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Combatting Alcoholism with Science
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Dr. George Koob became the director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in January of 2014. As director of NIAAA, Dr. Koob oversees a wide range of alcohol-related research, including genetics, neuroscience, epidemiology, prevention, and treatment. Prior to his tenure, Dr. Koob led a 10-year, NIAAA-funded, multi-institutional consortium dedicated to identifying the molecular basis of alcoholism.
After receiving his Ph.D. in Behavioral Physiology from Johns Hopkins University in 1972, Dr. Koob was a post-doctoral fellow in the Department of Experimental Psychology at the University of Cambridge. Dr. Koob has spent most of his career at the Scripps Research Institute, leading cutting edge research on the neurobiology of alcoholism and addiction. At Scripps, Dr. Koob served as the director of the Alcohol Research Center as well as the chair of the Scripps’ Committee on the Neurobiology of Addictive Disorders.
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The mission of the National Institute on Alcohol Abuse and Alcoholism is to “provide leadership in the national effort to reduce alcohol-related problems.” Since becoming the director of NIAAA in January of 2014, what have you done to help accomplish this mission?
We haven’t done anything in particular that is earth shattering, but we are in the process of doing a strategic plan for the next five years. In that process, we have identified areas that we think need special attention. Some of these are areas we have been working on for a long time, but we will continue to focus on them like fetal alcohol syndrome and alcoholic liver disease. Another area of strong interest is the effects of alcohol on underage drinking. Since I joined NIAAA, we have identified this as a particularly egregious problem for society. While the good news is that the percentage of young people engaging in underage drinking is going down, the intensity of drinking in adolescents, underage drinkers and even middle-aged drinkers is going up. What we are finding is that people are binging much more dramatically with much more intensity. Such binging, of course, has lots of pathological consequences so that’s become a focus area.
I am not a neo-prohibitionist. We went that way back in the day, and it had a lot of deleterious consequences.
Some of the other areas we are focusing on include the interaction of alcohol with post-traumatic stress disorder and the interaction of alcohol with the aging population. We are trying to develop a biosensor online that can measure alcohol intake similar to a Fitbit. We want to examine the low-level effects of alcohol in the sense of where does alcohol actually interact in the brain at a molecular level and how does it produce its effects. Believe it or not, that is largely unknown.
One thing I have taken on is a much greater interaction with the press. I do one to two interviews a week. We have been doing our best to translate the evidence-based science that has been done at NIAAA to the public. Speaking with reporters and journalists seems to be the best way to go about accomplishing that goal. People have been seeking us out more and more to access fact-based information and have their questions answered or, at least, addressed.
Beyond educating the public, we have a major interest in prevention. We have a big initiative about to be launched in a few weeks for prevention of underage drinking in college students. It’s called "College Aim" and will be on our website. It will be a menu of options for colleges and universities to choose from if they want to implement prevention programs. Some will be individual prevention programs, some will be community based, but this resource will provide a central place to find out how much such efforts cost and how well they have been validated.
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One final thing is that we are well aware that only about 20% of people with alcohol use disorder get any treatment whatsoever. We hope to address that issue and we are creating a division of medications development to improve treatment options. We also are trying to find ways to engage physicians, psychiatrists and medical professionals in general by teaching alcohol and addiction treatment, prevention and new research to them. We particularly want to focus on the medical school level and the residency level.
Before becoming the director of the NIAAA, you led a 10-year, NIAAA-funded, multi-institutional consortium dedicated to identifying the molecular basis of alcoholism. Can you tell us about the results of this effort and how it improved our understanding of alcoholism? Did it help to confirm the concept of alcoholism as a disease?
The answer for the last part of the question is yes. This was an ambitious enterprise and probably helped lead me to taking the job as director of NIAAA. There were multiple sites across the Western United States that I helped to coordinate to understand the genetic basis of alcoholism while also standardizing the animal models in relation to research protocols. We had to find individuals who could integrate the diverse findings and bring them into the domain of making effective predictions. In a couple of years, we were able to pull that all together and it led to some reasonably productive findings, including identifying a whole series of genes involved in neuroinflammatory actions that are activated during the development of excessive drinking in animal models.
