In Celebration of Stephen (Istvan) Szara ( 1923-2021)
By
Thomas A. Ban
On August 1, 2021 Stephen (Istvan) Szara, an Emeritus Fellow of the American College of Neuropsychopharmacology (ACNP), passed away in Kensington, Maryland. At the time of his death, he was 98 years old Szara, a pioneer of modern neuropsychopharmacology was first, in the mid-1950s, to describe the psychomimetic properties of dimethyltryptamine (DMT), a psycho-toxic end-product of tryptophan metabolism (Szara 1956). Subsequently, his negative findings about the presence of adrenochrome in the plasma of normal subjects and schizophrenic patients, in the late 1950s (Szara, Axelrod and Perlin 1958), was the coup de gráce of the adrenochrome hypothesis, the first biochemical hypothesis of schizophrenia (Ban 2011a; Shorter 2005, 2011a).
Stephen Szara was born March 21, 1923 in Budapest. He earned a PhD in chemistry in 1950 and a medical degree from Semmelweis University in 1951 in the city of his birth.
While teaching microbiology and biochemistry after graduation, he became interested in (1) “psychotogens,” i.e., substances which can induce psychopathology, and in (2) Abram Hoffer’s adrenochrome hypothesis of schizophrenia. After unsuccessful attempts to obtain lysergic acid diethylamide (LSD), the “psychotogenic” substance at the center of interest in those days, from Sandoz, the Swiss pharmaceutical company which manufactured it, he settled on studying the active principles of cohoba, a plant used as a hallucinogen by South American Indians. He chose dimethyltryptamine (DMT) as the substance of his first study. While conducting his research with DMT at the National Institute of Neurology and Psychiatry of Hungary, at the premises of an old asylum (Lipotmezo) in Budapest with the active participation of the medical staff of the Institute, in October 1956 the Hungarian uprising (October revolution) broke out (Shorter 2011b).
After fleeing, Szára’s first stops included Vienna and West Berlin where he worked nominally as a “visiting scientist.” In fact, in both places he was just taken in and given shelter. But in Vienna Hans Hoff, the professor of psychiatry and neurology, gave him some lysergic acid diethylamide (LSD) to let Szára compare the hallucinatory experiences with it and DMT (Shorter 2011a).
In 1958 Szára became a visiting scientist at the National Institute of Mental Health (NIMH) with the promise of an appointment at Joel Elkes’ Clinical Neuropharmacology Research Center, situated in Washington, DC, at St. Elizabeths Hospital. But when Szára arrived in Washington, the labs weren’t ready yet, so he spent the next two years working with Julius Axelrod in Building 10 of the National Institute of Health (NIH) on the metabolism of diethyltryptamine (DET) (Shorter 2011a).
In 1961 Szára became chief of the psychopharmacology section of NIMH; a decade later he was pushed out of the intramural side in an internal political struggle and had to give up lab research. He found himself, in 1971, as an administrator on the extramural side: chief of the clinical drug studies section of the Center for Studies of Narcotics and Drug Abuse in Rockville, Maryland. In 1974 the Center was enlarged to become the National Institute on Drug Abuse (NIDA) and Szára became chief of the biomedical research branch, organizing controlled clinical research on marijuana.
Szára’s last move in the federal establishment was to become chief in 1980 of the biomedical branch in NIDA’s division of preclinical research. He retired in 1990 (Shorter 2011a).
Szára, a member of the Scientific Advisory Board of the Heffter Research Institute, was an Emeritus Fellow of ACNP and the Collegium Internationale Neuro-Psychopharmacologicum. A recipient of the Alcohol, Drug Abuse, and Mental Health Administration Administrator's Meritorious Achievement Award and the Kovats Medal of Freedom of the American Hungarian Federation (2005), Szara was elected Honorary Member of the Hungarian Association of Psychopharmacology in 2007.
Stephen Szara was interviewed by Leo E. Hollister on April 16, 1997, in Washington, DC for ACNP’s “oral history” project (Ban 2011b). An edited version of this interview was included in Volume One (Starting Up), edited by Edward Shorter, of the 10-volume series (An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews), edited by Thomas A. Ban (Ban 2011b; Shorter 2011b).
The full text of this edited interview is presented below.
LH: Today is April 16, 1997, and we’re in Washington, doing interviews on the project of the History of Early Years of Psychopharmacology sponsored by the American College of Neuropsychopharmacology. Our guest this morning is Dr. Stephen Szára. Welcome, Stephen.
SS: Thank you.
LH: It’s been a long time. That’s the trouble when you retire, you get lost. Tell us, Steve, I think you have an interesting history of being educated and raised in Hungary, and then making a career in the United States. How did this come about?
SS: Well, to start at the beginning, I got my first training in chemistry. I did my DSc work in chemistry, physics and mathematics in Budapest. Then while I was doing my thesis work in organic chemistry, across the hall – across the garden, really – of the campus of the University of Budapest, there was the Institute of Biochemistry of the Medical School, which was headed by Albert Szent-Györgyi, I don’t know if you remember his name.
LH: Oh, yes, of course. He was one the biggest scientists of that time.
SS: I think he got the Nobel Prize in 1937 for his work on Vitamin C and oxidative metabolism in the muscle.
LH: Muscle metabolism, yes.
SS: I was quite interested in biochemistry at that time, and while I was still working on my organic chemistry thesis, I actually took some biochemistry courses. We were allowed to cross over to another Institute. And I was really interested in it, but I wasn’t involved in biochemistry until, I think, 1950. Let’s go back for a moment. This was during the war, World War II, and at the end of the war, I started to take courses in medicine. I didn’t really want to become a physician, a practicing physician. I wanted to do research from the beginning. So I thought, I am going to take a few courses in biochemistry, and maybe pharmacology, and maybe anatomy. And then I started to get really involved in my studies and I decided that I might as well just go through the whole thing, so that’s how I got into medicine.
LH: With no intention of being a medical practitioner?
SS: No, no intention. I was primarily interested in biochemical research, and after my thesis work I got a position in the Department of Microbiology and Immunology of the Medical School. There were problems at the time that had to do with political issues, and eventually the Communist Party took control over many of the organizations at the universities, and that particular Institute was kind of disbanded; the professor disappeared, some people went to jail and I was transferred to the Department of Biochemistry. That was back in 1950; I was still in medical school, in my last year. I got my medical degree in 1951. It was in 1950 when I shifted over to the biochemistry department as assistant professor.
