Dr. Amy Lasek, Ph.D., is an Assistant Professor in the departments of Psychiatry and Anatomy and Cell Biology at the University of Illinois at Chicago. After giving an excellent talk at our program “The Science of Addiction” earlier this year (see the trailer HERE, and the full video HERE), I caught up with her to ask some followup questions.
C2ST: Is there anything that you wish you had gotten to say at the program that you didn’t get to.
Dr. Amy Lasek: I didn’t really talk much about new therapeutic areas. I think there are a number of promising candidate drugs in the pipeline for treatment of alcohol use disorders and alcoholism. Some of these target the stress system in the brain, for instance the HPA (hypothalamic-pituitary-adrenal) axis and other areas that are responsive to stress hormones like cortisol. There are some interesting new therapeutics that are being developed based on that. We know that alcoholics have an altered response to stress, and that may promote continued drinking behavior.
C2ST: Is that stress response unique to people with alcohol use disorder, or is that common across other addictions, as well?
AL: You know, it looks like there are some commonalities with other addictions, so I think people are also looking at this, for instance, for cocaine addiction, and starting to look at new therapies that might be useful. Some of the things they are looking at are drugs that are already FDA-approved for other disease indications. This means that we may not have to develop a new drug, but there is already something there that could basically be repurposed for use in addiction.
C2ST: That sounds fantastic. An area that I know you didn’t get to talk about at all in your talk was your own research. I wonder if there is anything in that area that you wanted to say more about.
AL: Sure. We’ve been looking at new genes that have been characterized for their role in addiction, and one of the genes we found encodes an enzyme called a kinase. It has actually been well characterized for its role in promoting different types of cancer. The name of the gene is ALK—anaplastic lymphoma kinase—and there are a lot of new studies out there showing that inhibitors against ALK have actually been successful for treating certain types of lung cancer. So we’ve been looking at this gene for both alcohol and cocaine addiction. In our mouse models we found that treating the mice with the ALK inhibitors decreases binge-like drinking behavior. We also found that this inhibitor decreases the rewarding properties of cocaine. So it may be that something like an ALK inhibitor, which is totally new and used for cancer therapy, could be useful for treating addiction.
C2ST: So that’s another example of off-label drug prescription.
AL: Right, that may be off-label, and some of these ALK inhibitors are very new and they’ve only been approved for lung cancer, so they’d probably have to be evaluated, but it would be a new way to target addiction.
C2ST: That sounds great. Since you brought up genes that are involved in addiction, you mentioned in your talk that the heritability of addiction across different types is in the area of 0.5, and you listed a couple of genes that are involved. But insofar as we know that there is a pretty good genetic influence, how many genes have been actually identified that are involved in addiction.
AL: At least for alcohol use disorders, there are not that many genes that have been identified. There are, I would say, probably less than 100 that have really come out of these genetic studies. But I think part of the issue is that when we’re looking at the whole genome for associations between genes that may cause behavior related to addiction and alcohol dependence, we don’t yet have the statistical power to find some of these genes. And part of the reason is that we don’t have enough individuals in the data set, and so adding more people that have alcohol use disorders to studies would be helpful. I also think it’s complicated because not just one gene is going to be involved. Addiction is not the type of disease where you have one gene change and that definitely causes a disorder. It’s actually a combination of many different genes that would predispose somebody for risk. So you could imagine that there could be for instance hundreds of different genes that might be changed and might predispose someone for risk. Each gene would contribute a small amount to the risk, so it’s going to be the combination of many different genes that are going to be involved in the disorder.
C2ST: I know that in the last few years, researchers have begun to leverage big data to make discoveries about different psychological conditions—I know it’s been used for schizophrenia and autism, and I think some more—do you know of any current efforts that are under way to use the same kind of methods to study both the genetic causes and also to just better characterize the different forms of addiction.