The neuroinflammatory discovery opened up the door to understanding how alcohol affects the brain, interacting with the stress axis and affecting the autoimmune reactions. Things were just starting to come together during the last two years that I was directing the consortium. Since I left, this theme has continued. We really identified a whole area of neuroinflammatory activity associated with excessive drinking. In the process, the Drinking in the Dark (DID) Paradigm of binging that John Crabbe and his colleagues developed at Oregon while working with mice and the Chronic Intermittent Ethanol (CIE) Exposure Dependence Model have both been widely adopted in the field as a result of this work.
If you look at the standardization of procedures brought on by the work done, the consortium was a great success. Moreover, we pulled in a whole bunch of young people into this research and people from outside the alcohol field who are now quite interested in alcohol research.
As the director of the NIAAA, you oversee a wide range of alcohol-related research, including genetics, neuroscience, epidemiology, prevention, and treatment. In the past year, what segment of this research has produced results that surprised you? What were those results and why did you find them surprising?
It mostly was just things that were already in the NIAAA portfolio that I just didn’t know about. My specific focus had always been on neurobiology. We had been making significant progress in understanding inflammatory pathways in alcoholic liver disease, and, as a result, we may have some novel treatments coming up for alcoholic liver disease. We’ve also had some success with our medications development that were somewhat unexpected.
Varenicline, a partial agonist for the nicotine receptor in the brain that is used for smoking cessation, showed in a human clinical trial that was part of an NIAAA study that it could be used as a potential treatment for alcohol dependence. We discovered that ghrelin which is known as the hunger hormone and plays a major role in food intake might also produce alcohol cravings as well.
In addition, there is a burgeoning interest in oxytocin as a possible target for alcohol intoxication that may be disrupted in alcohol dependence. Our clinical team is working on trying to understand the pharmacokinetics of oxytocin when given to humans. The project is looking to discover whether oxytocin treatment decreases symptoms of withdrawal from alcohol and decreases drinking in people who have been consuming alcohol heavily for long periods and are physically and psychologically dependent on alcohol.
I did not know about the College-AIM project before I got to the NIAA, but I think it’s a brilliant idea. A recent epidemiological study that just came in showed an increase in alcohol dependence and alcohol use disorders in the past 10 years. It kind of goes on and on: There are so many things that are being accomplished at the NIAAA.
For example, we have some really dynamite epigenetics data from our Fetal Alcohol Spectrum Disorder program suggesting that there are genes that are turned on and that can convey this vulnerability if you drink during pregnancy. They may not be active unless you drink, which is highly intriguing. We made huge strides in the diagnostics related to Fetal Alcohol Spectrum Disorder and Fetal Alcohol Syndrome thanks to 3D-imaging combined with brain imaging.
We also have a really impressive study on the neurodevelopment of adolescents from 9 to 10 years old with brain imaging and cognitive testing We already are picking up how profoundly alcohol can affect normal neurological development with a decrease in grey matter that results in increased impulsivity as they get older. It has led to an enormous multi-institute prospective study on drug and alcohol abuse in adolescence with approximately 10,000 9 to 10 year olds that will include the participation of NIDA, the National Cancer Institute, and a whole herd of other institutes. It will be funded soon; it was one of the major things I didn’t know about when I first came to the NIAAA that I am very excited about today.
You began your career by studying the neurobiology of emotion, including how the brain processes reward and stress. Can you explain how this research applies to alcoholism and addiction? Is emotion the reason why addiction and alcoholism are so difficult to overcome?
In my opinion, yes. The short version is that I have come to believe from the literature and also from my own work in the field that negative reinforcement is a much more prominent component of the motivation to drink excessively than previously thought. Withdrawal has always been a conundrum in the field of addiction. People put a lot of weight on physical withdrawal, especially with opiates and alcohol, then they realize that relapse had occurred much later than the point when the people had been detoxified. They basically argued that withdrawal wasn’t very important. They kind of threw the baby out with the bathwater.
