Conversation with Michael A. H. Russell


In this occasional series we record the views and personal experience of people who have specially contributed to the evolution of ideas in the Journal's field of interest. Michael Russell came to Britain from South Africa. Over a professional life-time he has made varied and fundamental contributions to the study of nicotine dependence.

A: I would like to start by asking you a bit about your background, your childhood. I think you grew up in South Africa and went to school there before you came to England?

MAHR: Yes, I was born in South Africa in 1932 and I did indeed go to school there. My mother was English, and we used to come over to England almost every year from the time I was about 3. She would visit her five siblings, so we had plenty of relatives here. That stopped in the war, of course. I did all my schooling in Cape Town. I then managed to secure a place at Oxford to study law, but in my last term at school I did constitutional history, which I found so boring that I switched to medicine. But Oxford had far fewer places in medicine so I could not go there at first. I started the medical course at University of Cape Town. Towards the end of my first year, Oxford contacted me and said there was a place for me as someone had dropped out. I jumped at that, accepted it, finished my year and then came over to Oxford—one term late in January 1952. I was 19 then. One did the preclinical work at Oxford, and then most of us in those days did our clinical training at London teaching hospitals. I chose Guy's Hospital.

A: While you were at Oxford you also got involved in more than just the medical curriculum—you were a bit of a sportsman, I think?

MAHR: Not a great one. I gave work the priority; but I was quite a good swimmer and took up swimming for one term to get a half-Blue. It was rather unpleasant going up to Cowley Baths and training in a short pool. Although I was also fairly good at rugby, I did not make a Blue at Oxford. I got as far as the Greyhounds (the second team) and went on a Greyhound tour to Germany, where we played against British Army teams. It was at Guy's doing my clinical that my rugby was really useful to me. I played for the first team for 3 years, and for United Hospitals. All the consultants—indeed, the whole hospital, used to know the members of their rugby team—and I am sure that is why I got good house jobs at Guy's for the whole of my preregistration year. It is quite a help, being able to stay in your teaching hospital—you just pick information up because you are doing the work, whereas if you go to a small country hospital, it is not so academic of course.

‘All the consultants—indeed, the whole hospital, used to know the members of their rugby team—and I am sure that is why I got good house jobs’

A: When you qualified at Guy's did you already at that time have a clear sense of where you wanted to go in medicine?

MAHR: No, in fact I went back to South Africa. I thought I might be a general practitioner (GP). So I went back there and did some junior doctor positions starting with obstetrics and gynaecology, thinking it would be useful for a GP. This was in Groote Schuur Hospital, the University of Cape Town teaching hospital. I did several house jobs. The second one was in neuropsychiatry—neurology and psychiatry were mixed—and Henry Walton was the main psychiatrist there. He was an inspiring teacher and he made me interested in psychiatry. He was English and came back here to become professor at Edinburgh. It was in that time with him, only a 6-month appointment, that I found learning to understand people's thoughts, feelings and behaviour much more interesting than dealing with abortions or caesarean sections, or indeed the functioning of their hearts, bowels, liver or stomach, etc. I decided to do psychiatry, but it was a long time before I actually started training in psychiatry. In those days psychiatry was a bit of a Cinderella subject—psychiatrists were not considered as important as physicians or surgeons—they were rather looked down upon. So what it was necessary to do if you wanted a good position in psychiatry was to train as a physician first and obtain your MRCP (Member of the Royal College of Physicians). Incidentally, even to get training in psychiatry at the Maudsley you had to have something extra, such as an MRCP or PhD. To obtain the MRCP in those days you needed a great deal of clinical experience to pass; it was quite a hard thing to do then. So I remained at Groote Schuur Hospital and did more jobs there, even though we knew that we would be coming over to the United Kingdom when I was ready to study psychiatry. I did registrar positions at Groote Schuur Hospital for a couple of years and was a senior medical registrar there for a year.

A: By that time you had met your wife?

MAHR: Yes, Audrey was a nurse at Groote Schuur Hospital. We both decided we were not going to stay in South Africa. The political situation was unpleasant—it made you feel guilty and, through endless arguments about it, we alienated many of our friends. It was really very unpleasant. During my year as a senior registrar I took the Fellowship of the College of Physicians of South Africa—their equivalent to the MRCP. Then, in January 1964, we left South Africa to come to the United Kingdom. I wanted to get the Membership quickly, so within about a week of arrival here I sat it for the first time and unfortunately failed my final viva. You were allowed to sit it twice a year only, so I sat it 3 months later and managed to pass. Then we decided to take a year off to travel. We were young and this was a good opportunity. I knew more medicine and basic science than I really needed, so I secured a place to come and start training at the Maudsley in October 1965, rather than October 1964. So, we had well over a year off to travel around the world, which was a wonderful experience. We set off to go overland to Delhi in India on a coach tour, which was really interesting, but because of our South African passports we were not allowed entry to Pakistan. We left the coach in Isfahan in Iran and were on our own from then on. We flew to Delhi, went on to Calcutta by train, flew to Bangkok and then Hong Kong. On arrival in Hong Kong we had almost run out of money. Fortunately, I got a job as medical registrar at the Ruttonjee Sanatorium in Hong Kong. It was a TB hospital, run by St Columbine nuns—lovely Irish ladies who were very kind to us. It was situated right in the Central Wanchai area of downtown Hong Kong, very stimulating. We stayed there for about 6 months, saving up money. We took a trip to Canton in China, which was quite hard to get into in those days. So we saved enough money in Hong Kong and then headed on towards home. We got back in October 1965 in time to start at the Maudsley. We came back through Taiwan and then Japan, where we had 3 weeks. No tourists there then, language was a huge problem which was great fun, and then via Hawaii to Los Angeles. There you could get a Greyhound bus ticket with unlimited mileage for $90 for 90 days of travelling—we went all around the States. In the bus you meet and talk to people and their character varies as to whether you are right down South, or in New York or Boston. We went from top to bottom, west to east.

