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E-Cigarette Summit - Dr Jacques Le Houezec

Chair: It gives me great pleasure to introduce Dr Jacques Le Houezec who is a Consultant in Public Health and Tobacco Dependence in Rennes in France. Jacques is going to be speaking about nicotine safety in the context of e-cigarette use and tobacco dependence.



Dr Jacques: Thank you, Ann. Good morning everybody. Starting with my disclosure. I’m a Consultant but I’ve been in this field, trained as a neuroscientist, working on nicotine for 30 years now.


I would like to first of all pay a tribute to someone who paved the way to all of us I think and was a great source of inspiration for my own work, and it’s Michael Russell, and Michael Russell had visionary points a long time ago about what nicotine was and why people were smoking. I’m sure in this citation that I usually place everywhere I can because it’s so true, that what we need is something that will replace tobacco smoking. I’m sure he would be very pleased to see what is going on these days.


So, people are smoking for nicotine. This study showed clearly more than ten years ago that people were getting the nicotine they need from cigarettes, whatever type of cigarette it was. People are able to take from 1mg to 3mg of nicotine from each cigarette but on average they will take something around 1mg. They can do that because they can change the way they inhale the smoke, they can take larger puffs, keep it longer in the lungs, and smoke more frequently. If they need they can take up to 3mg of nicotine or even more. And by doing this actually when you change the way you take nicotine you can also modify the effects of what you get from a cigarette. If you are a smoker, if you were a smoker, you can remember that you can do what you want if you want to relax or if you want to stimulate yourself, you can use the same drug. But this study also clearly demonstrated that there was no such thing as a light cigarette.


Another illustration of the self-titration phenomenon, smokers are able to self titrate the nicotine from smoke, is this study from Neal Benowitz where smokers of about 30 cigarettes a day were put on patches. There were four different levels; 0mg, 21mg, 42mg or 63mg of nicotine, and they wear the patch for a week and they are still able to smoke. Even with 63mg of nicotine on board from the patch, they were still smoking about 12 cigarettes per day. However, if you look at the table here, you can see that they adapted the way they were smoking, and when they had 63mg of nicotine every day from the patch the nicotine they took from each cigarette was reduced. And you can also see it here on the other graph reflecting the inhalation of carbon monoxide and you can see that when they had 63mg of nicotine on board they were puffing less, their CO levels were down. So clearly showing again that people can adapt and self-titrate nicotine. So, this also is important in terms of e-cigarette use. There is no concern to have about overdosing with nicotine. The first sign of overdosing is nausea and every smoker knows about it. So there is no problem with this.


The strengths of the dependence to cigarettes are due to the inhalation process, the fact of inhaling smoke in the lungs. Inhalation brings nicotine very fast to the brain in ten to fifteen seconds and that’s faster than an intravenous injection. And this is the key of the addictive effect of cigarettes and problems, because makes them more addictive than other forms of puff tobacco use or pure nicotine use. And this is because it creates a desequilibrium between the arterial levels of nicotine which, in a way, represent what is going on in the brain and the venous levels or peripheral levels. With cigarettes, you have this huge difference between the arterial levels and the venous levels here in blue, and that’s explained partly why the nicotine has an effect on the brain and why when you use a slower absorption product like NRT you never get this figure because the absorption is too slow to create these desequilibrium, so the nicotine blood levels are homogenised and you don’t get the hit from the nicotine. On this graph which I took from Lynne’s recent paper, you see that e-cigarettes can deliver effective nicotine concentrations. What we don’t know yet is what is going on at the arterial level, but what we can imagine from the data that we have is that probably e-cigarettes are somewhere between cigarettes and NRT’s, probably that could also explain why some smokers will find it more effective to quit smoking than NRT. So, tobacco dependence is certainly more complex than just nicotine dependence or nicotine addiction. There’s more than nicotine in tobacco; nicotine is only one among seven thousand chemical substances in the smoke, so clearly there are other products in the smoke or in the tobacco that participate to the dependence process. A recent paper, a couple of recent papers actually, show that when you use particular matter extract from tobacco and particularly from roll your own tobacco, you give rats more incentive to press on a bar than when you give them even cigarette extract or pure nicotine. So that’s something very interesting. This is new, and it really points out that there are other products. We know already there are monoamine oxidase inhibitors like norharmane, harman and norharmane, and acetaldehyde, you have, and probably other substances.