My view of withdrawal has nothing to do with the shakes. I don’t think alcoholics drink because they have the shakes. The shakes will be a sign to them that they’re not going to be able to hold down any food until they drink, but what really drives drinking in these kind of terminable stages of alcoholism is that the people just don’t feel normal unless they are drinking. This is a key part of the maintenance and the etiology of drinking. You can take it to the extreme of the old self-medication hypothesis and argue that people are only drinking to medicate some illness, but I don’t really take it that far.
I think people begin to drink because they enjoy drinking and they enjoy the feelings that they have when they are drinking because their reward system is activated. When they excessively drink, however, there are adaptations that take place in the brain to counter that rewarding effect, and those adaptations begin fairly early. You end up drinking to fix the problem that drinking caused. When you’ve reached that point, you’ve reached the point where I would define it as an alcoholic or an alcohol dependence. If you want to put it in DSM-V criteria, I would say that’s 4 to 6 of the DSM criteria being met out of 11. Anyway you want to define it, when you reach that point where you’re drinking alcohol to fix the problem that alcohol caused, and I’m talking about negative emotions, then you’re digging the hole deeper and deeper.
That’s not the only thing involved. You’re probably ruining your pre-frontal cortex when you drink excessively. I also want to add that the earlier you drink excessively, the more likely you are to ruin your pre-frontal cortex. Adolescents may be doing developmental damage by such drinking. It’s important to realize that the prefrontal cortex controls not only impulsivity, but also controls your stress response. In a sense, you are unleashing the demons from the dark side of your brain.
I really think that dysphoria is a major component of why people drink excessively once they’ve engaged. It makes the treatment for some individuals very difficult. I think we have neglected this part of the addiction process. That’s why I put a lot of emphasis on stress and negative emotions. We now know the stress systems are engaged in excessive drug-taking and, in particular, excessive alcohol intake. For that reason, there’s a lot of work going on now on the stress interaction and its relationship to excessive drinking.
We also know that most relapse occurs during negative emotional states. At the very least, when it comes to alcohol, we know this to be true in almost 70% of the cases studied. It’s also true for relapse with most other drugs and nicotine as well. The basic sciences have really been obsessed with the reward system, and the reward system is critically important. Without it, you don’t get on in the world, and you don’t find the nectar and the flowers. The reward system is probably how you enter the addiction cycle. But once you have gotten into the addiction cycle, the negative reinforcement plays a key role. I can go on forever, but that’s the short version.
That was a great short version and a great answer, Dr. Koob. Thank you for that. Here’s the next question: Do addicts lose control as their substance abuse disorder takes charge of their brain? Is this difficulty related to what you have described as the abstinence violation effect? In your answer, can you define the abstinence violation effect as well?
The abstinence violation effect is a social psychology phenomenon that was identified by a number of researchers in the past and it’s been rediscovered over time. Rodents show this effect as well so it’s not entirely cognitive. From a social psychology perspective, it really means that you indulged when you were planning on being abstinent. You basically say, “Oh, I’ve done it so I might as well just enjoy myself,” and you let loose. That can be driven by guilt and dysphoria that goes something like this; “I give up. I’ve relapsed so I’m a terrible person. I feel awful and the only way I can fix it is to drink some more.”
There’s nothing wrong with abstinence. If you’ve been involved with cognitive behavioral therapy or you work a 12-step program, you find ways to deal with a break or a relapse. It’s not catastrophic. But the abstinence violation effect in relation to alcohol can be catastrophized in a cognitive social psychology sense.
In animals, it’s different. I don’t really think rats are really looking at it in a cognitive way. In that case, there’s probably some change in the brain that involves a miniature version of what we study in more dependent animals. It’s a mini-dependence that sets the stage up for the alcohol to be more reinforcing when you reengage. In a social drinker, you may not have a beer for a few weeks. When you go to a picnic, that first beer you have tastes really good. This is a minor example of the reinforcement that applies in the abstinence violation effect. Then again, you may be really thirsty because it’s hot outside.