AL: Definitely, like you said for schizophrenia, there have been efforts to use whole-genome wide searches and more sophisticated analysis methods to find new genes. That’s definitely being applied to addiction. Again, when you start talking about the big data analysis, you need lots and lots (tens of thousands) of individuals, and that’s what researchers found with schizophrenia. They are finding more significant associations of genes with schizophrenia, and getting better results when they increase the statistical power by having more individuals. So that’s definitely something that needs to be done for alcohol use disorder and other types of addiction. The addiction field is a little bit behind because accumulating enough people to look at that type of study is kind of complicated.
C2ST: To follow up on that, we know that substance use disorders are more common than schizophrenia, so why is it harder to get big sample sizes for that than it is for addiction.
AL: Well I think the fact that people don’t seek out treatment is part of the issue. With schizophrenia, it’s been much more accepted as a real psychiatric disorder, and more accepted by the general public and by the medical community as something that needs to be treated as a medical condition. And so getting the subjects may be a little easier for schizophrenia, whereas for addiction there is a lot of stigma attached to it. I can’t remember the numbers that Chris Holden had, but something like only 10% of people actually seek out treatment, and the way they are seeking out treatment isn’t through a medical provider, such as an MD at a research institution, it’s actually through rehab treatment centers which aren’t researching addiction. They’re doing treatment, and the treatments aren’t necessarily evidence-based. So I think part of it is a cultural, social, or a public health issue.
C2ST: So if you had the ability to re-engineer how we think about these things, what steps would you take to improve the quality of research?
AL: We need the public to be aware that addiction is a major health problem, first of all. Also I think then we will get more funding from the federal government. That’s directly related to how we can improve the quality of research, because your taxpayer dollars go to funding research. Once people are really aware that addiction is a major public health problem, that people need medical treatment, and that we need research to study the effectiveness of addiction treatments, it sort of flows from there that we would get the budget increase from the federal government, for example from the NIH (National Institutes of Health).
C2ST: Coming back a little bit to the heritability of addiction, I know that in your work, in order to study these disorders you induce addiction in laboratory animals. I wonder whether you see any variability in susceptibility to addiction in your laboratory animals, and if there is anything we can learn about that, given the heritability of addiction.
AL: There is definitely variability in the laboratory animals. It depends on what you’re looking at, but different animals will drink different amounts of alcohol and part of that is genetic—for instance, when we’re looking across different strains of genetically identical mice, there’s variability that’s likely due to genetics. But there is also variability within a strain of genetically identical mice—you may have differences in drinking, for instance, in those mice. And that actually may be due more to environmental factors. We’ve tried to control for that in the lab, but maybe there is some difference in how the mice were raised by their mothers, for instance. And so we see variability there, and the hypothesis of that is that it’s epigenetics. Epigenetics is a catchy term that’s been used a lot in the media, but it’s basically defined as “above the level of the gene”. It is not changes in the genes themselves, but changes in the way that those genes are regulated or expressed. We are just beginning to understand how epigenetic changes are altering behavior and how that accounts for some of the behavior differences between individuals as well. That definitely is an area of interest, and we’re working on that in my lab too—trying to understand the regulation of the genes, in addition to the changes in specific genes, and how those changes might control addiction.
C2ST: I’m hoping to talk a little bit more about epigenetics and what that means for this. It’s not enough that we have variation in a person’s environment that can contribute to the variation in substance use disorders, and it’s not enough that we have variation in genes, as well, but how the genes are regulated. What does this mean for us?
AL: The way I like to think of it is actually—I was talking about the environmental contribution is also about 0.5, so there’s a big contribution of environment. And my feeling on the environment is that that’s epigenetics, basically. So your environment can determine how genes are regulated in the brain. Basically that’s the level of epigenetics. All those life experiences that people have—early childhood experiences, exposure to drugs of abuse and alcohol during adolescence—that actually can have effects on the epigenome. It’s changing the way that genes are regulated in the brain, and that is changing behavior. To me, the environmental component is tightly related to the epigenetics.
