September 30, 2015

Stanton A. Glantz, PhD

New study shows smokers smoke less and quit more after big cuts in nicotine in cigarettes

Nicotine is the addictive chemical in cigarettes and the FDA has the authority to require that the nicotine levels in cigarettes to be reduced (although not eliminated).
The suggestion has been made for some time that the FDA should cut the level of nicotine in cigarettes (and other tobacco products) to such a low level that the cigarettes would no longer be addictive.  The biggest concern with this suggestion is that, because smokers smoke to deliver nicotine to their brains, cutting the nicotine content in cigarettes would lead to so-called smoker compensation, where smokers smoke more cigarettes or inhale more deeply in order to get their usual level of nicotine and increase the damage to their health by effectively smoking more. 
Indeed, this is exactly what happened with people who smoke the industry’s “light” cigarettes, which are designed to encourage this (unconscious) behavior.  (The FDA and a federal court now prohibit the companies from using terms like “light” and “mild” to trick smokers, but the companies simply dropped the words and color-coded the packs, something both the FDA and Department of Justice have let them get away with for years.)
Today the New England Journal of Medicine published an important and very well done study. “Randomized Trial of Reduced-Nicotine Standards for Cigarettes,” that showed that this does not have to be the case.
Rather than using the gimmicks that the cigarette companies use to trick smokers into thinking that they are using low nicotine cigarettes, the cigarettes used in this study actually had less nicotine
People in the study were given cigarettes with different amounts of nicotine.  Neither the smokers nor the people conducting the study knew who got which cigarettes.  The investigators followed the smokers for 6 weeks and carefully measured their smoking behavior.
Surprisingly, there was no smoker compensation.
Quite the contrary, the smokers who had been given the cigarettes with the lowest amount of nicotine (0.4 mg of nicotine per gram of tobacco vs. 15.8 mg/g for typical commercial cigarettes) smoked 30% fewer cigarettes than people smoking higher nicotine cigarettes.
In addition, people smoking the very low nicotine cigarettes also experienced less craving and were twice as  likely report quit attempts than people smoking the cigarettes with the usual level of nicotine (34.7% vs. 17%).  This finding is particularly important because none of the people recruited to participate in the study said they wanted to quit smoking at the time that they were recruited.
Biological measures also confirmed that the people using low nicotine cigarettes did not change the way that they smoked in a way to get more of the other toxins in cigarettes, another important piece of evidence that smoker compensation was not happening.
This result has very important policy implications:  It shows that if the FDA wanted to (and the Obama Administration allowed them to) issue a rule immediately cutting the nicotine levels by 94% from the current average of  average of 15.8 mg/g to 0.4 mg/g, smokers would not only tolerate it, but they would likely smoke less and be more likely to try and quit altogether.
Moreover, with such low levels of nicotine, kids would probably not take up smoking.
For this to happen, however, the FDA would have to impose similar cuts in nicotine for all tobacco products, including cigars, smokeless, and e-cigarettes.  Otherwise, there is a good chance that people would simply shift to these products or use them to supplement the nicotine they get from cigarettes.
Given this fact, it is unfortunate that the accompanying editorial by Michael Fiore and Timothy Baker the journal published, “Reduced-nicotine cigarettes – A promising regulatory strategy,” did not argue for such a policy.  Instead, they began with the Michael Russell’s 39-year-old hypothesis that “people smoke for the nicotine but die from the tar,” and only argued that nicotine reductions should be for “combustible” tobacco.  In fact they suggested that “as the nicotine yield of combustible cigarettes declines, addicted smokers might switch to other nicotine-containing products, including smokeless tobacco products or electronic nicotine delivery systems [e-cigarettes].”   Most astonishingly, they say that “the development of new products (e.g., an FDA-approved agent that safely and effectively delivered nicotine to [lungs] might further accelerate the decline in combustible cigarette use.”
Leaving aside the fact that such devices have already exist and have been approved by the FDA (nicotine inhalers available for smoking cessation by prescription), this statement explicitly assumes that nicotine is safe.  There is an entire chapter in the 2014 Surgeon General’s report on the dangers (beyond addiction) of nicotine.
While Russell had a good idea 39 years ago, it should not be elevated to the level of dogma.  Current regulation needs to be made taking into account the fact that we now know more about nicotine than we did when he made his suggestion in 1976.
As I noted in an earlier public comment to the FDA, here is how Russell explained his idea that, "It's not the nicotine that kills half of all long-term smokers, it’s the tar” in a later paper:

Since people smoke mainly for nicotine and fail to quit because they are addicted, and since they die mainly from the tar, carbon monoxide and other harmful gases taken in alongside nicotine, and since they chew and snuff tobacco for nicotine but die largely from the nitrosamines and other carcinogens in tobacco, it seems logical to offer either a cleaner product or, better still, an acceptable source of purer, less contaminated nicotine.[i]