ARRIVING AT THE MAUDSLEY

A: In 1965 Sir Aubrey Lewis was still in his pomp at the Maudsley as Professor of Psychiatry and running the show with a rod of iron.

MAHR: Yes, we had to come in on Saturday mornings then, when Sir Aubrey held a big seminar. Occasionally you had to present the topic and got challenging questions. You were not allowed to refer to notes, and there were no slides. Some people were terrified by that. The Maudsley training was very tough and competitive. I was lucky to be on Sir Aubrey's professorial Unit for my first 6 months, with Bob Kendell as my senior registrar (SR), and Mike Gelder, who recently retired from the Chair in Psychiatry at Oxford, was my consultant. Bob Kendell was very helpful as a SR. If you had to present a case he would tell you what should be done, and what references you should read. Mike Gelder was interested at that time in the treatment of transvestites with electric aversion therapy in collaboration with Isaac Marks. As Gelder's registrar I was the one who collected the data and did the treatment. I was incredibly fortunate to spend my first appointment as trainee registrar working so intimately with two such outstanding researchers as Marks and Gelder.

A: What was it that attracted you to smoking?

MAHR: I was aware, of course, that it was a major health hazard which we had failed to control effectively for many years. This was also the age of learning theory and behaviour therapy. I was so impressed with the effects of electric aversion on transvestism that I thought it might work on smoking. So I decided to do a pilot study of its effects on smoking as the basis of my DPM (Diploma in Psychological Medicine) dissertation.

‘I was so impressed with the effects of electric aversion on transvestism that I thought it might work on smoking.’

A: Were you yourself a smoker at that time?

MAHR: Yes, usually no more than 10 a day, and only when drinking tea, coffee or alcohol. I gave it up in 1967. It was quite difficult for a couple of weeks, especially when chatting over coffee after lunch. I got over this by drinking the coffee quickly and going back to my desk. My wife was, and still is, a never-smoker and non-drinker, which made it easier for me.

FIRST FOOTSTEPS IN SMOKING RESEARCH

A: So that was your very first involvement with smoking as a subject for research?

MAHR: Yes, a pilot trial on electric aversion therapy for smoking for my DPM dissertation. Both Griffith Edwards and Isaac Marks were enormously helpful as supervisors. Griffith also provided space for me in the Addiction Research Unit (ARU) and acted as Consultant in charge of the cases. I also had to learn about the typical problems of giving up smoking and how to advise and support subjects. For this I sat in at many sessions of the flourishing Smoking Advisory Clinic in Islington, run by Dr Howard Williams and Mr Ken Robertson.

A: So this would have been 1969 or so when you were starting to really read in the area of tobacco and started looking at the literature?

MAHR: No, I started slightly earlier, 1966 or 1967. My DPM dissertation would have been completed by July 1968 when I became a senior registrar, and I would have been reading avidly all this time. Griffith advised and helped me obtain a 3-year Medical Research Council (MRC) project grant to conduct a controlled trial of electric aversion therapy for smoking, which included funding a psychologist and a statistician. The results were disappointing and took a long time to write up. Although electric aversion therapy suppressed smoking, it was only a placebo effect. It was in July 1969 that I completed my year as a senior registrar and joined the ARU as a research worker. The best advice Griff ever gave me was that to do good research you had to do it full-time, which I did, thinking it would be for only 3–4 years and look good on the CV for getting a consultant post at a teaching hospital. I did write up a little paper on my pilot trial which was published in the British Medical Journal[1], and then I wrote a review on ‘Cigarette smoking: the natural history of a dependence disorder’[2].

UNEQUIVOCAL IDENTIFICATION OF THE SMOKING HABIT AS NICOTINE DEPENDENCE

A: Looking back, that was a truly seminal paper, because that was really a very clear and unequivocal statement that smoking was basically all about giving yourself nicotine. It was here and there in the literature, but it was certainly a somewhat heterodox view at that time. Would you agree?

