In this occasional series we record the views and personal experience of people who have specially contributed to the journal's field of interest. Charles R. (‘Bob’) Schuster is Professor of Psychiatry and Behavioral Sciences and Director, Substance Abuse Research Division, Addiction Research Institute, at Wayne State University, in Detroit, Michigan. He has made fundamental and varied contributions to the application of learning theory to understanding of drug taking and drug dependence.
A: Bob, if there is an organizing principle in your career, it has been the application of learning theory very broadly to problems of drug abuse. How did you become interested in behavior and psychology, and how did you become a drug abuse researcher? Does this date back to your days as a university undergraduate?
CRS: I would go back even further. My mother was an excellent musician and I started to play the trumpet when I was 5 years of age. My older sister Bette was a poet and a jazz lover. She went to the nightclubs in Philadelphia and met a lot of jazz musicians and invited them to come and play at our house on Saturday afternoons. We provided food and drink but it helped that Bette was beautiful. Anyway, the people who came would encourage me to play with them. I got to play with a lot of well-known guys from the big bands and by the time I was 15, I started playing in local nightclubs. So, my high school career was sort of a disaster. I did manage to be a C + student but that was because my mother was a schoolteacher as well as a musician. I had a certain amount of knowledge just because of the household that I lived in, but it certainly was not due to working hard in school. By my senior year of high school, two of my friends were using heroin intermittently. Later they got hooked on heroin and are not alive today. I saw many musicians who shot up heroin die young. That scared me out of the music business and into college.
‘I saw many musicians who shot up heroin die young. That scared me out of the music business and into college.’
A: So to what college?
CRS: I could not get into a regular college, so I went to a two-year community college and my grades improved. I transferred to Gettysburg College where I received excellent training in biology and experimental psychology. My first stint in graduate school was at the University of New Mexico where I got a degree in physiology and physiological psychology. I was a student of George Peterson, who had been a student of Carl Lashley. I did brain research; very little in the way of behavioral research. For Dr Peterson behavior was really a means of understanding the brain. My master's thesis was on the behavioral consequences of severing the corpus callosum in the rat. Well, I did not ask the right questions and found nothing. I did not get much training in behavior at the University of New Mexico but I got a good grounding in scientific method and the physiology of the brain.
A: The next move?
CRS: After that I came back to the East Coast. I did not immediately go for my doctorate. I went to work first as an endocrine biologist at Temple Medical School. While there, I served as research assistant to a visiting professor by the name of Bernard Zondek, who was famous for his studies of estrogen and the Ascheim–Zondek pregnancy test. I learned a great deal of endocrinology from him and he pronounced when he was leaving ‘Ach my boy—your future is assured—you have worked with Zondek!’. At that time, something that really did affect the rest of my life occurred. Smith-Kline & French (SKF) bought the US marketing rights for chlorpromazine from the Rhone-Poulenc Pharmaceutical Company. After several months of successful marketing they realized the financial potential for medications for the treatment of psychiatric disorders. But, SKF did not know how to identify such drugs. At that point they received a proposal from Don Bullock, a Columbia University trained psychologist, to set up a laboratory using behavioral assays to screen for new psychiatric medications. Don Bullock was given a year's contract by SKF and I was hired as his assistant. So, around 1956 I joined SKF. After 6 months of being there I was put in charge of the laboratory for several years. By that time SKF decided that behavioral pharmacology was here to stay and that they needed someone with more training than I had, so they hired Roger Kelleher to take over the laboratory and I went back to school to get my doctorate.
AN EMERGING INTEREST IN BEHAVIORAL PHARMACOLOGY
A: After SKF?
CRS: Fortunately for me I attended a lecture Joe Brady gave in Philadelphia. He and Sherman Ross of the University of Maryland had just been given a psychopharmacology grant by NIH. Joe Brady at that time was a Captain in the army, stationed at the Walter Reed Army Institute of Research (WRAIR), but he was also a professor at the University of Maryland. Joe asked me whether I wanted to join the laboratory to get my doctorate. I said I wanted to do that but I was concerned about my financing it since I was married with two children. He offered me an instructor's salary, because I knew something about pharmacology. So I went to the University of Maryland, only to find out that they had not even considered that they needed an analytical balance to prepare drugs.
A: They were all psychologists?
CRS: Yes. One of my first big contributions was to teach everyone how to weigh out drugs, how to make drug solutions, and various kinds of injection procedures. Because of Joe Brady's connections at WRAIR I got to meet a number of great behavioral analysts who were there because of the draft. When a PhD psychologist was about to get drafted, Joe could arrange for them to be assigned to his place at Walter Reed.
A: There were also a lot of neuroscientists there?
