Three members of the FDA Tobacco Products Scientific Advisory Committee (TPSAC), in an article published in the current issue of Tobacco Control, acknowledge the lack of a scientific basis for mandating reduced nicotine levels as a means to achieve a profound reduction of tobacco-related morbidity and mortality (see: Hatsukami DK, Perkins KA, LeSage MG, Ashley DL, Henningfield JE, Benowitz NL, Backinger CL, Zeller M. Nicotine reduction revisited: science and future directions. Tobacco Control 2010;19:e1-e10).
The paper reviews the scientific basis for the idea of requiring reductions in nicotine levels in cigarettes. The FDA Tobacco Act allows the Agency to reduce, but not to eliminate nicotine in cigarettes. Anti-smoking groups, such as the Campaign for Tobacco-Free Kids and the American Cancer Society, have boasted that this is going to result in millions of lives being saved. The paper, however, reviews the actual research and demonstrates that there is presently little scientific evidence to support the contention that reducing nicotine levels will save any lives, much less millions of lives.
First of all, the article points out that there is no known threshold below which nicotine is not addictive and below which cigarettes would not be addictive:
"Although studies of the threshold for nicotine discrimination have been conducted, to date no systematic human study has examined the threshold dose for the development or maintenance of nicotine addiction nor directly examined the best approach for reducing levels of nicotine in cigarettes to maximise public health benefits."
Moreover, the article points out that existing evidence indicates that cigarettes with very low nicotine levels are still effective in reducing nicotine craving and still produce pharmacologic effects associated with nicotine. Apparently, the article concludes, even very low doses of nicotine are capable of binding to receptors and causing pharmacologic effects:
"Laboratory studies show that denicotinised cigarettes produce acute subjective effects similar to those of nicotine cigarettes. For example, denicotinised cigarettes have been shown to reduce craving and negative affect due to withdrawal during short-term abstinence periods from usual brand cigarettes. The acute withdrawal relieving effects are found not to be due to expectancies for nicotine or the simple motor aspects of smoking (eg, handling), highlighting the importance of smoke inhalation per se. Denicotinised cigarettes and standard nicotine cigarettes can produce similar self-reported liking and satisfaction in smokers although another study found results to the contrary, and can produce similar delays in the latency to smoke (ie, the time to smoke a cigarette) or reductions in the amount of subsequent smoking of nicotine cigarettes. Denicotinised cigarettes may also be as acutely reinforcing as nicotine cigarettes in dependent smokers, suggesting that denicotinised cigarettes may serve as an effective short-term substitute for nicotine-containing cigarettes when the latter are unavailable." ...
"The responses observed with denicotinised cigarettes may be because non-nicotine sensory aspects have acquired reinforcing effects, non-nicotine constituents other than nicotine are reinforcing, or that low levels of nicotine are sufficient to maintain smoking behaviour because these levels can produce effects of physiological significance, at least acutely. For example, recent brain imaging studies show that smoking a single very low nicotine cigarette results in significant (23%) occupancy of α4β2 nicotinic receptors, which are considered the primary receptor subtype mediating nicotine's reinforcing and other behavioural effects. Thus, the reinforcing and mood effects of very low nicotine cigarettes may be attributable, in part, to nicotine's pharmacological effects. Other evidence also suggests that very low level nicotine exposure may have important pharmacological effects. This includes in vitro studies showing that significant nicotinic receptor desensitisation, a potential contributor to nicotine addiction, can occur with nicotine doses below a threshold for activating receptors, which mediates nicotine's acute reinforcing effects. In summary, abrupt switching to denicotinised cigarettes does not appear to result in significant withdrawal symptoms and may maintain similar levels of smoking reward and reinforcement in the short term."
The article also points out that animal studies indicate that extremely low doses of nicotine in animals are still capable of producing nicotine dependence:
"While NSA in animals typically decreases at unit doses below 0.01 mg/kg, unit doses as low as 0.003 mg/kg have been shown to maintain NSA in rats above saline extinction levels when substituted for a higher training dose (eg, 0.03 mg/kg), though variability between subjects is apparent (see also De Noble and Mele and Donny et al). No animal studies have specifically characterised the reinforcement threshold dose of nicotine during acquisition of NSA in adolescents or in the context of progressively reducing the unit nicotine dose during maintenance of NSA in adults."
