Addicted to Nicotine: A National Research Forum

Details

Monday, July 27, 1998 - 12:00am to Tuesday, July 28, 1998 - 12:00am

National Institutes of Health, Bethesda, Maryland

Contact

National Institutes of Health and The Robert Wood Johnson Foundation

United States

Meeting Summary

Description

A 2-day national conference held at the NIH campus (Natcher Auditorium) focusing on the latest research findings about the behavioral, cognitive, and neurobiological sources of nicotine addiction, prevention of tobacco product use, and state-of-the-art treatment strategies.

Objectives

This conference will enhance awareness and increase knowledge of nicotine addiction and its role in initiating and maintaining tobacco use including:

Role of genetic, biological, behavioral, and sociocultural risk and protective factors
Role of economic factors, advertising and ease of access in initiating tobacco use
Breakthroughs in the neurobiology of nicotine addiction
Current issues in the treatment of nicotine addiction
Role of behavioral and pharmacological treatment approaches

Introductions

Dear Colleague:

On behalf of the National Institute on Drug Abuse (NIDA), welcome to Addicted to Nicotine: A National Research Forum. I would like to extend a heartfelt thanks to our partner, The Robert Wood Johnson Foundation, for their generous support in planning and conducting this important event. I would also like to acknowledge the assistance of our cosponsors, the National Cancer Institute, National Institutes of Health, and the Office on Smoking and Health, Centers for Disease Control and Prevention.

This research forum comes at a time of particular opportunity to improve our nation's health. Scientific advances over the past 20 years have shown that nicotine addiction is chronic, often relapsing, and treatable. Research has shown that biological, behavioral, and social factors must all be considered in implementing effective treatment and prevention strategies. This research forum will highlight state-of-the-art neurobiological, behavioral, cognitive, and prevention findings emerging from more than two decades of research. Specifically, this fonun will enhance awareness and increase knowledge of nicotine addiction and its role in initiating and maintaining tobacco use including:

The role of genetic, biological, behavioral, and sociocultural risk and protective factors
The role of economic factors, advertising, and case of access in initiating tobacco use
Breakthroughs in the neurobiology of nicotine addiction
Current issues in the treatment of nicotine addiction
The role of behavioral and pharmacological treatment approaches

Drug addiction research should not only be useful, it should be used. I hope this forum provides helpful information and strategies that can be applied to our continued efforts to prevent and treat nicotine addiction in the United States.

Sincerely,
Alan I. Leshner, Ph.D., Director

Dear Colleague:

The Robert Wood Johnson Foundation is pleased to welcome you to this important and timely conference, Addicted to Nicotine: A National Research Forum. I would like to thank the National Institute on Drug Abuse (NIDA) for joining us in sponsoring the conference. I also extend my gratitude to our partners and cosponsors who helped make this conference possible, the National Cancer Institute, the National Institutes of Health and the Office of Smoking and Health, Centers for Disease Control and Prevention.

This promises to be an engaging and informative forum. We've come a long way in our understanding about nicotine addiction and effective treatments for it. The scientific advances and interdisciplinary learning that will be showcased over the next two days are helping to change the way our society views tobacco and nicotine addiction.

But we still have much to do to assure both that we learn more about the addiction and that the best practices and treatments for nicotine addiction are used routinely by health care providers. It is our Foundation's hope that the breakthroughs and state-of-the-art knowledge that emerge from this forum will set us on a new course for preventing and treating nicotine addiction. If this occurs, it would greatly improve the health and healthcare of all Americans.

Sincerely,
Steven A. Schroeder, MD

Cosponsored by National Cancer Institute, NIH and Office on Smoking and Health, CDC

Section 1 - History and Pharmacology

Nicotine Delivery Systems

John Slade, M.D.
Robert Wood Johnson Medical School
University of Medicine and Dentistry of New Jersey

Introduction

Tobacco use, specifically use of the cigarette and the cigar, is rising among young people in the United States, and smoking rates among adults have been stagnant throughout most of the 1990s.

The cigarette kills half of those who continue to use it. Among those living who use cigarettes regularly, 500 million will be fatally poisoned by these devices. If present trends continue, the annual death toll from tobacco in 2020 will exceed 10 million, and this number will not be diminished if no one begins using cigarettes from this day forward: These future victims are already smoking.

The tobaccos of commerce are indigenous to the Western Hemisphere. Native Americans used Nicotiana tabacum and N. rustica extensively for pharmacologic purposes, both ritually and recreationally, throughout the Americas prior to the era of European exploration. The Spanish, Portuguese, and English adopted their cultivation and curing practices in developing commercial products. The major forms of tobacco adopted by Europeans were cigar, chew, snuff, and pipe tobacco. Cigar smoke tends toward the alkaline, and alkalinizing agents were often used in chew and snuff mixtures. An alkaline environment favors the free-base form of nicotine, which is readily absorbed across mucous membranes. The main sites of nicotine absorption for all of these products are the mucous membranes of the mouth and nose.

Beginning around 1839, a novel approach to curing tobacco was developed on the farm of Abisha Slade, south of the Dan River, between Moon and Rattlesnake Creeks, in Caswell County, North Carolina. It involved the use of high temperatures and charcoal. Mr. Slade taught many of his colleagues in Virginia and North Carolina the new technique as well, and further refinements by others led to what is recognized today as the flue-curing process. The high sugar content of flue-cured tobacco resulted in a more acidic smoke than varieties containing less sugar, such as those used to make cigars. This characteristic results in nicotine being ionized and held in solution in the aerosol droplets of smoke. The smoke from flue-cured (also called "bright" or "Virginia") tobacco is less irritating and easier to inhale than the smoke from, for example, a conventional dark cigar tobacco because of the lower content of unionized, free-base nicotine. Most of the nicotine in smoke from flue-cured tobacco (and from a conventional American-blend cigarette) is readily absorbed only if it is inhaled.

A contrasting approach to the development of a nicotine delivery device that facilitated inhalation was developed on Java just after the turn of the 20th century. Cloves, which contain the potent local anesthetic eugenol, came to be mixed with dark tobaccos. Clove cigarettes are today the major delivery device used in Indonesia for inhaled nicotine.

Machinery to make cigarettes inexpensively, tobacco blends that facilitated inhalation, modern railroad networks, mass media advertising methods, the safety match, and, quite probably, the promotion of competition fostered by the dissolution of the Tobacco Trust in 1911, combined, by the time RJ Reynolds introduced Camel cigarettes in 1913, to create the conditions that led to the cigarette epidemic.

By midcentury, health concerns about cigarettes led manufacturers to modify their products in ways that provided the appearance of safety. Without regulatory oversight, manufacturers added filters and made brazen claims of health benefit. Among the prominent filters of the 1950s was the Micronite Filter for Kent cigarettes. The original Kent filter was crocidolite asbestos, and the company had reports from two independent electron microscopy labs by 1954 that asbestos was present in the smoke from these cigarettes. Nonetheless, Lorillard continued to use asbestos for another 2 or 3 years. Overall cigarette consumption, which had fallen on the early news of lung cancer risk, rebounded on the strength of unproven filter claims.

In the wake of the 1964 Report of the Surgeon General's Advisory Committee, the industry redoubled its efforts to provide products that appeared less dangerous while continuing to offer no actual proof of safety. The era of the "low-tar" or "light" cigarette, supported by the test method of the Federal Trade Commission (FTC), which continues to this day, had begun. The chief scientist at RJ Reynolds told management in 1965 that a test method such as this would mislead consumers. Unrestrained by effective regulation, the industry developed products that had hopeful test results taken when machines smoked them, but that performed like their high-tar predecessors when actually used by consumers. The mix of toxins changed as blends and additives were adjusted to maintain nicotine delivery and flavor under the "low-tar" dictates of public relations. These changes in cigarette design have been associated with a shift in the cell type of lung cancer from small cell to adenocarcinoma. For all practical purposes, the "light" brands are no less addictive and no less poisonous than those that do not make this claim.

Not only have "light" cigarettes not been significantly less toxic than the products they have supplanted, these products have successfully competed with abstinence, making it less likely that people stop smoking altogether.

The regular, hard-pack version of Marlboro has a nicotine content of 13.5 mg, and its FTC nicotine rating is 1.1 mg, while the "light" hard-pack version has a nicotine content of 13.0 mg and an FTC nicotine rating of 0.8 mg. The regular version features 13 percent filter ventilation and the "light" version 22 percent. A consumer may actually obtain as much as 3 mg or more of nicotine from either of these products.

Cigar use has rebounded in recent years in association with a marked increase in industry-generated promotional activity. In 1997, 22 percent of high school students, including 11 percent of females and 31 percent of males, were current users of cigars. A cigar may contain more than 400 mg of nicotine, and the nicotine can be delivered across the buccal mucosa or be absorbed in the lung, depending on whether smoke is inhaled.

Moist snuff products exhibit a range of pH (and, hence, free-base nicotine availability), which correlates, for U.S. Tobacco, the leading manufacturer, with what company officials have called a "graduation strategy." The company sells sweet, low-delivery products to novices and high-potency products to those who are addicted, while making intermediate offerings available in the product mix as well.

A number of novel, cigarette-like devices have recently been developed by several of the major cigarette makers. Philip Morris and RJ Reynolds are testing these products in ways that resemble conventional assessments of new drugs. It appears that emissions from these products are similar to emissions from at least some existing brands of so-called ultra low-tar cigarettes. It is not yet clear which specific cigarette brands these products might directly compete with.

Four nicotine delivery devices are now approved by the Food and Drug Administration as temporary aids to achieving abstinence from tobacco use: patch, gum, nasal spray, and vapor inhaler. As an example, nicotine gum is available with two levels of nicotine content, 2 mg and 4 mg, which deliver about 0.8 mg and 1.5 mg of nicotine, respectively, at the most.

What We Know

All commercial tobacco products are effective nicotine delivery devices.
Tobacco products are designed to have specific nicotine delivery characteristics.
All commercial tobacco products are toxic when used as intended.
So-called light cigarettes are not less toxic, and consumers have been deceived.
Novel tobacco products that resemble cigarettes have deliveries that are similar to those of some commercially available cigarettes.
Medicinal forms of nicotine are less reinforcing than tobacco products, and nicotine patches are not reinforcing at all.

What We Need To Know More About

How are tobacco products made, and what considerations have gone into their design?
What are the most appropriate ways to test tobacco products for regulatory and public education purposes?
What steps can be taken to reduce the toxicity of tobacco products?
What steps can be taken to reduce the addictiveness of tobacco products?
What are the thresholds for establishing and sustaining nicotine dependence?
What are the effects of systematically lowering the nicotine content of tobacco products?
What criteria might be appropriate for allowing health claims to be made for novel nicotine delivery devices that resemble cigarettes?
Should more direct competition between tobacco products and medicinal nicotine delivery devices be encouraged?

Introduction

Twenty percent of our nation's annual deaths are the result of side effects of nicotine dependence caused by cigarette smoking and other forms of tobacco use. This has continued despite the repeated efforts of the vast majority of cigarette smokers to quit. We now understand that this seemingly irrational behavior is strongly driven by the pharmacologic actions of nicotine on the brain and that cigarettes and smokeless tobacco products are extraordinarily effective at maximizing the addictive effects of nicotine. This presentation will summarize some of the seminal research findings that have led to these conclusions and highlights fundamental questions that must yet be answered if we are to be able to more effectively prevent tobacco dependence among youth and treat those who are dependent.

What We Know

As articulated by the Director of the National Institute on Drug Abuse, "...addiction (including tobacco) is fundamentally a brain disease...the problem is it's not just a brain disease. Addiction itself is actually a result of a combination of environmental factors, historical factors, and the physiological state of an individual, like one's genetic background. They all come together through the brain to produce addiction." This description recognizes the importance of an addictive drug's pharmacologic action in the brain but also implicitly recognizes that there are a variety of factors which go beyond the chemical structure of an addictive drug to contribute to addiction. We have understood since the turn of the twentieth century that nicotine was a potent substance affecting the nervous system that acted with great specificity to produce certain effects (such as stimulation of muscular activity and heart rate), that its effects depended on the dose that was administered, and that tolerance (diminished responsiveness), would develop with repeated doses. Although various scientists and clinicians concluded early in the twentieth century that nicotine was an important determinant of tobacco use, it was largely the research of NIDA and NIH that conclusively demonstrated that nicotine met all of the criteria of a highly addictive drug and that cigarettes maximized these addictive effects. More recently, this research has characterized pharmacologic effects of nicotine in the brain and elucidated basic mechanisms of the nicotine addiction process.

The pathophysiologic basis of nicotine addiction is now understood to include nicotine's effects on structure and function of the nervous system, such as the development of excess brain nicotine receptors (upregulation), and the nicotine administration and nicotine withdrawal produced alternation in the brain electroencephalogram, cerebral metabolism, and neurohormonal levels. In addition, the effects of nicotine on the brain also enable nicotine to serve as a reinforcer, which can strengthen behaviors leading to its continued ingestion in both animals and humans, even if there are adverse consequences of ingestion. Nicotine exposure can also become a means to control mood and appetite, body weight, and possibly serve other useful functions upon which individuals may also become dependent. Abrupt abstinence in chronic users is often accompanied by deficits in brain function and cognitive function which impair the ability of the dependent person to perform occupational tasks. Moreover, NIDA and NIH research showed that nicotine replacement therapy, such as a nicotine patch or gum, can prevent or reverse such withdrawal-associated cognitive deficits as well as other withdrawal symptoms. These same studies almost universally demonstrated the importance of the dose of nicotine as a determinant of its effects - both desired and undesired.

Studies of the nature of nicotine's effects over time (pharmacodynamics) and the relationship of these effects over time show that nicotine's rising and falling levels (pharmacokinetics) following administration were related to the form of nicotine delivery and to the speed of its reduction from its peak levels in the blood (the half-life). It is now clear that the form of nicotine delivery is a major determinant of addiction potential: Tobacco smoke inhalation produces explosively rapid and high doses of nicotine to the arterial blood which feeds the brain and other organs, smokeless tobacco products provide somewhat slower but very high dose levels, and the nicotine replacement therapies generally provide slower and lower levels of nicotine delivery than tobacco products. It is also now clear that the half-life of nicotine is longer than previously thought, averaging about two hours, and that inhalation of cigarette smoke produces arterial blood nicotine levels that are several times higher than those previously measured in studies of venous nicotine blood. These studies have had implications for the development of nicotine replacement therapies and have provided considerable guidance to developing medications which retain therapeutic efficacy while producing minimal addictive effects.

Studies of cigarettes and smokeless tobacco products revealed both to be highly engineered drug delivery devices that act not only to provide users with controllable doses of nicotine but also to maximize the addictive effects of nicotine. For example, smokeless tobacco products varied in their acidity and alkalinity such that products marketed as "starter products" (a tobacco industry term) were more acidic and hence slower in their nicotine dosing characteristics than products marketed to experienced smokeless tobacco product users. Cigarette engineering and chemistry appears to incorporate even more elaborate methods of nicotine dose control.

Taken together, NIH research provided the primary scientific foundation on which the Food and Drug Administration was able to support its conclusion that nicotine in tobacco products was an addictive drug and that cigarettes and smokeless tobacco products were drug delivery devices. Yet many major questions about the nature and course of nicotine addiction process remain unanswered and must be addressed if we are to significantly reverse the ravages of the tobacco-caused disease epidemic.