C2ST: I know that there are some cases where epigenetic properties can be passed down to a person’s children, or even grand children, is there any evidence of that in substance abuse?
AL: I don’t think we know for humans if that’s the case. There are some new studies that in which researchers have started to look at that—it’s kind of a difficult thing to look at in people. In animal models you can start to look at transmission through generations of the epigenetic changes. It does appear that there may be epigenetic changes that occur in a parent that, as a result, changes the way the genome is organized in the sperm and the egg, and then that gets transmitted into the offspring. So there is a little bit of evidence for that, and it’s a really interesting thought that you can have something that happened in a parent’s life that changed the way their genes are expressed, and then that somehow gets transmitted to the offspring.
C2ST: So there’s, at least potentially, an extent to which substance use disorders can run through families in ways that go beyond shared genes.
AL: Right. So that’s the hypothesis now, and there’s still a lot of work to be done to figure that out. And it’s complicated because when you’re dealing with people, you’re dealing with the genetics and the epigenetics, and so it’s hard to disentangle those things. But I think with the animal models we can start to control for each of those factors and then look at how that affects the offspring. But yes, that would be the idea that there are epigenetic changes as well, and they contribute to addiction.
C2ST: Let’s talk about the range of addictions. So when people hear the word “addiction,” they usually assume that it refers to intoxicants like alcohol, heroin, etc. But we also hear about things like sugar and caffeine being addictive. Is that a real thing?
AL: I think it is. I think that, for instance, food addiction, such as sugar. Sugar affects the same neural circuitry as other drugs of abuse (the dopamine system). But the extent of the effects in the brain are much less than those of drugs of abuse. Drugs are really like a sledge hammer on your dopamine system. There may be certain individuals, because of their genetics, who may be more predisposed to become—I hate to use the word “addicted” to sugar—but who may have more of a problem. I wouldn’t call sugar a drug, because people don’t lose their jobs over it, or lose their families, or have physical dependence on it. But there are some characteristics of behavioral addictions that have characteristics of drug addiction. The overlapping neural circuitry contributes to that. But it’s much less of a problem than being addicted to drugs of abuse, just because the drugs have such a strong effect on the brain. Again, there’s the idea of gambling addiction, which of all the behavioral disorders is the most well-characterized as far as having a genetic component. But I think in terms of sugar and caffeine, it’s still not completely clear—they do not have effects that are as strong as other drugs.
C2ST: Just to summarize what you just said, the typical drugs of abuse, like heroin, present to the brain a supernormal stimulus, whereas things like sugar and sex create a brain stimulus that’s within the normal range, so only one is making the brain do things that it isn’t designed to do.
C2ST: And related to that, the five-second definition of addiction that Chris Holden gave at the program was “continued use despite harm.” So something like sugar is a normal part of our diet, and you can develop type II diabetes after many years, but I can eat cake for breakfast and go to work and not lose my job, but I can’t do heroin for breakfast and not lose my job.
C2ST: The way that you might look at addiction versus the way Chris Holden might look at addiction might be a little bit different. He’s looking at it from a clinical, diagnostic perspective, and you’re looking at it in terms of what it does to the brain. Is there a way that you might think of or define addiction that might be different from the clinical definition?
AL: No, I wouldn’t want to change the definition of addiction, I just think that when you take the characteristics of addiction, we’re trying to find the underlying neural mechanisms that cause it. For instance, doing something that causes you harm and continuing to do it. So how do you model that in an animal, that compulsive behavior, despite the fact that it may be causing you harm. So what are the mechanisms in the brain that cause that to happen? Where in the brain are we seeing changes that might be related to that compulsive behavior. So I wouldn’t say that we have a different definition, it’s just that we’re trying to take individual components of that definition and really try to understand what the mechanisms are, and if we understand that then we may be able to treat it a little better. The problem is that, in animals, you can’t really model things 100%. They are just models, just pieces of the puzzle, so we use as many different models that we can to try to figure out how we explain these underlying mechanisms.
