DRUGSTORE COWBOY July 30, 1998

Pre-Movie Introduction:
Dr. Bruce Fuchs:
Hello everyone. Welcome to the second film in our 1998 summer film series, Science in the Cinema. My name is Bruce Fuchs. I am the director of the Office of Science Education and that office sponsors this film series and has sponsored it for the past five summers.

We're lucky to have with us as our guest tonight, Dr. Alan Leshner, who is the director of the National Institute on Drug Abuse. I will be back to introduce him after the film. But before we start our film tonight, which is Drugstore Cowboy, a 1989 film starring Matt Dillon and Kelly Lynch–a pretty rough film, as many of the films are on drug abuse, Dr. Leshner has asked me to show you a single slide to give you a definition of addiction–something that he would like you to think about as you view tonight's film. And then he'll discuss the concept of addiction further after the film and you'll be free to ask any questions of him. You'll see that the slide says "What is addiction–it is compulsive drug seeking and use in the face of negative consequences." And I think tonight's film is certainly going to illustrate some of those negative consequences for us. So let's go ahead and watch Drugstore Cowboy and we'll be back after that.

Post-Movie Discussion:
Dr. Bruce Fuchs:
Good evening again. We've just watched Drugstore Cowboy, a 1989 film starring Matt Dillon and Kelly Lynch. We wanted to do a film that depicted drug abuse, and we actually chose this film for its fairly grim and unglamorous depiction of drug abuse. Unlike many films that you'll encounter, there is very little attempt to gloss over or glamorize the down side of drug addiction. We're pleased this evening to have with us one of the world's foremost experts in drug addiction. He's Dr. Alan Leshner. He is currently the director of the National Institute on Drug Abuse. Dr. Leshner received his bachelor's degree from Franklin and Marshall College, where he studied psychology. He got his master's and Ph.D. degrees from Rutger's University, where he studied physiological psychology. He then became a professor at Bucknell University for about 10 years. During that time he had visiting appointments at the Postgraduate Medical School in Budapest, the Wisconsin Regional Primate Center. He was a Fulbright Scholar at the Weizmann Institute in Israel, and then after that period of 10 years, left to join the NSF–the National Science Foundation–where he held a variety of senior-level positions. In 1998 [sic–1988], he joined the National Institute of Mental Health where he served both as deputy director and acting director for a period of time. And then in 1994, he was appointed as the director of the National Institute on Drug Abuse. NIDA, I will tell you, supports about 85 percent of the world's drug abuse research. And so please help me welcome its director, Dr. Alan Leshner [applause].

Dr. Alan Leshner:
Thank you very much. I was going to start out by saying that advances in science over the last decade have totally revolutionized our fundamental understanding of the phenomena of drug abuse and addiction and then I watched the movie and realized that the truth is that it actually captured in its essence some of the essential issues, but I am going to put it into somewhat more modern terms if I can make the slides work.

Basically, I've spent a lot of time trying to figure out a way to conceptualize what I think is a fundamental point about drug use. You know, we spend a lot of time talking about risk factors, what makes people more or less likely to use drugs, but the truth is that the majority of people who have the majority of risk factors never use drugs. And so I've done an in-depth analysis and come to this tremendous insight that there really are only two reasons that people use drugs: either to feel good or to feel better.

And those are actually two different groups of people out there in the world, and it matters tremendously because both the prevention approaches and the treatment approaches you would use for them are different. There is a subset of people who use drugs simply to feel good. Those are what we call sensation or novelty seekers, and there's another group of people who feel terrible to start with and they use drugs to make themselves either feel normal or to feel better. We call those people self-medicators.