At the Scripps Institute, you focused on the neurobiology of stress, mapping out how a specific behavioral response triggers the nervous system to produce the sensations that lead to stress and anxiety. What do you believe is the connection between the neuroregulation of stress (a note to our readers—meaning how the brain regulates stress), the neuroadaptation to stress (meaning how the brain adapts to stress), and the onset of addiction and alcoholism? Can you also define “new stress” and the role it might play as a trigger for addicts and alcoholics?
The way I look at stress is that it can be either an acute challenge or it can be a chronic state. The chronic state is likely to drive negative reinforcement. When someone feels a low level of dysphoria or irritability, something that acutely suppresses the stress system feels really good. The argument would be that alcohol releases your endorphins and dopamine to make you feel good normally, but if you’re stressed, it makes you feel even better because it’s acutely suppressing the stress system.
With alcohol, the problem is that within even a couple of hours, those pleasurable effects wear off, the suppression of the stress system wears off, and there’s kind of a rebound with vengeance of the brain and the hormonal stress systems. That rebound has been pretty well documented in both animals and humans. What’s even more insidious is that alcohol, like other drugs of abuse, when the reward transmitters are released, another receptor system called the dynorphin that hasn’t really been talked about much is activated as well. It activates the kappa opioid receptors that produce dysphoric effects in the brain In other words, the dynorphin feeds back and shuts off the reward system when the kappa opioid receptors function as negative reinforcers, producing conditioned aversive effects.
This mechanism is part of our normal makeup and is a protective function. If we get engaged in too much reward, we shut it off. The system has a safety valve in the form of a feedback shutoff. The question I once asked in a paper is why would we have what I called Hedonic Calvinism? Hedonic Calvinism is a bit of an oxymoron because John Calvin was a noted ascetic. He believed you did all of your pain and suffering on earth so when you went to heaven, things were really cool. Still, why would biology limit your Hedonic activity. One reason might be that if you are over-indulging, the next predator down the road is going to indulge in you.
There are biological limitations in terms of how much pleasure we should be experiencing. For example, why aren’t we copulating all the time? The reason might be that we have a brain system that’s created to prevent us from doing that. Why would it prevent us from copulating all the time? Simply put, we are highly vulnerable to other predators or any other major catastrophe in the environment in that state. The stress system has an intimate interaction with the reward system. I don’t think that’s been well understood, although I have written about it in recent years. The two systems talk to each other and help to regulate each other. A little bit of stress can activate the reward system. Skydiving is such an example. But a lot of reward can activate the stress system.
Once it’s activated, the other insidious part of the stress system—think road rage—is that it stays activated. It stays activated for a long period of time. It’s built into us as animals for the stress system to remain activated. If you’re chased up a tree by a predator, the best solution is to stay up the tree. If you come back down, the predator is going to eat you because he’s hanging out down there and waiting for that to happen. You actually stay activated and stressed for a good reason. But this really works against you if you’ve been overindulging in alcohol. First, you’ve compromised your reward system and now you’ve activated your stress system. You’ve just set yourself up for what I would call a major spiraling distress.
As far as new stress goes, new stress just generalizes to any low-level stressors that a person might have as part of who they are. We know that childhood abuse is more represented in alcohol abuse. And 30-50% of individuals with post-traumatic stress disorder end up with an alcohol disorder as well. We know the interaction between new stress and those low-level stressors is intimate. New stressors can act as cues and triggers for relapse even though you’ve done the best job possible during cognitive behavioral therapy. Maybe you’ve worked through some of those past stressors, maybe you’ve taken mindfulness training to deal with the PTSD, but a new stressor comes along and just reawakens some of those pathways in the amygdala part of your brain that are well-greased and off you go.
It’s a tough challenge. That’s why in Alcoholics Anonymous, the people are very proud when they receive a chip, even after 15 years or more, because they remain very vigilant even years after they have achieved sustainable sobriety. One always has to be vigilant about how this stress component is going to interact with someone with a history of an alcohol use disorder.
You hope to provide a framework for further research that could identify the basis for individual differences in vulnerability to addiction. Could such research lead to a test where we would know at the point of birth whether or not a person has the potential to be an alcoholic or addict? Would such a designation be almost like the mark of Cain for a person, a sense that they are cursed to one day become an addict, or do you see it as an extremely effective method of prevention?