LH: In medical school, did you have separate institutes of different disciplines or was it all combined?
SS: No, there was a separate institute for each separate discipline.
LH: Biochemistry and all?
SS: In that particular campus that I was in, pre-medical subjects were taught in the departments of biochemistry and physiology, and the medical students came to study chemistry, physics, etc.
LH: Now, did you do any clinical work at all?
SS: Well, I did some later on. When I was in my last year in medical school, I did one year of internship, and during the internship, I met a young fellow who was working in a mental hospital in the outskirts of Budapest. He came to me one day and said that the hospital was very much interested in doing research in the biochemistry of mental illness, and they were interested in organizing a laboratory in the hospital. He asked me whether I would be interested in starting there.
LH: Until that time you had no training in psychiatry?
SS: No, I had no training in psychiatry. I just had my year of internship.
LH: So, you considered yourself a biochemist?
SS: Yes. I went to see the Director of the mental hospital, and asked her, “What should we do in the biochemistry of mental illness? You know,” I told her, “mental illness is somewhere up in your brain there.” And we didn’t know much about the chemistry of the brain at that time. But, as it turned out, there was a publication a year before that by Hoffer, Osmond and Smythies. I don’t know whether you remember it. They had two papers, I think in the Journal of Mental Science, in which they were proposing a biochemical hypothesis, the adrenochrome hypothesis, of schizophrenia.
LH: Hoffer, Osmond and Smythies were popular in those days.
SS: Very popular. Later on I got involved in the issue of whether adrenochrome is present in the blood.
LH: I assume by that time, in Budapest, you were able to get hands on the world literature?
SS: Yes, we had subscriptions to a lot of the prominent English and American journals.
LH: At that time, were you able to read English?
SS: Yes, I could read English, but I couldn’t speak it. As a matter of fact, I studied internal medicine from an English textbook. So, in 1953 I decided to accept the job in the psychiatric hospital and to start some research related to the biochemistry of schizophrenia. I got involved with the work, and became interested in LSD. We knew about LSD since Stoll, in 1947, published the first paper on the experience of Hofmann with the substance. The story had been picked up in relationship to the indole hypothesis of schizophrenia. I was thinking to do some research in that area and decided to try to get some LSD. So I wrote a letter to Sandoz, the company that made LSD, and I got back a letter essentially saying: “we are unable to send you any LSD.” Well, I understood what the reasons were. This was during the peak of the Cold War and there were some allegations of brainwashing with hallucinogens, so they were reluctant to send any LSD behind the Iron Curtain. In my desperation, I was asking myself, “oh, what can I do for which I don’t need LSD?” As it happened, while keeping up with the literature, I saw in 1955 in the Journalof the American Chemical Society an article published by Fish, Johnson and Horning about the chemical content of cohoba, the snuff used by the native Indians in South America for religious purposes. Chemical analysis had identified four compounds in it: dimethyltryptamine, bufotenine, dimethyltryptamine-N-oxide, and bufotenine-N-oxide. Bufotenine had been claimed to be psychoactive; Fabing had done some work with it, but nobody knew much about dimethyltryptamine (DMT).
LH: Who wrote that article?
SS: Fish, Johnson and Horning.
LH: I thought it might have been Dick Botnish from Harvard.
SS: Are you referring to Dick Schultes?
LH: Dick Schultes.
SS: But going back to Fish, Johnson and Horning, they identified bufotenine and said that it was probably the active ingredient. However, the Fabing report wasn’t very convincing. Others who tested bufotenine reported on flushing of the face and a lot of other primarily vegetative effects with the substance. So, I was not sure whether bufotenine was really the active ingredient. There was nothing about DMT in the literature, so. I decided to go back to my old institute where I did my thesis work and ask them whether they could synthesize some DMT because I would like to test it and find out what it does. This was at the end of 1955, beginning of 1956, and to make a long story short, with the help of my old friend, Miomir Mészáros, I synthesized a few grams of DMT. When I tested it in animals, first on rats, then on mice and ultimately on cats, it turned out to be active biologically and pharmacologically. From these data I guessed what would be approximately the active dose for DMT in humans. I thought it would be interesting to see whether it had hallucinogenic effects. DMT has some effects in animals, but who knows whether they’re hallucinating? You can’t ask them!
I decided to take DMT myself first. I started with a very small amount, like the amount Hofmann took of LSD; I used a quarter of a milligram. So, I started very carefully with a quarter of a milligram. I waited for a few hours and since it had no effect on me, I took half a milligram, then 1 milligram without any effect. And so, I went up to, I think, 100 milligrams orally. It had no effect at all. At this point I became discouraged. The substance seemed to be active in animals, but it didn’t do anything to me. I knew what to expect from a hallucinogen because half a year before taking DMT, I was inspired by Huxley’s book, The Doors of Perception and I took mescaline. But I did not get that from the oral doses of DMT. Someone in the hospital made a suggestion that maybe I should try to inject it.
LH: Yes, it was given to the animals by injection.
SS: I was hoping that maybe I could avoid getting the injection, but apparently I couldn’t avoid it, so I went down to the pharmacist in the hospital and asked him to make a preparation of DMT that could be given by injection. After the preparation was ready, I started injecting it into myself, intramuscularly. Starting with a small dose, a quarter of a milligram per kg, it was inactive, I felt no noticeable effect. After increasing the dose to half a milligram per kg, I thought I saw something that started to look like visual, perceptual distortions. At the next test I injected three quarter milligram per kg, and as I weighed about 75 kg at that time, it was a total of about 55 milligrams. Two minutes after the injection I was up in seventh heaven. It was amazing. It came very fast; I could hardly keep my eyes open; everything started to move around; the faces had become distorted, in just the same way as with mescaline or LSD.
LH: So, that was your first real hallucinogenic experience.