Well, whichever the reason, and I won't harp on that–maybe we can come back to that. The truth is that people are using drugs to modify their mood, their perception, their emotional state. And the way in which drugs do that is by modifying their brains. And therefore, I think, we're fond of saying that the major reason that people use drugs is that they actually like what it does to their brains, whether it's to feel good or to feel better. And this is your brain on drugs. For those of you who may know me, I'm incapable of giving a talk anywhere without brain slides. In 1998, we have tremendous sophistication and understanding of what drugs do to the brain–how they produce changes in mood, perception and emotional state.

The top row, these are functional MRI–magnetic resonance imaging scans. The top row shows you actually an odd diagonal slice through the brain, showing activation in different brain areas of a cocaine addict given an intravenous injection of cocaine, compared to the same individual given a saline injection. And basically the point is that we can look into the brain of a living, breathing, awake, behaving individual as he or she experiences a drug experience and see activation in various areas, and they like it. They like it because it actually causes in the base of the brain a spike in a chemical called dopamine, and that dopamine spike is characteristic of every abusable substance, whether it's alcohol, heroin, nicotine, cocaine, amphetamines, marijuana. Even though they all have their own effects, they all have that common effect. So people use drugs ‘cause they like what it does to their brains.

The problem, and I think the movie illustrated this, the problem is that prolonged drug use actually changes the brain in fundamental and long-lasting ways that persist long after the individual stops using the drug. And this one, I hope you can see it clearly, this is actually the brain of a vervet monkey. The measure here is the ability to produce that substance, that neurochemical dopamine, and you need dopamine among other things for the normal experience of pleasure. So if you can't produce it, actually not only do you not experience pleasure in normal ways, but many people experience severe depression.

Now, the measure here is the ability to produce dopamine. Red, yellow and white is more, blue is less. What you see on the top row, in the base of the brain is a normal ability to produce dopamine. This monkey then got two shots of amphetamine a day for ten days. And four weeks later, that's four weeks after the last drug shot, you see that decrease in the ability to produce this important neurochemical. Six months later, it's still reduced. It's 80 percent back at a year and 100 percent back later. The point here is simply to illustrate that prolonged drug use changes the brain in ways that last long after the individual stops using the drug.

What we believe is that it's as if there were a switch in the brain, that is, that you begin in a state of voluntary drug use, where the initial use of drugs is in fact a voluntary choice. It's a decision. You use it ‘cause you like what it does to your brain and then it's as if there were–this is a metaphor, right, you don't actually have a little switch in your brain–but it's as if there were a switch in the brain, and after prolonged drug use, what actually happens is the switch flips. And you move from a condition of voluntary drug user to where we had that initial slide, compulsive drug user.

What's important in addiction is not what most people think of, which is physical dependence–you know, having withdrawal symptoms when you stop using a drug, but actually the compulsion to use drugs in the face of negative consequences. And that's what the brain change results in. That is, you use drugs, you like what it does to your brain. Over time, the switch flips. Some people are more or less vulnerable to switch-flipping. For some people it switches more quickly than others. But ultimately, when it switches, you move into a qualitatively different state. What we say is that drugs hijack your brain. They literally, in some sense, capture and take over your brain. The consequence of that is that they take over your mind, and then, as was so dramatically depicted, they take over your life.

I wanted to do that just to give us a little bit of an introduction and I hope that we can have a discussion around some of these issues, but I just summarized for you actually everything that science has taught us after 20 years. That is, drug abuse is a voluntary behavior, but drug addiction is a disease. It's a disease of the brain that comes about because of what prolonged drug use does to the brain, thereby, resulting in that state of compulsion that's the essence of addiction.

Let me make one more comment and then I'll open the floor. I was very struck by the insightful comment that Bob made when he was talking about his experience that you can't talk an addict out of being an addict, or you can't talk an addict into just giving it up. And that's true. That also took us 20 years to discover scientifically. But the phenomenon is a state of compulsion and it's very difficult for people to conceptualize that, but I thought that that was beautifully depicted in this not beautiful movie.