CRS: Great neuroscientists. Bob Galambos who discovered the bat's Sonar system of navigation gave lectures on neurophysiology. I received training in both behavior and neuroscience. There was also a neuroendocrinologist by the name of John Mason at WRAIR. He was measuring hormonal changes in rhesus monkeys subjected to stress. The problem was how to avoid stressing the animals when getting blood samples. He developed a surgical procedure for implanting chronic jugular catheters, running them under the skin up to a pedestal that was attached to the skull. He could attach a line to the catheter and remove blood remotely. I looked at that, and I said if he could take blood out, then I could put drugs in. Suddenly I remembered the jazz musicians I had seen injecting heroin and other drugs. I wondered whether or not drugs of abuse would serve as positive reinforcers in animals. But, what drug should I use? Well, morphine was the obvious choice. When I began, I was convinced that I was going to have to do something tricky to make a healthy rhesus monkey self-administer a drug. At that time psychoanalytical theories about heroin addiction attributed it to the avoidance of guilt caused by homosexual ideation since opiates decrease sex drive. I did not think that I could study that in monkeys. So, the first thing that I did was to see whether I could get animals to self-inject anything intravenously. I did a study with Bob Clark and Joe Brady (Clark et al. 1961). We used water-deprived monkeys to see whether we could get them to self-inject saline. Now, saline is not a very good source of fluids, but nonetheless, we were able to get them to lever press for intravenous saline. I was heartened by that.
‘I wondered whether or not drugs of abuse would serve as positive reinforcers in animals.’
CRS: At the same time, I thought, well, I know how I can get drugs to serve as positive reinforcers in animals—I can make them a conditioned reinforcer. How do you do that? First of all, make them a discriminative stimulus. So, my doctoral dissertation was on drugs as discriminative stimuli in monkeys. I was able to show that lever-pressing maintained by food reinforcement would come under the stimulus control of an intravenous injection of epinephrine (Schuster & Brady 1964). I thought, if I can do that, then maybe I can make morphine a discriminative stimulus and therefore a conditioned reinforcer because of the association with food. I never got around to doing that, because I learned that Jim Weeks was able to get morphine to serve as a reinforcer in physically dependent rats. Travis Thompson (a postdoctoral fellow in the laboratory) and I decided to make monkeys physically dependent and then let them go into withdrawal, which would be relieved by an injection of morphine. Monkeys quickly learned to lever press for morphine injections. In the first major study we did, we made a morphine injection contingent upon completion of a FR/FI chain schedule of reinforcement (Thompson & Schuster 1964). They were allowed access to 3.0 mg/kg of morphine on this chained schedule once every 6 hours. They also worked to avoid electric shock for an hour before the drug component and lever pressing was reinforced on a VI schedule with food for an hour after the drug component. Using monkeys trained on this schedule, we did some fascinating studies. We demonstrated that withdrawal enhanced the reinforcing effects of morphine. We also showed that, while they were in withdrawal, their food and shock avoidance maintained behaviors were disrupted. After they were allowed access to morphine the behavior maintained by electric shock and food returned to normal. We were able to show that the stimuli associated with morphine could also temporarily return their behavior to normal. In other words, we got a conditioned morphine-like effect! These studies were very exciting for me. I was able to see the parallels between these animal studies and what I had observed in humans in my earlier days as a jazz musician. We had a model of human drug addiction (Schuster & Thompson 1969).
A: At the time you did that study with Travis Thompson, I imagine few people were doing behavioral pharmacology research in the area of drug abuse. The primary interest had been in developing psychiatric medications.
CRS: There had been a few studies in this area that I knew about—Shirley Spragg had gotten a chimpanzee to choose a box containing a morphine-filled syringe when in opiate withdrawal. Nichols had gotten rats to respond for a morphine injection, as had Jim Weeks. I knew of work on physical dependence on drugs that people like Maurice Seevers, Gerry Deneau and others at the University of Michigan had published. That was not my interest. I was interested in drug self-administration. So, there was not a heck of a lot of behavioral research at that time.
A MOVE TO THE UNIVERSITY OF MICHIGAN
A: So what happened next?