SS: Yes, my first hallucinogenic experience with DMT. Yet half an hour later, everything was gone. Everything. I also tested DMT on a colleague of mine who was assisting me in the hospital when he told me that he would like to try it. Then, the word got around. At the time, there was no drug control, the kind we have today. It was just pure science. So, the word got around and several other people volunteered. We eventually collected 36 or 37 experiences from 30 volunteers. Everyone got about 1 milligram per kg. Although this was not a scientifically designed dose-response study, it did establish in a large population that DMT was unequivocally hallucinogenic in people when given in the dose of 1 milligram per kg. This research was done in 1956. By the end of the summer, we decided that we would write it up and send it in for publication, because DMT seemed to be a very interesting new type of hallucinogen. Its effect doesn’t last for 12 hours as does mescaline, or 6 to 8 hours as LSD. It was obviously a different kind of hallucinogen, and I thought it would be interesting to do more work with it. I thought that it was appropriate to write up our findings as a preliminary report and get it published. So, I sent the report to Experientia, a Swiss journal. They accepted it and the paper was published the same year, I think it was in November.
But in November 1956, things were disorganized in Hungary. There was a revolution in October, and the Russian troops came in and suppressed the revolution. They decided to bring back the old Communist rule. At that point in time I realized that I didn’t have a future there. I wasn’t a member of the Communist Party. As a matter of fact, I found a secret report on me, when, during the revolution, the Communist Party archive was opened up. According to the report my main crime was that I was western-oriented; I was reading western literature and sent my paper on DMT for publication to a western journal. As a matter of fact, I had sent a paper before this to Biochimica Biophysica Acta in 1951 or 1952. So, I was western-oriented, that was my major crime in the eyes of the Communist Party.
LH: So there was, essentially, a political crusade against you?
SS: It was. I was Chief of the Laboratory in the psychiatric hospital and didn’t have any chance for advancement. I had a small laboratory with 4 or 5 people working with me. During the short period of time I was working in the hospital I got involved with some clinical work and not only with human volunteers, but also with patients. Dr. Böszörményi, whom I was working with, had suggested that we should try DMT in some of our alcoholic patients and in some schizophrenic patients. We began testing the drug and we found out that it was also active in those populations. It did not have as pronounced an effect as in normals, but it was a noticeable effect as measured by the questionnaires we used.
LH: You were still using DMT?
SS: Yes, dimethyltryptamine. I also synthesized some 13 different derivatives of it. I had the diethyl, dipropyl, dibutyl and several other homologues. The dibutyl was inactive, while the dimethyl, diethyl and dipropyl were active in animals. In humans, we had only tested the dimethyl and the diethyl derivatives at that point. Then I left Hungary, I escaped illegally. I had to. There were two hundred thousand people who voted with their feet and left Hungary after the revolution, mostly through Austria. Once in Austria, I went to Vienna to see Dr. Hoff. Do you remember Dr. Hoff?
LH: Oh, he was head of pharmacology.
SS: No, he was head of psychiatry.
LH: Oh, Hoff, oh yes.
SS: H-o-f-f.
LH: Yes. He was professor of psychiatry in Vienna; I knew him only by name.
SS: I also met H. O. Arnold and G. Hofmann who were in Hoff’s Institute. You may remember their names. They were publishing some interesting stuff at the time. They had done some work on LSD as well. So I decided that I’d get in touch with them. As a matter of fact, they were very kind to me. When I told them I was a refugee, they said, “there is a room here which we use for psychotherapy, and at night if you want to you can sleep in there, but by 7:00 o’clock in the morning, you’ll have to clear out.” But they were nice. They gave me a little shelter over my head. And while pulling out a little bottle from my pocket, I said, “I have a little dimethyltryptamine here with me, you know, if you are interested.”
LH: You were a pusher.
SS: Then I asked them, “Could you give me some LSD to try, I would be very curious to see how it would compare with my experience with mescaline, dimethyltryptamine and diethyltryptamine.” They said, “We have a protocol here. You have to go through it and you can get tested.” So, I got LSD while I was there as a refugee, and it was a very interesting experience.
LH: Was it similar to dimethyltryptamine, but longer-lived?
SS: It was similar, but longer-lived. I took the LSD early in the morning, like 9:00 o’clock and at 4:00 o’clock in the afternoon, they said, by now it should be all over and you may go home. I decided to walk to a large hall where the evening meal was served for refugees in Vienna at that time and sat down for dinner. By then, it was 7:00 or 8:00 o’clock in the evening. There was a huge mural painted on the wall and as I looked at it I said, “those darn things, those figures are moving.”
LH: That’s a late onset.
SS: Yeah, for a while they moved, and then they quieted down and everything was back to normal. The effects of LSD are longer lasting than the effects of DMT, and they come back in waves.
LH: How much had you taken?
SS: One hundred micrograms. That’s a relatively small dose.
LH: That’s a rather modest dose.
SS: So that was my experience with LSD. Then I decided to stay with my sister, who lived in Berlin, which at that time was still surrounded by East German and Russian troops. So, the only way for me to get there, as a refugee, was to fly over the Eastern Zone to Berlin. Once I was there, I got in touch with the people at the local Free University of Berlin. It happened that I met Hanns Hippius, who was working there at that time. They had a lab at the University and they said, “you are welcome to come here and do some work if you are interested.” And I started to learn German. We had German in school back in Hungary. For eight years, we learned German. So, the German came back pretty fast and, as a matter of fact, in a few months I gave a seminar in German about the kind of effects I had experienced with hallucinogens.
LH: I take it that you were able to speak and understand German by then?
SS: Yes. I was there for almost a year. I didn’t realize that if you are a refugee, once you resettle from the first country, which was Austria, in a second country, in my case Germany, I was not considered a refugee anymore. However, I wanted to come to the United States; that was my final goal. I knew that this is the place where much of the action is in the particular area I was interested in. But I had no chance or very little chance to come here, because I was already settled in a second country. But I was still interested and started correspondence with people whom I knew from the scientific literature and I did eventually get three offers: one from Bob Heath down in New Orleans, who had been looking for a psychiatrist. The second, I forget the name of the scientist who offered me a job, was in Philadelphia. And the third was from Joel Elkes at the NIMH, who was organizing a laboratory at St. Elizabeths Hospital. As I was thinking over which offer should I take, I saw a film in Berlin, which at that time was a new film with Marlon Brando. It was A Streetcar Named Desire, based on a Tennessee Williams play. I don’t know if you’re familiar with it, but the movie takes place in New Orleans. And my impression of New Orleans was so bad that I didn’t want to live there. Marlon Brando was playing a bum, and everything was dirty, hot and sweaty there. I said, “I do not want to go to New Orleans; Pennsylvania would be nice, but the NIMH is more prestigious.” I decided I’d take the job with Joel Elkes. So that’s how I got to Washington.