MAHR: Yes, it was certainly more forthright than the 1964 report of the US Surgeon General, which referred to tobacco use as ‘habituating’, and more in tune with the 1988 report which referred to nicotine as the drug in tobacco which causes addiction, and goes on to say that the underlying processes are similar to those that determine addiction to heroin and cocaine. But for me it was all there in print in 1967, in a volume of the Annals of the New York Academy of Sciences. There was a paper by Schmiterlow et al. using autoradiography following radioactively labelled nicotine given intravenously to mice. It shows the brain full of nicotine after 5 minutes; after 30 minutes it has all left the brain and distributed to other parts, e.g. the stomach, the liver and kidneys [3]. That just showed you where the nicotine went. Thirty minutes after a cigarette is about the time a smoker begins to feel like another. That volume is full of papers on the effects of nicotine, including nicotine self-administration and even smoking in monkeys [4]; and finally, an excellent paper on impairment of performance on sustained simulated driving in deprived smokers [5]: all there in 1967, as is evident in my paper. Indeed, it was in 1967 that Lucchesi et al. showed that intravenous nicotine significantly reduced cigarette consumption compared with the saline control [6]. Murray Jarvik was also contributing to this field well before me.

A: You were satisfied in your own mind that the evidence pointed clearly to nicotine. So what did you feel was the next step; did you feel mapped out for you what you needed to do to progress research in the area?

MAHR: The priority for my ‘map’, as you put it, was to find a measure of smoke intake. Initially we used carboxyhaemoglobin (COHb) as a measure of smoke intake, and of course for validating abstinence. I linked up with Peter Cole. He had a laboratory at St Bartholomew's Hospital which measured COHb. We collaborated with Peter for many years. Indeed, our first joint study published in March 1973 was a demonstration of passive smoking using and exposing ARU staff during a weekly meeting at which one or two subjects had reports to present [7]. All the windows were closed, smokers were asked to chain smoke and I think Griffith obliged by smoking a large cigar (without inhaling). Several unsmoked cigarettes were kept burning in ashtrays. Another thing we collaborated on with Peter Cole was CO yields of cigarettes. We wanted to look at CO yields, so Peter Cole rigged up a suction pump and Clare Wilson, who was one of the psychologists helping us, went up there and puffed different cigarettes onto this suction pump and measured the CO yields—did it with plain versus filter cigarettes, and just showed that cigarettes did vary very much in CO yields and therefore we should have these printed on the packets too. We were able to do some of these simple little things very quickly.

We did start looking at some titration studies quite early on in 1975, using CO as an intake marker and giving people cigarettes with high (3.2 mg) and ultra-low nicotine (< 0.3 mg) yields, and showing that they tended to smoke harder to compensate for the ultra-low-yield cigarette and substantially reduced CO intake from the high nicotine cigarette [8]. In fact, Heather Ashton had already been looking at the effect of nicotine on some behavioural tasks, using standard and low nicotine cigarettes as a source of two doses and noticed that on low nicotine cigarettes people took more puffs. Chris Frith at the Institute of Psychiatry also showed increases in the puff rate on lower nicotine cigarettes. Both these studies were about 1970–71. So it was not us who actually discovered it, although we did demonstrate it quite well when we could measure blood nicotine. After all, puffing tells you only about what is taken into the mouth.

BLOOD NICOTINE ASSAY DEVELOPED AS A VITAL RESEARCH TOOL

A: You set about developing a blood nicotine assay. You must have hired Colin Feyerabend back in 1973 hot out of university? You employed him specifically to develop the blood nicotine assay?

MAHR: Yes, he was quite young. It was Isaac and Rand's paper in Nature in 1972 showing exquisite measurement of blood nicotine that inspired me [9]. I contacted Roy Goulding, Director of the Guy's Hospital Poisons Unit, because I had known him when I was at Guy’s. I showed him Isaac and Rand's paper and he said yes, we could do that for you. Then we recruited Colin; to fund him and his equipment, etc. we persuaded the DHSS who supported our GP advice study [10] that measures of blood nicotine were necessary to validate abstinence. Colin published his first paper describing his method in 1975 [11], but this was preceded by a paper on blood and urinary nicotine levels in non-smokers [12], and our nicotine titration study on blood nicotine levels after smoking high, medium and low nicotine cigarettes [13], both published in 1975 also. Colin went on to improve his analytical methods and published a microextraction method that required very small samples [14], a paper on removing sources of contamination [15], e.g. by smoking in the laboratory, and finally in 1980 a very rapid gas-liquid chromatographic method of cotinine assay [16]. But it was 1985 before we published a pharmacokinetic study showing a biphasic decline in plasma nicotine concentrations with initial and terminal phases [17].

BUILDING A RESEARCH TEAM

A: So you had the beginnings then of getting a research team around you. I think you mentioned Elizabeth Armstrong as someone who first worked with you, then Martin Raw came along quite early on, I think, to work on the clinic. What about Julian Peto—was he the statistician?