The paper also points out that it is unknown whether reducing nicotine levels would have any effect on decreasing youth smoking:
"The dose of nicotine that will lead to extinction of smoking may not be the dose that is associated with the onset of dependence symptoms or nicotine addiction. Studies conducted with adolescent smokers suggest that the potential threshold for onset of nicotine addiction is likely to be substantially lower than the five standard nicotine cigarettes per day suggested by earlier research. Several cross-sectional and longitudinal studies have shown that youth smoking on a less than daily basis nevertheless report onset of dependence symptoms. About half the youth smokers who reported 1 or more symptoms reflective of a loss of autonomy over smoking had smoked on average 2 cigarettes 1 day per week, and half of those who met WHO International Classification of Diseases, 10th edition (ICD-10)-defined dependence reported smoking cigarettes a month, or 1–2 cigarettes per day. That symptoms of dependence can develop with low rates of smoking is consistent with results from a small study of adults demonstrating about 50% occupancy of α4β2 nicotinic acetylcholine receptors (nAChRs) for 3 h after just 1–2 puffs on a 1.2–1.4 mg nicotine yield cigarette. Similarly, other prolonged brain effects (long-term potentiation of the excitatory transmission to the brain reward centres) have been observed after brief application of low concentrations of nicotine (0.5–1.0 μM). Human and animal studies have shown that the adolescent brain is more vulnerable and sensitive to nicotine's effects. For example, adult smokers who initiated smoking during adolescence exhibit greater cigarette consumption, lower likelihood of trying to quit and increased risk of relapse compared to those who started smoking later in life. Adolescent rats and mice might also be more sensitive than adults to the rewarding and reinforcing effects of nicotine, as indexed by greater conditioned place preference, faster acquisition of nicotine self-administration (NSA) and higher baseline NSA rates compared to adults (see also Shram et al). What remains unknown are the effects of low dose nicotine cigarettes in adolescents and whether there is a dose that reduces the probability of sustained cigarette use."
Importantly, the article points out that there could be adverse consequences of reducing nicotine levels in cigarettes:
"In the literature concerning human and animal trials, there is a scarcity of data on the effects of reduced nicotine doses on smoking or nicotine intake and on other responses. Even if a threshold reinforcing nicotine dose is identified and a non-addictive cigarette can be produced, it will be important to determine whether there are other adverse effects from the nicotine exposure that occurs in adolescents who nonetheless experiment with such cigarettes. The threshold for nicotine's reinforcing effects may be higher than the threshold for nicotine's other potentially adverse effects, including enhancing vulnerability to other drug use. ... Therefore, low level nicotine exposure in adolescents experimenting with cigarettes designed to prevent nicotine addiction could potentially produce risk of addiction to other drugs of abuse." ...
"Among potential concerns are: (1) a switch to other drugs of abuse, particularly among populations smoking for social reinforcement, self-identity, or self-medication purposes; (2) dual use of tobacco products, such as reduced nicotine cigarettes with oral tobacco or small cigars, which may lead to greater exposure to toxicants, especially if these other tobacco products continue to contain higher nicotine levels; (3) use of reduced nicotine cigarettes as starter products. Just as low freebase nicotine smokeless tobacco products served as starter products for higher nicotine and more toxic smokeless tobacco products, these reduced nicotine cigarettes may lead to the use of other tobacco products with higher levels of nicotine, unless these other products also contain low nicotine levels; (4) illicit cigarette marketing and smuggling including through the internet and through territories that do not require reduced nicotine content of cigarettes; (5) product tampering or manipulation (such as adding nicotine to the product); and (6) industry manipulations (eg, nicotine analogues, companion products to increase nicotinic effects)."
Ultimately, the article concludes that reducing nicotine levels would not necessarily result in an improvement in the public's health, and that surveillance would be necessary to determine the effects of such a policy:
"If nicotine reduction is enacted, then large-scale surveillance is needed in order to understand the population-level impact of such changes. Marketplace monitoring and assessing unintended consequences (smuggling, nicotine spiking, new product introductions, etc) will also involve broad surveys."