LH: And you picked a place, too, where there were many more disciplines involved. Bob Heath was kind of a loner. He worked his own path and had very innovative ideas, but no one else around would interchange with him; whereas, at St. Elizabeths, I guess Joel Elkes had a more interdisciplinary team.
SS: I was very lucky that I came here. The laboratories, however, were not ready yet. They were converting the fifth and the ground floor in the William A. White building into laboratories and offices, and the laboratories were not ready. Joel Elkes said “Listen, Stephen, there’s some very interesting work going on in Building 10, at NIH, in Julie Axelrod’s lab. I talked to him and you can probably stay there, and work with Julie until these labs are ready.” So, I went there and Julie was nice and very accommodating. He said, “Stephen, if you are interested in applying biochemistry to pharmacology and psychiatry, this is a good place to work on that.” A lot of people worked there, among many others, Danny Freedman.
LH: Now, we’re talking about late 1950s?
SS: Actually, it was late 1957. In 1957 I did go into Axelrod’s lab and, as a matter of fact, I stayed there for about two years, because I liked it. He’s a very, very innovative guy in terms of developing new methodologies. When I told him that I was interested in the metabolism of dimethyltryptamine, he immediately told me that I could study the metabolism of DMT very easily, and suggested some methodologies I might want to use. He also told me the way to detect metabolites in the blood and in the urine, so I could work out the details. I understood from him that I could probably collaborate with some people on the second floor of the NIMH; that there was a normal volunteer group there on whom they were testing new drugs, and some hypotheses, and that they also had a large chronic schizophrenic population. I teamed up with people there and studied the rate of metabolism of diethyltryptamine (DET) in normal volunteers and schizophrenic patients. We had some very interesting results that we presented at the Third World Congress of Psychiatry in Canada in 1961.
While I was in Julie’s laboratory, Hoffer published a paper claiming that he detected adrenochrome in the blood of schizophrenic patients and he made a big claim that adrenochrome was the schizotoxin which produces schizophrenia. Seymour Kety got involved in the discussion, and he said “Listen, this is a very interesting and a very important finding. If it is true, it may be a breakthrough in psychiatry.” But Julie said that there was some deficiency in Hoffer’s methodology and there was no proof about the presence of adrenochrome at all in the laboratory tests. There were no controls, so who knew what he was measuring? So, Julie said that we should check it out.
I don’t know exactly how Julie managed it, but he eventually got two milligrams of adrenochrome and told me how to develop the methodology using that two. Then I got busy and developed a spectrophotofluorometric methodology with proper controls. To prove that it was a sensitive and specific methodology I showed that we could recover as little as 0.02 microgram of adrenochrome added to plasma and measure it. And I said, “Let us try some blood from schizophrenics and see if there’s indeed something to Hoffer’s claims that there is adrenochrome in their blood.” We tested about six or seven schizophrenic patients at the Clinical Center; we collaborated with Irv Kopin who helped us to draw some blood, and then we tested the blood samples. They were all completely negative.
I don’t know exactly how but we got feedback from Hoffer, saying that only those schizophrenics who are acutely hallucinating have adrenochrome in their blood. As it happened, all the patients at the NIMH were chronic patients who were barely hallucinating any more. Dr. Kopin found out that across the street at the Naval Hospital they had a few acutely hallucinating schizophrenic patients, so we drove over and drew blood from them. We drove back to NIH and ran the samples through the test and they were also all negative.
We were quite disappointed and thought, this is probably going to go nowhere, and were ready to drop the whole project, when our lab director, Seymour l, said to me, “You know, Stephen, this is a very important finding, even though it is negative; it is important to make a statement and publish a short note that there is no evidence that adrenochrome is present in the blood of schizophrenics.” He said, “It can prevent people going up a blind alley in a wrong direction.” So we published the paper in 1958 in the American Journal ofPsychiatry. It was a one-page paper, and Hoffer reacted to it strongly. He was outraged. He wrote a letter to the editor of the American Journal ofPsychiatry and we answered it defending our data. Subsequently, in the late 1950’s in the pages of Psychosomatic Medicine, our paper and Hoffer’s reaction spawned an open debate between John D. Benjamin and Abram Hoffer. Benjamin pointed out that the way “Szára and Axelrod approached the problem of adrenochrome in the blood was the way to do research in this area,” using careful controls and proper methodologies. It was a big debate but eventually it quieted down.
LH: Well, I think one of Hoffer’s contentions was that it was a very fragile molecule and could be easily reduced.
SS: It forms spontaneously when an epinephrine solution is exposed to light for an extended period of time.
LH: By oxidation.
SS: It is an oxidation product. Julie Axelrod, at that time, was involved with mapping all the catecholamine metabolism pathways, identifying all the metabolites, and he said that there was no room for metabolism to any other substance, at least in the amounts that Hoffer was claiming. Julie said that he could account for about 98 percent of the metabolites for epinephrine, so there was no room for adrenochrome. Anyway, the paper was published and that was probably the end of the adrenochrome hypothesis.
LH: Well, Abe Hoffer was an interesting person, wasn’t he? He’d get an idea, a wild one, and thought it was real. But one of the interesting things about Abe’s career is that his most important discovery had nothing to do with psychopharmacology. It was that nicotinic acid reduces cholesterol levels.
SS: I knew that he was using nicotinic acid.
LH: He was using nicotinic acid in those schizophrenics, and in the process they were doing a lot of chemical measuring; and it turned out that cholesterol would go down and that was the birth of nicotinic acid as a treatment for hypercholesterolemia, which is still being used.
SS: That’s interesting.
LH: It’s a very effective agent, so that’s a paradox in his career. Now, you were doing all this work while you were at St. Elizabeths, you had a nice building there where they had laboratories on the first and top floor and the wards in between. Did you run across Tony Hordern at that time, the Australian?
SS: No, I don’t think so.
LH: Well, he was a clinician, so you might not have, but didn’t you write a book with Weil-Malherbe?
SS: Weil-Malherbe, yes. That was at the end of my stay at St. Elizabeths in the late 1960s that he asked me to collaborate with him. He was very much into the catecholamine business and he asked me if I want to join him in a book, which was entitled The Biochemistry of Functional and Experimental Psychoses. He reviewed the functional side of it, focusing on the biochemical aspects of psychoses.