C2ST: Another sort of in-the-middle item is nicotine. Again, it’s not an intoxicant, it maybe falls into the same category as caffeine.
AL: It’s a psycho-stimulant. I don’t study nicotine, but it’s definitely highly addictive. There are many, many people who have trouble quitting smoking. I wouldn’t say necessarily that it interferes with people keeping their jobs and things like that, but it’s definitely addictive. There is dependence, and it’s harmful to the point where we know that smoking leads to lung cancer. Again, the same mechanisms in the brain are involved with nicotine addiction. It’s kind of interesting, because, again, it’s not like heroin, with obvious negative consequences that happen very quickly after use, but I think it’s still a major public health problem.
C2ST: This also might be another situation where the usual definition that we’ve been talking about here might be a little strange. Is there an extent to which the clear harm done by smoking tobacco that any use of tobacco at all is use despite harm?
AL: Yeah, I think cutting back on smoking is probably better than not cutting back on smoking, but not smoking at all is the best thing you can do. I don’t know if we know how much you can smoke and be okay, and not put yourself at risk of developing lung cancer and emphysema. Which is an interesting idea, because maybe not smoking at all is the best thing you can do. With alcohol, that’s not exactly the case. You can be a moderate drinker, and actually moderate drinking has been shown to have some health benefits. So I’m not sure exactly how to answer that, but it’s an interesting idea.
C2ST: I know that this isn’t exactly your area, but do you know whether nicotine addiction causes the same changes in the brain that things like heroin and alcohol do? You talked during the program about how abuse of these substance leads to damage in the brain regions that are involved in things like self control, and does nicotine affect the same brain regions?
AL: I think it does affect the same brain regions, you’re right that it isn’t really my main area, I’ve mostly been working on alcohol and cocaine, but definitely there are receptors, at least in the very early binge intoxication phase, in the areas of the brain that are involved in the reward system, and nicotine is definitely involved in that system, and I don’t know the literature on it that well, but I’m sure that there are also changes that occur in the limbic system and the emotional centers of the brain. I wouldn’t be surprised if there are some effects on the prefrontal cortex. It may not be as dramatic as the other drugs, in terms of the type of damage that occurs, but if you think about nicotine abuse, people tend to get anxious when they haven’t had their cigarette, and they go through withdrawal, and so it wouldn’t surprise me if there are effects in the amygdala and some of these brain regions that modulate negative emotional states during drug withdrawal.
C2ST: This goes back a little bit to a discussion we had earlier. We tend to casually use the word “addiction” to refer to the pathological use of a variety of different compounds, but to what extent is this one thing? For example, in a practical sense, there is an idea in the common lore that if a person is addicted to, say, cocaine, and they stop using cocaine but they start using, let’s say, heroin. Will they immediately start using heroin in the same fashion that they were using cocaine in, or do they then have to develop a new addiction to the heroin?
AL: That’s a good question. There are a lot of people who are poly-substance abusers. They use many different drugs. And there is evidence from the animal studies that you can develop a cross-addiction. An animal that’s become addicted to cocaine, for instance, will self-administer more heroin, so they are already showing escalated use. So I think there is some evidence that you can be addicted to multiple drugs at once, and maybe there are changes in the brain that have already occurred that are not necessarily specific. But that may not necessarily be true of all individuals, so maybe certain people are more predisposed to that than others. Some people say, “well, my drug of choice is alcohol,” and that’s pretty much the only substance they abuse (other than nicotine) instead of other drugs of abuse. But there are other people that will use many different types of drug to get high.
