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http://www.nejm.org/doi/full/10.1056/NEJMp1509510#article

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Reduced-Nicotine Cigarettes — A Promising Regulatory Pathway

Audio Interview

Interview with Dr. Michael Fiore on the potential for regulation of nicotine levels in cigarettes to help smokers quit.
In 1976, tobacco researcher Michael Russell wrote that “People smoke for the nicotine but they die from the tar”1 — suggesting a potential regulatory pathway for eliminating the key harms arising from tobacco use. That is, by reducing or eliminating nicotine from combustible-tobacco products, we might be able to dramatically reduce their use and smokers' dependence on them, averting the harm they caused.

More than 30 years later, in June 2009, President Barack Obama signed legislation that permits the reduction of levels of nicotine, tobacco's primary addictive agent. Section 917 of the Family Smoking Prevention and Tobacco Control Act states that the Tobacco Products Scientific Advisory Committee of the Food and Drug Administration (FDA) shall provide advice, information, and recommendations to the secretary of health and human services on several issues, including “the effects of the alteration of the nicotine yields from tobacco products” and “whether there is a threshold level below which nicotine yields do not produce dependence on the tobacco product involved.” The legislation also contains a provision that prohibits the FDA from “requiring the reduction of nicotine yields of a tobacco product to zero.”

Benowitz and Henningfield first proposed a systematic reduction in nicotine content as a means of weaning Americans off cigarettes, estimating in 1994 that a limit of 0.4 to 0.5 mg of nicotine per cigarette might prevent or limit the development of addiction.2 Such very-low-nicotine cigarettes would be fundamentally different from earlier “light” or “low-tar-and-nicotine” cigarettes in that the tobacco itself would contain so little nicotine that smokers could not extract substantial levels no matter how they smoked. By contrast, “light” cigarettes developed and marketed by the tobacco industry in the 1970s and 1980s included design features for which smokers could compensate (e.g., by covering ventilation holes) in order to obtain more nicotine.

A nicotine-reduction proposal put forth by Benowitz and colleagues in 1998 was intended to both prevent the development of tobacco dependence among young people and wean current smokers off cigarettes. Its premise, supported by considerable research, was that smokers would not smoke very-low-nicotine cigarettes over the long term.3 The proposed reduction was to occur gradually, so as to minimize the hardship of withdrawal in current smokers. Recent research, however, suggests that a long weaning period may be unnecessary. In addition, given evidence that if other combustible tobacco is available, smokers will use it to supplement low-nicotine cigarettes,4 a nicotine-reduction policy would probably have to encompass all types of combustible tobacco.

Reducing the nicotine content of combustible tobacco is not without risks. For instance, people who are already addicted to conventional cigarettes might compensate for reduced nicotine yield by smoking more cigarettes or smoking them more intensively. Such compensation might increase smokers' exposure to the harmful toxicants of combusted tobacco, including tar, carbon monoxide, and other carcinogens. However, studies, including the one by Donny et al. in this issue of the Journal (pages 1340–1349), tend to show only modest compensation in response to a reduction in nicotine yield.

In addition, 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 (ENDS), such as e-cigarettes, e-cigars, and e-pipes. Such a shift might confer a net health benefit to the extent that such products are less harmful than combustible tobacco, but their use might also sustain nicotine dependence, encouraging continued use of low-nicotine cigarettes. We don't know how common such sustained “dual use” would be, nor can we predict its health consequences.

Finally, the development of new products (e.g., an FDA-approved agent that safely and effectively delivered nicotine to the alveolar bed) might further accelerate a decline in combustible-cigarette use and change the risk–benefit ratio.

The current study by Donny and colleagues adds to a growing literature supporting the feasibility and potential benefits of a national nicotine-reduction policy — one that, in our view, could help to end the devastating health consequences of combustible-tobacco use. The researchers found that as compared with smokers of standard-strength cigarettes (containing 15.8 mg of nicotine per gram of tobacco), regular smokers who switched to very-low-nicotine cigarettes (0.4 mg per gram) for 6 weeks had reductions in nicotine exposure, numbers of cigarettes smoked, and nicotine dependence. Moreover, they attempted to quit smoking at a rate double that of participants smoking standard-strength cigarettes (34.7% vs. 17% at 30-day follow-up). We believe these data support exploration of a national nicotine-reduction policy, and we recommend that additional attention be paid to low-nicotine cigarettes as a potential clinical smoking-cessation resource.

Of course, as Donny et al. note, such results do not necessarily reflect what would occur over much longer use of low-nicotine cigarettes, in a broader population, with the possibility of dual use of other nicotine-delivery systems, and when there is no prospect of access to higher-nicotine cigarettes (i.e., if all combustible-tobacco products had to be low nicotine). It is also difficult to know the extent to which manufacturers and smokers could “game the system” by modifying their tobacco products (e.g., selling high-nicotine “black market” cigarettes or spiking low-nicotine cigarettes with more nicotine). Nevertheless, we think that a national nicotine-reduction strategy could play an important role in preventing another generation of young Americans from becoming dependent on cigarettes and reducing smoking prevalence among inveterate smokers, who might either abstain entirely or replace combustible cigarettes with presumably safer alternatives such as nicotine-replacement medications and ENDS.

We recommend that the FDA consider developing and implementing a nicotine-reduction policy that encourages the use of nicotine products at the low end of the continuum of risk for such products. As Mitch Zeller, who would later become the director of the FDA Center for Tobacco Products, stated in 2013, “Anyone who would ponder the endgame must acknowledge that the continuum of risk exists and pursue strategies that are designed to drive consumers from the most deadly and dangerous to the least harmful forms of nicotine delivery.”5 Our ability to transition smokers to the use of less harmful nicotine-delivery systems would be greatly improved if the makers of products (such as e-cigarettes) that reputedly cause less harm would seek FDA approval for them, providing evidence that they are safe and effective as smoking-cessation aids and that they yield benefit at both the individual and population levels.

If people smoke for the nicotine but die from the tar arising from tobacco combustion, why not disassociate the two? We are increasingly convinced that reducing the nicotine content of combustible-tobacco products would undercut the motivation to smoke, that young people who continued to experiment with cigarettes would not become dependent on them, and that adult smokers would either get their nicotine from another source that is markedly safer or quit using nicotine altogether.

Smoking kills half the people who engage in it long term, robbing them of 10 to 15 years of life, according to the Centers for Disease Control and Prevention. Given the size of the current population of U.S. smokers, we can expect at least 20 million Americans to die prematurely if they continue to smoke. Reducing the nicotine content of combustible tobacco to levels that will not sustain dependence seems to us to be the most promising regulatory policy option for preventing those 20 million premature deaths.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

SOURCE INFORMATION

From the Center for Tobacco Research and Intervention and the Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison.

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References
Russell, MALow-tar medium-nicotine cigarettes: a new approach to safer smoking. Br Med J 1976;1:1430-1433
Benowitz, NL, Henningfield, JEEstablishing a nicotine threshold for addiction: the implications for tobacco regulation. N Engl J Med 1994;331:123-125
Henningfield, JE, Benowitz, NL, Slade, J, Houston, TP, Davis, RM, Deitchman, SDReducing the addictiveness of cigarettes. Tob Control 1998;7:281-293
Benowitz NL, Nardone N, Dains KM, et al. Effect of reducing the nicotine content of cigarettes on cigarette smoking behavior and tobacco smoke toxicant exposure: 2-year follow up. Addiction 2015 July 21 (Epub ahead of print).
Zeller, MReflections on the `endgame' for tobacco control. Tob Control 2013;22:Suppl 1:i40-