LH: It was a review of almost all the biochemical aspects.
SS: It was a very nice book. I wrote a chapter on the experimental psychoses, produced by drugs such as LSD and DMT and reviewed that literature. Now, you might think if you write a review book like this it becomes just another publication in the literature and then people forget it. We also forgot about it until the end of the 1980s. In the meantime some of the ideas discussed in that book apparently inspired David Wong. I don’t know if you know him from Eli Lilly. He is one of the pharmacologists who had developed Prozac (fluoxetine). He apparently did give credit in his publications for the inspiration that he got from our book for the development of Prozac, but we didn’t know about it until the middle of November 1990, when Dr. Wong was giving a lecture at the NIH about developing new drugs. At the beginning he had the cover of a book on the screen for several minutes while explaining how important that book had been in inspiring him to work on new selective serotonin reuptake inhibitors such as Prozac. I didn’t know about this at that time; I wasn’t there, but people from the institute would come back and tell me that “your name was on the cover of the book, and you were credited for the inspiration in the development of Prozac.”
LH: Did they have any idea of the importance of serotonin?
SS: The importance of serotonin is an interesting question, because most of the medical literature in psychiatry at that time was focusing on the catecholamines while serotonin was kind of pushed into the background but the review by Hans Weil-Malherbe was covering both sides. Hans tried to create a very balanced review of the involvement of both serotonin and catecholamines, and he made the point that transmitters probably don’t act just alone but are interacting with each other and serotonin may be just as important as catecholamines. He also reviewed some of the early biochemical findings in depression and in schizophrenia. So, he gave a balanced picture, and Wong apparently picked up on this because of the very interesting statement in Hans Weil-Malherbe’s chapter that the metabolism of tryptamine was changed in depression.
LH: I think the reason you probably didn’t follow the line of emphasizing only catecholamines was because in Europe there was much more interest in serotonin; both of you were transplanted and that gave you a broader perspective than if the book had been written by a purely American author.
SS: I think you are right about the European emphasis on serotonin. It was Garattini who was interested in serotonin. He invited me to present my paper on dimethyltryptamine in 1957 at an international meeting in Milan. I don’t know if you were there. That was a symposium organized by Silvio Garattini on psychotropic drugs. It was published in a monograph. It was the success of the Milan meeting that led to the founding of the CINP, the Collegium Internationale Neuro-Psychopharmacologicum.
LH: This was about in…?
SS: In May 1957. Garattini invited me to present my dimethyltryptamine work and I chose to talk about my self-experiments with the four hallucinogens: mescaline, LSD, DMT, and DET. I made as concise a comparison as possible on the basis of my personal experiences. And I think it was at that meeting that I met somebody from Joel Elkes’ lab who interviewed me, and based on that interaction, Joel Elkes hired me without actually seeing me.
LH: Somewhere along the line you learned English.
SS: When I was in Berlin, I had a girlfriend, a German girlfriend, who could speak English, and we went over my paper that was written in English, so that I could learn how to pronounce the words. I gave my paper in Milan in English, but I learned to speak English only after I came here. Obviously, you don’t learn a language that late – I was thirty-something – without keeping your accent.
LH: I always remember Dan Efron’s famous statement, “The international language of science is broken English.”
SS: That’s very true.
LH: How long did you stay at that laboratory?
SS: About ten years.
LH: So, that would be 1958 to 1968.
SS: About 1969.
LH: Did you continue during that time your work on hallucinogens?
SS: Mostly hallucinogens. We did some very interesting clinical work as well. I don’t know if you want to hear about that, but we tried to test the effect of DET on alcoholic patients. There was a claim in the literature that LSD and the so-called psychedelic drugs could be very useful in treating alcoholics.
LH: Again, Abe Hoffer and a couple of other Canadians.
SS: A number of claims had been made, so we decided to see what our drug could do. We set up a team that consisted of a psychotherapist who’s his name was Vourlekis, and another fellow who came to work with me, whom you knew very well, because he has also worked with you, Lou Faillace. We decided to do a double-blind study on alcoholics, using what we called an active placebo. The substance we used was a derivative of DET, namely 6-fluoro-diethyltryptamine, in which we substituted the 6th position of the indole ring with fluorine. It turned out to be a substance which wasn’t hallucinogenic any more, but still produced some autonomic effects so the patients felt they received something. We had maybe a dozen patients who had been chronic alcoholics for about four to ten years, and the psychotherapist, Vourlekis was involved with the patients until the effects of the drug wore off. He also conducted most of the tests and followed up the patients. We thought we did see some improvements, but they were unfortunately only temporary, lasting for about six months. We did a follow up two years later, and those patients who received DET did not differ significantly from any other alcoholic patients in their drinking habits.
LH: It’s surprising that you mentioned Lou Faillace. I’d never heard of him until I did some work with STP (2, 5-dimethoxy-4-methylamphetamine), the amphetamine homologue. Sol Snyder was working on it as well at the same time. I visited Sol in Baltimore, and said, “Well, there’s no use publishing our papers separately, at least for the preliminary report; why don’t we combine them?” So, the paper came out, Snyder, Faillace and Hollister. I didn’t know who this Faillace guy was. I guess he was a fellow at that time, doing the clinical work. And as luck would have it, in 1986, when I decided to leave California and come to Houston, Faillace became my boss. He was the Chairman of the Department in Texas when I joined. So I guess the moral of the story is, treat all of the young people gently. You never know when they’ll wind up as your boss.
SS: I met him again recently. NIDA organized a meeting on hallucinogens and Lou was invited and I saw him at the meeting. That’s when I last saw him.
LH: Well, I became interested in LSD in alcoholics through a group led by a guy who was essentially an engineer, named Hubbard – not Ron. They were going around the country charging people $600.00 a pop for one session with LSD with the idea that one session would cure you. So Jack Shelton and I did a study; and Joe Levine and Arnold Ludwig did a study; and perhaps it was your group, I don’t know, it was a third group; all independently. None of us knew that the others were doing it. We all came to ultimately the same conclusion; that although there might have been a transitory effect, it was not long lasting, and I think that sort of finished the idea off. But it’s amazing that story with hallucinogens, how it captured the imagination, and it’s coming back now, isn’t it?