And the other study from the same group also showed that when you give mecamylamine which is an antagonist to nicotine effects you actually see that comparing nicotine self-administration and tobacco extract actually mecamylamine counteract the nicotine effect, but not fully the tobacco extract. So probably showing that there are other than the nicotinic system involved in the process which we know, but new studies are always interesting to learn more.


So, why do people smoke? Well, they smoke for nicotine but probably not only for nicotine. Vapers, they vape for pure nicotine. There is no combustible product in their product, but there’s still some impurities because the nicotine used in e-liquids is the same nicotine as the nicotine used in NRT’s, it’s just an extraction from tobacco because it’s much cheaper and easier to just extract nicotine from tobacco than to synthesise it. And if you synthesis it, you obtain an racemic compound with both L and R nicotine while we know that the only the L nicotine is active, and only L nicotine is present in tobacco, so it’s easier and cheaper to use nicotine. But, there are still some impurities even if you use the pharmaceutical grade nicotine; there is always something. So, is it safe in the end? Is it less addictive than tobacco since we’ve seen that nicotine is only part of the game?


Another concern is about the safety, and recently I was really pleased because this is something I’ve been looking for for years. I spent two years with Neal Benowitz working on nicotine and he is certainly an expert on nicotine safety. I’ve always seen this reference to the lethal dose of nicotine somewhere between 30 and 60mg, and we couldn’t believe that because we’ve seen reports, case reports, of accidental or voluntary poisoning, and realised that because of very specific pharmacology of nicotine it was barely understandable that such a low dose would kill somebody. But we’ve been looking for years for the sources of this and as Bernd Mayer who just published a short paper here a couple of weeks ago showed it was like a circular reference and everybody was citing the same reference without really looking at what was in there, and there was nothing except going around, you know. And, actually, he looked at the whole literature even in German and so on and from that this is probably coming from one hundred years ago, people trying to swallow nicotine themselves and find out what were the effects. But it was not really based on even animal research.


So, if we agree with the 60mg dose, lethal dose, it will give LD 50 which means a dose that will kill half of the animals or humans whom you will feed them with, that will give you an LD50 of 0.8mg per kilogram, which is not in accordance with what we know from mice or rats which have held LD50 much higher. So, taking the problem in reverse mode, if you smoke a cigarette and you take about 2mg of nicotine from the cigarette, that will give rise to a plasma concentration, arterial plasma concentration, of about 13 nanograms per mil. A smoker will have usually a plateau level of nicotine during the day between 30 and 40/50 nanograms per mil. Based on the oral bio-availability of nicotine which is very low because when you swallow nicotine it enters your stomach where there’s a very low PH and nicotine needs a high PH to be well absorbed, so partly because of that and partly because of the first path metabolism nicotine is metabolised by the liver at the first passage at least at 70%, and this assumes 80%. Based on this, an oral dose of 60mg would give rise to a plasma level of about 180 nanograms per ml which is high but not that much.


But several reports have shown that people having much higher doses and a couple of recent ones from Denmark showing that a woman took about 1500mg of nicotine, and there was no fatal issue. So based on all this literature, Ben Meier took the assumption that a very conservative limit of lethal dose would be about 2mg per mil in the blood which is about 4mg per mil in plasma which is half of the total blood volume. And this would actually give us a lethal dose which is at least 20 fold higher than the one we’ve heard for a hundred years. So, no, nicotine is not as dangerous as we’ve seen in all toxicology textbooks and so on, and smokers and vapers actually know exactly how to use it. There’s no problem that nicotine should be handled with care but there’s also no need to overestimate the effects of pure nicotine. So, based on this, we can say that the lower limit is not 60mg but probably something between 500 and 1000mg, and that’s still a conservative proposition. And that will give an LD50 then of something between 6 and 13mg per kilogram. Even from the literature, we know that nicotine poisoning is rarely fatal. Even in children. There were a few reports here showing that here in ten cases of children who ingested tobacco the dose ingested when it was up to 1mg per kilogram actually didn’t give much of an effect except, well, the first symptom is nausea and then vomiting is coming next. And taking it up to 6mg per kilogram which is the lower limit of what I just showed for the LD50 obviously gives strong symptoms but in all cases within five days children recovered with no complications. It’s very often seen in adults. We can go over this. There is one death report from a two year old kid from Israel. We saw it in the news, I think it was The Times from Israel, but actually we never heard afterwards if it was really due to the e-liquid she was supposed to have swallowed. So if anybody knows the following of this I am happy to hear about it, but I don’t know personally, and I don’t think there are any other cases reported. If I… yeah. I remember when I started to look at nicotine and working with Neal Benowitz I read a fascinating book on how shamans from South America were using tobacco and get nicotine intoxication up to the fact that – they were trained from their young age to take tobacco, tobacco extract, from anywhere in the body even eye drops, I won’t say much more. And they get huge tolerance to nicotine and they could take large, large, large amounts of nicotine up to the fact that they would use it in religious ceremonies. They get intoxicated at the point they look dead, but because nicotine is eliminated very rapidly, the half-life of nicotine is two hours, so after a night like every smoker will have no nicotine in his or her blood. These shamans were going back to life. You can imagine the power they had. They were using the power of nicotine.