What We Need To Know

The reversibility of the nicotine-induced changes in brain structure must be more thoroughly elucidated if we are to develop more effective treatment strategies, be they nicotine maintenance or new medications, for individuals whose brains do not readily recover. For example, what factors explain the differences in vulnerability or resistance to developing dependence in people who are exposed to nicotine? How do developmental and maturational factors function to either increase of decrease the vulnerability to developing dependence among youth by altering the reinforcing and other effects of nicotine?

Understanding the threshold dose for a cigarette to serve as an addictive product and the total daily nicotine intake necessary to sustain addiction is important in elucidating the addictive process and also to enable rational regulation of tobacco products, including the setting of standards for products that might be considered denicotinized.

We need to understand the contribution of tobacco and tobacco smoke constituents, both the naturally occurring ones and tobacco product additives and engineering, to addictive and other effects which contribute to compulsive tobacco use.

We need to determine how the effects of nicotine, and the kinetics of various nicotine delivery systems, might vary across diverse populations including children and adolescents, elderly persons, and racial/ethnic minority populations.

We need to better understand the diverse potential beneficial effects of nicotine and other tobacco product constituents on health so that people will be able to obtain the safest possible forms of nicotine delivery or the benefit of other medications to replace the deadly tobacco product delivered form.

Section II: Nicotine-Individual Risk Factors for Initiation

Ethnicity, Gender and Risk Factors for Smoking Initiation

Robin Mermelstein, Ph.D.
Health Research and Policy Center
University of Illinois at Chicago

Introduction

The prevalence of cigarette smoking has increased significantly among youth over the past several years. In 1991, 27.5 percent of high school students smoked cigarettes, compared with 36.4 percent in 1997. These overall rates mask important racial/ethnic and gender differences, however. Smoking is more common among white students (39.7 percent) than among Hispanic (34.0 percent) and black students (22.7 percent). The racial/ethnic differences are particularly striking among females; more than two times as many white females currently smoke (39.9 percent) as black females (17.4 percent), and almost five times as many white females are frequent smokers (20.1 percent) compared with black females (4.3 percent). Earlier data have shown high prevalence rates among American Indians and low prevalence rates among Asian-American and Pacific Islander youth, especially females. Smoking among black youth has shown the greatest increase since 1991, almost doubling from 12.6 percent in 1991 to 22.7 percent in 1997.

What might explain these ethnic and gender differences? What accounts for the relative resiliency of black and Asian-American females, and how do they differ from white females? This paper presents highlights of racial/ethnic and gender differences in risk factors for smoking and identifies questions for researchers to address.

What We Know

Although there is a plethora of studies on risk factors for initiation, the majority focus almost exclusively on white youth, and as a result, we know much less about how risk factors for smoking may differ among the racial/ethnic and gender subgroups. Generalizing findings from the studies of white youth may be inappropriate, and few studies have specifically compared racial/ethnic and gender subgroups. There are, however, some hints at important differences across the subgroups.

The Relative Role of Family Versus Peer Influences. Peer smoking and peer-group identification are consistently strong predictors of smoking among white adolescents, but are far less consistent predictors of smoking among other adolescents, especially among African Americans. Among whites, parent and family factors play a much less important role in predicting onset. Cultural differences in the importance of family and value on family messages may moderate the power of peer influence. Data from qualitative studies of several ethnic groups found that nonwhite youth reported stronger antismoking messages and perceived consequences for smoking from parents than did white youth. Youth who were not white reported the strong belief that youth smoking was disrespectful to parents, and there was a strong value placed on not "shaming" the family (especially among females).
Perceived Negative Consequences of Smoking. Although the majority of youth acknowledge the health consequences of smoking, survey data show that American Indian students are less likely to agree with such statements. Asian-American female students are more likely than other groups to agree that there is strong social disapproval of smoking. Racial/ethnic and gender subgroups may also differ dramatically in the perceived negative consequences of smoking that are not health related. Qualitative data indicate that African-American girls are unique in their view of smoking as "risky." For African-American girls, smoking may be seen as the first step "down a slippery slope" and incompatible with a promising, successful, and healthy future.
Societal/Cultural Expectations. Such expectations may place white female adolescents at increased risk and may be protective of females in other ethnic groups: White females may be at increased risk for smoking because of smoking-related expectations that are reinforced through broader sociocultural attitudes of the mainstream society. These include beliefs that smoking helps to (1) control weight, and thinness is desirable; (2) control mood, notably anger, stress, and depression, for which white females may be at increased risk; and (3) enhance one's image of being independent and sophisticated, characteristics that are idealized in cigarette advertisements targeted to females and that might uniquely apply to white female adolescents.
Identification with mainstream, white society may influence how much youth from other ethnic groups endorse these beliefs as well. In contrast, strong cultural antismoking norms for females may protect some ethnic minority femalesÑnotably Asian-Americans and Pacific Islanders and, to some extent, less acculturated Hispanic females. There is a strong sentiment among these groups that smoking is not appropriate for girls, is "unladylike," and ruins a girl's reputation.
Popular Media/Entertainment. Celebrities and other public figures may influence the appeal of smoking and be differentially relevant to racial/ethnic and gender subgroups. Messages about smoking appear everywhere to youth, notably in entertainment outlets (music, television, movies) that may appeal to youth. Qualitative data suggest that youth are very aware of the smoking status of public personalities (e.g., music and entertainment figures) and often cite that appealing personalities have positive smoking messages (through image, behavior, in music). The prevalence of smoking in the entertainment media may have increased during recent years.

What We Need to Know More About

More Specific Examination of Ethnic and Gender Effects. The relationship between smoking and certain risk factors may vary by racial/ethnic and gender subgroups, and the prevalence and relative importance of risk factors may vary as well. We need to identify and compare more specifically predictors of smoking and protective factors among the racial/ethnic and gender subgroups.
More About Parental/Familial Influence. Qualitative data suggest that parental messages about smoking matter, although quantitative data may suggest that parental influences wear off over time, primarily for white youth. We do not know, though, how parental smoking and verbal messages about smoking interact and are interpreted by youth from different subgroups. We need to know more about the consistency and strength of parental messages, how they vary developmentally with the youth, how they interact with other risk factors, and how these can be enhanced to inhibit youth smoking.
More About How Youth Cope With Negative Moods. Mood management is a primary reason for smoking across all youth subgroups. We need to know more about why some youth choose to cope with negative moods by smoking, whereas others might choose other substances, behaviors, or coping strategies and whether these vary by gender and ethnicity.
Investigation Into Whether Factors That Protect Youth in Some Subgroups Can Be Diffused to Others. We need to explore whether some of the strong "countermandates" against smoking that exist for African-American and Asian-American females can be diffused to other subgroups or whether these protective factors are truly culture specific.

Introduction

Initiation of tobacco use is most likely to occur prior to age 18, and initiation during childhood or adolescence is associated with an increased likelihood of daily tobacco use as an adult. For example, 89 percent of adult daily smokers began using cigarettes by or at age 18, and 71 percent began smoking daily by or at age 18. There seems to be considerable individual variation in vulnerability to initiation of tobacco use and progression to regular use and dependence. The 1994 Institute of Medicine report highlighted the need to identify factors that influence individual vulnerability to nicotine addiction.

There is a growing body of research that suggests that a number of types of psychopathology that occur during childhood and adolescence are associated with an increased risk for tobacco use. The purpose of this presentation is to assess the relationship between several types of child and adolescent psychopathology and tobacco use. Types of psychopathology to be discussed include conduct problems (e.g., oppositional defiant disorder, conduct disorder); attention-deficit hyperactivity disorder (ADHD), and internalizing disorders (depression, anxiety disorders).

What We Know

The strongest evidence for connections between child and adolescent psychopathology and tobacco use is for conduct problems, ADHD, and depression. There is much weaker support for a connection between anxiety disorders and tobacco use.

Conduct Problems. The relationship between child and adolescent conduct problems and subsequent tobacco use appears to be quite robust. The relationship has been demonstrated both cross-sectionally and longitudinally and in community and high-risk samples. Conduct problems have been operationalized as dimensions (e.g., oppositional and aggressive behavior) and as DSM categories (e.g., conduct disorder). They have been measured as early as the first grade, although most studies have assessed conduct problems in middle childhood and adolescence. Conduct problems have predicted various aspects of tobacco use, including age of initiation and regular (e.g., daily) smoking. There have been minimal gender differences; when they do exist, they have shown the relationship between conduct problems and tobacco use for boys but not girls.
ADHD. A number of prospective studies have documented a relationship between ADHD (or ADHD symptomatology) and tobacco use. Many of these studies have been with clinical samples of boys, although the relationship has been found for boys and girls in community samples as well. ADHD is associated with more frequent tobacco use and an earlier age of initiation. The relationship between ADHD and tobacco use seems to be mediated in most cases by coexisting conduct problems. Youth with comorbid conduct problems and ADHD are at especially high risk for tobacco use. In some studies, ADHD alone, in the absence of co-occurring conduct problems, has not been associated with later tobacco use.
Depression. Several cross-sectional and longitudinal studies (primarily with community samples) have shown that the presence of depressive symptoms or a diagnosis of major depression is associated with an increased likelihood of tobacco use or nicotine dependence. This finding holds after controlling for other types of psychopathology and social/contextual variables. Prospective studies have demonstrated that depression in adolescence is associated with increased levels of tobacco use 1 year to 9 years later. There has been minimal evidence of gender differences. There appears to be a reciprocal relationship between depression and tobacco use, suggesting that the relationship may be due to common genetic and/or environmental vulnerability factors.
Anxiety. In contrast to other forms of child and adolescent psychopathology, relatively less attention had been paid to various anxiety disorders and symptoms and their possible relationship to tobacco use. There has been great variability in how anxiety has been conceptualized across these few studies, and most studies have failed to find a significant relationship between anxiety and tobacco use. One cross-sectional study demonstrated a relationship between a composite measure of DSM anxiety disorders (for boys, but not girls) and tobacco use. However, in other cross-sectional and longitudinal studies, DSM anxiety disorders, avoidant personality disorder, and "shyness" were not associated with subsequent tobacco use.

What We Need To Know More About

Effects of a Particular Psychopathology on Various Aspects of Tobacco Use. Does the psychopathology increase the risk of tobacco use in general (and thus lead to more tobacco users), increase the risk of tobacco use at an earlier age (which is associated with increased risk of dependence), or both? Does the psychopathology affect initiation, regular use, and/or dependence? Are these effects specific to a particular subtype of the disorder? To what extent do these effects hold across different types of psychopathology?
Comorbidity of Psychopathologies. With the exception of comorbid conduct problems with ADHD, relatively little is known about whether youth who are comorbid for other psychopathology (e.g., conduct problems plus depression, depression plus anxiety) have increased risk status with respect to tobacco use.
Protective Factors. Why do some youth with these psychopathologies not use tobacco? Do they differ in their risk profiles and/or in the timing of risk factors?
Moderators. How are the effects of these psychopathologies on initiation of tobacco use moderated by factors such as gender and ethnicity?
Mechanisms and Processes. Simply knowing that a child/adolescent displays a particular disorder and is therefore at increased risk for initiation of tobacco use is only part of the story. What are the "active ingredients" of various psychopathologies that put these youth at high risk for tobacco use, that is, what are the mechanisms and processes by which they are more likely to use tobacco than other youth? To what extent is the relationship between psychopathology and tobacco use due to a common risk factor(s)? Greater attention to the identification of various developmental pathways that culminate in tobacco use should facilitate progress in this area. (This has important implications for prevention.)
Intervention. What are the implications of the associations between child and adolescent psychopathology and tobacco use with respect to intervention? Does the provision of effective intervention for the psychopathology prior to tobacco use also decrease the risk of subsequent tobacco initiation or progression (i.e., does the intervention serve a preventive function with respect to tobacco use)? Are broadband interventions directed specifically at the prevention of tobacco use in children and adolescents differentially effective with individuals who display these various psychopathologies?
Cohort Effects. As tobacco use becomes increasingly frowned upon by society, will it become increasingly associated with conduct problems, a feature of which is "rebelliousness"?

Introduction

The goal of this presentation is to review the use of genetically informative samples to clarify the causes of variation in the use of tobacco products and in nicotine dependence. While a number of studies in rodents have suggested genetic influences on brain nicotine receptors and the development of tolerance to nicotine, this presentation focuses entirely on data from humans.

What We Know

To What Extent Is Smoking Heritable? Eight studies, published between 1958 and 1995 from seven different countries, have reported some measure of concordance for "smoking status" in samples of monozygotic (MZ) and dizygotic (DZ) twin pairs. These studies together contain 891 MZ pairs, of whom 660 or 74.1±1.5 percent are concordant for smoking status. The parallel figures for DZ twins are 1,072 pairs, of whom 602 or 56.2±1.5 percent are concordant.
There are several reasons to be skeptical of these results. Several measures were used, although most studies examined either current or lifetime regular smoking. Given the importance of peer group exposure in smoking initiation and the evidence that MZ twins socialize more closely in adolescence than do DZ twins, the MZ/DZ difference could be partly a result of environmental effects. This issue can be partly addressed by four small sample studies of MZ twins reared apart. Of the 108 pairs, concordance for smoking status was seen in 82 or 75.9±4.0 percent, a figure similar to that seen in MZ twins reared together. In addition, three investigations examined whether the greater similarity for smoking in reared together MZ versus DZ twins could be the result of environmental effects and concluded that it could not be.

More recently, correlational and heritability analyses of lifetime regular smoking in adult MZ and DZ twins have been reported in five samples containing a total of 4,719 MZ and 3,147 same-sex DZ pairs. The weighted correlation in liability to lifetime regular smoking was +0.80 in the MZ pairs and +0.53 in the DZ pairs. These results suggest that the heritability of liability to regular smoking is likely 50 to 60 percent. Of note, twin resemblance also appears to be influenced by the family environment, which appears to contribute approximately 25 percent of the variance in liability. Finally, one adoption study of cigarette smoking reported significant correlations for cigarette consumption between biological parents and their offspring (+0.21 ) and biological siblings (+0.11 to +0.30), but not between adoptive parents and their adoptive offspring (-0.02) or adoptive siblings (+0.05).

These data show that tobacco consumption, especially in the form of cigarettes, is substantially influenced by genetic factors. Some familial resemblance for smoking behavior is also mediated through familial environmental factors.
Is Nicotine Dependence (ND) Heritable? Several twin studies have examined characteristics that indirectly reflect ND, particularly smoking persistence (i.e., current versus former smoker) and number of cigarettes consumed. Among twin pairs where both members have used cigarettes, these studies uniformly find greater resemblance in MZ versus DZ pairs for persistence or for number of cigarettes consumed. Heritability estimates for these proxy measures of ND are mostly in the range of +0.50 to +0.70. In female-female twin pairs from the Virginia Twin Registry, ND was directly assessed utilizing items from the widely used Fagerstrom Tolerance Questionnaire and from DSM-III-R, and attempts were made to clarify the relationship between the risk factors for smoking initiation (SI) and ND. Significant commonality was found in the risk factors for SI and for ND. However, there also was evidence for familial factors (which are probably at least in part genetic) that specifically influence the risk for ND given prior SI. Results suggest that "new genes" are expressed by exposure to smoking that influence the probability of development of ND. Estimate of the heritability of ND in this sample was about 70 percent, of which about one-third was due to genetic risk factors expressed subsequent to SI.
The available information strongly suggests that the pathway to ND is complex and involves multiple genetic and environmental risk factors. Substantial evidence indicates that smoking behavior is significantly influenced by genetic factors, although not to the exclusion of a range of social environmental factors. Although considerably less is known about the role of genetic factors in the etiology of ND per se, accumulating evidence also suggests that genetic factors play an important role here as well. Efforts at prevention and treatment of both SI and subsequent ND may need to take in account the large individual differences in vulnerability that are, in part, genetically determined.