SS: Yes, I read in the newspaper, LSD is very easily available, and people take it without a second thought; they are there for the experience. It’s unfortunate, but I hope these drugs eventually prove to be useful. They are very powerful and they do produce something in our brain that affects our mind and this interaction between the brain and mind is a fascinating phenomenon. I have a preoccupation about it, because I think that their major and most important effect is probably losing the ego boundaries. After you take LSD you feel that you are one with the whole world, with the whole universe. When your ego boundary disappears you feel one with your fellow beings, so there’s a very interesting social facilitating effect there, which is probably there all the time, but we are not aware of it. The hallucinogens give us a key for getting into that particular part of our brain/mind relationship that establishes a boundary of how far our ego is extended. When you drive an automobile, your ego includes the automobile and you, driving together.
LH: Another intriguing thing about LSD was that it would produce these profound mental effects in relatively small doses. 2 micrograms per kilogram was more than enough for a pretty good experience and, when you think of it, there aren’t too many substances that have that potent a physiological effect. Vitamin B12 is one of those substances; 1 microgram per day makes a difference between having a normal blood count and having pernicious anemia. Another example is botulinum toxin; but there aren’t too many compounds that are as potent. I think that LSD had a big attraction because it was feasible to consider that something equally potent or even more so, could be produced endogenously and make people schizophrenic. However, the endogenous psychotogen idea fell into disrepute and hasn’t been followed up very much. A new interesting story I learned much later in life from Ernst Rothlin, the Sandoz pharmacologist; he was visiting me and said, after Hofmann had his inadvertent experience with LSD, he decided he ought to take it again to prove it was the substance that produced the effects. He discussed with Rothlin what the dose should be. Hofmann wanted to take about 200 micrograms and Rothlin, being a cautious pharmacologist, said, oh, I think I’d only take 30 or 50. Well, Hofmann ignored Rothlin’s advice and, of course, he had a whopping reaction.
SS: I hear that Hofmann took 250 micrograms.
LH: If he’d taken the dose Rothlin recommended he might have missed LSD’s psychomimetic effect.
SS: Talking about LSD, a few years ago, in 1993, there was a meeting in Lugano organized by Sandoz to celebrate the 50th anniversary of the discovery of LSD and Hofmann, I think he was 86 at that time, was still very alert and very up to date with work involving LSD and the ergot alkaloids. He showed us a film about how he discovered LSD and what his experience was. It was very interesting to hear it from him on a firsthand basis.
LH: Did you ever study psilocybin?
SS: No, I never got around to studying psilocybin.
LH: But you did some studies with mescaline?
SS: The only study that I had done with mescaline was taking it and experiencing it.
LH: Because they’re all really a part of the same group, clinically, and virtually indistinguishable; although, the dose is different by orders of magnitude. The only person I know who is doing some work currently with hallucinogens, and we’re sending him grant support, is a fellow named Rick Strassman in New Mexico or Arizona.
SS: Well, he was in New Mexico up to, I think, a year ago, and he moved to either Seattle or some other place. But at that time I was in touch with him. He had called me up a number of times, because he’s the only one who is following the DMT story in a very systematic fashion. He got around the bureaucratic red tape that involves the use of these drugs, and eventually he established a good research group.
LH: So, after you finished at St. Elizabeths in 1968, what did you do then?
SS: Well, at that time, I was kind of pushed out of the laboratory. I don’t want to name names, but it was a difficult situation.
LH: Had Joel left by that time?
SS: Joel had left by that time, and other people also had to go. It was a difficult time, and I had to decide what to do next. A position opened up at the Extramural Branch of NIMH. They had a Drug Abuse Center; the exact name was Center for Studies of Narcotics and Drug Abuse. Bob Peterson was involved in recruiting new people, and he thought that I could be useful to organize some new work there, so I decided to accept it, and I made the switch at that time. It was a forced switch, but I don’t think that I have regretted it because I got involved with some very interesting stuff. It was not only new subjects and new drugs. I had an opportunity to meet with a variety of scientists working in that area. I became first Chief of the Clinical Studies Section, and, then in 1974, when the Center was enlarged to become the new National Institute on Drug Abuse, I became Chief of the Biomedical Branch. In the Clinical Studies section, which I first had, the main question, the main thrust, was to do some controlled clinical studies with THC (tetrahydrocannabinol) and marijuana. That was the first project I was involved in, and I remember reading in one of your books, which you had written at the time, that marijuana is probably one of the only drugs in which more experimentation had been done in humans first, rather than animals, or something like that. So, that was probably part of the impetus, among others, to do some more clinical studies and more controlled studies, because all the experimentation you referred to involved people taking drugs on their own, without knowing how much they were taking, without any controls. The main point was you ought to do some controlled clinical trials and that was my first job. In the first year when I got involved with organizing the program, I was actually sending out RFPs, Requests for Proposals. We had contract money and we decided to do a number of studies. We got a group going at UCLA, Sid Cohen was the first principal investigator on that, and then we had the San Francisco group with Reese Jones, and we also organized overseas studies in which we decided to study the health effects of marijuana in long-term users in Jamaica, Costa Rica and also in Greece. So we had a number of studies.
LH: Epidemiological studies in Jamaica and Greece.
SS: Yes, epidemiological studies including the study of medical histories and health effects, if any, as a result of chronic use. We also supported a number of other grantees studying marijuana and THC, and eventually we organized a meeting, I think it was in 1975, held in Savannah, Georgia, where we invited all the people who were involved in these studies, including you. You may not have been able to make it, but you sent in a paper, and we included that in the proceedings, as you were one of the first who studied THC. So, it was important to have documentation of what was known at that time about THC. This was also necessary, because, in my capacity at NIDA, I was responsible for sending over to the FDA reports about basic laboratory studies on THC for the Master File that FDA has to keep for any drug that is being tested for potential therapeutic use. Eventually THC has been approved, in a capsule form, to treat nausea in cancer patients on chemotherapy, so that was the only medically relevant and important result of this particular study. We also had a grantee at UCLA, Donald Tashkin, who has done some very good work about the effects of marijuana and tobacco separately and together on the lungs of chronic smokers.
LH: I think we can generalize and say, any time you take smoke in your lungs it’s bad for you.
SS: Yeah, that’s it. Actually it is that simple, and it’s costing us millions of dollars to document it and this is the result. So that was my role in the THC studies at NIDA that I had to follow very closely. It was very important to visit all of the sites occasionally.
