National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 5, 2010 • Volume 7 / Number 19

Featured Article

Experts Urge Further Research on Nicotine Reduction to Decrease Tobacco Addiction

An illustration that shows how nicotine attaches to nerve cells in the brain at receptors on the cell membrane. Nicotine attaches to nerve cells in the brain at receptors on the cell membrane, initiating a series of electrical and chemical signals that trigger release of dopamine by other brain cells. Dopamine plays a role in the reinforcing effect of nicotine on the brain. Reducing the amount of nicotine in cigarettes and other tobacco products may reduce their addictiveness. (Source: NIDA Notes Vol. 20, No. 2 August 2005)

Tobacco control experts are calling for additional research on reducing the nicotine content of cigarettes and other tobacco products. Nicotine reduction, they wrote in an article published online October 1 in Tobacco Control, has the potential to profoundly affect smoking rates in the United States, but many outstanding questions remain and will require a focused and collaborative research effort.

Momentum for examining nicotine reduction (a decrease in the amount of legally allowed nicotine per cigarette to levels that do not initiate or sustain addiction) grew with the passage of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) in 2009. The Act gave the FDA regulatory authority over the manufacturing, marketing, and sale of tobacco products in the United States. This regulatory authority includes setting standards for the ingredients of tobacco products, including nicotine, the main substance responsible for tobacco’s addictive nature.

“Of all the measures that could be taken under the FSPTCA, reducing the addictiveness of cigarettes has the greatest potential to significantly reduce tobacco-related mortality,” said the article’s lead author, Dr. Dorothy Hatsukami, principal investigator of the NCI-funded Transdisciplinary Tobacco Use Research Center (TTURC) at the University of Minnesota.

“If you do that,” she continued, “you could prevent people who experiment with cigarette smoking from becoming dependent, and you would also facilitate cessation among those who are already dependent.”

Two meetings, held in 2007 and 2009 and sponsored by NCI’s Tobacco Harm Reduction Network and the University of Minnesota TTURC, brought together experts from diverse disciplines to review the scientific evidence on nicotine reduction and identify priorities for future research. Their recommendations appear in the October 1 paper. (See the box at the bottom of the page.)

“We wanted to bring people in the field together to identify research needs,” said Dr. Cathy Backinger, chief of NCI’s Tobacco Control Research Branch and a co-author of the paper. “Because it’s not clear yet what the best approach is to reducing nicotine in cigarettes, nor what effects doing so will have, we need a multidisciplinary group to answer the questions we identified.”

To date, research on nicotine reduction has provided some evidence to support the concept that it could reduce the addictiveness of cigarettes. Studies have shown that very-low-nicotine cigarettes can minimize withdrawal symptoms in smokers who switch to these cigarettes and that they also reduce the number of cigarettes smoked in the long term, as smoking ceases to provide the expected rewards.

In one study, 25 percent of participants quit smoking even though they had not enrolled in the study with the intent to quit. (The trial was intended to test the effects of cigarettes with progressively lower nicotine content on the exposure to carcinogens.) And recently published preliminary data from another clinical trial showed that 36 percent of participants given cigarettes containing 0.05 mg of nicotine as a smoking cessation aid remained abstinent 3 months after treatment, compared with 20 percent of participants using a 4 mg nicotine lozenge.

A major unanswered question remains: What is the threshold dose of nicotine associated with addiction? Complicating the question is the likelihood that this dose may be different for adults and for adolescents, whose developing brains may be more sensitive to the addictive effects of nicotine. “Men also may have a different threshold dose compared with women, and it might even differ between races,” explained Dr. Hatsukami. “Clearly we need additional research in this area.”

Researchers also need to determine whether chemicals other than nicotine produce some of the reinforcing addictive effects of tobacco. Chemicals found in tobacco, such as nornicotine, anabasine, and monoamine oxidase inhibitors, may mediate the reinforcing effects of nicotine or have effects of their own.

“Eventually, we may not just think about reducing nicotine levels; we may actually think about measuring and reducing the overall addictiveness of cigarettes,” said Dr. Hatsukami. “That would cover a number of constituents or any other chemicals that could be added to a tobacco product to make it addictive.

“One of the main points of this article was to make people aware that we need to be very strategic and comprehensive in this research, in order to either support or refute the concept of nicotine reduction,” she continued. “It’s a call for research and also a call to provide resources to look at this area because of the potentially profound effect it could have on public health.”

—Sharon Reynolds

Nicotine Reduction Research Questions

In an article that appeared October 1 in Tobacco Control, experts in the field identified many outstanding questions relevant to nicotine reduction research and compiled a subset of questions for a proposed research agenda, including:

  • What is the threshold nicotine dose for addiction in different populations (e.g., adolescents and adults)?
  • What other influences (e.g., environmental cues) affect the threshold nicotine dose?
  • What are the effects of reduced-nicotine cigarettes on the brains of both adults and adolescents, including the nicotine receptors?
  • Can reduced-nicotine cigarettes cause compensatory smoking (for example, smoking more cigarettes or inhaling more deeply), and if they do, can such behavior be reduced with concurrent use of nicotine-replacement therapy or other interventions?
  • What effects do reduced-nicotine cigarettes have on vulnerable subpopulations of smokers (e.g., those with mental illness or those severely addicted to tobacco products), and how can potential negative consequences in these populations be safely managed?
  • What tobacco product ingredients and design features influence addictiveness in addition to nicotine or in concert with nicotine?
  • How would the public react to a marketplace containing only reduced-nicotine cigarettes?
  • How could the public health value of reduced-nicotine cigarettes best be communicated to the general population?
  • What are the potential unintended consequences from widespread introduction of reduced-nicotine cigarettes, and how can they be monitored and mitigated?