MAHR: No, we had Upendra Patel as our statistician. He was relatively junior but good and supported Elizabeth Armstrong with the aversion therapy trial and also many other studies. Clare Wilson joined us before Martin Raw. Unlike Martin and Elizabeth, who were clinical psychologists, she was a psychologist. She took part in our nicotine titration studies of 1973 and 1975, and in one of our earliest nicotine gum studies showing that nicotine gum suppressed ad libitum smoking and aided cigarette withdrawal [18]. She also conducted most of the work for our GP advice study of 1979 [10]. Julian Peto was one of Griffith's very superior statisticians and he helped me enormously, first with an analysis of the effect of price changes on cigarette consumption by men in Britain from 1946 to 1971 [19]. Data on consumption of manufactured cigarettes in terms of number of cigarettes per capita per year were kindly provided by Geoffrey Todd, Director of the Tobacco Research Council, who I came to know quite well and who occasionally treated me to lunch in his favourite restaurant in Victoria, when Whitstable oysters were in season. Griffith's research administrator, Celia Hensman, put me in touch with Mr Cardy of H. M. Customs and Excise, who provided invaluable details of increases in tobacco duty and manufacturers’ prices. Julian Peto performed the rest, including correcting price changes to take account of changes in the value of money and internal purchasing power of the pound. For every 1% increase in corrected price, consumption fell by about 0.6%, indicating that the demand for cigarettes is ‘inelastic’, i.e. an indication of dependence. A similarly low elasticity for tobacco products (− 0.5% was found by a Cambridge economist for the years 1920–38). Peto also helped me to develop a motivational typology of smokers. The Royal Statistical Society invited me to give a talk on it; it so was reassuring for me to have Julian there to answer the questions! There were some fairly tough ones from the floor and Julian just took it in his stride. That was published in 1974, in the Journal of the Royal Statistical Society[20].

NICOTINE REPLACEMENT TAKES OFF

A: You were firing on all cylinders! Can I ask you about the whole business of nicotine replacement, because that has been one of the major themes of your career—it links interest in nicotine, as the drug in smoking, with cessation methods and developing effective treatments, and brings in issues to do with compensation and so on. That involvement with nicotine replacement goes back many, many years.

MAHR: It goes back many years before we thought of it. In the early 1940s Lennox Johnston injected smoking doses of nicotine subcutaneously or intravenously into volunteers. He reported that non-smokers found it unpleasant, but smokers almost invariably found it pleasant and, given an adequate dose, were disinclined to smoke for some time. It also relieved withdrawal craving [21].

A: When did you first come across Ove Ferno?

MAHR: I think I came across him first at the Second World Conference on Smoking and Health, which was held at Imperial College London, in 1971 at which, incidentally, in a session on less harmful smoking Ernst Wynder, with support from several others, strongly advocated the use of low tar, low nicotine cigarettes, by legislative control if necessary. I can remember from the floor saying rather humbly that we ought to consider whether it would not be safer to focus on getting the tar down rather than nicotine down and I quoted the two English studies by Heather Ashton and Chris Frith which had shown that if you drop the nicotine, smokers tend to puff harder to maintain their nicotine intake and thereby possibly take in more tar.

‘Ernst Wynder strongly advocated the use of low tar, low nicotine cigarettes . . . I can remember from the floor saying rather humbly that we ought to consider whether it would not be safer to focus on getting the tar down rather than nicotine down’

A: Do you remember what the response was to that question?

MAHR: They did not take any notice.

A: So you met Ove there. Did he have prototypes of the gum with him?

MAHR: Yes, and I think they held a small symposium chaired by Hannah Steinberg. There was a rather poor presentation of their work with it by Ove's colleagues Ohlin and Westling. I do not recall Ove speaking. Anyhow, I was not very impressed. I think I even tasted it, and thought the taste rather foul. Of course, it was unbuffered at that stage, but I did not chase it up with as much interest as I should have. Perhaps we were too busy. It was 4 years later, during the Third World Conference in New York in June 1975, by which time the gum was buffered, I recall going on a couple of long evening walks with Ove in the Central Park area, talking non-stop together. He told me about the success that Westling was then having in his clinic. I was very impressed with Ove, his charm and modesty, and developed a deep respect for him. We have remained good friends ever since. Following this meeting he invited me to visit Sweden, where I met some of his colleagues in Helsingborg and visited Westling's clinic in Lund. This certainly aroused our interest in the gum and we started to study it almost as soon as I got back. In a pilot study we found that plasma nicotine levels produced by 10 pieces of 2 mg nicotine gum taken hourly and chewed for at least 30 minutes were less than half the levels found after a cigarette; but 4 mg gum used in the same way could produce plasma nicotine levels similar to those of smoking [22].

CLINICAL TRIALS WITH NICOTINE GUM

A: Was that before Martin Raw conducted his first trial of the gum?

MAHR: Yes, that would have been 1974, about the time Martin joined us, so it would have been about then that he started working with the gum.

A: So your involvement started quite early on before they decided to go for it as a commercial product?