I guess I am more of an optimist that we will develop the neuroethics to properly manage this ability to predict vulnerability. As intelligent beings, I don’t think we’ll ever reach the point where it becomes a curse. It is going to be an issue that every disease studied at the NIH is going to have to deal with. We’ll probably never get to the point where we can absolutely predict that someone’s going to become an alcoholic. We’ll just be able to say with a little more precision that a person is more likely to be susceptible. I don’t think we’re ever going to be able to say that one gene predicts alcoholism. It’s a symphony of genetic loading and protein expression that leads in that direction.
What we learn from the genetics will be a way of supplementing what we already know from personal and family history. Whatever information we develop, I don’t think it will be a curse. Any information that leads us to a healthier lifestyle is going to be good for us.
You spent a lot of time at the Scripps Research Institute working on a cocaine vaccine that is designed to trigger the human immune system to create antibodies against the drug and prevent it from affecting the brain. At Cornell Medical College, Dr. Ronald G. Crystal has been working on a vaccine as well. What is the current state of the Scripps vaccine? Is your old research team at Scripps still developing the vaccine? Are they working in conjunction or in competition with the Cornell scientists?
Dr. Kim Janda is the person at Scripps who is overseeing and managing the work on the cocaine vaccine, and he has started all the work on these vaccines. Kim is the archetype of the Scripps researcher; he’s completely out of the box, he does wild and crazy things, but he’s really smart and what he manages to accomplish is just amazing. At Scripps, we started with the cocaine vaccine, and Kim’s now also working on a heroin vaccine. Ron Crystal, in collaboration with Kim and myself, attached a virus to the cocaine vaccine to increase the immunity reaction, and that’s now about to start clinical trials. We’re really excited about that development. But there’s no competition; it’s a collaboration between the three of us. Ron is doing most of the clinical work on the cocaine vaccine while Kim is doing work on the vaccine itself, refining it and creating better versions of what’s already there.
What I’m particularly excited about is the heroin vaccine that Kim has developed. We did all the work on that vaccine, and it’s a particularly cool vaccine. It not only makes antibodies to heroin, but to morphine as well. The vaccine produces antibodies to a constantly changing drug target. We call it the Star Wars vaccine because it makes antibodies to all the metabolites of heroin. The problem with heroin is not the heroin, but the morphine. Heroin doesn’t bind very well to the opiate receptors, but morphine does. Kim is now engaged in obtaining funding to bring that vaccine to clinical trials.
One thing that is clear from the work at NIAAA is that there will never be a vaccine for alcohol. Everyone tells me that such a vaccine is basically impossible. But the work on the cocaine vaccine and the heroin vaccine is continuing, and we are all friends, and we are hoping the work will bring us to home base soon.
In an interview with Bill Moyers, you mentioned the “hedonic system,” and when asked what that meant, you went on to clarify, “Pleasure system. Reward system. Reinforcement system…. I see it as a motivational system in our brain which gives us a tendency toward organized activity and guides us in our everyday lives.” In layman’s terms, can you describe how this reward system becomes so severely compromised by addiction?
The reward system gets activated by drugs of abuse. All drugs of abuse activate the dopamine system. Some drugs activate the endogenous opioid system as well, in a very dramatic fashion as well. When it comes to drugs of abuse, they activate either, or sometimes, both the dopamine system and the opioid peptides, and they interact. One of the key roles of the reward system is to bring you back to the place where you will be rewarded. Whatever leads a person to a reward on an ongoing basis will be connected to specific cues. This is why the alcoholic in long-term recovery will unconsciously get off the highway at the exit that he used in the past to go to the bar. Going to the bar to drink and hang out meant the reward. The exit was the cue.
Once those cues have been locked in, as you continue to activate the reward system over and over again, it’s the cues that elicit the release of dopamine and not the drug itself. While the drug does continue to release dopamine, there’s a great deal of transfer of the activation to the cues. As you anticipate the drink or the drug by a specific set of cues, almost in a Pavlovian way, you feel the rush.