Note that Russell presented this idea as a hypothesis, not as established fact.
He then summarized the understanding of the biological mechanisms through which smoking causes cancer and heart disease:

Health risks of nicotine
While it is patently obvious that nicotine alone must be less harmful than nicotine plus tar plus noxious gases, decisions about policies for opening the market to cleaner nicotine replacement products and gradually phasing out tobacco will depend crucially on the health risks of nicotine. As mentioned earlier, it is assumed that there is no great objection to drug use and addiction per se. Nicotine addiction is not harmful. Unlike many other addictive drugs, nicotine does not disturb consciousness, impair judgement or social behaviour and, if anything, it enhances rather than impairs cognitive and psychomotor performance and the capacity to work.  The key question is the extent to which nicotine or its metabolites contribute to the harmfulness of tobacco.
Nicotine has no role in tobacco-related cancers, which are responsible for 30% of all cancer deaths, neither is it implicated in chronic obstructive lung disease. The possibility of endogenous formation of carcinogenic nitrosamines from nicotine metabolites has been suggested. However, it has not been demonstrated and, if it occurs, the amounts would be negligible compared with those present in tobacco and formed when it is burned.   It is likely that nicotine is implicated in the cardiovascular risks of cigarette smoking and that carbon monoxide also plays a part. However, to date no definitive epidemiological studies have identified the cardiovascular risks of individual smoke components.  Nicotine activates the sympathetic nervous system and increases circulating levels of adrenaline, noradrenaline and vasopressin. Through these mechanisms it causes peripheral vasoconstriction and may also contribute to atherogenic and thrombogenic processes. It probably increases the adverse consequences of ischaemic heart disease. Propranol largely abolishes the deleterious effects of smoking on mortality following a first heart attack indicating that adrenergic mechanisms are involved. This strongly implicates nicotine which is the only smoke component with effects on adrenergic systems.
In contrast with cigarette smoking, the cardiovascular risks are negligible in primary pipe and cigar smokers who have never smoked cigarettes and who tend not to inhale deeply. It is not clear whether the difference is due to the slower rate of buccal absorption from non-inhaled pipe and cigar smoking, to lower steady-state nicotine levels, or to lower CO levels. Similarly the lack of evidence that use of smokeless tobacco poses a cardiovascular risk is open to various interpretations.
In summary, nicotine has no part in tobacco related cancers and chronic obstructive lung disease, two of the major causes of tobacco-related premature deaths. There is some evidence that it contributes to the overall cardiovascular risks of smoking.  These risks appear to be most evident when nicotine is rapidly absorbed through the lungs. However, it must be said that the evidence is discounted by two experts more competent than I am to assess it. They state: "That nicotine has a role in the cause of cardiovascular disease has its adherents, but the evidence is not compelling".  [citations omitted]

While this was a reasonable summary of the evidence decades ago, it does not reflect important things that we now know about the mechanisms by which smoking causes disease and the adverse effects of nicotine:

While we cannot fault Russell for not anticipating these findings, these are well-established and biologically important effects.  It is time for everyone, whether commentators or the FDA, to move beyond 40 year-old thinking about nicotine and make decisions based on the modern evidence base. 
Most important, Fiore and Baker’s recommendation ignores the primary implication of the new study, which is that substantially reducing the nicotine in cigarettes will lead people to smoke less and quit moreIndeed, Fiore and Baker present a prescription for maintaining the nicotine epidemic.

[i] Russell M. The future of nicotine replacement. British J Addict 1991;86:653-658.

[ii] Institute of Medicine.  Secondhand Smoke Exposure and Cardiovascular Effects: Making Sense of the Evidence.  2009.  Also see Barnoya J, Glantz S. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005 May 24;111(20):2684-98.

[iii] Institute of Medicine.  Secondhand Smoke Exposure and Cardiovascular Effects: Making Sense of the Evidence.  2009.  Also see Barnoya J, Glantz S. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005 May 24;111(20):2684-98 and Grana RL, Benowitz N, Glantz SA.  E-cigarettes: a scientific review.  Circulation 2014 May 13;129(19):1972-86. doi: 10.1161/CIRCULATIONAHA.114.007667.

[iv] Grando SA.  Connections of nicotine to cancer.  Nature Reviews Cancer 2014:  14:  419–429.  doi:10.1038/nrc3725  Published online 15 May 2014.  See also Zhu BQ, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA, Cooke JP.   Second hand smoke stimulates tumor angiogenesis and growth. Cancer Cell 2003 Sep;4(3):191-6.

[v] Neunteufl T, Heher S, Kostner K, Mitulovic G, Lehr S, Khoschsorur G, Schmid RW, Maurer G, Stefenelli T. Contribution of Nicotine to Acute Endothelial Dysfunction in Long-Term Smokers.  J Am Coll Cardiol 2002;39:251– 6.

[vi] US Surgeon General.  The Health Consequences of Smoking: 50 Years of Progress. 2014 Chapter 5: Nicotine.


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