What We Need to Know More About

Which Specific Genes Influence Smoking Behavior and ND? In the past several years, the gene-finding methods of human molecular genetics have begun to be applied to a range of complex, genetically influenced human traits, including ND. These studies are still in their infancy and have produced no definitive or replicated results. Given the complexity of this trait, quite large sample sizes may be required. A number of plausible "candidate genes" for ND are under investigation, including enzymes that metabolize nicotine, nicotinic receptor subunits, and dopamine receptors that may modulate the hedonic response to nicotine. It is likely, but by no means certain, that important advances will be made in this line of research in the upcoming decade. The existence of such studies that examine SI is uncertain.
How Do Genetic Risk Factors Influence Risk for Smoking and ND? Do these risk factors largely operate on broad domains of personality or on specific biological systems (e.g., nicotine metabolism, brain nicotinic or dopamine receptors)? Might there be a dynamic interaction between genetic and environmental risk factors, such as temperamental traits influencing the selection of peer groups and lovers, that in turn affects the risk for smoking initiation?
Are Genetic Risk Factors for Smoking the Same for Males and Females? Some studies show lower correlations in smoking behavior among opposite-gender versus same-gender fraternal twin pairs, suggesting distinct familial influences on smoking in men and women.
How Specific Are the Genetic Risk Factors for Smoking and ND? To what extent are liability genes for smoking or ND unique to tobacco products versus shared with other forms of psychoactive substance use? Do the genetic risk factors for smoking or ND also predispose a person to psychiatric disorders such as major depression or anxiety states?

Introduction

Nicotine metabolism might be relevant to nicotine addiction since metabolism influences a person's exposure to the psychoactive substance nicotine. Individual variation in nicotine metabolism may play a role in a person's level of smoking, as well as the transition from initiation to maintenance of a smoking behavior pattern. Slower nicotine metabolism permits longer exposure to nicotine and therefore may yield fewer cigarettes smoked per day. Slower metabolism in naive smokers may potentially reduce the likelihood of their becoming regular smokers, which is related to more aversive symptoms from nicotine exposure. Persons with faster nicotine metabolism may smoke more cigarettes per day to maintain nicotine levels and be more likely to develop and maintain a smoking pattern. While there are numerous factors that affect initiation of smoking behavior, nicotine metabolism could be one important aspect. Since there is a paucity of research on nicotine metabolism in youth, a brief review of salient aspects of nicotine metabolism in adults provides a basis from which to extrapolate.

What We Know

Nicotine metabolism is complex. Nicotine, a highly lipid-soluble alkaloid, is converted to cotinine in a two-step process involving cytochrome P450 and aldehyde oxidase. Nicotine is eliminated primarily by hepatic metabolism by way of C-oxidation to cotinine, the major metabolite. While nicotine has a relatively short half-life of about 2 hours, cotinine has a half-life of approximately 20 hours. Therefore, cotinine provides a more stable marker of exposure in the person since there is less variability in cotinine throughout the day than that observed for nicotine.

Possible explanations for different levels of the metabolite cotinine in persons who have similar smoking rates include differences in nicotine absorption and distribution, differences in the depth and duration of inhalation during smoking, differences in swallowed, nicotine-laden saliva, the effect of mentholated cigarettes on smoke constituent exposure, genetic differences in nicotine metabolism, and differences in cotinine elimination. Variables affecting the biotransformation of nicotine have been identified. Several studies indicate that male smokers may metabolize nicotine faster than female smokers. Daily activities, such as consuming a meal, increase nicotine metabolism. An average 42 percent increase in nicotine clearance approximately 1 hour after beginning the meal may be related to increases in liver blood flow with the meal. Smokers typically smoke after meals, and decreased plasma nicotine caused by increased nicotine clearance with increased hepatic blood flow could contribute to the urge to smoke.

To illustrate differences in individual metabolism variability in the natural environment, several studies have identified higher cotinine levels in African-American compared with Caucasian smokers, resulting in lower smoking rates among African Americans. In a two-factor study of menthol preference and ethnicity, African-American women smoked significantly fewer cigarettes per day than did Caucasian women, and yet their average cotinine level was significantly higher. There were no differences by ethnicity on smoking topography measures except for a longer exhalation duration time in Caucasian women. There were significant effects of mentholated cigarettes across ethnic groups since half of each group preferred nonmenthol cigarettes based on stratified recruitment. Menthol smokers had larger puff volumes, higher cotinine levels, and shorter time to first cigarette. Menthol cigarettes are the predominant choice of African-American smokers and thus have implications for clinicians working with African-American youth exposed to this type of cigarette, with its higher tar and nicotine content.

Higher levels of cotinine in African-American smokers compared with Caucasians may also be related to the findings of a recent study of nicotine and cotinine clearance in African-American and Caucasian smokers assessed with dual-labeled nicotine and cotinine infusions. While clearance of nicotine was similar for African Americans and Caucasians, the clearance of cotinine was significantly slower in African Americans.

Genetic variability in nicotine metabolism is another important factor in understanding interindividual differences of consumption and exposure. In vitro studies have identified several different cytochrome P450 isozymes in the C-oxidation of nicotine. CYP2A6 and CYP2D6 have displayed genetic polymorphisms suggesting that individuals who lack these enzymes may be poor metabolizers of nicotine. It was recently reported that 60 to 80 percent of nicotine is metabolized to cotinine by CYP2A6, which is polymorphically expressed as the wild-type and two null alleles CYP2A6*2 and *3. Cotinine formation in human liver microsomes was significantly correlated with CYP2A6 levels leading to the conclusion that CYP2A6 is the principal cytochrome P450 involved in nicotine metabolism. Variation in CYP2A6 was identified as the major reason for interindividual differences in nicotine kinetics in human liver microsomes. In other work, smokers homozygous for wild-type active CYP2A6 alleles smoked significantly more cigarettes per day than heterozygous smokers (carriers of one defective CYP2A6 allele). A significantly lower prevalence of CYP2A6 v1, the variant allele that encoded an inactive enzyme, was identified among African Americans (0 percent) versus English Caucasians (17 percent). In another sample, the prevalence of two variant alleles of CYP2A6 was 2.6 and 6.6 percent in Caucasians and .9 and 13.9 percent in Canadian Native Americans. While earlier studies had examined the potential role of CYP2D6 in nicotine metabolism, a recent study reported that CPY2D6 was not important in nicotine metabolism in human liver microsomes. In addition, CYP2A6 has been shown to metabolically activate procarcinogens such as aflatoxin B1 and N-nitrosodiethylamine; thus, the polymorphism of CYP2A6 is important as a factor of cancer susceptibility.

Smoking initiation is multifactorial, with nicotine metabolism being only one factor. Extrapolating what we know about adults, we can postulate that there is variability in nicotine metabolism among youth related to differences in nicotine absorption and distribution, differences in the depth and duration of inhalation during smoking, the effect of mentholated cigarettes on smoke constituent exposure, genetic differences in nicotine metabolism, and differences in cotinine elimination. Plasma nicotine half-life in "chippers" (persons who smoke fewer cigarettes intermittently) was similar to the nicotine half-life in regular smokers. This provides information about nicotine levels in persons with smoking patterns that may resemble youth in smoking initiation. The chippers' lower smoking rate did not yield increased nicotine levels as a result of diminished nicotine disposition or clearance. A small study of adolescent smokers reported lower blood cotinine levels than those in adults with comparable smoking rates. However, investigators postulated overreporting of smoking rate by adolescents as one explanation for the differences. Other biological measures of smoke constituent exposure in youth in initiation phases are lacking.

Individual differences in sensitivity to nicotine address the range of response to a specified drug dose. Sensitivity has been described in relation to the initial experiences with smoking and individuals subsequently becoming smokers or nonsmokers. Smokers classified as "more dependent" recalled significantly more pleasurable sensations with initial smoking experiences than less dependent smokers. The ratio of pleasurable to unpleasant sensations was significantly higher in more dependent versus less dependent smokers. It was proposed that those who become smokers are more sensitive to the reinforcing properties of nicotine and are undeterred by the negative effects. In addition, examination of first-dose sensitivity to nicotine in mice indicated that those more reactive initially developed greater tolerance and were more willing to self-administer.

What We Need to Know More About

Characterization of nicotine metabolism in adolescents in the experimentation phase of smoking initiation.
Examination of differences in nicotine metabolism and susceptibility to nicotine addiction in adolescents.
Description of smoking topography and nicotine metabolism in adolescents from multiple ethnic groups in the smoking initiation phase.
Examination of nicotine sensitivity in the smoking initiation phase.
Assessment of the prevalence of CYP2A6 variant alleles in the initiation phase and their relationship to the transition to becoming a regular smoker.

Introduction

This presentation will outline what we know about one gene, CYP2A6, its role in the risk for becoming a nicotine-dependent smoker, and how its function alters the number of cigarettes consumed by smokers.

What We Know

Approximately one-third of the global population older than age 15 smokes. Smoking is associated with a higher incidence of many diseases, including cancers and respiratory and cardiovascular diseases. Approximately 50 percent of initiation into smoking dependence is genetically influenced, while persistence of smoking and the amount smoked have approximately a 70-percent genetic contribution.

Nicotine is the primary compound in tobacco that establishes and maintains tobacco dependence. In humans, 60 to 80 percent of nicotine is metabolized and inactivated to cotinine, principally by the genetically polymorphic CYP2A6 enzyme. Three CYP2A6 alleles have been identified: wild-type (CYP2A6*1) and two defective alleles (CYP2A6*2 and CYP2A6*3). Each individual has two copies of this gene, one each from the maternal and paternal sides. An individual can have two active forms of the gene and have normal nicotine removal (metabolism), one active and one defective copy and have reduced nicotine removal, or two defective copies, which we predict will drastically reduce their nicotine removal.

Protection Against Becoming a Smoker. We hypothesized that individuals with impaired nicotine metabolism (carriers of a defective CYP2A6 allele[s]) would be protected from becoming tobacco dependent. When learning to smoke, individuals often find the nicotine unpleasant (e.g., causing dizziness or nausea), and where nicotine metabolism is decreased in individuals, the aversive effects might last longer. Therefore, these individuals may be less likely to become dependent smokers. We found that 20 percent of the nonsmoking population were carriers of defective CYP2A6 alleles. In contrast, in dependent smokers (DSM-IV and Fagerstrom criteria) with or without alcohol dependence, only 10 percent of the individuals had CYP2A6 defective alleles (20.1 percent [N = 213] versus 11.7 percent [N = 317], p < 0.01, chi-square; OR = 1.9, 95-percent confidence interval 1.2-3.2). These data demonstrate that impaired nicotine metabolism protects against becoming a dependent smoker. In fact, even a single CYP2A6 defective allele (i.e., heterozygosity) is sufficient to significantly reduce by twofold the risk of tobacco dependence. This protects approximately seven million North Americans from becoming smokers. Individuals with two defective alleles (i.e., homozygosity for defective alleles) may be protected to an even greater extent. The individuals with two defective alleles represent about 1.5 percent of the nonsmoking population; assessing the degree of protection from smoking in these double-defect individuals will require evaluation of over a thousand smokers.
Decreased Cigarette Smoking. Dependent smokers adjust their smoking to maintain constant blood and brain nicotine concentrations, suggesting that dependent smokers with impaired nicotine metabolism need to smoke fewer cigarettes. In other words, because nicotine is removed more slowly in these people, the restocking of the nicotine can be done at longer intervals, resulting in their smoking fewer cigarettes. Within the tobacco-dependent group, those who had one defective and one active CYP2A6 gene copy smoked significantly fewer cigarettes per day and per week than smokers without impaired nicotine metabolism ([carriers of two CYP2A6 active alleles], 129 versus 159 cigarettes/week, t-test p < 0.02). Again, these data confirm that CYP2A6-mediated nicotine metabolism is a significant determinant of smoking behavior; heterozygosity in a single gene, the CYP2A6 gene, significantly decreases both initiation of dependence and drug-taking behavior. Interestingly, the decrease in cigarette smoking was observed to a far greater extent in male smokers than in female smokers. This might be caused by kinetic differences between genders. A more likely explanation is that females regulate their smoking less specifically for nicotine than do males. For example, preloading females with nicotine has less effect on reducing their smoking and craving than it does in males. Nicotine replacement therapies also fail more often in females than in males.

What We Need to Know More About

While these data clearly demonstrate a role for genetically variable nicotine metabolism (as mediated by the CYP2A6 gene) in smoking dependence and tobacco carcinogen exposure, many issues still remain to be elucidated.

How Does Defective Nicotine Metabolism Protect Against Nicotine Dependence? While we know that nicotine metabolism is reduced in individuals with a defective CYP2A6 allele(s) and that these people are protected against tobacco dependence, we have not demonstrated how this protection is imparted. We need to gain a better understanding of the role that gender plays in smoking behavior and nicotine regulation. The data clearly show that females are equally protected by this gene defect from becoming dependent smokers, but that the effect is smaller than in males with respect to cigarette consumption. In addition, this gene has only recently been characterized; therefore, many new defective alleles will be identified over the next few years. In keeping with other genes in the CYP family, the frequency of defective alleles varies profoundly across ethnic groups. This may be part of the reason for ethnic differences in smoking and tobacco-related diseases.
Cancer Rates. Tobacco smoke contains nitrosamines that can be activated to carcinogens by CYP2A6; therefore, individuals who carry CYP2A6 defective alleles may also be less efficient at bioactivating tobacco smoke procarcinogens to carcinogens. Thus, individuals carrying CYP2A6 defective alleles may have a decreased risk of developing tobacco-related cancers and other medical complications for three reasons: (1) They have a decreased risk of becoming a smoker; (2) if they do become tobacco dependent, they smoke less than those without impaired nicotine metabolism; and (3) they may activate fewer tobacco-related procarincogens. These three factors suggest a significant reduction in tobacco-related cancers for carriers of a CYP2A6 defective allele(s) that must be confirmed experimentally.
Existing and Novel Therapies. The CYP2A6 genotype (whether one is a carrier of defective copies or not) may significantly affect nicotine levels from nicotine sources other than cigarettes, such as existing nicotine replacement therapies (NRTs) (e.g., patch, gum, nasal spray). This may be of growing importance because NRTs are used increasingly for long-term tobacco dependence maintenance and for treatment of other syndromes (e.g., Alzheimer's disease, Tourette's syndrome, ulcerative colitis). The protective effect of impaired nicotine metabolism (carriers of CYP2A6 null alleles) on the risk for becoming tobacco dependent and in lowering the number of cigarettes smoked, as well as in reduced procarcinogen activation, suggests that inhibiting this enzyme may provide novel therapeutic approaches to prevention and treatment of tobacco smoking. The manipulation of CYP2A6 activity must be explored.