LH: Well, the therapeutic use of THC or marijuana is becoming a very politically sensitive issue now in states that conduct plebiscites to approve its use without any scientific basis. It’s rather remarkable that in spite of all the studies on the therapeutic uses, nobody has tried to assess smoked marijuana vs. orally administered THC.
SS: Maybe they have done that in our study at UCLA in which Frank was involved.
LH: Who did it?
SS: Ira Frank. Ira Frank became the Project Director of the UCLA project.
LH: Years ago Ira incidentally found that THC lowered intraocular pressure.
SS: That was part of a study that compared smoked marijuana with smoked placebo and oral THC.
LH: I think glaucoma is a dead issue as far as the therapeutic use of THC is concerned.
SS: Sounds like it is.
LH: Most people who have glaucoma are old, and I can’t see old people wanting to be stoned all day while controlling their eye pressure.
SS: Yes, as a matter of fact, it is a very unpleasant side effect for those people.
LH: Traditionally, glaucoma has been treated with local instillation, and there are now a great variety of different drugs to treat it. Besides, I think THC is not much different from alcohol in terms of the reduction of intraocular pressure, but again, who wants to be drunk all day, so I consider that a dead issue. The only three therapeutic issues I think that need to be resolved are smoked marijuana vs. oral THC in nausea and vomiting for people on cancer chemotherapy; smoked marijuana vs. oral in terms of appetite stimulation and weight preservation in people who have the wasting syndrome of AIDS. And possibly more studies, because there aren’t very many, on its effect on spasticity in neurological diseases like multiple sclerosis or other diseases where you have muscle spasms. But all the other indications, I think have died out by now, or are totally unrealistic. But there could be a lot more done in that one area.
SS: The only hitch is the FDA’s resistance to having a drug that cannot be well standardized. To standardize a smoke is almost impossible and the FDA is very reluctant to even consider a smoked drug to be used in any context, so that’s the end.
Okay, let’s just go to some other area. I understand you want to have some discussion about all the drugs that I have been involved in. At NIDA, in the early 1970s the opiates came into focus, mostly as a result of Bill Martin’s initiative that there is probably more than one type of opiate receptor we have to consider. But at that time there was no known isolated opiate receptor, not even a direct demonstration that opiates are binding onto specific receptors. In 1971, we organized a meeting at the Center for Studies of Narcotics and Drug Abuse, with I think, 50 or so people attending. I don’t know if you were present at that meeting, because it was related primarily to opiates. We had rounds of discussion for three days, on the question of where the Institute should put its money, in terms of opiate research. How should we proceed? Some of the conclusions were that obviously the molecular aspects of the receptors would have to be worked out in a more detailed fashion and some money should be put in that area. And this is what happened. We did establish, I think it was in 1971, eight Drug Abuse Research Centers. Some of them were almost exclusively oriented to research on opiates, like Avram Goldstein’s group and a few others. Sol Snyder’s group, in the beginning, was not into opiates. They were into amphetamines, primarily, and into catecholamines.
LH: I was talking yesterday to Candace Pert.
SS: I saw her recently and I was reminded that she was working with Sol as a student at that time.
LH: She said after she’d been working on the problem for a couple of months and hadn’t gotten any results, Sol got impatient and said, “Well, let’s go on to something else.”
SS: And once they identified the opiate receptor with a reasonable certainty, using specific binding of radioactive labeled naloxone with very high specific activity, they managed to measure more reliably the localization and density of specific binding sites in the brain; that, apparently, eluded Avram Goldstein who had started this strategy earlier.
LH: Well, you know, there were so many people in the story of the opiate receptor and the endogenous ligands that it’s hard to say who deserves the most credit, but I really think that Avram Goldstein was very fundamental in it, because he had started the research on the opiate receptor as early as 1971. He gave a paper at the IUPHAR meeting, in which the problem he had was distinguishing non-specific from specific binding, but that was because he didn’t have ligands with high enough specific activity. And then, a year or two later, he described something called a pituitary opioid-like material, which eventually turned out to be dynorphin, so he was right in the forefront, both in the receptor and the ligand area. But, almost simultaneously with Candace’s work, along came Terenius and Eric Simon. And, of course, Kosterlitz and Hughes came in 1975 with the endogenous ligand. He must have been involved in the beginnings with LAAM, levo-α-acetylmethadol.
SS: Yes, Avram was very instrumental in pushing LAAM for the treatment of heroin addiction.
LH: Isn’t it incredible it took 18 years before it got accepted?
SS: There were a number of stumbling blocks as you are clearly aware. LAAM was not a clean drug in some sense, but everybody was willing to go along without any hesitation, until eventually it became accepted. So, in 1975 and 1976, NIDA was discussing, how we should acknowledge these people’s contribution to drug abuse research and they established an award. I was asked to suggest who would be the appropriate persons to get an award and we apparently settled on six of the leaders of research groups who were involved.
LH: The Pacesetter Award.
SS: Yes, it became known as The Pacesetter Award. Avram Goldstein, Sol Snyder, Eric Simon, John Hughes, Hans Kosterlitz and Lars Terenius, were the people who eventually got this award. It is obvious that Candace Pert was very upset that she was left out of this group and we did, indeed, have some serious discussion about it, but she was still a graduate student at that time.
LH: I remember when the older Governor Brown was governor of California. He made a famous statement in which he said, “Every time I appoint a judge, I make 99 enemies and one ingrate,” and I think that’s sometimes the way awards work, so you can’t win. Well, you’ve had a long career both in clinical and laboratory research, as well as administration. What do you think we should do about the war on drugs? Are we going to win it, or are we losing it, or should we change our tactics?
SS: It depends on who you ask. If you ask me as a medical scientist, I would prefer that most of the available money would go to research on treatment and prevention. That would be probably better spent than putting all this money on airplanes and spraying the fields.
LH: So you would prefer treatment vs. interdictions?
SS: I would prefer that more money be put in the treatment area.
LH: And, what’s the evidence for the effectiveness of these treatments? Is it all that good, once you get past methadone?
SS: Probably not, but at least it makes some people, not everybody obviously, well enough to make a contribution to society, to take a job and be a useful citizen, even though they are on methadone or continuing methadone, but they are still more respected citizens than those who are just keeping on injecting illegal stuff.