MAHR: Oh yes. The company president and the scientific advisory committee had resisted supporting the gum for some 4–5 years, despite Ove's position as Vice President and Director of Research and Development for pharmaceutical research and for the medical department. Ove mentioned that they had a new president, Eric Schyberg, who might be more positive, and asked me to attend the next board meeting, which I did gladly. He also advised me that the most important person on the scientific advisory committee to convince was Börje Uvnäs, a member of the selection committee for the Nobel Prize. It may have helped, because the gum was licensed for use in Switzerland in 1978 and Uvnäs had questioned me quite closely as to whether I thought ‘it had a future’.

To go back to your earlier question: Martin Raw joined us in about 1974 as clinical psychologist in charge of our Smokers’ Clinic. He had already carried out a project on smoking for his MPhil involving advice on stopping smoking to patients in the waiting rooms at King's College Hospital. He found that the quit-rate almost doubled if he wore a white coat. His rapport and understanding of patients’ needs and problems was exceptional, whether seeing them individually or in groups.

A: What did Martin then tackle?

MAHR: Being a psychologist, it is not surprising that Martin Raw chose a psychological treatment for his next study. Rapid smoking was a form of aversion therapy, involving subjects smoking their usual brand of cigarettes in a rapid and continuous way, inhaling one puff every 6 seconds until no further smoking could be tolerated. It was not clear whether the aversiveness and subjects’ tolerance limits were determined by nicotine intoxication or local irritation of the mouth and respiratory tract. No one seems to have compared it with or without inhalation. This form of treatment was developed by Ed Lichtenstein and his colleagues and studied extensively between 1971 and 1976. It was hailed initially as an ‘outstanding exception’ to the disappointing trend of low success rates and high relapse rates in smoking cessation therapies. The method certainly became used widely throughout the United States, and in numbers running into thousands in commercial programmes run by Schick Laboratories. When concern was expressed rightly about the potential risk of excessive intake of nicotine and carbon monoxide to subjects with cardiovascular disease, the fears were stilled by the lack of a single case report of a serious adverse event by Schick. Being the good clinician he is, Martin Raw's first concern was with the potential risk of rapid smoking. We found that rapid smoking produced much higher blood nicotine levels than normal smoking, but there was no evidence that the degree of nicotine and carbon monoxide intoxication produced had any relation to the reduction in the desire to smoke just after the session, or to the decrease in cigarette consumption on the following day [23]. In a study of dependent smokers assigned to rapid smoking, cue exposure or simple support, Martin Raw found no significant differences between treatments. The overall proportion who stopped smoking was about 22% at the end of treatment and 14% at 1 year follow-up. In comparison with this 14% success rate at 1-year follow-up after psychological treatments, a 1-year success rate of 38% was obtained by use of 2 mg gum in a similar sample of smokers attending our clinic [24].

‘In comparison with this 14% success rate at 1-year follow-up after psychological treatments, a 1-year success rate of 38% was obtained by use of 2 mg gum’

A: There was then further follow-up of this line of work?

MAHR: In June 1980, nicotine chewing gum (Nicorette) was released in the United Kingdom as a prescribable drug to help people give up smoking. At that time the findings on clinical efficacy were not yet convincing. Out of five placebo-controlled trials, three showed significantly better short-term success rates. However, after 6–12 months’ follow-up the differences were not significant. Meanwhile Martin Raw had been gaining experience of its use in our smokers’ clinic, enabling us to optimize its efficacy by ensuring that patients’ expectations of the potential benefits of treatment with the gum are realistic and that they understand how it should be used. An extreme case might believe that all they need do is chew the gum and it will stop them smoking, as an aspirin relieves a headache. The reality is that they should not only be highly motivated to stop, but ready to make a firm decision to stop completely on a given day when no special event or undue stress is expected within the next month or so.

So following Martin Raw's encouraging results with the 2 mg nicotine gum in the comparative study in our clinic, we went on to conduct a full-scale randomized double-blind trial. The trial was supervised by Martin Jarvis, who had joined us fairly recently This was the first really good trial to show how effective it was—we achieved a very good success rate and very clear 1-year follow-up validated success rates. At that stage it had not been licensed in America. They were so desperate to get us there that they flew Martin Jarvis and me across on Concorde and back first class, when we could sleep, and so we just went for that one day and back again; it is amazing how fresh one felt after that. It was on the strength of that that it was accepted in the United States. Just being known everywhere suddenly was amazing, and that is because we had seemed to have struck a thing. This was in 1982.

THE NASAL ROUTE FOR NICOTINE SUBSTITUTION

A: As well as the gum, you took an early interest in the nasal route of administration for nicotine. Can you tell us how that came about?