Section III: Nicotine-Environmental Risk Factors for Initiation

Economics

Frank J. Chaloupka, Ph.D.
Department of Economics
University of Illinois at Chicago

Introduction

Over the past three decades, numerous econometric studies have researched the impact of tobacco control policies on cigarette smoking and other tobacco use. These studies examine the applicability of a fundamental principle of economics - the downward sloping demand curve - to tobacco use. This principle states that as the price of a product rises, the demand for that product falls. To economists, price includes not only the monetary cost of purchasing a product but also the time and other costs associated with buying that product and the health consequences and other costs from using the product. Because of the addictive nature of smoking, economic theory predicts that changes in behavior in response to changes in price will not occur quickly, as it would for the use of nonaddictive goods, but that the effects of permanent price changes will grow gradually over time.

What We Know

Several clear conclusions have emerged from the large and growing number of econometric studies of the demand for cigarettes and other tobacco products. Permanent, inflation-adjusted increases in cigarette prices, which could be achieved by increasing cigarette taxes, will lead to significant reductions in cigarette smoking. Estimates imply that every 10-percent increase in price reduces cigarette demand among adults by approximately 4 percent; similar findings are obtained for other tobacco products.

The reductions in smoking resulting from increased prices are not limited to reductions in the number of cigarettes smoked, but also include significant reductions in smoking prevalence. Recent estimates imply that a 10-percent increase in price reduces smoking prevalence by 1 to 2 percent, while reducing the duration of the smoking habit by approximately 10 percent.

Cigarette smoking is clearly addictive in that current cigarette demand depends on past smoking. The most important policy implication of this is that the long-run impact of a permanent price increase or change in tobacco control policy will grow over time. Estimates suggest that the long-run effect of a permanent price increase is approximately double the short-run impact.

Economic theory and several recent empirical analyses imply that the price sensitivity of youth cigarette demand is inversely related to age, in part due to the addictive nature of cigarette smoking. Recent estimates indicate that youths are up to three times more sensitive to price than adults, with a 10-percent price increase reducing youth smoking prevalence by up to 7 percent while also reducing cigarette consumption among continuing young smokers.

Other tobacco control policies, particularly increased information on the health consequences of smoking, strong restrictions on cigarette smoking in public places and private workplaces, and counteradvertising campaigns, lead to significant reductions in overall cigarette demand and smoking prevalence. Tobacco products appear to be substitutes for one another. Increases in the price of cigarettes, for example, have been found to increase the use of other tobacco products, while also reducing cigarette smoking.

What We Need to Know More About

While much is known from economic research on cigarette demand, there is much more to learn. Advances in econometric methods, more and better data, and increased interdisciplinary research can help to address many of these issues.

Existing econometric evidence is based on the small changes in price that occur cross-sectionally and over time. Little is known about the impact of large price increases on cigarette demand; what is known comes primarily from the new field of behavioral economics. This issue can be partially addressed using more recent U.S., as well as international, data.

We need to know more about the compensating behavior of smokers in response to price and policy changes that may offset some of the health benefits. One study suggests that some smokers respond to price increases by switching to longer and/or higher tar and nicotine cigarettes. Similarly, little is known about the potential substitution between tobacco products and other licit and illicit addictive substances in response to stronger tobacco control policies. The very limited evidence suggests that increases in cigarette prices not only will reduce cigarette smoking but also can reduce alcohol and marijuana use. Much more research is needed, however, to clarify these relationships.

More research is needed on the impact of prices and tobacco control policies on the pathways and trajectories of smoking. This is particularly true with respect to the process from first use, through experimentation, and eventually to addiction, as well as with the processes around cessation and reinitiation. Better longitudinal data are needed to address these issues.

Information about the effects of the pricing, availability, and marketing of nicotine replacement products on both the demand for these products and on cigarette smoking and other tobacco use is needed. This is particularly relevant to both the long-term use of these products as part of a broader market for nicotine delivery products that includes cigarettes and the potential for abuse of these products.

While much is known about the independent effects of price and tobacco control policies, more research is needed on the interaction among these policies. There may be important, unrealized synergies among policies that could enhance the effectiveness of tobacco control.

There is mixed evidence from the econometric literature on the impact of advertising and promotion and other industry activities on cigarette demand, particularly on initiation, experimentation, and the transition to addiction in youth. This is largely the result of a lack of good data on industry activities and limitations of econometric methods for using available data. More disaggregated measures, better measures of exposure, improved econometric methods, and more interdisciplinary research would help to address this issue.

Relatively little is known about the differential impact of prices, tobacco control policies, and other important determinants of demand in various subpopulations. The limited existing research suggests that there are important differences with respect to age, race and ethnicity, gender, and socioeconomic status. More clarification of these differences is required.

What We Know

Ever since the introduction of the first machine for mass-producing cigarettes, innovations in advertising and promotional techniques have been a trademark of the cigarette industry. Before the health effects of tobacco use were well known, leaders of the tobacco industry credited the large expansion in the number of people who smoked in the first half of the century to the effectiveness of the advertising and promotional campaigns. These campaigns achieved their effect in part by convincing 14- to 17-year-old adolescents to begin to smoke. In 1967 the tobacco industry introduced the first "woman's" cigarette, again with a large and innovative advertising campaign. Sales surged, but the only effect on attracting new smokers occurred in girls 14 to 17 years of age, and the effect was higher in those who received fewer years of formal education.

A long-term decline in trends of both per capita cigarette consumption and in the proportion of adolescents initiating smoking started in 1973, shortly after the advertising ban on the broadcast media. This decline was associated with an almost exponential increase in tobacco industry expenditure on advertising and promotion of cigarettes. Recently released confidential tobacco industry documents clearly indicate the concern of senior members of the tobacco industry shortly after this decline became manifest and reveal their solution to focus on the youth market.

The major innovative campaign, predicted by these confidential industry documents, was the Joe Camel campaign, which was launched in 1987. The size and nature of this campaign drew major comment in the advertising professional journals. This cartoon character was very attractive to young children as well as to young adolescents, and it was noted that increases in market share had occurred mainly in younger smokers. The unprecedented decline in adolescent smoking over a 12-year period was halted, and the incidence of initiation of smoking in the 14- to 17-year-old age group began to increase again.

These data add up to a strong circumstantial case that tobacco industry advertising and promotional activity encourages adolescents to smoke. The case is made stronger by the observation that the brand preferences of underage smokers are far more strongly linked to advertising expenditure than are the brand preferences of adults. Furthermore, the placement of advertising for these brands that are preferred by adolescents occurs differentially in magazines with a high adolescent readership and is considerably lower in magazines without a significant adolescent readership.

Simple awareness of specific popular advertising messages does not appear to be associated with later smoking behavior. However, advertising and promotions of persuasive communications aimed at increasing sales and awareness, by itself, is not a good measure of an individual's receptivity to persuasive messages. The literature on persuasive communications emphasizes the need to ensure that the target audience is exposed to the message, pays attention to the message, and understands the message. Optimally, the target audience develops a positive affect toward the message and positive cognition toward the product. However, marketers note that an additional incentive (such as a promotional item or a free sample) is often needed to achieve the increase in sales.

Two longitudinal studies reported that a single question probing receptiveness to advertising messages in general was strongly predictive of which adolescents became smokers. A cross-sectional analysis of California adolescents who had never smoked demonstrated that a measure of receptivity to advertising and promotion was associated with being susceptible to smoking. A longitudinal followup of adolescents in this study who were at the lowest risk to become smokers demonstrated that having a favorite cigarette advertisement or having or being prepared to use an industry promotional item was the major predictor of which adolescents progressed toward becoming a smoker. The analysis suggested that the promotional item category of receptivity was about 50 percent more influential than was the advertising item category. However, this is counterbalanced by the fact that many fewer adolescents were in this higher level of receptivity. After controlling for the influence of parents and peers who smoke, this study estimated that 34 percent of all experimentation could be attributed to tobacco advertising and promotional activities.

There is considerable evidence that tobacco industry advertising and promotion are one of the major influences on the uptake of smoking by the young. This evidence includes (1) studies of changes in adolescent initiation of smoking with the introduction of new campaigns, (2) studies of receptivity of adolescents to the messages and images in tobacco industry advertising and promotions, and (3) a longitudinal study demonstrating that receptivity to advertising and promotions predicted future smoking behavior in minimum-risk adolescents.

What We Need to Know More About

The above evidence presents a fairly convincing case that tobacco advertising influences adolescents to start smoking. How much evidence do we need in order to take public health action to protect adolescents and children?

Future research should attempt to replicate the results of the longitudinal followup study of minimum risk adolescents.
If public policy action is undertaken to remove this environmental influence encouraging adolescent initiation, then studies should document the effectiveness of the public policy on adolescent receptivity to advertising and promotion and demonstrate that a reduction in receptivity was associated with a reduction in smoking initiation.

If this evidence leads to restrictions in advertising and promotional practices, it will be very important to study whether such restrictions lead to a reduction in the receptivity of adolescents and children to industry messages and whether such restrictions are associated with a decline in smoking initiation.

Introduction

Efforts to prevent the initiation of smoking must focus on children because nearly 90 percent of smokers start by the age of 18. Traditionally, public health efforts aim to reduce young people's demand for tobacco products through school-based tobacco education, price increases, and restrictions on tobacco advertising and promotion. In order to start smoking, however, young people must have a supply of tobacco products. Reducing youths' access to tobacco is a newer approach to preventing their tobacco use.

Policies with this goal are widely advocated, have strong public support, and have become a focus of Federal, State, and local tobacco control efforts in the past decade. These interventions generally aim to prevent the sale of tobacco products to minors. Laws in all 50 States have long prohibited tobacco sales to minors, but they are not enforced and compliance is poor. Most local and State efforts try to improve compliance with existing laws. Also appearing are measures to strengthen existing laws in ways that are expected to reduce youth access to tobacco. These measures ban vending machine sales of tobacco, self-service displays of tobacco products, sale of single cigarettes, and possession of tobacco by minors.

The Federal Government has taken two actions. In 1992 Congress passed legislation (Synar amendment) requiring States to act to reduce the sale of tobacco to minors in order to be eligible for substance abuse block grant funds. Regulations implementing this law went into effect in 1996. In 1997 Food and Drug Administration regulations established 18 as the national minimum age of tobacco sale and required vendors to verify a purchaser's age. Evidence about the impact of youth access policies has begun to accumulate, but because the supply-side approach to reducing youth tobacco use is relatively new, many questions remain about its effectiveness and role in the spectrum of tobacco control policy. A caveat: Reducing adults' access to tobacco in order to discourage their tobacco use is not a policy seriously considered by the public health community. The sale and use of tobacco by adults is legal, and the public health consensus is that prohibiting this would have no net benefit.

What We Know

It Is Known Where and How Youths Obtain Cigarettes. In surveys, youths consistently report having little difficulty obtaining tobacco products. Over half of teen smokers regularly purchase their own cigarettes, and commercial sources of tobacco (especially convenience stores, gas stations, and vending machines) are consistently cited as primary sources by youths. Noncommercial sources (friends, relatives, older adolescents) also contribute, especially for younger teens and those just starting to smoke. Because younger teens have more trouble buying cigarettes than older teens, they rely more on vending machines or on shoplifting, which is facilitated by self-service displays of tobacco products. The availability of single cigarettes ("loosies") is also thought to facilitate youth smoking.
Compliance With Existing Laws Banning Tobacco Sales to Minors Is Poor. Despite laws in all 50 States that prohibit the sale of tobacco to minors, studies have repeatedly shown that cigarettes and smokeless tobacco can be purchased by adolescents in test buys at rates averaging 67 percent of attempts.
Merchant Education Alone Does Not Work. Educating merchants about tobacco sales laws has not produced sustained improvement in merchant compliance. Embedding merchant education in a communitywide public health campaign that raises awareness about youth access achieves better results, according to an unpublished study, but requires intensive efforts.
Active Enforcement of Tobacco Sales Laws Changes Retailer Behavior. The failure of merchant education led to a focus on active enforcement of tobacco sales laws. In controlled studies, active enforcement consistently reduces the proportion of stores that sell tobacco to minors in a test buy (also known as a "compliance check"). It is more effective than merchant education. More frequent inspections produce better results.
The Effect of Enforcement on Adolescent Tobacco Use Is Uncertain. Enforcement improves merchant compliance with tobacco sales laws, but whether this reduces young people's access to tobacco or tobacco use, as has been assumed, is not established. In several uncontrolled studies in single communities, teenage smoking was reduced after enforcement programs achieved very high levels of merchant compliance. More recent controlled studies have not replicated this finding. In one, merchant compliance increased more in three Massachusetts towns that enforced tobacco sales laws than in three matched controls, but enforcement was not associated with a fall in adolescents' self-reported access to tobacco products or tobacco use. Similar results were found in an unpublished study of 13 New York communities. However, a randomized controlled trial in Minnesota reported a small reduction in youth smoking in seven small rural towns assigned a community organizer to help them adopt and enforce tobacco sales laws compared with seven control towns not receiving this assistance. The intervention in this trial was more intensive than simple law enforcement, and whether the results could have been achieved with a less comprehensive intervention is unclear.
The Effectiveness of Multilevel Governmental Regulations Is Unclear. A number of local, State, and Federal actions have already been taken to reduce youth access to tobacco. Their effectiveness is yet to be determined. There is no evidence that tobacco industry programs designed to prevent youth access are effective.

What We Need To Know More About

The first wave of studies examined intermediate endpoints (merchant compliance with laws). Studies using access to tobacco and tobacco use as endpoints are just beginning to appear. There is some evidence that restricting access to tobacco may discourage young people's tobacco use, but the exact nature, intensity, and duration of interventions necessary to achieve this result are undefined, and many questions remain:

Can Enforcing Tobacco Sales Laws Reduce the Availability of Tobacco to Youth? What level of retailer compliance with the laws is sufficient to produce a meaningful reduction in young people's access to tobacco? Some investigators postulate a threshold effect such that merchant compliance rates of 90 percent or greater may be necessary in order to meaningfully reduce youth access to tobacco, but this has not been empirically tested. What characteristics of an enforcement program (e.g., frequency of inspection, size of fines) optimize retailer compliance?
Will Reducing Young People's Access to Tobacco Prevent or Delay Onset of Tobacco Use? Will it do so by reducing the rate at which youths experiment with tobacco, make the transition from occasional tobacco use to regular use, and/or develop nicotine dependence? Some investigators hypothesize that reducing access to tobacco will have the greatest effect on stopping the transition from occasional to regular tobacco use. How long is the lag time between implementing a program and observing an effect on smoking behavior? Will the effect be observed for teens of all ages or only younger ages, as some evidence suggests?
How Will Young People's Sources of Tobacco Change as Commercial Sources Become More Restricted? Young people also obtain tobacco through noncommercial means (friends, relatives). What interventions might reduce young people's access to tobacco from noncommercial ("social") sources?
What Is the Impact of New Federal Policies Aimed at Reducing Youth Access to Tobacco? How effective is enforcement of the FDA regulations, and how effectively are the Synar regulations being implemented? What impact do the regulations have on rates of compliance with tobacco sales laws or adolescent smoking rates? Is there a relationship between state rates of underage tobacco sales and youth smoking rates?
Some States and Communities Have Adopted Laws That Prohibit Minors' Possession of Tobacco. These are supported by the tobacco industry, but the public health community's opinion is divided. Do youth possession laws have a net positive or negative impact on youth attitudes, access to tobacco, or tobacco use? What is the effectiveness of newer approaches to reducing youth access, including banning self-service displays of tobacco?
What Is the Relative Effectiveness of Efforts To Reduce the Supply of Tobacco Compared With Those That Aim To Reduce Demand? What is the marginal cost and benefit of adding youth access interventions to demand-reduction programs, or vice versa? Will either work alone, or are both necessary to achieve reduction in youth smoking?