CRS: After we had done our first monkey study Travis Thompson and I went to NIH to see Nathan B. Eddy, who was a giant in the field of opiate pharmacology and addiction. He read extensively despite the fact that he was virtually blind. The floors underneath his office had to have struts put in because the floors were collapsing from the weight of his books. We told him about this study we had done and he suggested that we present the results at the upcoming meeting of the Committee on Problems of Drug Dependence in Ann Arbor. So, Travis and I went to the meeting at the University of Michigan. Maurice (Mo) Seevers, who was the chairman of the pharmacology department there, heard the presentation and knew that I was available. They offered me $12 000/year. I did not even ask about space; I had no idea what I was getting myself into but it looked like a great opportunity for me to work with some great guys in pharmacology. I had just gotten an NIH grant for $28 000 to study drug self-administration in rhesus monkeys and thought the University of Michigan would be a good place to do the research. So I moved to the University of Michigan in 1962, and had 5 marvelous years there. I had to run a laboratory section for the medical students so I learned to do all the classic pharmacological preparations—isolated guinea pig ileum, stop flow kidney preparations, etc. In addition, all of the pharmacology faculty went to every medical student pharmacology lecture. We all sat at the back of the amphitheater and had coffee after the lecture was over and discussed it. When it was my turn to give the lecture, I was sweating bullets. There were a dozen faculty members as well as 150 medical students. It was stressful, to put it mildly. But, I learned a little about pharmacology. Another great thing about the University of Michigan was that John Falk was there in the Department of Pathology. We became very close friends because of our shared passion for jazz and behavior analysis. I learned a great deal from John about many things. He is a real scholar who today in retirement is publishing books of poetry.
A: Please tell us about Maurice Seevers, who you mentioned a few times. He is quite a notable figure in addiction research.
CRS: Dr Seevers was one of those incredibly influential people. He had trained more pharmacologists than anyone else in the country at that time. He was a very forceful, domineering kind of gentleman. Loud, at times crude, but smart as can be. He was an MD/PhD anesthesiologist. He had published studies on the behavioral effects of cocaine in dogs back in 1929. He observed ‘sensitization’ to the effects of cocaine that is now such a hot topic in neurobiology. In the years prior to the time I came to the University of Michigan, he and several other people in the department had been studying drugs in humans: themselves. I should point out that at that time pharmacologists and chemists frequently tested drugs on themselves. It was a different era. Anyway, they would get together and ingest a drug they were interested in studying. It could be an opiate, barbiturate, cocaine. The one drug that really scared Mo was cocaine. He told me: ‘When I took cocaine, I felt that I could carry the world on my back. I liked that feeling and I’ll never take it again.’
‘at that time pharmacologists and chemists frequently tested drugs on themselves. It was a different era.’
A: How do you account for this pharmacologist, a significant leader in the field of pharmacology research, wanting to hire a psychologist and being so interested in the behavioral aspects of addiction?
CRS: Well, to tell you the truth, I did not know the answer to that until I talked recently with Tomoji Yanagita in Japan. Dr Yanagita told me that Dr Seevers had received an NIH grant, but the reviewers had said that he should get a behavioral pharmacologist to work on it. I never knew that until now. I would not be surprised if Joe Brady, my mentor, was the reviewer who said that, because he was on the review committee at that time. Tomoji Yanagita, Gerry Deneau and Mo Seevers had done drug self-administration studies at the University of Michigan but they were not interested in the behavioral aspects, they were interested in studying the toxicology of self-administered drugs (Deneau et al. 1969).
A: You were fortunate again in landing in a very rich research environment at the University of Michigan in those days.
CRS: Absolutely, there were a number of interesting people there. Ed Domino was there, he was very active in central nervous system (CNS) pharmacology with nicotine and other agents. I was able to recruit as my research assistant a young man, James H. Woods, who was just finishing his doctorate. When I left the University of Michigan, Jim took over the laboratory and with his colleague (and wife) Gail Winger they have had a productive Drug Abuse Research Center there for over 30 years. Since Chris-Ellyn Johanson and I have moved back to Michigan we have been working with them on that Center grant.
NEW OPPORTUNITIES AT THE UNIVERSITY OF CHICAGO
A: Why did you leave the University of Michigan?
CRS: I left because I was contacted by Jerry Jaffe, one of the giants in the field of addiction, who at that time was a young psychiatrist at the University of Chicago. Jerry was setting up a publicly funded drug abuse treatment program for the State of Illinois. He wanted to recruit me because I had done some of the earliest work on the effects of i.v. nicotine on human smoking behavior (Lucchesi et al. 1967), and Jerry was interested in a broad array of addictions. He decided that he would like to have me join him if I could see my way to accepting support as his Associate Administrator for the state's program. Here I was, a psychologist, with training in pharmacology, but with little human research experience. But Jerry and Daniel X. Freedman (Chair of Psychiatry at the University of Chicago) asked me to come to Chicago to join him in setting this program up. Never being one to pass up an opportunity like that, I left my tenured position at the University of Michigan for a non-tenured Associate Professorship at the University of Chicago . . . it was the greatest move I ever made. Again, I walked into an incredibly rich environment. Danny Freedman was supportive of my work. Eberhard ‘Uhlie’ Uhlenhuth became a close colleague who published extensively with our drug abuse group. Jerry Jaffe was there until President Nixon took him to become the Director of the Special Action Office for Drug Abuse Prevention. I got the opportunity to start working in a treatment setting, and although I am not a licensed clinician I started to do things like group psychotherapy with addicts, became involved in methadone maintenance treatment and so forth. The work on opiates eclipsed any further work on smoking as an addiction.