MAHR: Well of course, right from the start I knew that nasal snuff had once been the dominant form of tobacco use in Europe. We had the occasional snuff user coming into our smokers’ clinic. We used to take a peak blood nicotine after dosing, and we were just so impressed with how rapidly nicotine was absorbed from the snuff—it just shot up. This was an interesting indication of the potential of the nasal mucosa, so we were keen to perform a few more studies on people's snuffing. The most enjoyable was a trip down to a meeting of a Society of Snuff Users in Wellington, in Somerset, to obtain blood samples out of as many snuff users as possible [25]. We went in the early afternoon, conducted the study, and finished up centrifuging the blood samples in the local hospital at 1 a.m. the next morning. They had all sorts of strange competitions, such as taking as much snuff as you could in a minute without sneezing. We took novices and also regular dependent users from the competition—there was one chap who pretty well fainted. He came on with a terrible rash and shaking. At the time we thought it could have been a response to the venepuncture. He did not look good at all. When we saw what his blood nicotine was, we could appreciate that. It was the highest blood nicotine I have ever encountered. But with the novices we tried they did not take much, so it was clear that snuffing technique was important.

‘They had all sorts of strange competitions, such as taking as much snuff as you could in a minute without sneezing.’

A: So actually that work on snuff was instrumental in the development of the nasal nicotine spray. Didn’t you do quite a lot of joint development of that with the Swedish people?

MAHR: We suggested it to Ove, yes. He produced some in a nice little plastic container that just had a couple of drops in, so you put it in your nose and squeezed it. It seemed to absorb reasonably quickly. Ove would just send us some prototypes and we would give him some quick results and send them back and then he would send some more. There was a little bit of trial and error there and some clearly did better, but they were the sort of studies that you just performed in three or four people at most.

A: That eventually led to the nasal nicotine spray?

MAHR: Yes, but it took a long time and the company needed pushing. Another company then also started producing them—it was Astra, another Swedish company. Their product was much blander and more acceptable and almost as good in blood levels, but not quite. It probably would have been a better product. They were quite expert on nasal inhalations as well. What finally put them off was that they were using freon as the propellant in their spray, and that was a greenhouse gas and a ban on that came in.

A: Now when there are all these wide-ranging nicotine replacement products, do you think that that line of development has reached its limit, or is there scope for coming up with better nicotine replacement products?

MAHR: I think the patch is limited to an extent, but still very useful. The only possibility for something better would be something that got closer to the rapid absorption and so would give people an agonist effect. We know the nasal spray can do that, but it has got to be taken properly. The dose is half what we showed is needed to give a 10–12 nanogram per ml rise of nicotine inside 5 minutes. It does not do that. It is difficult to see what could be better than smoke particles. We have found one way—it was what I call a low resistance inhaler, but with current inhalers you have to suck really hard and you can take only a puff-sized draw. There is a delay which prevents lung delivery—it is in your mouth, then you inhale. What you really need is something that enables you to take a full inhalation, so you can take a litre or more by filling your lungs and breathe straight in. Then it can be relatively weak, but enormous in quantity—to put that amount into a 40-ml puff, it would have to be quite strong with the delays. Pharmacia did produce one like that and it did seem to work, but it was all breaking at Pharmacia then, this sort of thing, and they were concentrating on their other puffer. There was one that did work like that and give you a big rise—a low resistance inhaler. They did not pursue it.

THE ROYAL COLLEGE REPORTS

A: Can I just go back a bit, because there is one thing I wanted to ask you about the period around 1970–71. That is, I believe you were involved in the preparation of the 1971 Report to the Royal College of Physicians, which was their second report on smoking. Was it Charles Fletcher who approached you?

MAHR: Yes, Charles Fletcher was always very nice and supportive of me, partly because there were relatively few people focusing on the kind of work with smoking that we were doing at the ARU. The smoking problem had become his major interest and he served as Secretary and was the moving force within the Committee responsible for the first RCP report, Smoking and Health, published in 1962, which had a major impact internationally. He was also secretary of the Committee for the second RCP report, Smoking and Health Now (1971) and the third report, Smoking or Health (1977). An eminent psychiatrist had served on the first two reports covering the psychological aspects in a section headed ‘The Smoking Habit’. Charles was very dissatisfied with the draft this psychiatrist had produced for the second report and asked if I could spice it up a little anonymously, which I was very happy to do for him. For the third report I was listed as a bona fide member of the Committee. The eminent psychiatrist had by then retired or died. Charles was a very active editor so that what one submitted was not always recognizable, but often greatly improved.

WINNING MRC PROGRAMME GRANT SUPPORT

A: Lots of work, but what were you doing about funding?

MAHR: A little while later in early May 1978 one of the Medical Research Council's administrative staff phoned me and gave me about the biggest surprise I have ever had. She invited me to apply for an MRC Programme Grant and as this would require my having a tenured position, I would be appointed as a member of the MRC's External Scientific Staff. I said that to plan an application I would need to know roughly how large the grant might be. She replied ‘whatever you think you might need’, and she added that to make it easier for me she would send in confidence a copy of a recent Programme Grant application that the Neurosciences Board had commended as especially well written, and this was indeed a great help. My last question was to ask why they were being so kind to me, to which she replied that someone important and powerful had recommended it. My first thought was that it might have been Charles Fletcher. Then I thought it might have been Griffith, who was incredibly helpful to me with putting the application together as well as possible, and transferring some of the staff funded on his grant to my proposed grant and vice versa, our purpose being to maintain the harmony and integration within the Unit as a whole. Anyway, the proposal was approved by the Neuroscience Board of the MRC in June 1978. I became a member of the MRC External Scientific Staff with the programme grant entitled ‘the Psychological and Pharmacological Basis of Tobacco Dependence’.