C2ST: I want to talk a little bit about diagnosis. With psychological diseases in general, health professionals rely very heavily on self-reporting for diagnosis, whereas for things like diabetes, we have objective, physiological tests to see if you have diabetes, we don’t rely on just personal reports. I know that there are certain psychological disorders for which they are developing blood tests. I believe I’ve heard that depression and schizophrenia are both having blood tests developed for them. At the program, Chris Holden said that diagnosis can be difficult because people aren’t always honest about their drug use. So it seems like here there is a particularly important role that objective, physiological tests might play, and I wonder if anyone was working on that kind of thing for addiction.
AL: Yeah, I think that’s an interesting concept, the idea of biomarkers, things that we can test in your blood to figure out if you have some characteristic of a disease. I think it’s sort of early, but there are people working on that. They are trying to figure out whether we can characterize based on somebody’s biological criteria how to treat their addiction. But it’s very early stages. You can obviously do a drug test and look at metabolites for different drugs with a urine test. You can tell if people have taken drugs or not, and I think it would be interesting to match the severity of their disease with a self-report and see if there is a way to think about how you would treat somebody who has certain biological characteristics. It may be more useful in stratifying patients in terms of how you would treat them. Maybe in the next five or ten years we will have a better idea of how to objectively map characteristics of addiction. One of the ways of doing that is also epigenetic changes, so if you take a drug over and over, that’s your environmental exposure, and you’re changing the brain in an epigenetic way, rather than a genetic way, and can that be reflected in a blood test or something, to look at those epigenetic changes.
C2ST: From where you stand, what do you think is the biggest question in your field right now that, when answered, will lead to better fundamental understanding or better treatment of this disease?
AL: I think the biggest issue is really how can we prevent relapse. If we knew, really solidly, the mechanisms in the brain that cause relapse, and we could then go back and target those areas of the brain, or molecular factors. That would be the most useful thing in the field. And obviously, preventing people from becoming addicted would be even better, but that’s almost impossible to do, I think. The issue is really how do we keep people from relapsing. Addiction is a chronically relapsing disorder, and people who get treatment want to get better, but then they have trouble in their lives and they relapse. I think understanding that, and trying to find new treatments based on that would be the best thing.
C2ST: Do you have any books or articles that people could look at for further reading on this topic?
AL: I don’t think people are aware of two websites: the National Institute on Alcohol Abuse and Alcoholism (NIAAA.nih.gov). I don’t think people are always aware that they can go to the NIH website and find interesting facts about addiction, news about alcohol, how it affects people’s health, and new treatments. This is really the source for facts that you can trust. What’s on that website is evidence-based. The other website is NIDA—the National Institute on Drug Abuse.
C2ST: Thank you so much, this was great.
AL: You’re welcome.
There is a very popular TED talk by Johann Hari titled, “Everything you know about addiction is wrong.” I asked Dr. Lasek whether she had seen that, and whether she agreed with his comments. She had not seen it, but followed up a few days later by e-mail:
Dr. Amy Lasek: I listened to the TED talk yesterday. It was very interesting. I do not disagree with the points that Johann Hari outlined in his talk. I did have a few comments.
He begins by making a comment about people being given opiates for surgery or taking drugs (during the Vietnam war) but not everyone taking these drugs becoming an addict. He then goes on to state that an enriched environment i.e. “rat park” may explain why some people become addicts and some do not. I agree that the environment plays a role in the development of addiction and that changing the environment can help with addiction recovery. However, I think this is only part of the picture. A genetic predisposition makes some individuals more vulnerable to the effects of drugs, and this can interact with the individual’s environment.
If you look at the numbers of people who use alcohol or drugs of abuse, only a small percentage of people become addicted. This has also been shown in animal studies, where we see individual variability. Again, part of this may be due to the individual’s environment, but also their genetics.
When it comes to treatment, I do agree that supporting people by providing a good environment, helping them get back on their feet, having positive relationships etc rather than punishing them is the way to go. I would agree that large lifestyle changes and a supportive environment are necessary for the maintenance of abstinence. However, many individuals will also need treatments, which may involve pharmacotherapy and cognitive behavioral therapy in addition to large changes in their lives.