Answer: Actually, an unnamed predecessor of mine as a NIDA director did an unwitting tremendous disservice to this country by describing methadone as a substitute for heroin. Okay, it is true that methadone occupies the same brain receptors that heroin and morphine occupy, but pharmacologically, that is, in the way in which it affects the brain, it's actually much more similar to natural opiates–endorphins and enkephalins–than it is to heroin. What happens with methadone is that it appears to occupy those brain receptors and thereby, in some way, reduce the craving, reduce the compulsion to use drugs. It's analogous more to a replacement treatment, I would say, than a substitute treatment. It also is the case, by the way, that it's a tremendously effective medication because there are many, many people living totally functional lives who've been on methadone treatment for 10 to 15 years. They don't experience those same kinds of peaks and valleys that people experience when they're using heroin. They don't have those tremendous mood changes. Some methadone patients do report some mild buzz experience, but, by and large, methadone patients don't experience any kind of a high. It's as if it were a replacement treatment.

Question: In your very first slide you talked about negative consequences. Is there an altered perception on the part of the addict of such consequences?

Answer: There's no question that for an addict the primary and most powerful motivator in his or her life becomes the drug. You know, I once had a very humbling experience. I was being my eastern liberal self visiting a drug treatment program talking to this young man who was taking me around and I said gee, you know, your self-esteem must be so much better now that you're clean and living the good life, looking like me. And he said self-esteem has nothing to do with it. You need to understand when you are an addict, you don't have low self-esteem and you don't have high self-esteem. When you are in the midst of addiction, all there is is drug. It is the only motivator. It's not that women don't love their children when they are cocaine addicts and sell their children. It's that the most powerful motivator in the world seems to be that compulsion to use drugs. So they actually appear not to be affected by the negative consequences. It's hard to say whether they experience it, but I think that's very individual. But at a minimum, the compulsion is a more powerful motivator than anything.

Question: I'm wondering is it possible for people in a methadone clinic to also be taking drugs?

Answer: There are people who use drugs while still on methadone. Methadone does not precipitate withdrawal. That is, it's not an antagonist–it's an agonist–and so there are people who continue to use heroin. They use less heroin and the data are basically that methadone treatment reduces drug use by about 70 percent overall but it does not obliterate it. It is not a magic bullet. It's very important that, as much as addiction is a brain disease, it's not just a brain disease. It has behavioral and social context components to it, and therefore, the best treatments combine medication with behavioral and social treatments. Methadone by itself will not do it.

Question: In your presentation it appears that the brain recovers after a period of time. If there's continued use, is there any permanent damage to the brain?

Answer: Whether there's a permanent effect of drug use is -a- dependent on the particular drug being used and -b- of course the measure that you're taking over time. We believe that some of these very dramatic kinds of effects like the one I showed you do recover over time but if you think about it, since memory, any memory, is in fact encoded in a change in the brain, there is some permanent change and we know behaviorally that people, of course, can have craving elicited 20, 30 years later. This is the longest measurements we have of a change being followed over time. We've seen changes after cocaine in humans that persist four to five months that are very dramatic and we don't really know whether the brain ever goes back fully to wherever it was before, but it certainly is changed.

Question: The depiction of the drastic event in the movie caused Bob to turn around his life and go to rehabilitation. Is this something that happens from your experience, that a drastic event in an addict's life will turn his life around and will seek rehabilitation? And if so, this is psychological impact so how do you really deal with that?

Answer: Our best estimate is that about 15 percent of addicts seek treatment in any year. You know, hard core addicts. And it's not clear what precipitates it. There's a glib response which is that most addicts certainly believe that people only go into treatment because they've been court- mandated or mommy-mandated. You know, that you're forced in some sense to go into treatment. You don't, by the way, need to want treatment. That's a myth. Coerced treatment does work, in contrast to popular belief. But the literal trigger to go into and begin a treatment program I think can vary tremendously. There are people who decide, you know, I'm done, I'm finished, but it's a very small minority of people who are able by themselves to just exert that amount of will.