‘in early May 1978 one of the Medical Research Council's administrative staff phoned me and gave me about the biggest surprise I have ever had. She invited me to apply for an MRC Programme Grant’

A: That was the beginning of a long and fruitful relationship with the MRC, because they supported your work for 20 years.

MAHR: Yes indeed. It enabled us to provide more secure support for Martin Raw than short-term project grants from the MRC or DHSS. Above all, it enabled us to recruit Martin Jarvis, who was awarded tenure when we obtained additional support from the Imperial Cancer Research Fund in early 1988.

A: Another thing which you were advocating early on is what is now known as the question of product modification, or how to make smoking less harmful for those who will persist in smoking. I think it was about 1973 when you first published a paper about the case for safer smoking. Could you tell us something about that?

MAHR: Yes. I think it was fairly obviously that nicotine itself was not the main source of all the harm that tobacco caused and in fact apart from its effect on the fetus, it is probably pretty safe, especially if not given very rapidly. I think it was fairly clear then that people smoked for nicotine, but died for other reasons. Because nicotine itself was what people wanted, why should you not look at it that way? Low yield cigarettes, which were low in everything, were obviously not the answer, because people puffed them harder to obtain enough nicotine. They then took in the tar and harmful gasses at the same time. So one had to propose the medium nicotine, low tar approach, which seemed very logical.

A: How did that go down with government?

MAHR: They were not listening. We did write to the Hunter committee and tell them what we thought, and that is possibly why Froggatt, when he was chairman of the Independent Scientific Committee on Tobacco, listened more. There was a time in fact when low yield cigarettes did have a better nicotine to tar ratio.

THE STUDY ON THE IMPACT OF GP ADVICE

A: There have been so many areas where you have mapped out the territory in smoking and we have covered some of them—compensation, the idea of safer smoking, dose measurement and passive smoking—but the huge contribution that you have made has been the whole business of ways of helping people to quit. You have done much on nicotine replacement, we have talked about that a bit, but also probably your most cited paper was on simple advice from a GP to patients coming to see them in the course of their routine clinical load. Where did the idea for that study come from?

MAHR: I do not know how the idea came, but it was just apparent that there were many smokers to treat and also many smokers did not especially want treatment—they were not motivated seriously enough. It did seem that many GPs would have access to lots and lots of smokers—I think it is something like 70% of smokers who are likely to visit their GP in any 1 year. Over a 3- or 4-year period it would be practically 90% of smokers would visit their GP. There had been some data from America that people listened to doctors more than other people, which is something you would pretty well expect, so it did seem that if it had even a small effect it would be very worthwhile. So that is what we tried fairly early on. The other thing was that GPs would not do too much, either. You could not expect them to do a great deal; they are too busy, but that does not mean to say that they should do nothing. After the success of the trial of GP advice we tried to expand it to getting the gum used within general practice, so we looked at advice alone and compared it with advice plus nicotine gum. The plain advice simply did it by motivation, it did not increase the success rate of those who actually did try, whereas the gum given as well as the advice not only made more people try to give up, but it increased the success rate of those who did try. Of course, if the doctors had all been trained much better, they could perhaps have achieved better results, but this was really to see what GPs could do relatively easily and therefore in large numbers.

‘It did seem that many GPs would have access to lots and lots of smokers—I think it is something like 70% of smokers who are likely to visit their GP in any 1 year.’

Then we became even more ambitious, because we wanted to see if we could change the prevalence in the practice populations by GPs doing different things. We needed quite a few practices, so we had team practices who would give cessation help with a great deal of support from our smokers’ clinic. We gave them clear instructions, the way to go through it, and put posters up in their surgeries, that kind of thing. We gave them a great deal of support and they could refer people to the clinic if people wanted to come. So those were the most intensive practices. There was a group of practices which had less support and a group who had no support at all. Then we had a control district, where we had just ordinary controls with nothing offered. We simply measured in the same way.

A: Did it work?

MAHR: It did work, yes [26,27]. This was kept up for some time and the prevalence decline was actually much sharper in the ones that had had more intensive help. There was a decline in that population which was much greater than the gradual decline, which was going on anyway.

RELATIONSHIPS WITH THE TOBACCO INDUSTRY

A: One area I would like to ask you about is the whole business of the tobacco industry, which is of course these days the ultimate pariah industry. You must have come into contact with the industry in many different forms earlier on in the 1970s. What sort of dealings did you have with them?