A: Work on methadone?
CRS: Jerry was interested in studying a long-acting methadone-like drug, alpha acetyl methadol, for opiate maintenance. Paul Blachly, a psychiatrist in Oregon, said he had a supply of the drug left over from an analgesia research study—an unopened bottle that was 18 years old. He sent us this 18-year-old bottle of the drug, which we decided to call LAAM (for l-alpha acetyl methadol, or long-acting methadone), and the first thing we did was to break it open and hand some of it to Kristna Kaistha, who was our chemist. He ran it on thin layer chromatography and came up with one spot, so we concluded it was still good. We called up Ed Washington, who was in charge of a methadone maintenance treatment program, and asked him to recruit four people to participate in a study of this new long-acting medication. He sent them over and we decided that we would not transfer them to LAAM that day. Rather, what we did was to give them their usual dose of methadone but changed the flavor of Kool-Aid it was put in. So, we changed the patients from raspberry to lemon. Immediately, within an hour, one of the guys had hysterical paralysis in his legs and another had a panic attack that required massive doses of Valium to handle. Fortunately, we had not done anything but give them methadone that day. If we had given them the LAAM that day, we would have never used that drug again. The other two guys were mellow so we gave them LAAM the next day and it worked like a charm. Subsequently, we carried out a random assignment, single-blind study in 21 patients, and we published this study in the Journal of the American Medical Association (JAMA) maybe 6 months later (Jaffe et al. 1970). There were no human investigation committees; there were no regulations about human research. There was informed consent, because I did tell them exactly what we were doing, but it was different than human research today.
After Danny Friedman left Chicago to go to UCLA the psychiatry department had several acting chairs—I was the chair for a year. Can you believe it? A non-physician, non-clinician drug abuse researcher as the Chair of Psychiatry at the University of Chicago. I did my best and the department survived.
‘There were no human investigation committees; there were no regulations about human research.’
A: At Chicago you were given the opportunity to continue your animal research and establish an animal laboratory, so let us talk a little about your work there.
CRS: After about a year, I transferred my animal laboratory research from the University of Michigan to the University of Chicago, and one of my graduate students, Marvin Wilson, came over and helped me set up the laboratory. In addition to having an appointment in Psychiatry, I was also appointed in both the Departments of Pharmacology and Behavioral Sciences. That meant that I could get great graduate students from both of those departments. The thing that I liked about Chicago was being able to be involved with human treatment and clinical research while at the same time continuing my animal research. I look at that as a great situation, because there are things that cannot be researched in humans, and could only be researched in monkeys, and vice-versa.
A: At this time you became interested in methamphetamine?
CRS: One of the major reasons I was interested in this was because I met some kids from Southern Illinois University who were able to obtain pure Crystal, as they described it, which was methamphetamine. The methamphetamine had been stolen from Abbott Laboratories in North Chicago—bottles of it. They proceeded to take it around the clock and not very surprisingly developed a toxic psychosis. Tragically, one of these young people was a woman who was diabetic and died during her ‘meth’ escapade. After being thrown out of school they came back to Chicago and I somehow made contact with one of them. I told him that I would like to meet with him and his friends to learn more about methamphetamine abuse. They would not come to my office in the hospital, but they did agree to come to my apartment. The late Pierre Renault (who was at that time a young psychiatrist that I was mentoring) and I met with them every week for several months. Although they told us that they had stopped using methamphetamine they appeared to me to have terribly flattened affect. Obviously, we did not know whether this was a pre-existing condition or a consequence of their use of methamphetamine. I could not study this experimentally in humans, so I decided to do it in monkeys. That is how that whole line of research on the toxicity of amphetamines and other stimulant drugs got started.
A: By the time of your work in Chicago, the powerful reinforcing effects of drugs were well established, even in the absence of physical dependence. One of the new directions of your animal research in Chicago was to study factors influencing drug choice. Tell us a little about your interests in this area?
