob, I really appreciate your presentation. I work on a statewide level. We're really trying to get our efforts up with alcohol use disorder. My question I would ask you is the place of contingency management for alcohol use disorder and more broadly. Why I ask the question is you see its utility in studies. We see it limited. You bring it up in a public or broad use, and you get so many comments about not paying people to, you know, stay sober or stay away from drug use. I just ask you about your thoughts on the use of that in programs. I'm very positive about contingency management. I actually, I was trained as a physiologist, but I had a good bit of training in behaviorism, and it works. And it's a very good way of getting people to stop doing whatever they're doing, at least initially, which gives the brain time to start to recover. And that's my position on contingency management. You know, it's a way, it's one of the most effective treatments for stimulants. But it works for alcohol, according to the data I've seen recently. And I think, you know, there's something going on about how much money each state's willing to let people pay and that kind of thing, but I'm not up to date on the local issues. But I think contingency management has been proven to be effective in the short term. And I think, as I said, it gives the brain a chance to start the recovery process. Thank you. So does motivational interviewing and cognitive behavioral therapy, but, you know, they're all part of the armamentarium. So for someone like me, the more you can put that on your website, I'll appreciate that. I hear you. Thank you. Next online question. Is there any utility to using naltrexone to help reduce alcohol consumption on an episodic basis for those who use moderate amounts of alcohol? I believe they use naltrexone this way in some other countries. Yeah, this is known as the Sinclair method. And, you know, they use it in Europe. And there are studies showing that it can be effective. I just saw one recently. It was done in the United States. So, you know, naltrexone basically blocks the mu-opioid receptor. And alcohol releases enkephalins and endorphins, which titillate the mu-opioid receptor. So if you're blocking the mu-opioid receptor, the kind of general report in human laboratory studies is people say, well, you know, the first drink was a little bit OK, but it doesn't really do much for me on the second drink. And so that's the kind of anecdotal report you get with naltrexone. And rodents stop drinking, you know, so, or at least their drinking is blunted significantly. So you know, I think there's probably merit to that if it's utilized properly. Thank you. Can you please speak in the mic? So nalmethine is a similar drug. Yeah, nalmethine is the drug. It is approved in Europe, which is for like at-risk drinking. And it can be just used before drinking episode to prevent heavy drinking. Yeah, nalmethine is very similar to naltrexone, but it's a little more potent at the mu-opioid receptor. I've actually given nalmethine to rodents, not people. One could argue that we could have a bigger impact potentially by influencing community attitudes, public policy, as physicians in our role as advocates. And I wonder, does the NIAAA have some great resources for the physician working in treatment settings? Do you provide information, guidance around advocacy for similar reasons? We just did a blog on policy where we support policy issues. We fund this metric of measuring how marijuana and alcohol sales change with each different state and community. And so we've been funding that since I became director, and it allows us to start to look at how availability of marijuana and availability of alcohol and both of them together are influencing all the metrics from alcohol use disorder to consumption. So that's called APIS, and I forget what the acronym stands for. And that was in a recent blog you said? Yeah, on policy. We can't set policy as an institute, but we can provide the evidence that guides policy. And so we've supported over the years a lot of studies that show that advertising can contribute to drinking. And the group that's being targeted and outlet density is a factor that contributes to increased pathology associated with drinking. You know, there's the great old studies showing that when a town goes wet after it's been dry, that's the terminology for when they allow alcohol to be sold in bars and they allow alcohol to be served at restaurants. The old data, Tom Babour published this work many, many years ago, shows that pathology increases as the towns have more availability of alcohol. So we have those data. I mean, you raise an important question as to whether we get those data out appropriately, and that's a good question that I'll think about. I think it's public perception that we have to change. You know, the data you're providing is not out there, as you said. People aren't aware of the harmful effects. And the local community has to vote. And it's analogous to the smoking, you know, the great improvements we've made in smoking from the time when physicians smoked in front of the patients to, you know. It is part of College AIM. I didn't talk about College AIM, but we sent out, I didn't even have anything to really do with this except to champion it once I became director, because they had already developed this before I came on board. But this is a menu of prevention options for college students, and it went to every university and college in the United States, and we repeatedly send it out there. But some of the options for prevention are community options, like outlet density, like guarding young people to make sure that they actually are 21 years old and not, you know, using their brother's ID card or their sister's ID card. And so, but you raise a slightly separate point, which is that, are we getting that information out to the general public? And maybe we're not. I mean, you know, it is a good question. And you can crowdsource it using physicians and other healthcare professionals to help get that word out. And we should crowdsource it with social media. That's another thing. Thank you. But I got to think about how we do that without me getting in trouble. This is an online question, and I believe we only have time for one more question after that. So, in terms of prevention, early education on alcohol and substance use at the middle school and high school levels for students and families appears to be a reasonable priority. Do you know of any advances in this direction? We're