What We Know about access to tobacco includes the following:

Young people consistently report having little difficulty obtaining tobacco products.
Most teen smokers regularly purchase their own cigarettes from stores and, to a lesser extent, vending machines. Noncommercial sources (friends, older adolescents, relatives) are also used.
Compliance with existing laws banning tobacco sales to minors is poor because the laws are not enforced.
Merchant education interventions alone do not work to improve compliance with tobacco sales laws.
Active enforcement of tobacco sales laws changes retailer behavior, but whether this reduces young people's access to tobacco or their tobacco use has not been established.
A number of local, State, and Federal actions have already been taken to reduce youth access to tobacco; their effectiveness is yet to be determined. Tobacco industry-sponsored programs do not work.

What We Need to Know More About

Can the enforcement of tobacco sales laws reduce young people's access to tobacco? What level of retailer compliance with the laws is sufficient to produce a meaningful effect, and what are the characteristics of an optimal enforcement program?
Will reducing young people's access to tobacco prevent or delay the onset of tobacco use?
What interventions will reduce young people's access to tobacco from noncommercial sources such as friends and relatives? How will youths' sources of tobacco change as commercial sources become more restricted?
What is the impact of the new Federal policies, the FDA and Synar regulations, aimed at reducing youth access to tobacco?
Do youth possession laws have a net positive or negative impact on youth attitudes, access to tobacco, or tobacco use? What is the effectiveness of other new approaches to reducing youth access, such as banning self-service displays of tobacco?
What is the relative effectiveness of efforts to reduce the supply of tobacco compared with those that aim to reduce demand for tobacco? Will either work alone or are both necessary to achieve reduction in youth smoking?

Introduction

Several types of prevention programs have been shown to delay or reduce youth tobacco use for periods of 1 to 5 years and more. These are evidence-based programs. However, they are not widely used. With few exceptions, adolescent tobacco use rates have been stable or have increased in the 1990s. The challenge for prevention researchers is to identify critical components shared by these effective prevention programs and then to evaluate factors that are most likely to promote their adoption, implementation, and diffusion to schools and communities throughout the United States.

What We Know

Prevention programs, unlike policy and community organization interventions, require the direct participation of youth. Effective programs train youth in psychosocial theory-based resistance skills and/or general social skills, with an emphasis on resistance and assertiveness. Some programs include skills to counteract social influences on tobacco use, for instance, the glamorized images of tobacco use in the media and peer pressure. Others use the social learning theory techniques of instruction, including modeling, role-playing, discussion, and extended skills practice involving group interaction between youth and trainers. In contrast, didactic, atheoretical, knowledge programs have no effect on tobacco use.

Effective prevention programs engage the school, parents, and media programs or combinations of these. The majority of prevention programs are based in schools. For these, effects depend on the use of standardized teacher (or other leader) training, fidelity of program implementation (program delivery as designed), and interactive homework activities to extend skills practice. Magnitude and maintenance of effect depend on the number of sessions and the use of staggered booster sessions; 1- to 3-year effects on tobacco use onset and monthly use have been reported with a minimum of seven sessions, and effects up to 5 years were shown with a 30-session program involving boosters.

School programs adapted to community agency settings, such as the Boys and Girls Clubs, have also shown effects on onset and monthly use for up to 2 years. Parent programs, by themselves, have increased parent-child communication about tobacco use. Mass media programs, by themselves, specifically television programs illustrating prevention skills and/or the social consequences of using tobacco, have shown some effect on changing youth attitudes, perceived norms, and risk of tobacco use. Parent and/or media programs delivered with a school program, however, have shown effects on monthly and weekly tobacco use that exceed a school program alone and last up to 4 years. Finally, multicomponent community programs that have as a basis a school program, with supportive parent, media, and community organization components, have shown effects lasting up to 8 years, on daily as well as monthly and weekly tobacco use.

Program adoption by schools and communities is associated with readiness for prevention as indexed by needs assessment, public commitment, and set-aside resources for the program. Program implementation, limited to the study of school programs, is associated with school climate, specifically principal support of teachers to teach a prevention program. Prevention program diffusion appears to be related to existing credible networks to sanction and diffuse a program.

The following three aspects of tobacco use prevention programs constitute current research knowledge:

Significance and Size of Program Effects. Basis in psychosocial theory; skills to counteract social influences to use tobacco; use of interactive social learning methods of training; standardized teacher (or other program leader) training; interactive homework activities; fidelity of implementation; and multiple program components in addition to a school program.
Maintenance of Effect. Boosters, multiple program components in addition to a school program with community support.
Adoption, Implementation, and Diffusion. School or community readiness for prevention; principal (for school program) support for teaching a prevention program; existing, credible networks for diffusion.

What We Need to Know More About

It is not clear whether tobacco use prevention programs alone or drug abuse prevention programs that include tobacco are more effective. The question may be important in schools and communities where immediate public priorities and funding for prevention vary, for example, in communities that have just adopted a no-smoking ordinance versus communities that are fighting an illicit drug problem. This question bears on readiness for prevention.

Research on predictors of adoption, implementation, and diffusion of evidence-based programs is scanty relative to outcome research. Studies assigning schools or communities to different prevention program options could be designed, either randomly or by choice, with variables such as perceived relative advantage used to predict adoption and diffusion. Predictors of implementation need to be identified, and interventions then should be designed to enhance implementation.

While comprehensive school programs and multicomponent community programs that include a school program appear to produce the largest and most lasting effects on youth tobacco use, little is known about why this is the case. Is it the number and frequency of prevention messages across different community settings, or staggering of program delivery across years, or both? Answers to these questions have important implications for designing future tobacco use prevention programs. For example, if number and frequency is the issue, then an effective tobacco use prevention program could be easily implemented in schools, without requiring the time or resources to involve the rest of the community. New and existing studies could vary some of their program parameters to evaluate these questions, perhaps as component studies within larger research designs.

Little is known about the relationship of prevention program effects to youth tobacco access and policies in the community in which a program is implemented. Specifically, are prevention program effects larger if the program teaches or cues youth to existing policy, or vice versa? Are their messages consistent, for example, and are programs and policies support oriented rather than punishment oriented? Do tobacco vendors or law enforcement officers refer youth violators to prevention programs? These questions could be addressed immediately in current prevention studies by systematically evaluating program and policy content and communications among program deliverers, enforcement personnel, and vendors.

Finally, two questions relate to the effectiveness of prevention programs for preventing addictive tobacco use. First, although more comprehensive prevention programs have shown to delay and reduce daily as well as monthly tobacco use prevalence rates, relatively little is known about whether prevention programs have differential effects on youth who may have different natural trajectories of tobacco use. For example, is a prevention program effective for youth who are not currently exposed to tobacco and therefore would not normally use tobacco for a year or more after the program (a delayed trajectory)? Is the pressure resistance taught in a prevention program enough to make a half-a-pack-a-day smoker want to quit? Second, what is known about the capacity of universal (whole population) prevention programs to recruit, link, or otherwise encourage current smokers to participate in cessation programs? The first question could be evaluated in existing longitudinal prevention studies. The second may require new research studies and the development of adolescent smoking cessation programs.

The following questions about tobacco use prevention programs require answers:

Is tobacco-specific prevention or drug abuse prevention that includes tobacco more effective?
What predicts adoption, implementation, and diffusion of evidence-based prevention programs?
Why are multicomponent programs that include a school program more effective overall than school programs?
Is the degree of effectiveness of a prevention program related to youth tobacco access and policy in the community in which the program is implemented?
What is the capacity of universal prevention programs to affect youth who are at different stages of tobacco use during intervention and to prevent addictive smoking?

Section IV: Biology of Nicotine Addiction

Neuropharmacology and Biology of Neuronal Nicotinic Receptors

Kenneth J. Kellar, Ph.D.
Department of Pharmacology
Georgetown University School of Medicine

What We Know

Nicotine's important effects on the brain, spinal cord, and autonomic nervous system are mediated by nicotinic cholinergic receptors. These receptors, which normally respond to the neurotransmitter acetylcholine, exist as several subtypes that differ in the details of their exact structure and characteristics, but each forms an ion channel through the cell membrane that allows sodium, potassium, and calcium ions to flow into or out of the cell when the receptor is activated by nicotine. This in turn typically leads to depolarization of the cell and an excitatory response. For example, nicotine stimulates cells in the adrenal gland to secrete epinephrine (adrenaline) into the blood, and thus it activates a number of systems collectively involved in the body's "fight or flight" responses.

Nicotinic receptors are found on neurons throughout the brain, including the cerebral cortex, thalamus, hypothalamus, hippocampus, basal ganglia, midbrain, and hindbrain. They are often associated with the cell bodies and axons of major neurotransmitter systems, and they appear to influence the release of several different neurotransmitters, including catecholamines, acetylcholine, GABA, and glutamate. Nicotine, in fact, stimulates the release of dopamine and norepinephrine in specific neuronal circuits thought to be closely involved in so-called reward functions. This action may underlie the addictive liability of nicotine; in fact, its action to stimulate dopamine neurotransmission in these specific reward circuits is consistent with the actions of other well-known drugs of abuse, such as cocaine and amphetamine.

In addition to its actions in the brain's reward circuits, nicotine stimulates the release of certain pituitary gland hormones, such as prolactin and ACTH. Measurement of nicotine's effects on these hormones offers a window on its in vivo pharmacological actions and can be used to assess how acute and chronic exposure to nicotine affect its receptors. For example, in rats a single injection of nicotine stimulates prolactin release, but a second injection given any time up to several hours after the first is ineffective, indicating that the nicotinic receptors are desensitized. This desensitization is reversible, and within about 12 hours after the first nicotine injection, receptor function is restored.

In contrast, after chronic exposure to nicotine (for 10 days), a single injection does not stimulate prolactin release even up to 8 days after chronic exposure has ended. This suggests that the function of these receptors is lost permanently - the receptors are inactivated as opposed to desensitized. Nicotine-stimulated prolactin release does return about 14 days after the last exposure to nicotine, time enough for new nicotinic receptors to be synthesized by the neurons involved.

One of the interesting and more unusual aspects of nicotine's effects on brain nicotinic receptors is that chronic exposure to nicotine in rats, mice, and humans actually increases the density (number) of these receptors. Thus, in rats or mice exposed to nicotine for 7 to 21 days, the density of these receptors is increased by 30 to 100 percent in many areas of the brain. In the brains of smokers, the density of the nicotinic receptors is 100 to 300 percent higher than in nonsmokers. The higher density of receptors, however, may not necessarily translate into an increased level of functions mediated by these receptors. Quite the opposite may be the case, as demonstrated by the prolactin studies described above. On the other hand, recent studies that examined nicotine-stimulated dopamine and norepinephrine release in vivo found that administration of low doses of nicotine could actually increase the release of these neurotransmitters in some brain areas.

What We Need to Know More About

This difference in how chronic administration of nicotine affects nicotine-stimulated prolactin release and dopamine release in vivo probably reflects fundamental differences in the regulation of the subtypes of nicotinic receptors that mediate each of these responses. Thus, a critical task is to identify the receptor subtypes that are associated with the pharmacological actions of nicotine in altering neurotransmission and ultimately behavior. The means to accomplish this task are beginning to emerge in the form of new methods and tools to localize and identify the specific receptor subtypes in specific areas of the brain and spinal cord and in peripheral nervous tissue. These include new high-affinity ligands to label the receptors, subunit-specific antibodies that allow determination of the subunit composition of the receptor subtypes, patch-clamp measurements of the conductance, and rapid regulation of the receptors' ion channels. In addition, new approaches to studying the characteristics of the receptor subtypes and to determining their roles in vivo have been developed using the methods of recombinant molecular biology, including the production of stably transfected cell lines that express a single subtype of nicotinic receptor (which allows precise characterization of that receptor's properties) and knockout mice lacking a specific subunit of the receptors.

A fundamental question is, Which subtype(s) of nicotinic receptors are involved in the rewarding aspects of nicotine's actions? Is it the receptor that is inactivated by chronic nicotine and thus does not fully function after chronic exposure to nicotine? Is it the receptor whose function is actually increased during chronic exposure? Or is it a combination of receptor subtypes? And beyond the neurobiology of nicotine's actions on its receptors is an even more intriguing question: How do nicotine's effects on neurotransmission lead to alterations in the fundamental drives and behaviors associated with addiction? The means are available to begin to address these questions, and the answers are likely to have relevance to more than just nicotine addiction.

Introduction

Nicotine in tobacco exerts its actions on physiology and behavior by binding to nicotinic receptors in the brain. These receptors are large proteins spanning nerve cell membranes that normally translate the external signal of the neurotransmitter acetylcholine into an electrical signal that affects processes inside the nerve cell. These "nicotinic acetylcholine receptors" (nAChRs) can affect nerve cell function because they act as a gate for the passage of positively charged sodium, potassium, and calcium ions across the cell membrane. This ion flow can then increase the excitability of nerve cells and, most notably, can result in increased release of neurotransmitters that neurons use to communicate with other nerve cells. Outside of the brain, nicotinic receptors are also found in muscle and in nerve cells of the autonomic (fight or flight) nervous system. These receptors are also activated by nicotine and contribute to physiological responses to tobacco.

Each functional receptor is made up of five components, or subunits, which are similar to each other in sequence and structure. These subunits combine together like a wagon wheel to form the ion pore that is opened by binding of nicotine or acetylcholine. Nicotinic subunits are divided into several families. Those found in muscle form one family; the two other families are both found in nerve cells but have different structures. One family can make functional receptors only when at least one alpha-type subunit combines with at least one beta-type subunit to make up part of the five-component receptor (alpha2-alpha6 combined with beta2-beta4). The second family are able to make functional receptors even when all five components of the receptor are identical (alpha7-alpha9).

What We Know

Despite the many different subunits expressed in the brain, experiments indicate that nAChRs in the autonomic ganglia are primarily composed of alpha3 and beta4 subunits, whereas brain receptors are primarily composed of alpha4 and beta2 subunits, with the other subunits combining with these receptors in subsets of nerve cells. alpha7 subunits are present in many brain areas, including the hippocampus and the cortex, and appear to be able to make functional receptors on their own. One important question for ongoing research is which of the effects of nicotine on the central nervous system are mediated through alpha7 subunit-containing receptors and which are mediated through nAChRs containing the beta2 subunit. It is known, for example, that the alpha7 subunit is present at high levels in the hippocampus, an area of the brain involved in learning and memory. In addition, it is known that many nicotinic subunits, including alpha3, alpha4, alpha5, alpha6, beta2, beta3, and to some extent alpha7, are present in the mesolimbic dopamine system, an area of the brain thought to be involved in rewarding properties of drugs of abuse. These are therefore receptors that might contribute to cognitive and rewarding aspects of nicotine.

Given this wide diversity of receptors sensitive to nicotine, it is of interest to determine which subtypes of the nAChR mediate the effects responsible for tobacco consumption. A particularly useful tool in this search are transgenic animals that lack specific subunits or subtypes of the nAChR. These types of animals, termed "knockout" mice, can be generated using modern genetic engineering techniques and have been extremely useful in determining the functional role of many proteins that have been identified through molecular cloning. Mice lacking the beta2 subunit of the nAChR have been developed, as have mice lacking the alpha7 subunit. The beta2 subunit mutant mice have been used to examine the reinforcing properties of nicotine in an animal model.