CRS: Drugs like cocaine, amphetamine, barbiturates and opiates would be readily self-administered by monkeys. Then the question became, are some drugs more powerful positive reinforcers than others; how can you study the relative reinforcing properties of drugs? Is cocaine a better reinforcer than amphetamine? Is heroin a better reinforcer than some other opiates? Conventional drug self-administration procedures would not tell you much about that because the number of injections that an animal would take in a session would be more a function of the dose or the duration of the action of the drug, than the magnitude of its reinforcing effects. We decided to look at some other ways of doing this. Chris-Ellyn Johanson, a graduate student (who later became my wife), did her doctoral dissertation studying drug choice as a method of assessing relative reinforcing efficacy of two drugs. She did a number of studies comparing various drugs in this way (Johanson & Schuster 1975). I had some great postdocs who helped to teach the graduate students. Bob Balster was particularly outstanding as a researcher and mentor to the graduate students.
I was at the World Health Organization (WHO) in Geneva, Switzerland, when one of the chemical laboratories associated with them isolated a compound called cathinone, which was extracted from the khat plant. Khat is chewed by many of the people in Somalia and elsewhere in that region of the world. The WHO gave me a couple big bottles of cathinone to bring back to the United States. We found that monkeys self-administered it. Then we wanted to compare it to cocaine. When we did that we found that choice of cocaine or cathinone was completely dependent upon the dose. Whichever drug had a higher dose was chosen (Johanson & Schuster 1981). We published that, and a few months later I got a call from the editor of High Times. He said, ‘Hey man, I hear you got some stuff that is as good as cocaine!’ I thought, ‘oh damn, what evil have we wrought!’ Fortunately, cathinone has not caught on as a major drug of abuse or I would blame myself.
‘Then the question became, are some drugs more powerful positive reinforcers than others; how can you study the relative reinforcing properties of drugs?’
A: Another important development in your research in Chicago was the establishment of one of the first human behavioral pharmacology laboratories, based conceptually on your work with animals.
CRS: Yes, I decided after a couple of years that being an administrator at the State of Illinois drug abuse treatment program was limiting to my research. So I moved out of the position and with Danny Freedman's support established the Drug Abuse Research Center at the University of Chicago. It was at that time that I started to do basic drug abuse research with humans. I did studies looking at the reinforcing effects of codeine and pentazocine and compared them to methadone (Schuster et al. 1971). I began doing laboratory studies to see whether or not drugs like chlorpromazine, that affected avoidance behavior without affecting escape behavior in animals, would also do that in humans. It did (Fischman & Schuster 1979). Chris-Ellyn Johanson and Marian Fischman, who became Research Associate Assistant Professors after they finished their doctorates, were the real movers in the establishment of the human behavioral pharmacology area. Marian did the work on cocaine and Chris-Ellyn investigated the behavioral pharmacology of amphetamines and benzodiazepines.
A: Were you interested in marijuana research?
CRS: Another human laboratory study that stands out in my memory is one I did with Pierre Renault with marijuana smoking (Renault et al. 1971). At that time people thought that marijuana users never got high the first time they used the drug. There was a theory that initial exposure induced enzymes so that when people subsequently smoked marijuana they got high from some new type of CNS active metabolite. I was suspicious of this idea. I had seen young musicians smoke marijuana for the first time and I realized that it was probably the fact that the naive smoker did not smoke it the same way. They did not inhale as much smoke, did not hold it as long in the lung, and so forth. So, we developed a standardized marijuana smoking procedure. We used a display of lights which told people when and how long to inhale, and how long to hold it before exhaling. Inexperienced smokers did not have the verbal behavior to describe the marijuana experience in the same way that experienced smokes did, but they showed comparable physiological changes. This was one of the first attempts carefully to quantify the effects of marijuana on physiological and psychological parameters.
FROM CHICAGO TO THE DIRECTORSHIP OF NATIONAL INSTITUTE ON DRUG ABUSE (NIDA)
A: Why did you leave the University of Chicago?
CRS: In 1986, I got a call asking me whether I would be interested in applying for the job of Director of NIDA. I thought at first that it was a joke since this was during the Reagan years, and I was known as a capital L—liberal. But it was for real—they wanted me to come down and interview for the job. So I said, OK, why not? Joe Brady had taught me that you never turn down a job you have not been offered! So I went for the interview and I was told subsequently that the discussion of my son's problems with marijuana convinced a committee member that I should be the next director of NIDA. Anyway, I was offered the position. After discussions with my wife Chris-Ellyn, we decided that I should accept the job. So, we left our positions at the University of Chicago and moved to the Washington DC area, where I became the Director of the National Institute on Drug Abuse. This was one of the most exciting and scary things that had ever happened to me.
‘In 1986, I got a call asking me whether I would be interested in applying for the job of Director of NIDA. I thought at first that it was a joke since this was during the Reagan years, and I was known as a capital L—liberal.’
A: Tell us some of your experiences at NIDA.