The Rest of the Story
Once again, the anti-smoking groups have been tricked by Philip Morris into supporting federal legislation that does more for Philip Morris than for the public's health. The Campaign for Tobacco-Free Kids, in negotiating the legislation with Philip Morris, agreed to the clause that prohibited the FDA from eliminating the nicotine in cigarettes, and only allowed the agency to reduce nicotine levels. As a result, the agency is powerless to mandate changes in cigarettes which would actually result in a dramatic reduction in their addictive potential. As is clear from the article, even with low levels of nicotine, cigarettes retain strong addictive potential as only a minute amount of nicotine is necessary to occupy enough nicotine receptors to produce a pharmacologic effect.
Even more troubling than the fact that the Campaign for Tobacco-Free Kids was duped by Philip Morris in the negotiations over the tobacco legislation is the fact that the Campaign is boasting about how this provision in the law is going to save millions of lives. The Campaign is apparently unaware of the science which demonstrates, quite convincingly, that even low levels of nicotine are capable of producing reinforcing pharmacologic effects.
But the most troubling aspect of the story is the conclusion of the paper: "Reduction of nicotine in tobacco products could potentially have profound impact on reducing tobacco-related morbidity and mortality. ... an organised and multidisciplinary effort should be established to set priorities and goals..., engage appropriate scientific, research and government communities/organizations, shape the direction of research, and ensure that efforts stay focused on the ultimate goal of understanding how nicotine reduction could impact the morbidity and mortality of tobacco use."
After a comprehensive review of the literature in which the authors convincingly demonstrate that the science base does not support the idea that reducing nicotine levels will substantially reduce the addictive potential of cigarettes and that such a policy could have severe negative public health consequences, they still conclude that reducing nicotine levels is a desired public health policy which should be vigorously pursued, and that millions of dollars of taxpayer money should be funneled into research to study a policy which quite likely might be doomed to failure from the get-go.
There is a strange disconnect between the scientific evidence presented in the review and the conclusions and recommendations of the article.
For example, while the authors state that: "switching to denicotinised cigarettes does not appear to result in significant withdrawal symptoms and may maintain similar levels of smoking reward and reinforcement," they nevertheless conclude that reduction of nicotine levels could have a profound impact on tobacco-related mortality. If the levels of smoking reward and reinforcement are not substantially reduced in very low-nicotine cigarettes, then how would such a reduction have a profound impact on tobacco-related mortality? The conclusion just doesn't follow from the scientific evidence.
In trying to understand why the science is so divorced from the recommended policies and the strategic agenda, I can only point to two possibilities.
First, as researchers in the area of nicotine science, the authors have a vested interest in promoting research funding into their area of expertise. This is a financial conflict of interest that appears to be influencing the conclusions and recommendations of the article.
Second, all three of the TPSAC authors and two additional authors of the paper have a vested financial interest in maintaining the paradigm that nicotine is the agent responsible for smoking addiction because they have financial ties to pharmaceutical companies which manufacture nicotine replacement or smoking cessation pharmaceutical products:
"DKH has received grant funding from Nabi Biopharmaceuticals to conduct nicotine vaccine clinical trials. JEH provides consulting support for GlaxoSmithKline Consumer Health through Pinney Associates on an exclusive basis on issues related to tobacco dependence treatment, has financial interest in a potential new oral nicotine replacement product and serves as an expert witness in litigation against tobacco companies. NLB serves as a consultant for Pfizer and as an expert witness in litigation against tobacco companies. MZ provides consulting support to GlaxoSmithKline Consumer Health through Pinney Associates on an exclusive basis on issues related to tobacco dependence treatment. KAP has served as a consultant to Cypress Bioscience."
That pretty much says it all. With this magnitude of conflict among the study authors, there is no way we could expect an objective set of recommendations and conclusions. And, by the way, this is exactly the reason why I have argued that scientists with financial conflicts of interest should not be making national policy recommendations.
The rest of the story is that there is a complete disconnect between the scientific base and the policy agenda in tobacco control today. Financial and political influences have wrested the policy agenda in tobacco control firmly away from the science base.