The nucleus accumbens (NAc) and the ventral tegmental area (VTA) are brain areas thought to be responsible for the reinforcing effects of nicotine. These areas form the mesolimbic dopaminergic system and are critical brain reward regions that mediate the reinforcing actions of many drugs of addiction. Nicotine, like ethanol, cocaine, and amphetamine, can increase levels of dopamine in the NAc, and lesions of the mesolimbic dopamine neurons attenuate nicotine self-administration in rats. Nicotine can stimulate dopamine release in the brains of wild-type mice, but beta2 subunit mutant mice show no increase in extracellular dopamine levels following nicotine treatment. Using the self-administration paradigm, it has been possible to examine directly the reinforcing properties of nicotine in these beta2 mutant animals. Wild-type mice will self-administer low-dose nicotine after they have been trained to self-administer cocaine. In contrast, mutant mice extinguish self-administration behavior when nicotine is substituted for cocaine.

These experiments demonstrate that the beta2 subunit is a necessary component of the receptor mediating nicotine reinforcement and suggests a method to determine other components of this receptor.

What We Need to Know More About

There are still many questions about nicotinic receptor function. Future experiments using mice deficient in various a subunits of the nAChR will identify the partners of beta2 in mediating the addictive properties of nicotine and could contribute to rationale drug design of a treatment for nicotine addiction. Much of what we know about the structure of neuronal nicotinic receptors is based on studies of the muscle receptors, and a great deal of structural information still remains to be gathered. In addition, more data are needed on the relative ion permeability of different subunit combinations in the brain. Electrophysiological studies are beginning to show how nicotinic receptors are able to exert their actions on nerve cells, but much more research is needed to characterize which subunits are responsible for the effects of nicotine on different neurotransmitter systems. Finally, the links among the molecular biology of nicotine receptors, their physiology, and the ultimate role of individual receptor subtypes in complex behaviors are just beginning to be established. A multidisciplinary approach to nicotinic receptor function could unite a large body of work on the behavioral pharmacology of nicotine with the newer body of knowledge on the molecular biology of these receptors.

Introduction

Positron emission topography (PET) is an imaging method uniquely suited to investigate the effects of drugs in the human and animal brain in a noninvasive way. PET uses radiotracers that bind selectively to the molecular targets for drugs, such as receptors, transporters, or enzymes that are involved in the synthesis and metabolism of neurotransmitters. This can be done at tracer concentrations that are devoid of pharmacological effects. Organic drug molecules can also be labeled with carbon-11 (C-11) by substitution of one of the stable carbon atoms. This does not change their pharmacological properties and enables the direct evaluation of their distribution and pharmacokinetics of the drug of interest in the brain. PET can also be used to assess the effects of drugs on brain glucose metabolism and cerebral blood flow, both of which can be used as markers of brain function.

Though few PET studies have assessed the effects of nicotine in the living brain, the following are some of the areas of investigation:

Labeled Nicotine. Both natural (-)-nicotine and its enantiomers have been labeled with C-11. Higher uptake of (-)-nicotine was seen in the cortex, thalamus, and basal ganglia than in other regions, while levels of the unnatural enantiomers were lower. However, the kinetics of (-)-nicotine were not altered by administration of unlabeled nicotine, indicating that binding of nicotine is predominantly nonspecific. The poor-specific to nonspecific binding ratio has precluded its use as a tracer to monitor nicotine receptors in the brain.
Nicotine Receptors. Nicotinic compounds with a high affinity for the nicotinic receptor have been developed to measure the distribution and concentration of nicotine receptors in the brain. One such compound is epibatidine, which has a high specificity for nicotine receptors (twentyfold more potent than nicotine) and little or no activity at other receptor types. The F-18 (t1/2 =3D 110 min)-labeled derivative of epibatidine showed very high-specific to nonspecific binding ratios in the human primate brain. This compound shows high-specific binding in the thalamus, which corresponds well with the high concentration of nicotine receptors in this brain region. The binding of epibatidine in the thalamus is almost completely blocked by pretreatment with nicotine. Unfortunately, epibatidine is very toxic, which has limited its use to investigation in nonhuman primates. Development of less toxic compounds will allow the performance of these studies in humans.
Imaging of the Nicotine-Addicted Subject. In spite of the fact that there are 45 million cigarette smokers in the United States, little is known about the neurochemical actions of tobacco smoke on the human brain, and very few imaging studies have examined these effects. Glucose metabolic activity has been compared in a relatively small number of smokers and nonsmokers, with one study reporting slight elevations in metabolism and a second reporting no significant differences. The acute administration of intravenous nicotine has also been reported to reduce brain metabolism.

More recently, monoamine oxidase A and B (MAO A and B) have been examined in the human brain. MAO breaks down neurotransmitter amines like dopamine, serotonin, and norepinephrine, as well as amines from exogenous sources. It occurs in two subtypes, MAO A and MAO B, which can be imaged in vivo using =5B11C=5Dclorgyline and =5B11C=5DL-deprenyl-D2 and PET. Using these ligands, it has been shown that cigarette smokers have a reduction in brain monoamine oxidase B (MAO B) of about 40 percent relative to nonsmokers and former smokers. Smokers have a 28-percent reduction in brain MAO A, relative to nonsmokers.

Nicotine does not inhibit MAO B at physiologically relevant levels. MAO A and B inhibition is associated with enhanced activity of dopamine, a neurotransmitter involved in reinforcing and motivating behaviors and in movement as well as decreased production of hydrogen peroxide, a source of reactive oxygen species. Inhibition of MAO by cigarette smoke could be one of the mechanisms accounting for the lower incidence of Parkinson's disease in cigarette smokers. MAO A and B inhibition by smoke may also account for some of the epidemiological features of smoking, which include a higher rate of smoking in individuals with depression and addiction to other substances. In this regard, MAO A inhibitors are effective in the treatment of depression.

What We Know

In addition to nicotine, cigarettes possess other pharmacological actions that may contribute to their reinforcing effects.
Cigarette smoking inhibits the concentration of MAO A and B, and this inhibition recovers after cigarette discontinuation.
There is a high concentration of nicotine receptors in the thalamus - a brain region involved with analgesia that may account for the analgesic properties of nicotine.

What We Need to Know More About

Develop better ligands to monitor nicotine receptors in the human brain.
Investigate the mechanisms responsible for MAO enzyme inhibition by cigarette smoking.
Determine the half-life for inhibition of MAO A and B by cigarette smoking.
Measure the levels of nicotine receptor occupancies achieved by doses of nicotine equivalent to those obtained when smoking a cigarette.
Measure the levels of nicotine receptor occupancies required for the nicotine patch to be effective in preventing nicotine withdrawal.
Evaluate the effects of chronic cigarette smoking on nicotine receptor expression in the human brain.
Evaluate the effects of chronic cigarette smoking on other molecular targets in the brain.

Introduction

Research on the effects of nicotine, such as acute mood responses or changes in brain function, is important in order to understand the consequences of tobacco smoking. However, to fully comprehend how these changes may help explain nicotine dependence or addiction, it is necessary to link these changes to tobacco use behavior or nicotine self-administration. The degree to which a drug is self-administered, more than an inert substance (e.g., placebo, saline solution), is generally taken as the measure of its reinforcing value. Examination of factors that alter nicotine self-administration behavior is critical to improving our understanding of how tobacco smoking is initiated and maintained, as well as evaluating potential interventions to help people quit smoking.

In most animal and human self-administration studies, nicotine is administered following a specific simple response (e.g., bar press, squeeze on a nasal spray bottle), and if this response subsequently increases in frequency, then nicotine is said to be reinforcing. Because tobacco smoke contains several thousand compounds besides nicotine, studies of smoking behavior are often limited in what they can reveal about the reinforcing effects of nicotine itself. However, procedures have been developed by which the drug nicotine can be administered to animals by intravenous infusion, isolating the influence of nicotine on behavior. Similarly, novel methods of administering nicotine to humans in the absence of tobacco smoke have been developed, enabling researchers to clarify the degree to which nicotine per se is reinforcing in humans.

What We Know

Both animals and humans will self-administer nicotine significantly more than placebo, demonstrating the reinforcing value of nicotine. As an example, among smokers trying to quit smoking, those given access to nicotine nasal spray will use it significantly more than those given access to placebo nasal spray. Since the only difference between the sprays is the presence of the drug nicotine, then nicotine must be what is reinforcing their spray use. Other evidence comes from the observation that tobacco cigarettes with the nicotine removed have not succeeded in the marketplace. Despite demonstrations from a number of different studies that nicotine is reinforcing, some have questioned whether nicotine is as dependence producing as other drugs. Recent animal and human studies indicate that the amount of self-administration behavior is at least as great, and the onset of dependence is at least as likely, if not more so, with nicotine use as with exposure to other drugs.

Animals and humans also vary their self-administration of nicotine in orderly ways to maintain steady intake following systematic manipulations of dose, response requirement, and availability of alternative reinforcers. For example, if the available nicotine dose is lowered, animals will often increase their rate of responding correspondingly to try and maintain the same amount of nicotine intake. Lack of effect of this dosing manipulation on responding for other reinforcers, such as food, shows that this behavior is specific to nicotine reinforcement. Similarly, if smokers switch to a lower nicotine yield cigarette brand, they almost invariably increase the frequency or intensity of their smoking to try and extract as much nicotine as they previously received from their higher yield brand.

Furthermore, animal research shows that nicotine self-administration varies according to a number of individual difference factors, such as species strain, and as a result of short- or long-term environmental experiences, such as consumption of alcohol, food deprivation, stress, and presentation of stimuli specifically paired with nicotine availability (e.g., lights). Although often not as clearly demonstrated, other research suggests that similar factors influence human nicotine self-administration. These factors include individual differences such as heredity and gender, as well as environmental experiences such as chronic or acute alcohol use, stress, and cues associated with smoking (e.g., being in the presence of a lit cigarette).

Finally, nicotine self-administration procedures have proven valuable in examining the potential effectiveness as well as addictiveness of pharmacological treatments for smoking cessation. For example, providing nicotine gum, patch, or spray subsequently reduces amount of smoking behavior in the lab among smokers, even those not trying to quit. Similarly, a drug that blocks nicotine's effects in the brain, mecamylamine, has been found to reduce nicotine self-administration in animals, to reduce nicotine's subjective effects in humans, and to aid in smoking cessation. It seems unlikely that any drug that fails to decrease nicotine self-administration over time will be promising as a treatment for smoking. On the other hand, controlled clinical research has shown that humans generally do not self-administer nicotine gum or patch substantially more than placebo gum or patch, probably because of the very slow rate of nicotine delivery from these products compared with smoking. This observation is an important piece of evidence indicating that gum and patch are unlikely to be abused.

What We Need to Know More About

Despite this recent progress, more data are needed regarding factors that influence nicotine self-administration in animals and humans. For example, What specific acute interceptive (subjective) and behavioral effects of nicotine are most reinforcing in animals and humans? Nicotine has a wide array of effects, and it is likely that only a subset of these effects is critical to maintaining self-administration, although what these effects are is not known. It is not even clear to what degree positive reinforcing effects (e.g., pleasurable mood) versus negative reinforcing effects (e.g., relief of withdrawal) maintain nicotine self-administration. Also, What is the minimum nicotine exposure (per cigarette and over what period of time) required in order to induce dependence, and similarly, What is the maximum exposure allowable that will still not likely lead to dependence? This information may be important in future regulation of nicotine-containing products, including cigarettes.

Research must address the behavior of nicotine self-administration as it directly relates to measures of brain functioning, such as neurotransmitter activity or nicotine receptor number and subtypes. Nicotine use is associated with a number of indices of brain function, but we need to know which of these are responsible for nicotine reinforcement and dependence and which are merely correlated with use.

Similarly, we need to know what differential effects of nicotine on mood or behavior or in brain function are related to individual differences in vulnerability to nicotine dependence. Heredity and environmental causes of variability in responding must act through specific mechanisms directly linked to nicotine effects, but these mechanisms are not clear. For example, some smokers may primarily self-administer nicotine for positive reinforcing effects while others may self-administer mostly for negative reinforcement, such as to relieve negative affect. The mechanisms responsible for these differential reinforcing effects between smokers need to be determined.

We also need to know what accounts for the striking persistence of nicotine use, even after lengthy periods of abstinence. To what degree do stimuli associated with nicotine intake (conditioned stimuli) contribute to the persistence of self-administration, and can these stimuli be sufficiently altered or eliminated to discourage self-administration?

Finally, we need to know how applicable to smoking in the natural environment are the observations of nicotine self-administration in the laboratory. For example, although human laboratory-based studies have shown that nicotine self-administration can be substantially reduced if the response requirement is increased sufficiently, it is not clear that such reductions would be as robust or long-lasting if this manipulation was instituted in the natural environment.

Section V: Psychobiology of Nicotine Addiction

Behavior/Cognitive Effects of Smoking

Stephen J. Heishman, Ph.D.
Intramural Research Program
National Institute on Drug Abuse

Introduction

It is well established that nicotine can function as a reinforcer to maintain self-administration behavior in humans and animals. In addition, tobacco use by humans is influenced by many factors, including the effects of smoking on performance, stress, and body weight. The relationship between these three factors and nicotine addiction will be the focus of this presentation.

Effects of Smoking on Performance

What We Know

Nicotine deprivation can impair attention and cognition and smoking or nicotine can reverse withdrawal-induced deficits. Performance impairment has been observed within 4 hours of tobacco deprivation. Many studies describing nicotine's "enhancement" of attention and cognition only demonstrated that nicotine reversed withdrawal effects.
Nicotine enhances finger tapping, attention, and under certain conditions, memory. It is well established that nicotine enhances tapping rate and motor responding in tests of focused attention. Recent evidence indicates that nicotine also enhances sustained attention and recognition memory. However, no studies have reported enhancement of sensory abilities, selective attention, learning, and other cognitive abilities.
Degraded attention and cognition following a period of nicotine deprivation can be a strong motivating factor to smoke to reverse such deficits, thus maintaining nicotine addiction. Nicotine's true enhancement of performance is of secondary importance in the maintenance of addiction because of the modest and limited effects.

What We Need To Know More About

The full range of conditions under which nicotine affects behavior must be determined. For example, attentional processes have been studied extensively, whereas few studies have examined nicotine's effect on learning. Few studies have attempted to control or manipulate environmental, psychological, and biological variables that influence nicotine's behavioral effects.
Dose-response relationships are not known for most of nicotine's performance effects. A small minority of studies have administered placebo and multiple doses of nicotine, and even fewer have reported nicotine plasma concentrations in order to understand the relationship between plasma levels and performance.
Does limited performance enhancement play a role in smoking initiation? It is unlikely that enhanced attention and cognition play a major role in adolescents' decisions to begin smoking, but no studies have been conducted.