CRS: A few weeks after I arrived, I got a call from a congressperson who asked what I would do if NIDA had $60 million more a year. The NIDA budget, when I got there, was $85 million total, and here they are asking what would you do with $60 million more? I called in my senior-level people and I said Okay guys, we have to have a proposal in two days to justify an increase of $60 million dollars. Fortunately, there were some real pros there; Jim Cooper, Marv Snyder, Elaine Johnson—I cannot name them all right now. We worked literally the entire night and through the next day. We got the $60 million dollar increase. I can tell you that was an absolute joy, because suddenly we were able to start doing important research in new areas.
Grants started coming in. I was really lucky that Lou Harris from MCV had taken a sabbatical year to serve as my Scientific Advisor. Lou discovered very quickly that we were being swamped with grant proposals. We did not even have shelf space to put them on. So he came in on a weekend with his carpentry tools and built shelves. In addition, our staff was not able to handle double to triple the number of grants that they ever handled. Fortunately, Lou, with his wisdom and organizational skills said, ‘Bob, would you put me in charge of this?’ I wisely said, ‘Lou, do it’. We kept all of the grants straight, had the shelves to put them on, got them reviewed in a timely fashion and funded a bunch of them. During the time that I was there from 1986 to 1992, the funding for NIDA went from about $85 million to a little over $400 million, and it continued to increase under the direction of Alan Leshner after I left.
A: During that same period of time it became known that drug abuse was an important vector for HIV/AIDS transmission. Tell us a little about that problem and your involvement with it.
CRS: I felt that it was incumbent upon NIDA to research interventions that might decrease the spread of the AIDS virus among intravenous drug users and their sexual partners (Schuster 1992). These interventions could take place in treatment programs as well as through street outreach workers. The message they carried was get into treatment— but if you will not do that, do not share needles. If you share needles, then use proper needle hygiene. We introduced the use of bleach as a disinfecting agent because that was readily available. Unfortunately, we were barred from using federal funds for needle exchange programs by the 1988 Drug Abuse Act. That act stated that no federal funds could be used to support needle exchange programs until the Surgeon General certified two things: (1) that it is effective in curtailing the spread of HIV infection; and (2) decreases active drug abuse. Well, that is absurd. Needle exchange programs are not going to decrease drug abuse; what we would hope is that they would not increase it. I argued with my superiors about this policy, and in large measure that was one of the reasons for me ultimately leaving the position of being the director of NIDA. Another major problem was that we were limited to a great extent in talking about the use of condoms, because that might encourage promiscuity in young people. It was a real battle to get advertisements out that would discuss the use of condoms. In the beginning, abstinence was the only thing that we were able to talk about.
A: Generally, what topics did you address at NIDA?
CRS: HIV infection was a major driving force behind NIDA's funding increases and this allowed us to increase treatment research. We argued that, if we could improve the effectiveness of treatment and bring people into treatment earlier, this would curtail the spread of HIV infection. So, we did a great deal of research on new behavioral approaches, new pharmacotherapies. LAAM, which I had studied back in the early 1970s, finally emerged again as a possible treatment drug. It was during this period that buprenorphine treatment research was started. It has finally made it to market this last year.
A: You enjoyed the NIDA experience?
CRS: The years at NIDA were absolutely phenomenal for me. It was, however, a constant battle with certain people in the government who felt only contempt for drug addicts. They looked at methadone maintenance as coddling of addicts—as simply another form of addiction. Methadone maintenance was a hard sell for me. I can remember going to a White House Conference on drug abuse, I believe in 1988, and I was booed when I talked about methadone as an effective treatment for opiate addiction. It was tough. After 6 years, I decided that I wanted to go back and do research. There were also other personal issues involving my wife's career and disagreements with my superiors regarding her appointment to a job within NIDA, so I decided to leave the position. But while I was there I learned a great deal about the broad policy issues facing the problems of drug abuse.
‘It was, however, a constant battle with certain people in the government who felt only contempt for drug addicts.’
A: No question, you were the right man for that job at the time. One thing I would like to discuss with you is your impact on the many other scientists that worked with you, carrying forward the traditions of your mentors into the training of a younger scientist. What are your thoughts about mentoring and about developing young scientists and how you approached that throughout your career?
CRS: First of all, I was blessed to have Joe Brady as my mentor. Joe was pretty much hands off. He said, ‘Okay, here is the equipment, here are the animals, do what you would like to do.’ He set the occasion for me to go into the laboratory and explore—a luxury that was incredible. I attempted to follow that with all of my graduate students; I gave them a basic education in pharmacology and behavioral analysis, and taught them to critically read the literature. After that within the loose constraints of the grants that supported our research, they had to develop their own research projects. That is what made research exciting for them—they felt they had ownership of the project. My role was to guide them, not direct them. I was also fortunate to have great graduate students and postdocs. They educated me as much as I educated them. I guess I would say that we learned together. Joe Brady is still a friend and confidant, someone from whom I still seek advice.