MAHR: Well, I valued relationships with them because they knew so much about tobacco, and quite a few conferences that one went to in America had tobacco industry people there as well. I formed quite a strong relationship with BAT (British American Tobacco), and they gave us quite a deal of help with some funding for enlarging the old prefab at 101 Denmark Hill, which the MRC knew about. They also gave us some technical help. They were very interested in my view that you should have medium nicotine cigarettes and lower tar ones. Some of their people, such as David Creighton, used to look at compensation and study it. It was not only me that mixed with them, it was OK to do it then. Other academics did as well. They would actually talk openly in ways that would not be acceptable now, I suppose. They had a place in Sussex, a lovely old house, and held conferences there. They would get people like Stan Schachter and Murray Jarvik to come to their meetings.

A: Do you think they were more open in sharing their research data at that time?

MAHR: Yes. Certainly the proceedings from those meetings were published. As far as America goes, I did not have close dealings with them, but I certainly visited Philip Morris and I had quite enjoyed William Dunn's book [28]. They invited me to visit them at one stage and I did go. William Dunn picked me up at the airport. I think he told me and showed me a little too much, from the company's point of view. I found BAT here was particularly helpful.

A: Perhaps they understood the issues better than any academics.

MAHR: I think so, yes, and I think they were genuinely interested in reducing the risk of smoking. But to do that you had to acknowledge that there was a risk, and that is what the industry in America could not do. The moment they admitted to giving a risk, then they could be sued, whereas I think it was a little easier here. Geoffrey Todd—I formed a friendship with him—was always very charming. He was quite helpful when one wanted population and time-trend series, because they used to have the main statistics that now one can obtain more effectively through the General Household Survey and some other regular polls. There was a time when the Tobacco Research Council (TRC) had all those sorts of figures—cigarette consumption and changes over the years. It did not really teach one an awful lot, but I liked it and we liked to hear what he was doing.

A: That really was in some ways a slightly different era, where there was more interchange with the industry than there is now. Similarly, what would you say about government and its approach to smoking in the 1970s and 1980s—did you have much time for them?

MAHR: I was never very good on the policy side, somehow. It did not interest me so much, although it should have because that is really where you achieve things. No, I think I was more just an experimentalist and I did not really feel the need to push some of the theories I felt were right. I would just like to demonstrate the theory and then if people wanted to conduct it or not that was hard cheese. I was more excited by the actual research and the results.

Perhaps one reason I was not especially popular with government people was that I used to be fairly outspoken; but then, that was just part of the excitement of having a Unit. I think we were all frank with what we thought. We were not unduly aggressive; sometimes people hit a little hard, perhaps, but then most of them were tough enough to take it. Ultimately I think we did function as a group. We all knew what each other was doing and thinking and all had a hand or say in things and I think that makes a big difference. I certainly did not ever say to anyone ‘No, don’t do that.’ If they wanted to try it, even if I did not believe wholly in it, they could try it and then we would see whether it worked or not. It was just great having such clever people around. I think our regular Friday meetings were important.

‘Ultimately I think we did function as a group. We all knew what each other was doing and thinking and all had a hand or say in things and I think that makes a big difference.’

LEADING A TEAM

A: What happened at those Friday meetings?

MAHR: It was informal. It got everyone together, it was the end of the week, and we all knew what each other was doing; no one could actually submit a paper without letting all of us read it and give out comments. We were not dictators; it was group pressure rather than me having control of the funds and exerting the pressure. Tender people might have felt it that way.

A: There was quite a lively exchange of views about papers and ideas.

MAHR: Yes, some people were just very good—even if it is simply improving a sentence it is useful. Some people were very good at writing and others not so.

THE FUTURE FOR NICOTINE

A: In the 1980s the penny finally dropped about nicotine for the academic and political world—they were all lining up one after the other—the Surgeon General, and now we have had a Royal College of Physicians Report. Many of the causes that you were advocating so forcefully 25 years ago are finally and firmly part of the agenda. What is your take now on society and nicotine—are you optimistic that society will find a better way of living with this drug, perhaps in a purer form, or do you think it is going to stick around in the same old polluted cigarette we have been living with for so long?

MAHR: That is tricky. I think among better-educated people in reasonably wealthy countries one might achieve some improvements, but one needs to find a better alternative nicotine delivery system. I do not think one has got to this yet. Unfortunately, I am not sure that the R. J. Reynolds approach is going to be quite good enough either. I think it is going to be very hard. Lennart Sorelius thought of a very practical way for doing something better in China, which needs to grow tobacco for their economy. He made the suggestion that a country such as that should make gum out of it. They are never going to not grow or produce any tobacco. But there will always be limitations with non-combustible forms of nicotine. Inhaling the smoke is such an effective route of delivery. I do not think it is ever going to be quite the same, unless it is through the lungs.

A: Do you think in 50–100 years from now society will have achieved a better modus vivendi with nicotine?

MAHR: I am sure they must have. I think good gum could be generously dosed and satisfy a lot of people if given a free market. But for more progress, I think one needs to know more about the actual pharmacology.

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