Effects of Smoking on Stress

What We Know

Stress results in increased smoking, but there is little evidence that smoking reduces stress. If nicotine reduces stress, then smokers should be less stressed than nonsmokers, and smokers should experience increased stress when they quit. However, surveys indicate that smokers are more stressed than nonsmokers, and studies show that individuals report feeling less stress after quitting smoking. It is possible that smoking exacerbates stress via negative moods experienced during acute nicotine deprivation between cigarettes.
Nicotine deprivation increases stress and negative mood states, and smoking or nicotine can reverse these changes. Nicotine withdrawal is characterized by feelings of stress, anger, and irritability. These mood changes can develop during the 30- to 45-minute interval between cigarettes in regular smokers. Smoking can rapidly reverse such negative moods.
Nicotine addiction is maintained by reversal of deprivation-induced stress and negative mood observed between cigarettes or during more prolonged periods of abstinence. There is no clear evidence that smokers experience true stress reduction compared with nonsmokers.

What We Need To Know More About

Does smoking produce true stress reduction or simply withdrawal relief? Currently, the most compelling explanation is that smoking modulates perceived stress and negative mood states through reversal of withdrawal effects, rather than genuine reductions in stress. However, there may be conditions under which smoking enhances mood and reduces stress in the absence of nicotine deprivation.
The mechanisms by which stress functions to maintain addictive smoking behavior are not well understood. Numerous psychological and biological changes occur during stress, and some of these perturbations in normal functioning may mediate smoking behavior. For example, the biochemical changes caused by stress and nicotine may play a role in smoking initiation, cessation, or relapse.
What interventions are effective in reducing stress experienced during smoking cessation? During acute nicotine withdrawal (first week after cessation), people experience increased stress and anxiety. However, by 2 weeks, negative mood states have returned to baseline and continue to decline with time. Little research has focused on ways to reduce the increased stress during early withdrawal. Such interventions could enhance smoking cessation efforts.

Effects of Smoking on Body Weight

What We Know

There is an inverse relationship between smoking and body weight; smokers weigh on average 6 to 9 pounds less than nonsmokers. The weight gain reliably observed after smoking cessation also averages 6 to 9 pounds, and smoking relapse returns weight to levels seen before cessation. Individuals who smoke heavily gain the most weight after cessation.
Changes in eating and energy expenditure are responsible for the body weight changes seen during smoking cessation and relapse. There is evidence that eating increases during the first few weeks of cessation. Smoking causes acute increases in metabolic rate that are repeated with each cigarette; however, chronic changes in metabolic rate are not associated with increased physical activity, nor does cessation result in decreased activity.
Nicotine decreases food intake and increases energy expenditure in animals, indicating that the changes in body weight seen during smoking cessation and relapse are due to nicotine.
Concerns over weight gain, rather than weight gain itself, contribute to continued smoking and appear to deter quit attempts, especially in women. There is no direct evidence that preventing weight gain after smoking cessation will increase cessation rates.

What We Need to Know More About

What interventions are effective in dealing with concerns about weight gain to enhance smoking cessation efforts? Because no effective interventions have been developed to counter the weight gain after cessation, research should focus on the perception of weight gain and helping ex-smokers deal with the small increase in weight relative to the substantial health benefits achieved from quitting smoking.
The importance of body weight concern appears to vary across age and gender. For example, white adolescent females report smoking for weight control, whereas black adolescent females do not. It may be that younger women have greater concern about weight control than older women. These age and gender associations have obvious treatment implications.
The psychological and biological mechanisms underlying the effects of smoking on body weight are not well known. A better understanding may lead to effective weight control interventions for smoking cessation programs.

Introduction

Increased initiation, decreased cessation, and increased nicotine dependence have been associated with several behavioral traits and disorders. These associations are often strong. Although the rates of current psychiatric disorders among smokers are small, more prevalent occurrence of simple psychological distress appears to undermine cessation.

There are three possibilities for explaining this association: (1) Behavioral variables could be causing smoking changes, (2) smoking changes could be causing behavioral changes, or (3) some third variable could be associated with both the behavior and the smoking pattern.

What We Know

Causality can be estimated from epidemiological data by examining the consistency, strength, temporal precedence, dose-responsivity, and biological plausibility of any association. Using these criteria, major findings thus far are as follows:

Psychological distress (e.g., dysphoria in teenagers), psychiatric disorders (e.g., attention deficit disorder), and substance use and dependence have prospectively predicted the onset of smoking and the inability to stop smoking in at least a couple of studies. Personality effects are weak. Interestingly, whether a past history of psychiatric disorders and drug dependence predict inability to stop is unclear.
Smoking onset prospectively predicts drug use and dependence and, although not well studied given the normal ages of onset, probably prospectively predicts psychiatric disorders.
Smoking cessation prospectively predicts psychological distress and in a few cases, probably predicts relapse of psychiatric disorders. Whether it predicts relapse to drug dependence is unclear.
In terms of third variable explanations, genetic makeup has very consistently predicted both behavioral variables and smoking. Whether behavior patterns, such as poor self-esteem and subassertiveness, cause both smoking and psychiatric disorders has not been studied.
Plausible biological and behavioral mechanisms are important in assessing causality, and several have been hypothesized to account for these associations. For example, smokers have less MAO A and MAO B, which should predispose them to depression. Also, patients with schizophrenia have an inability to habituate to repeated stimuli, which appears to occur because of differences in nicotine receptors in the brain. In animals and in humans, nicotine induces cross-tolerance to alcohol, perhaps increasing alcohol intake and thus dependence among smokers.

In summary:

Smoking onset, nicotine dependence, and cessation are associated with several psychiatric and alcohol and other drug abuse diagnoses. However, its association with the more common, less severe forms of psychological distress may be more important.
There are several plausible biological and behavioral hypotheses to explain whether smoking causes psychological problems, psychological problems cause smoking, or some third variable causes both.

What We Need to Know More About

First, several associations are debatable. Since the evidence is contradictory, large, generalizable studies are needed to determine whether smokers with a past history of alcoholism and depression have a more difficult time stopping smoking and whether smoking cessation can induce relapse to alcohol or other drug abuse or psychiatric disorders.

Second, the probability that those smokers who find it easier to stop, eventually do, suggests that comorbidity may be even more prevalent among the remaining future smokers. We need survey data to determine whether comorbidity is increasing or decreasing over time.

Third, we need to test existing hypotheses to account for comorbidity via experimental designs, including testing third variables that might account for associations. Replication will be important, as many hypotheses have one or two studies to support them, but no more. Until biological and behavioral mechanisms are elucidated, designing prevention treatment interventions for comorbid smokers will be difficult. The hypotheses that have the most evidence thus far, or are the more plausible, include the following:

Some genotype predisposes to both smoking and psychiatric/drug abuse problems.
Nicotine is a potent reinforcer in children with certain behavioral deficits (e.g., difficulty concentrating), because nicotine improves this deficit.
Smoking-induced changes in MAO predispose to depression.
Smoking induces tolerance to alcohol, which decreases the aversive effects of alcohol.

Fourth, we need to know whether treatments for psychiatric comorbidity influence smoking. For example, generalizable experimental trials could replicate whether methadone increases smoking, clozapine decreases smoking, and haloperidol increases smoking.

Fifth, we need to know whether treatments for smoking influence comorbidity. For example, generalizable experimental trials may show whether cessation increases or decreases drug use or sobriety in abusers of alcohol and other drugs, whether cessation precipitates relapse to depression, and so forth.

The following questions should be answered:

Do smokers with a past history of depression and alcohol or other drug abuse have a more difficult time stopping, and can cessation of smoking cause a relapse in these disorders?
Does comorbidity increase over time?
Which of the many mechanisms hypothesized to explain comorbidity are valid; that is, can these be shown in several experiments?
Does treatment of alcohol or other drug abuse or psychiatric disorders influence smoking, and does treatment of smoking influence the outcome of alcohol or other drug abuse or psychiatric disorders?

Introduction

Understanding differences among individuals in smoking and nicotine dependence can provide clues about the dynamics of smoking behavior and may provide a basis for enhanced treatment efficacy.

Variability in Nicotine Dependence

What We Know

A large proportion of U.S. cigarette smokers are addicted to nicotine to varying degrees.
More nicotine-dependent smokers are less likely to succeed at quitting and more likely to benefit from nicotine medications.
A very small subset of long-time, very light smokers seem to escape nicotine dependence. These smokers suffer no discernible withdrawal when quitting, and their smoking varies more across situations. Patterns of such light smoking run in families, suggesting the possibility of genetic influences.

What We Need to Know More About

Why do most smokers become nicotine-dependent, while some do not? What determines resistance or vulnerability to nicotine dependence?
Is the vulnerability to dependence determined by biological or genetic differences in responses to nicotine or other dimensions?
Does the pattern of acquisition of smoking and nicotine administration determine its development into nicotine addiction?
It has been suggested that lowering the nicotine delivery of cigarettes would help reduce nicotine dependence. However, we need to know how nicotine dependence is affected by changes in smoking patterns and by the nicotine delivery of cigarettes.

Contributions of Personality to Smoking

What We Know

Smokers score higher than nonsmokers on personality factors such as neuroticism (a tendency for emotional upset and turmoil) and sensation-seeking (an interest in thrills and novelty).
However, there is no consistent evidence supporting the role of a specific "addictive personality" in smoking. Personality differences are modest and not very specific to addictions.

What We Need To Know More About

Past studies of personality are necessarily constrained by our limited conceptualizations of personality traits and our ability to measure them. Would more refined and sophisticated measures of personality lead to clearer definitions of the personality characteristics of smokers?

Gender Differences

What We Know

Smoking was historically more common among men, but men and women now have similar smoking prevalence; smoking among men has dropped, and women have caught up. This pattern is evident in several developed countries. In the developing world, sharp gender differences are still the norm.
Even though prevalence has equalized, men still smoke more heavily than women.
More than men, women report that they smoke in order to deal with stress and emotion.
Despite their lighter smoking, women appear to be less successful at quitting smoking.

What We Need to Know More About

What is the basis of gender differences in smoking and quitting?

Are they related to differences between men and women in biologically mediated sensitivity to nicotine reinforcement or to differences in gender roles, which affect how men and women deal with emotions?
Can we use what we know about gender differences in smoking to tailor smoking cessation programs for men and women?

Section VI: Treatment of Nicotine Dependence

Psychological Interventions

Sharon M. Hall, Ph.D.
Department of Psychiatry
University of California at San Francisco

Introduction

For years, it has been agreed that psychological interventions that include the monitoring of smoking behavior within a structured program, as well as an emphasis on motivation, improve abstinence rates. Current questions address more complex issues. Among the most salient of these questions are the following: (1) Are specific interventions developed for defined diagnostic groups more effective with those groups than with those developed for the general population? (2) Are there methods of partitioning smokers, other than diagnostic groups, that provide a useful basis for developing targeted psychological interventions? (3) Do psychological interventions increase abstinence rates when added to pharmacological therapies? (4) What new therapies should be developed?

What We Know

Three kinds of psychological intervention are used in smoking cessation treatment: psychoeducational interventions, behavioral skill training, and cognitive-behavioral interventions. Psychoeducational approaches include information about smoking and health, information about strategies for quitting and maintaining abstinence, and group discussion to further understand and implement these changes. Behavioral skill training includes behavioral prescriptions, such as monitoring smoking situations, and practicing skills in the treatment setting and in the natural environment. Examples are rehearsal of cigarette refusal skills and relaxation practice. Cognitive-behavioral interventions include changing thoughts about smoking and quitting smoking and related situations and emotions. Treatment programs often include a combination of these three intervention types.

Matching Treatments to Diagnostic Groupings. There has been progress in matching patients to treatments. Specific populations with high smoking rates have been identified, including psychiatric patients, especially those with depressive disorders or psychosis, and patients with alcohol and other drug disorders. Smokers with major depressive disorder (MDD) have been the most extensively studied. For example, data indicate that smokers with a history of MDD were more likely to quit smoking in a cognitive-behavioral intervention than in a control psychoeducational intervention, but only when the psychoeducational intervention provided fewer contact hours than the cognitive-behavioral intervention.
These data suggest that increased therapeutic contact is helpful for smokers with a depression history. More than one therapeutic approach may be useful, and the best therapeutic content needs to be determined. Mechanisms of action underlying the increased effectiveness of more intensive, supportive treatments with depressed smokers have been suggested. Possibilities include increased or better sustained motivation or less increase in the poor mood that frequently accompanies quitting smoking.
Matching Interventions to Special Subgroups of Smokers. Some data suggest that smokers differ widely in readiness to quit. These data are especially relevant to smokers diagnosed with substance abuse or psychiatric problems, since such samples probably contain a relatively high proportion of smokers who are not ready to enter a traditional treatment program for smoking cessation. Such programs usually require a high and sustained degree of motivation to quit.
Other data show that psychological interventions can be successfully tailored to the individual smoker's readiness to quit. Computerized expert system interventions have been developed that are targeted at a smoker's self-professed level of interest in quitting, which may range from precontemplation, a stage at which the smoker has no interest in quitting, to contemplation, to preparation for action, to action itself. In at least one study, expert systems developed by this group have shown efficacy in increasing readiness to quit and improving abstinence rates.
Psychological Interventions and Pharmacotherapies. There is considerable evidence that combining psychoeducational or behavioral skill training interventions with nicotine replacement increases the abstinence rates found when smokers quit using nicotine replacement therapy alone. Several mechanisms have been suggested to explain this effect.

In summary, the following facts are known:

In treatment-seeking smokers, psychological interventions for smoking cessation are more effective than no treatment.
For at least one category of comorbid smokers, those with depressive disorder, psychological interventions increase abstinence rates.
Psychological interventions targeted to smokers who express a readiness to quit increase abstinence rates in samples of smokers who have not yet made a commitment to abstinence.
Psychological interventions increase abstinence rates when combined with nicotine replacement therapies.

What We Need to Know More About

Matching Treatments to Diagnostic Groupings. Data are lacking on psychological interventions with schizophrenic or psychotic patients. There are also few data on the usefulness of psychological treatments in alcohol- or other drug-abusing patients who smoke. Treating smokers who are already in recovery programs for nonnicotinic drugs may require less psychological intervention than is required for smokers who are not in recovery treatment. Much of the content of the treatment interventions offered for other drugs of abuse may easily generalize to cigarette smoking. This is speculative, and data are needed.

Matching Interventions to Special Subgroups of Smokers. More work is needed to develop successful interventions for smokers who have not yet made a clear commitment to quit. Current work is promising, but unique interventions designed to overcome the special barriers to quitting that plague special populations are needed and should be tested in rigorous, controlled trials by a variety of research groups. Because smokers not ready to quit may resist face-to-face interventions, development of other treatment modalities, for example, computerized interventions, is needed.

Psychological Interventions and Pharmacotherapies. We do not know whether psychological therapies increase the efficacy of antidepressant therapy for nicotine dependence. There are two large studies of successful antidepressant therapy of cigarette smoking. One used extensive psychological interventions; the other did not. Outcomes of the two studies were similar, although it is not possible to compare the studies. There are many crucial differences between them other than the provision of psychological intervention, including differences in the antidepressant drug used and in sample characteristics. Additional research is needed to determine whether the combination of psychological interventions with antidepressants increases abstinence rates, and if so, by what mechanism.

New Therapies. The field of late has been slow to develop new interventions based on psychological principles, instead turning its attention to issues of cost and cost-effectiveness and degree of generalizability. Nevertheless, at least one promising new therapy - scheduled reduction - has been assessed and its effects replicated. On the other hand, given the diagnostic, cultural, and motivational heterogeneity of smokers today, it is likely that many forthcoming innovations will be targeted to specific subgroups of smokers.