A: Could you say something now about what projects you are currently working on and what research you find exciting.
CRS: Where to begin? First, I am interested in treatment service delivery. When I came to Wayne State University in 1995, I established a Methadone Maintenance Treatment Program that serves as a training site for Addiction Psychiatry Fellows, clinical psychologists, social workers and clinical treatment researchers. When NIDA started its clinical trials network I decided that we should try to become part of that program. I organized a group of academics from the University of Michigan (Bob Zucker, Kirk Brower and Mort Brown), Michigan State University (Mike Liepman) and four Community Treatment Programs. We applied to NIDA and were selected to become the Great Lakes Regional Node of the NIDA/Clinical Trials Network. I am the Director of the GLRN node, which is one of 17 spread around the country. The program is designed to take treatment interventions that have been shown to have efficacy in controlled clinical trials to see whether they are ‘effective’ when implemented in community-treatment programs.
A: And how have you approached that challenge?
CRS: We have completed one study using buprenorphine for detoxification in a therapeutic community called SHAR located in Detroit. Therapeutic communities have traditionally been reluctant to use medications for the treatment of substance abusers. The problem is that many of the people who are addicted to heroin go into severe withdrawal if they are not medicated and leave the program. SHAR, under the direction of Alan Bray, has employed a physician who has used clonidine and antihistamines as a means of easing some of the symptoms of withdrawal. People were still leaving. So we convinced Alan and his staff to participate in a CTN study comparing clonidine to buprenorphine in a 14-day detoxification program. The nationwide results are not yet available; however, informally, the staff at SHAR was very impressed with the effectiveness of buprenorphine in easing the symptoms of withdrawal and retaining people in treatment. They are now getting set up to use it routinely. That is what the CTN is all about—to help improve the services available in community treatment programs.
A: How do you generally rate the relationship between the scientific findings and the community application in this arena?
CRS: I think there has been a tremendous gap between community treatment programs and the academic institutions where clinical research is conducted. That's why the Clinical Trials Network is so exciting. Alan Leshner deserves credit for starting this program at NIDA. The gap between research and practice exists in many areas of medicine—not just in the addiction field. But it is probably greater in the addiction treatment area. Most community treatment programs are run by individuals who have little training or opportunity to use the results of clinical research to improve the services they offer. They are under incredible pressures to generate clinical income with little time to read scholarly journals. Through the Clinical Trials Network we are beginning to address these problems.
A: One of the approaches that you have been influential in developing is the application of basic operant behavioral principles to addiction treatment. It is my impression that these behavioral approaches have been slow to permeate the broader addiction treatment community.
CRS: Behavioral contracting and contingency management are direct outgrowths of the recognition that drugs serve as powerful positive reinforcers for behavior. One approach to help people overcome their drug problem is to make non-drug reinforcers available contingent upon therapeutically desirable behaviors. The types of consequences that have been shown to be effective reinforcers are vouchers to be used for purchasing goods or services, or privileges such as take-home methadone doses. Contingency management interventions have been repeatedly shown to be extremely effective in initiating and maintaining drug abstinence, attendance at counseling sessions and adherence to medication regimens. The successfulness of this approach shows the importance of conceptualizing the problems of drug abuse in the framework of behavioral analysis. One of the criticisms of the contingency management approach is that the behavioral change does not last after the contingencies are removed. In fact, the behavior change does remain for some individuals.
BRAIN TOXICITY AND THE AMPHETAMINES
A: What else are you doing in research?
CRS: I still am interested in human laboratory studies. Chris-Ellyn Johanson along with Kirk Frey from the University of Michigan and I have a grant to investigate the neurobehavioral toxic consequences of high-dose methamphetamine abuse in humans. About 30 years ago at the University of Chicago, my colleague Lew Seiden and I did investigations of the effects of very high-dose methamphetamine administration in animals. Marian Fischman, who was a graduate student at that time, conducted her doctoral dissertation in this research area. She used monkeys that were exposed to escalating doses of methamphetamine over a period of several months. They ultimately were receiving very high doses comparable to those reported to be taken by ‘speed freaks’. After the drug regimen was discontinued the animals that survived recovered and appeared quite normal (Fischman & Schuster 1977). After 3–6 months they were sacrificed and we found that among animals that had been exposed to high dose amphetamine, the levels of dopamine and serotonin in the brain were reduced by about 50% (Seiden et al. 1976). Following that Lew Seiden and I (with of course a string of graduate students and postdocs) conducted many studies of amphetamines and related analogs in rats. We showed that after 4 days of high-dose administration of many of these drugs there was a long-term significant decrease in dopamine (DA) and/or serotonin (5-HT) levels in the brain, DA and 5-HT membrane uptake transporters, as well as rate-limiting synthesizing enzymes for DA and 5-HT. This opened up a whole research field and students who were around at that time, such as George Ricaurte, George Wagner and the late Kevin Finnegan, made a lifetime profession out of studying the mechanisms of neurobehavioral toxicity of amphetamine and amphetamine analogues.