Now, since we are talking about inhaling nicotine with e-cigarettes, what is the safety concern of inhaling nicotine, pure nicotine, because we don’t know that? We know for sure that inhaling tobacco smoke is dangerous but we don’t know about pure nicotine. This is just reporting that a study that used rats who were exposed to inhale nicotine five days a week for twenty hours a day at least for two years, which is like a long life for a rat. They couldn’t find any effect, any health problems, due to inhalation of pure nicotine. I think this is quite reassuring. The only effect they found which we found in tobacco smoking is that the body weight of the rats were lower.


Some concerns were raised because specific nitrosamines from tobacco, a cancer causing substance, can in certain conditions be formed from no nicotine in the body. But this alkaloid, nornicotine, is usually coming with nicotine, it’s just because of the extraction process. But, also, it was recently shown that apparently some NNN, some nitrosamine, could be transformed in the saliva of smokers, so that could be a concern. This effect is very small and we don’t know, it has not been shown in humans or in animals that it can cause cancer in the long term. We are exposed, everybody, not only smokers, even nonsmokers, we are all exposed to cancer causing substances at various doses and low doses, and low doses exposition is not always causing health problems, we know from other substances. In terms of toxicity, the dose and the longer the length of the exposure are key factors. One other reassuring stuff is coming from the Snus use in Sweden. It has been shown that there is no evidence of an increased cancer risk with Snus except for pancreatic cancer but this is also I think because snus is a tobacco product, it’s not pure nicotine.


Since I need to move forward, we have seen also that in the vapour of ecigarette, that also needs to be replicated, it needs to be followed because the products are evolving, but at least even if there are toxic substances in the vapour of e-cigarettes they are considerably lower levels than in tobacco smoke, so there is no doubt that tobacco smoking is really dangerous and in ecigarette vapours is much, much less and considerably less dangerous.


The last question is is this less addictive because, as I said, tobacco dependence is nicotine but not only nicotine? What’s going on if you use only nicotine? Is the dependence process the same? Is it less addictive? What we see from certain studies, I know Jean Francois is not agreeing fully on this, but I’ve seen it also. It seems that with time e-cigarette users tend to use lower levels of nicotine. Is it because of a reduction of dependence or is it because they get better at extracting nicotine from the product they have? It could be both. But it seems in any way that e-cigarette users feel less dependent with their e-cigarette liquids than they were with their tobacco cigarettes, and they can forget about it more often than they would have done with cigarettes.


So, in conclusion, yes, people smoke for nicotine but probably not only for nicotine. They know how to use it, they know to self-titrate, there is no concern of overdosing with nicotine in e-cigarette users. The lethal dose, well, there is a semantic problem here, the lethal dose has been set too low. It’s certainly at least twenty times higher than we all learn about. Long term use of pure nicotine has not been shown to pose health problems, and if there’s any health risk left they are very small. So pure nicotine seems maybe less addictive when used in e-cigarettes but the main message is that it is considerably less harmful. Thank you. [Applause]

Chair: Okay, thank you very much, Jacques, that was a very thoughtful and fascinating overview of nicotine safety and I’m sure that has raised some questions, particularly around debunking some of the myths about nicotine safety. In the interests of time we’re going to move straight on. There will be time at the end of this next presentation for questions and answers.    

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