The shift is when you take the drug and try to activate the dopamine system like you did before and suddenly it doesn’t work. It leads to what we call tolerance. The word is not used a lot by scientists anymore, but it’s a real phenomenon, and it’s part of the DSM-V criterion. I’ve never met anyone with alcohol use disorder who had not developed some form of tolerance. As tolerance develops, the reward system becomes compromised. The pioneering work of Dr. Nora Volkow has shown that once the dopamine system becomes compromised, it releases less dopamine despite the repeated administration of alcohol or other drugs. It is connected to the stress system we previously discussed and Hedonic Calvinism.
The onset of that tolerance is the beginning of the end, so to speak. Once the reward system becomes compromised, you overindulge to try to fix that problem. You keep taking more and more drugs or drinking more and more to get the same bang for the buck. In truth, you are activating the brain’s stress systems to an even greater extent. You are driving the reward system that you so desperately desire to activate into the ground. Eventually, you are drinking to fix the problem that the drinking caused in the first place.
You have contributed key reviews on the “dark side of addiction” in a number of prominent journals, including Annual Review of Psychology, Nature, and Neuropsychopharmacology. Can you explain what you mean by the “dark side of addiction” and how your work has helped to shine light on this darkness?
For me, the dark side of addiction is what we’ve been discussing. The dark side of addiction is the loss of the reward function and the triggering of the stress system. In the beginning, you were pulled to addiction by the high attractiveness of drugs, but this pull quickly gives way to the dark side. My argument is that it’s the consequence of overindulging in your reward system and triggering your stress system that becomes the central part of the story as the early attraction is removed. That’s what I call the dark side.
When I was in the early stages of my recovery from heroin and cocaine addiction, I honestly could not feel much of anything. My dopamine receptors had become compromised and needed time to recover. What would you recommend to people in the early stages of recovery to combat this experience?
Well, patience for one thing. You need time for those systems to recover. You particularly need time for the stress system to return to normal. The reward system does not act in isolation by itself.
There are many things you can do to help your reward system recover. Some of them are kind of obvious; healthy eating, regular exercise, reducing your stress level, cognitive behavioral therapy, even long after protracted abstinence. You need to engage in fruitful reward activities that are healthy. People with long-term sobriety tend to be engaged in many activities that they find naturally rewarding.
You need to strengthen the basic functioning of the reward system, but you have to be careful not to over-engage. You have to look out for stressors that you don’t even recognize as stressors. Sometimes a side comment from a family member can be enough to trigger the stress system. You not only have to strengthen the reward system; you also need to keep that stress system under control as much as possible.
Would you define alcoholism as being different from drug addiction? Should alcoholism be included under the umbrella of addiction? Are the legal status of alcohol and the history of prohibition the reasons why alcoholism is dealt with separately from other addictive diseases?
Alcohol is unique, and it rightfully deserves its own institute for all the reasons that you mentioned in the question. Alcohol is enjoyed by 70% of the population. Most of them don’t have a problem with it. Some do. Some may be vulnerable for different reasons. I am not a neo-prohibitionist. We went that way back in the day, and it had a lot of deleterious consequences. Some would argue the downside of prohibition is worse than the downside of alcohol use disorder.
I built my career on the idea that there are things we can learn about alcoholism that have implications for other addictions and there are things we can learn about other addictions that have implications for alcoholism. I learned a lot of things about alcohol in my brain studies that proved to be applicable to other drugs of abuse, but maybe not as dramatic. The way we work the institutes is complementary; a functional merge where NIDA and NIAAA are working well together on a whole number of projects.
There are aspects of alcohol use disorder like alcoholic liver disease and Fetal Alcohol Spectrum Disorder and the social issues that really are much different from other drugs of abuse. Whether you like it or not, alcohol is used widely as a social lubricant. Many would argue that it has beneficial effects. We are social creatures, and alcohol use loosens the tongue and allows people to interact more vigorously. Whether you drink or not, interacting with other human beings is one of the great ways in which we activate the reward system. Alcohol can facilitate that process in low doses and moderate doses. Alcohol use disorders are unique in terms of the biology, but I think they have a unique role in relation to society as well.