‘among animals that had been exposed to high dose amphetamine, the levels of dopamine and serotonin in the brain were reduced by about 50%.’
A: How far do you think the animal research bears on the human experience?
CRS: The obvious question is whether humans who have abused high doses of amphetamines also show changes in brain DA and 5-HT markers. So, a few years ago we submitted a grant to study humans that have taken very high doses of methamphetamine. To do this study we are using PET technology with a ligand that binds to the vesicular uptake transporter (VMAT). In addition we are using an automated neuropsychological test battery called the CANTAB developed by Trevor Robbins's group at Cambridge. We do not have many methamphetamine abusers in the Detroit area so we import many of our research participants from California. We are just finishing up several studies that I think are important.
PREDICTING THE ABUSE POTENTIAL OF CNS DRUGS
A: Another area of applied research that I know that you are currently very interested in, and where you have had a significant role over your career, is the issue surrounding the approval and regulation of medications as ‘controlled substances’. You were the primary mover behind a meeting that was held about 6 months ago on abuse liability assessment (Johanson et al. 2003).
CRS: Our society uses governmental regulations as a means of controlling access to drugs that have abuse potential. At the federal level we have the Controlled Substances Act (CSA) which passed in, I think, 1972. The CSA provides for differentially controlling drugs with different degrees of abuse potential. We use laboratory studies to predict the abuse potential of new CNS active drugs to determine whether they should be controlled under the CSA and what level of control is appropriate. A new medication may be controlled under the CSA because of its pharmacological similarity to medications already controlled. Thus, a full mu opioid agonist being marketed for the treatment of pain would probably be controlled in Schedule II of the CSA, as is morphine. If, however, it differed in other aspects of its pharmacological actions or was formulated in a manner to decrease its abuse potential, laboratory testing of its abuse potential would be warranted. Such testing would probably begin with drug self-administration studies to determine whether the drug will serve as a positive reinforcer in laboratory animals. If the animal data suggest that the drug has abuse potential it would then be evaluated for its abuse potential in human laboratory and later in clinical studies. Finally, the FDA may request that the pharmaceutical company marketing the drug conduct post-marketing surveillance studies to monitor its possible diversion and abuse. My group at Wayne State has conducted several postmarketing surveillance studies (Arfken et al. 2003), and is currently monitoring the new buprenorphine products Suboxone and Subutex, which are being prescribed by physicians for the treatment of opioid dependence. Post-marketing surveillance for the detection of diversion and abuse of a new medication is a new area of research and we are all learning as we go. Anyway, all of this is described in detail in the proceedings of the CPDD sponsored meeting on Abuse Liability Assessment conducted in October 2002 (Johanson et al. 2003).
A CAREER IN SCIENCE
A: It is very clear that you have enjoyed your work immensely and that what you are doing now is as important to you as to anything that you have done in the past. Tell us a little about the experience of a career in science and where it leaves you at this particular point in life.
CRS: Throughout my career, I have followed my nose. There is no other way to put it. I have met people who have planned their careers. I sure did not. If I saw interesting things, things that have turned me on, things that excited me—I would go there. I am blessed with the fact that I had a broad enough background in pharmacology, physiology and behavioral sciences so I could move into new areas. I am not an expert in many of the areas of research that I have worked in. But I know enough about them to talk to the experts and convince them that it would be great to work together on a project. So now I am doing functional MRI, PET scanning, things that I am obviously not capable of doing myself. I see these new techniques as tools for answering questions that I think are important. That is what keeps me excited about things. There are new toys to be played with all the time and new ways of approaching some of the age-old questions. Methamphetamine abuse has come back and I am working with PET experts to study possible long-term effects on brain dopamine systems. My colleagues, Drs Johanson and Manny Tancer here at Wayne State, are doing studies to understand the human pharmacology of MDMA using very sophisticated procedures. I am lucky to work with my wife Chris-Ellyn Johanson. We enjoy science together—but she also helps me to keep my life balanced with other things—novels, art, music and boating. All of these things keep me interested and excited about life and continuing to work. When it stops being exciting, then I will consider retiring.
‘Throughout my career, I have followed my nose. There is no other way to put it.’
A: We will look forward to the next chapters in an extraordinary career.