Question: I have another question turned in from the audience. In the movie it seemed that the different drugs were used interchangeably. It didn't seem to matter what they used as long as they used something. Is that realistic? Do they all hit the same receptors?

Answer: Ooh, that's a good question. There are two parts to that answer. First of all, very few people are actually pure anything addicts.

Question: There are certain classes of drugs such as selective serotonin-reuptake inhibitors and tricyclic anti-depressants that make people feel better yet are legal. Could you comment on what makes things like cocaine illegal? What makes things like Prozac legal and what does drug abuse -- how does drug abuse play into those decisions?

Answer: That's a complicated question in the sense that I don't know how the value decision was originally made, for example, to legalize tobacco that causes 435,000 premature deaths a year, or to legalize alcohol that causes 110,000 premature deaths a year. So there's a whole overlay of value issues that gets place on it. From a health perspective, our concern, of course, is with anything that interferes with normal functioning. And so most of the drugs that we study as abusable substances depend on how that drug is actually being used. Cocaine and cocaine derivative substances can be an effective medicine when used appropriately. Morphine certainly is an appropriate and useful treatment for pain. I think it's the self-medication that interferes with normal functioning that moves you into another domain. Yes sir?

Question: What happens to the brain after a person has stopped using drugs for a long time and do you make more brain cells? I've heard that drug use kills brain cells. Do you actually make more?

Answer: Some drugs kill brain cells. Most drugs actually don't kill brain cells. Methamphetamine is probably today's most neurotoxic substance–except for inhalants, which are the equivalent of drowning. But methamphetamine happens to be particularly neurotoxic, both to dopamine and to serotonin neurons. But most drugs don't literally kill brain cells, but they do modify brain function in significant ways. Originally, five years ago I guess we thought adults didn't grow brain cells and in the last few years we've realized that they do and I think that's changing. It appears that at least the major things we are measuring can return to normal over time, but we may be missing something critical, right. I just don't know.

Question: Another question from the audience. Are there any physiological characteristics that make people more propense to drug addiction, greater propensity?

Answer: Yes, there's tremendous individual differences in people's vulnerability to being addicted. Some people seem to be tremendously resistant to becoming addicted. Other people become addicted very rapidly. It's a myth that the first time you use a substance you become addicted automatically. I don't know about you, I was taught that in high school. That if you walk in a room where heroin is, you'll be a heroin addict for the rest of your life. That's not true. However, some people are very susceptible to becoming addicted, some people are less susceptible. That seems to be, in part, genetically determined. A number of studies have been done looking at heritability influence–genetic influences–on the likelihood of becoming addicted. And depending on the particular study, the heritability ranges are from 30 percent up to–I saw a study of 70 percent heritability, that is determining the individual differences. We actually don't know very much about what makes some people more or less susceptible to becoming addicted. I do believe myself that everyone ultimately would become addicted were they to use enough of a drug. I can't prove that.

Question: My question is this: you showed analogy of a switch where you go from voluntary to addiction. Have they ever used electric shock treatments to throw that switch the other way and possibly get rid of that? I'm just giving the same thing as analogy, not a physical demonstration of throwing a switch. I'd like to know if that has been used and have they used mind-breaking drugs, they also can change stuff in the brain and just switch things around with certain drugs and my last question would be is L-dopa involved in any of this at all?

Answer: L-dopa doesn't seem to do a whole lot to drug use. Your question actually is a very good one and coincidentally, yesterday I was looking at a history book and there was a picture in it from the narcotic farm at Lexington, you know, the old Lexington hospital. That's where my institute used to be, before me. And there was a picture in that of a guy getting electro-convulsive shock treatment ostensibly to treat the addiction. There is no evidence that it actually works. It is the case that for people who have comorbid mental disorders, we know that you need to treat both the addiction and the comorbid condition, whether it's depression, bipolar disorder, or schizophrenia. And that once you have the drug use under control treating the underlying disorder does obviously increase the likelihood that there will be success in the treatment. But your notion is an interesting one and coincidentally it was quite a picture. I should have shown that as a slide.