actually working on that right now. It's been something I've been pushing our division of epidemiology and prevention research to accumulate what we know about what works in middle schools and is effective in prevention. We know that D.A.R.E. doesn't work, but what actually does work? And some of the things that work, one of which I know is the good behavior game, it works very well. But some of these are, they're not exactly something that you can do in one afternoon. You know, these are things that require a lot of investing. So, stay tuned. Thank you. Please, go ahead. I want to thank my colleague here for bringing up the topic, because then I had enough courage to say what my question is. You know, I've been going to these meetings since 89 every time they're on the West Coast. And it's not, we really do need your putting the word out better, because just, for example, the decriminalization of marijuana, I personally have worked really hard, and I had the privilege, you need to let everyone know, I've been, 20 years, I've been quoting articles. There's a great article on the Journal of Clinical Psychiatry, volume one, issue number five, pages 45 to 47, that has a synopsis of the effects of marijuana, but in that they also talk about the combination with alcohol. And then, I just talked to the guy from the Psychiatric Times, I used to know the guy that was his predecessor when he was being persecuted by the Church of Scientology. I read that article in November before California criminalized it, and I personally called ABC, NBC, CBS, Fox, hey, CBS is the traffic thing that's here, Sinclair has bought not only them, but the one in L.A. and five different big metro areas, they refused to put that out there, that marijuana was the biggest crisis of our day from NIDA. And then, when they were decriminalizing it state by state, here in California, the newscasters actually on camera here in San Francisco, all the stations, would brought the substances and told you where you could buy them. And I told them, this was in that article, and it was the Journal of Clinical Psychiatry, that one I told you about, or this one that was making headlines in around November 2017, before in December they decriminalized it, this guy said he had had something with the DEA, a meeting in Arlington, Virginia, they've not put that out there. And the problem is here, that I'm going to say this to you, you don't need to know who it is, but many people who are psychiatrists have confessed to me over the years that, you know, I went to Stanford, and one of my friends divorced his wife for drugs and alcohol, and then he tells me in the early 90s that he's smoking weed with professors at the Stanford law, you know, medical psychiatry department in the law school. So that thing that's in that Journal of Clinical Psychiatry, volume 80, issue number 5, there's a lack of judgment, and people aren't aware, if anyone's done all that clinical, you know, work that I've done, but the problem is also that was in that news was that the California Highway Patrol had pleaded with our legislative body, it didn't get into any news that they'd already analyzed the data from Colorado and Washington State, but there were more deaths. And my demoralization was that there's a guy named Andrew who was doing a DUI check Christmas Eve. Excuse me. I just want to say that if you get the word out, you've got to talk to the psychiatrists that are running this place. The meetings have been having people, I know there are people that just don't think it's normal to talk about it because they confess to me that they do it, even addiction specialists. Excuse me. Yeah. So I want to say that to the younger people. I have to take. Please, please get the word out and understand I have a passion about preventing harm. I've had a number of my classmates die. Excuse me, ma'am. Yeah. That's all the time we have. I have to take another online question. Can you state your question in one line, please? Thank you. Sorry, we couldn't follow you, but after the session, if you would have a question, Dr. Coop will be happy to answer. Thank you. Final question. It's a little hard up here. We're getting lots of echoes, so it's not your fault. It's just, you know, so come up afterward and tell me the real story. So the final question here is, despite neurobiology of the rewards in the brain appears in the same area, why tobacco smoking and alcohol drinking are enhancing addiction of each other? Well, there are common elements to all the substances of addiction and the cycle, the three-stage cycle is common to all those drugs. So nicotine releases dopamine. Marijuana probably is acting on GABAergic mechanisms to influence the same circuitry to make you high. They all come and converge on some of these circuits, but from different points of intervention. So, you know, and once you've engaged the reward system and over-engaged the reward system, then this whole sequence of neuroadaptations take place, which are common to all the major drugs of abuse. You know, I mean, nicotine doesn't really get people as high as alcohol intoxication probably in a subjective sense. But you know, when you first start smoking a cigarette, you get pretty loopy, you know, but the tolerance develops very quickly. And now it's, now you're taking cigarettes just to quell the anxiety that probably not taking the cigarettes cause. And so all of these drugs, you know, hijack the reward system, but the part that's often left out of the equation is they definitely drive your stress system when they wear off. And so, you know, I always say there's no free ride in the brain. So you got to pay for whatever goodies you get. And that's particularly true about drugs. I mean, you know, all of you have probably got some big award or some huge accolade in your life. And then if you think about the day after you got that huge award or accolade, there's a little bit of a dip, you know, in the way you feel emotionally, you know, it's a withdrawal syndrome. All right. Well, that's part of the normal way our brains work. But when you take drugs, you just exacerbate that neuroadaptation. So there's a little bit of Kubian philosophy thrown in there. Thank you so very much, everyone. And thank you so much, Dr. Koop, for answering all these questions. Dr. Koop is still here. If you have a question or two, we'll be happy to answer. But thank you all for attending. Have a nice evening.

Dr. George Koob

National Institute on Alcohol Abuse and Alcoholism

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