LH: Naltrexone is an ideal drug for opiate dependence. It specifically blocks the receptor. It’s orally active, fairly long lasting and you don’t get high on it. Nobody ever gets addicted to it. So it’s a perfect drug for treating it, but nobody wants to take it. The only people who benefit from it are the high-class opiate dependent people like physicians, nurses, lawyers, and people in general who have a lot to lose if they lose their license. But if you don’t have a lot to lose and you have only a very little motivation, as most of the opiate addicts do, it doesn’t work
SS: It doesn’t give them a buzz that they can get from methadone.
LH: Well, that’s the beauty of methadone. Once you’ve got them hooked, they’ve got to stay with it, but the other problem is that as prevention, do you think a whole bunch of advertisements directed at kids are going to change the pattern?
SS: It depends on how it is being handled, I think. Some of the advertisements may provide education, perhaps making people aware of the dangers, especially if you have a child involved, because they feel themselves as invincible and think they’ll live forever, so they don’t care much about the dangers. But I think if the message is carefully worded and organized, it could be helpful for some people. It may not solve their personal problems, but it could benefit some people. I don’t have too much hope for anything that would be spectacular in terms of cutting back on drug abuse. In a free society there is no way to have it policed effectively.
LH: The area of hope I think is with smoking cigarettes. There has been a gradual but slow decline in the number of smokers, and of course, in part, that’s due to the fact that it’ll kill you and you’ve got a constant attrition, but aside from that, I think the social pressures that have been put on smokers have had a very positive effect in either reducing the number of smokers or reducing the amounts they smoke. But that’s taken a whole generation.
SS: What’s interesting, I don’t know if you were aware of it, but the situation you just described is probably valid only in the United States, and it may be completely different in other parts of the world. I can only speak from personal experience about the social attitude on smoking in Europe. When you go to Europe, there’s cigarette smoking everywhere, and I really can get sick; I just go to a restaurant, and practically everybody is smoking around me, and I can’t even smell the food. So society in general would have to recognize the potential problems, and I don’t know what kind of public education would be the best, but apparently some of those that have been effective in the United States could be tried. The social acceptance of smoking is still prevalent in Europe, and we’re not even talking about China and some of the other countries, where people are still smoking heavily.
LH: I guess Japanese men have the highest rate of smoking of anybody and, yes, societal attitudes play a big role, but it works so slowly that one can’t get very enthusiastic. Well, you had a very interesting career, spanning several countries and several languages. I think it’s very remarkable, obviously. Now, when you left Hungary, you left by yourself and no other family?
SS: Yes, I left Hungary by myself, and I got married here in the States.
LH: Do you still have family there?
SS: I have a sister who stayed back in Hungary. As a matter of fact, there were five children in our family and every one of us is ended up living in a different country. My older sister is still back in Hungary. My second sister is in Berlin, Germany. My third sister is in England. Unfortunately, she had a stroke, but she’s still alive. My brother is in Switzerland, and I’m in the United States.
LH: The Száras are worldwide. Well, I think you can be proud of what you did and I hope that you will keep active and interested in the field from now on as well.
SS: I’m trying to keep up with the research literature. In my spare time, I have a little computer and I’m trying to work out a model for the brain/mind.
LH: If you had to do it over again, would you do the same career? You might have a few qualifications, but on the whole, what do you think?
SS: On the whole, I’m not dissatisfied with the way things have turned out. At first, I was fretting and very distraught I had to give up laboratory research, back in 1970, but then, going into the administrative position, it gave me a slightly different perspective and a different way of leaving at least some of my footprints on the field. It was quite different than what I would have been able to do as a scientist. Eventually, I kind of settled down and made peace with myself that I did accomplish something in my life and I think the field is now moving at almost breakneck pace, which is tremendous. The only problem is that we are now deluged in a sea of data and we need some guiding principles or new tools, to find out which would be more relevant, more appropriate and more effective in trying to bridge the gap between where the drugs act at the chemical level to give rise to a behavioral response or subjective experience. How this gap could be bridged is going to be a major problem in the near future in our field, so we really need some bright ideas of how a drug acts on a receptor as a chemical, how it is translated or transformed into thinking, feeling, and eventually action and behavior. So this is a major gap, which still needs to be bridged. There are major advances in the area of brain imaging like the PET scan and fMRI, where we can actually look into the brain and see the areas that are lighting up as a sign of increased blood flow, presumably as a result of increased neuronal activity. These are very interesting new tools for getting a handle on what’s happening in our brain when we give a drug, but there is still no connection from the chemical level to the more global, neuronal level, so these gaps have to be eventually worked out before we can begin really making a major push forward.
LH: Well, maybe molecular biology is the answer.
SS: That’s probably part of the answer, but not the total answer.
LH: Thank you.
SS: Leo, it was a pleasure. Thank you very much for spending the time with me.
LH: Yeah, I don’t know where time goes.
SS: We may meet some other place and bump into each other as we did in the past, in Copenhagen or in Quebec, all kinds of interesting places.
LH: Well, I’ll probably go to the CPDD (College on Problems of Drug Dependence) meeting in Nashville this year. I’ve been cursed with poor health for the last three years and I had to miss the last two meetings, but I’ll go this time, maybe.
SS: Well, I will not be attending, but I will probably go to the ACNP meeting in Hawaii.
LH: Well, if we’d known you were going to be in Hawaii next year, we’d have done this interview over there.
References:
Ban TA. Preface. In: Shorter E, editor. Starting Up. (In Ban TA, editor. An Oral History of Neuropsychopharmacology). Brentwood: American College of Neuropsychopharmacology; 2011a.
Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Brentwood: American College of Neuropsychopharmacology; 2011b.
Shorter E. A History of Psychiatry from the Era of Asylums to the Age of Prozac. New York: Willey; 2005.
Shorter E. Dramatis personae. In Shorter E, editor. Starting up (In Ban TA, editor An Oral History of Neuropsychopharmacology Volume One) Brentwood: American College of Neuropsychopharmacology; 2011a.
Shorter E, editor. Starting Up. (In Ban TA, editor. An Oral History of Neuropsychopharmacology). Brentwood: American College of Neuropsychopharmacology; 2011b.
Szára S. Dimethyltryptamine: its metabolism in man; the relation of its psychotic effect to serotonin metabolism. Experientia 1956;12:441–2.
Szára S, Axelrod J, Perlin S. Is adrenochrome present in the blood? Am J Psychiatry 1958;115:162–4.
October 7, 2021