Question: Hi, could you say something about what treatments may be available in the future, which ones are in the works, and whether or not you think there is potential for a magic bullet at some point in the far future. How far away are we from that? What can we expect to see in say, 10 years or 20 years as far as new treatments?

Answer: Good question. It's my view that there will never be a magic bullet. I wish there would. I would be the most successful NIH institute director. I could solve the whole thing, drop the bullet in the water, and everybody would be okay. It's a complex biobehavioral disorder and ultimately the best treatments are going to have to address the biology, the behavioral, and the social aspects. Having said that, we actually have a large number of scientifically developed, tested behavioral treatments and a few, not many, pharmacologic treatments for addiction. We're making a lot of progress in understanding how to combine them effectively and my institute devotes almost a hundred million dollars a year to the development of new medications. We are taking the first two compounds for cocaine addiction into multi-site clinical trials this fall. We have a new opiate medication that will be far less abusable, we hope, than methadone and might actually get into doctors' practice, which is where we'd like to see it. So I would say in the next few years you are going to see some new medications for various addictions. They will use different approaches from the more traditional approaches and hopefully they'll be more effective, but there are treatments on the horizon.

Question: Another question passed in. When I speak with young people, they don't believe that marijuana is bad for you or as bad as alcohol which I enjoy moderately. What is the response to this opinion?

Answer: Marijuana is not a benign substance. Alcohol, by the way, is also not a benign substance whether the person enjoys it or not. There is a lot of misunderstanding about marijuana, some of it coming from the hyperbole and the exaggeration that we had through reefer madness. And we sort of had a pendulum swing. We actually know quite a bit about marijuana. Marijuana obviously affects your mood, your perception, your emotional state. It changes short-term memory. It's intoxicating. Studies have been done in our own labs that show it makes you do badly in the same drunk driving tests as alcohol does. The short-term memory effects for heavy users, not the acute effect, but for heavy users seem to persist 24 to 72 hours after that person stops taking the drug, so it can have a persistent effect. The big question people always ask me is is marijuana addicting. The answer to the question is marijuana is an addicting substance. The data are that for people 12 to 17 years -- I don't want you to think I answer this question six times a week. For people in the age range of 12 to 17, between 15 and 20 percent of those people who try marijuana meet medical criteria for marijuana dependence. Overall the number is 8 to 10 percent. That's comparable by the way to the levels of people becoming addicted whoever try cocaine or heroin or alcohol. Cigarettes are about 30 percent. That does not mean nicotine is the most addicting substance nor that marijuana is the most addicting substance. Those comparisons are sort of meaningless. But in my view, marijuana is not a benign substance. It's intoxicating and it has negative consequences.

Question: Yes, you mentioned self-medication and treating co-occurring mental disorders and substance abuse. Is there a correlation between an addict's drug of choice and a mental disorder?

Answer: That's a great question. We actually don't know the answer to that. Some of what seems to happen is that for those people who are self-medicating, they'll self-medicate with whatever they hit first. If it works a little bit, then they do well with it. I think the answer is that we don't know, but we do know that a lot of depressed people obviously like stimulants. This isn't a big shock. Heroin is probably not a great medicine for a depressive. But outside of that, a lot of it seems to be accident and what people-- at least I'm not aware if there is a systemic relationship between a particular disorder.

Dr. Bruce Fuchs:
Before I ask the audience to help me thank Dr. Leshner for his help here tonight, I will invite you all back next week to view Children of a Lesser God. Our guest expert is going to be Dr. James Battey, who is the Director of the National Institute on Deafness and Other Communication Disorders. Now please help me thank Dr. Leshner [applause].

Dr. Alan Leshner:
Thank you.