The following questions represent areas of research required to more fully elucidate the relationship between smoking cessation and psychological interventions:

Given that psychological interventions increase abstinence rates in smokers with depressive disorders, which interventions are the most efficacious?
By what mechanism do psychological interventions increase abstinence rates in smokers with depressive disorders?
Which psychological interventions, if any, are useful for smokers with other psychiatric and substance abuse disorders?
Can interventions for smokers who are not yet ready to quit be developed that are widely applied and useful with special populations and subgroups?
Do psychological interventions increase abstinence rates obtained with antidepressant drugs, and if so, is there an optimal intervention?
Should efforts to develop new psychological interventions be targeted to smokers in general or to specific subgroups?

Introduction

Approved nicotine replacement therapy (NRT) products that have shown a doubling of the stop rates in randomized control trials are nicotine gum, nicotine patch, and nicotine nasal spray. The former two are now available over the counter and the latter by prescription. Newer treatments recently approved for marketing in the United States include bupropion and the nicotine inhaler.

What We Know

Newer Approved Medications. Bupropion is the first nonnicotine pharmacologic treatment approved for smoking cessation. It is a monocyclic antidepressant that has both noradrenergic and dopaminergic activity. It is hypothesized that bupropion is effective for smoking cessation because of its dopaminergic activity on the pleasure and reward pathways in the mesolimbic system and nucleus accumbens. In a multicenter dose response study, smokers received either placebo or bupropion at 100 mg/day, 150 mg/day, or 300 mg/day for a 7-week treatment trial. At the end of treatment and at 1 year, the point prevalence abstinence rates were significantly higher in those assigned to the 150 mg and 300 mg groups compared with placebo. Furthermore, a significant dose effect was detected at all timepoints. In addition, there was an attenuation of weight gain during the treatment period for those who were continuously abstinent on the 300 mg/day dose. However, the attenuation of weight gain did not persist at 1-year followup. Side effects to bupropion greater than placebo were insomnia and dry mouth. The approval of bupropion is a great addition to the treatment alternatives, but more importantly, it has spurred the investigation of other drugs with a similar pharmacology.
The nicotine inhaler has also been shown to be effective in placebo-controlled trials. This device delivers a vaporized form of nicotine to the oral mucosa that does not reach the pulmonary alveoli. As with other NRT products, clinical trials have shown a doubling of the stop rate in those assigned to the active inhaler compared with placebo. The use of about six inhalers per day produces cotinine levels that are about 60 percent of the levels while smoking. Common side effects included throat and mouth irritation and coughing. One of the major benefits of the nicotine inhaler is that it mimics the behavior of smoking. It also lends itself to use with other NRT products or bupropion.
Combination Treatments. Though few studies have been reported, there is excellent rationale to use combined therapies for nicotine dependence. This is especially true when a slow-delivery form of NRT (patch) or other pharmacologic therapy is combined with a more rapid delivery system (nicotine gum or nicotine nasal spray). Nicotine gum, in combination with nicotine patch therapy, has been shown to reduce withdrawal symptoms better than either medication alone. Furthermore, when used in combination, the nicotine patch and nicotine gum produce significantly higher abstinence rates compared with nicotine gum alone. In addition, a single 1 mg dose of nicotine nasal spray was shown to provide more immediate relief for craving for a cigarette compared with a single 4 mg dose of nicotine gum. These findings provide a rationale for the "as-needed" use of nicotine nasal spray to control withdrawal symptoms, in combination with other medications with longer acting effects.
In an as yet unreported patch-bupropion trial, bupropion SR 300 mg/day was used in combination with a 21 mg nicotine patch. All three active treatment groups were more effective than placebo, and bupropion SR showed significantly higher stop rates compared with the nicotine patch. Though the combination of bupropion SR and the nicotine patch produced the highest smoking cessation rates, this was not significantly different than bupropion SR alone (p = 0.06). Nonetheless, because NRT and bupropion act on different parts of the neuron, the combination of the two makes pharmacologic sense.

Furthermore, use of higher doses of nicotine patch therapy (i.e., more than one patch at a time) may be appropriate for some more addicted smokers. This is especially important for heavy (2 packs/day) smokers, since they will be significantly underdosed using single-dose patch therapy. High dose therapy can also be used in smokers who previously failed single-dose therapy because their nicotine withdrawal symptoms were not adequately relieved. High-dose therapy has been shown to be safe and tolerable in smokers smoking 20 or more cigarettes per day. No trials to date have reported using more than two pharmacologic agents at a single time. However, in clinical practice, as many as four pharmacotherapies (three NRTs + bupropion) have been used simultaneously in patients with severe nicotine dependence in an inpatient treatment program.
Newer Treatments Undergoing Testing. A new NRT product, a sublingual tablet (which delivers 2 mg of nicotine), has been tested in a double-blind placebo control trial. There was a doubling of the stop rate and excellent relief of withdrawal symptoms and craving. The nicotine sublingual tablet was well accepted by the smokers. Though the method of delivery (transbuccal) is similar to nicotine gum, the sublingual tablet avoids the problem of proper use associated with the gum.
The antihypertensive mecamylamine has been found to have efficacy in smoking cessation in a small trial of smokers that concomitantly received a 21 mg nicotine patch. At the dose of 5 to 10 mg/day, side effects were minimal, the most frequent being mild constipation. This study was restricted to smokers ages 20 to 40; thus, it is unclear whether the side effect profile will be as acceptable in older smokers where the side effect of constipation could be a problem.
Promising Medications. Because of the known relationship between smoking and depression, other antidepressant drugs have been tested. The tricyclic antidepressant nortriptyline appears to have promise for smoking cessation. When used in combination with cognitive behavioral psychological counseling, 10 mg/day of nortriptyline was found to be effective for smoking cessation. The only other antidepressant that has been shown to have some promise is doxepin, but this study was limited by its small sample size.
Harm Reduction. Long-term nicotine replacement therapy appears to be safe and less harmful than continued smoking. However, there is no evidence that, when an adult reduces smoking, the harm is actually reduced, nor is there evidence that adults can sustain smoking reduction indefinitely, even with concomitant use of NRT. Furthermore, there is concern that harm reduction strategies may decrease the number of smokers who try to stop smoking.

What We Need To Know More About

What is the optimal dose and duration of treatment for NRT?
What is the optimal duration of treatment using bupropion?
What are the best combination treatments, and which smokers are best suited for combination treatment?
Assuming bupropion works through its dopaminergic/noradrenergic properties, what other drugs with a similar pharmacology should be tested for nicotine dependence treatment?

Introduction

At present, the best methods for treating tobacco dependence involve combined use of behavioral and pharmacologic therapies. Because they operate by different mechanisms, complimentary and potentially additive effects may be expected when behavioral and pharmacologic treatments are used in combination. This presentation will focus on nicotine replacement therapy (NRT) combined with counseling that includes support and relapse prevention problem solving, since these have been the most widely researched treatment methods.

What We Know

Absolute rates of successful quitting are enhanced by combined therapy compared with single therapies, with effects being additive or less than additive. There is evidence both that behavior therapy enhances the efficacy of NRT and that NRT enhances the efficacy of behavior therapy. Typical long-term (6 to 12 months) abstinence rates for single therapies are on the order of 20 to 25 percent, while combined therapies can produce long-term abstinence rates as high as 35 to 40 percent. Thus, combined therapies produce quit rates greater than those generally produced by either treatment intervention alone and substantially better than general population quit rates of 5 percent or less.

Three mechanisms have been suggested to account for improved efficacy with combined therapies: (1) enhanced compliance with treatment interventions, (2) independent effects on different outcome targets (withdrawal relief producing better initial abstinence versus new coping skills producing better long-term outcomes), and (3) independent effects on different populations such that some people benefit from pharmacotherapy and others from behavior therapy. Data are available only for the second mechanism listed.

Combined therapies appear to raise the absolute percentage of smokers who remain abstinent; this effect is apparent from the earliest postquit measurement timepoint. This is an important observation, as early smoking behavior is a very powerful predictor of subsequent success versus failure. Approximately 90 percent of smokers who have lapses during the first 2 postquit weeks of combined therapy go on to fail in that quit attempt, while only 50 percent of early abstainers ultimately return to smoking. The role of withdrawal suppression here is controversial. With the exception of craving, symptom suppression has not been reliably related to abstinence success.

Evidence for relapse prevention effects of therapies that extend beyond the initial few postquit weeks is sparse. In order to examine these relapse prevention effects, it is useful to start with a group of uniformly abstinent subjects who are then randomly assigned to experimental and control therapies. One such study showed that smokers who received behavior therapy had slower rates of relapse compared with those who received no treatment. The specific role of relapse prevention skills training in slowing relapse is unclear.

The following facts hold true for combined treatment for tobacco dependence:

Combined treatments produce additive effects on abstinence rates compared with single treatments.
Combined treatments can produce long-term (6 to 12 months) abstinence rates as high as 35 to 40 percent.
People who can go without smoking in postquit weeks 1 to 2 are more likely to succeed; combined treatments increase the number of early postquit abstainers.

What We Need to Know More About

Four issues stand out as important for future research and development:

Compliance. Compliance is important to ensure exposure to adequate amounts and durations of therapy components. We need to know whether behavior therapy enhances compliance with medications use (e.g., through instruction, monitoring, and support) and whether pharmacologic therapy enhances compliance with behavior therapy (e.g., by allowing the person to focus on behavior change rather than the discomfort of withdrawal). Including compliance measures in treatment outcome research would help to address this issue.
Early Abstinence. If combined therapies work by increasing initial abstinence success, how do they produce this effect? For example, is there an interaction between withdrawal suppression and social support provided by counseling that enhances abstinence rates? What is the role of relapse prevention coping skills, if any (e.g., does therapy prompt and support performance of existing skills versus teaching new skills)? Does either therapy act to attenuate the effects of early reexposure to smoking (slips and lapses)? For example, pharmacotherapy could attenuate priming effects of nicotine exposure while behavior therapy counteracted the abstinence violation effect. An increased focus on dynamics of early postquit weeks would be useful.
Relapse Prevention. We need to know whether any existing therapies can slow relapse, particularly after therapy ends; if so, how this is accomplished? For example, do people actually learn new skills or alter their behavior as a result of receiving behavior therapy, and does this prevent relapse? Would longer durations of medication or behavior therapy be helpful to slow relapse rates? Is there a safe time after which relapse is no longer likely? Increased focus on relapse prevention is important for improving the long-term success of combined therapies.
Treatment Delivery . Efficacious treatments are currently available, but these cannot have an impact unless they are used. We need to know how to improve access, affordability, and acceptability of both pharmacologic and behavioral therapies in order to take advantage of existing treatments (over-the-counter nicotine replacement is a good start) and how to strengthen the linkage between the two therapy types. This is a challenge, given that the majority of smokers prefer to quit on their own without seeking help.

The following represent areas that require additional research:

More about compliance interactions. Does either type of therapy enhance compliance with the other?
More about early abstinence. How do pharmacologic and behavioral treatments interact to increase early abstinence rates?
Can anything be done to counteract effects of slips and lapses?
More about relapse prevention. Do any existing treatments slow relapse? Can relapse be slowed by intensifying or prolonging existing treatments?
More about treatment utilization. How can access, affordability, and acceptability be improved for existing efficacious treatments?

Introduction

The primary care setting is an important place for promoting smoking cessation because a high percentage of people who smoke visit each year. In 1993, 80 percent of smokers had at least one contact with a primary care physician, with the number of average yearly contacts about six per adult. Physicians are creditable and respected, and patients are aware of their health at the time of the visit.

What We Know

Randomized clinical trials (RCTs) present excellent evidence that a brief physician-delivered intervention for smoking cessation, in a primary care setting, significantly increases patients' smoking cessation rates. As the portion of the physician-delivered intervention increases (ranging from 50 seconds to 15 minutes), so does the effect. RCTs have also demonstrated that the addition of pharmacotherapy and interventions by other providers and other modalities significantly enhances the effect of physician-delivered smoking intervention. In addition, RCTs conducted with targeted populations such as pregnant women and disease-specific populations have demonstrated greater efficacy of physician-delivered interventions with these populations compared with a general population of primary care patients. The physician as educator, facilitator, or counselor can be a powerful agent for smoking cessation in the primary care setting.

Unfortunately, despite widespread dissemination of preventive services guidelines and positive physician attitudes toward such services, the current level of smoking cessation intervention by physicians is not high. It is therefore a major research and public health concern. Reports indicate that fewer than 50 percent of smokers are counseled for cessation during office visits. Data also indicate that the likelihood of having been counseled to quit smoking is directly related to the number of health care visits.

Given that physician-delivered interventions have a positive effect on smoking cessation rates, it is important to consider interventions that increase the rate of implementation. Interventions to change provider behavior can be grouped broadly into three types: (1) provider education, (2) clinical systems and procedures, and (3) organizational policy. Education and training have been the primary methods used to alter provider care, the clinical system has made systematic use of medical record and computer reminders, and organizations have relied on performance measures and covered benefits. From an educational perspective, the dissemination of practice guidelines alone does not produce improvement nor do traditional Continuing Medical Education activities. When reminders are used alone, there are conflicting reports regarding their effect on physicians' implementation of smoking cessation intervention. There is a greater degree of implementation of intervention and of subsequent smoking cessation when education and reminders are used together.

What We Need to Know More About

There has been an evolving awareness that a policy intervention component is needed that includes the use of covered prevention benefits, incentives, feedback, and other reinforcements if providers are to be motivated to intervene in real-world settings. However, the elimination of financial barriers has not always seemed adequate. The role of public and organizational policy alternatives for increasing physician-delivered interventions needs testing.

Given the positive effect that physician-delivered and primary care-based interventions can have on smoking cessation, it is important to investigate a variety of methods to increase their rate of delivery and effectiveness. Examples of questions regarding systems interventions and policy interventions include the following: What are the best incentives or combination of incentives for physicians and patients? What are the most effective strategies that can be used to remind providers to intervene? How can each of these strategies best be implemented in different types of settings and systems?

Other research questions should address a stepped-care and patient-treatment matching model such as the one proposed by Abrams and colleagues for delivery of smoking cessation treatment into mainstream health care in order to be able to treat the general population of smokers at reasonable cost. The model includes brief counseling by physicians for the easier smokers and moves to more extensive interventions for the more difficult-to-treat smokers. The proposed model has not been tested and lends itself to the refinement of hypotheses and development of assessment and intervention methods to eventually be able to determine the efficacy and effectiveness of such a model and its application in real-world settings. Some sample questions are as follows: What is the most effective combination of physician and other provider interventions? What are the most essential elements of physician intervention? What is the best way to include pharmacotherapy? In addition, what interventions are effective for smokers with multiple risk behaviors?

Solberg and colleagues raised an important research question: How do we implement guidelines? They noted there is little evidence anyone has learned how to do this well. Studies conducted under well-controlled experimental conditions, as well as demonstration projects conducted under less well-controlled conditions in the clinical setting, provide the foundation for the next generation of effectiveness studies that address the role of various factors in the health care environment in the delivery of services. However, such factors (e.g., reimbursement policies, covered benefits) do not lend themselves well to tightly controlled randomized trials. Use of quasi-experimental designs and application of qualitative strategies are needed.

Introduction

The treatment needs of tobacco users may vary according to gender, age, and route of nicotine administration. Research is beginning to show that gender differences may exist in response to nicotine and tobacco use and that differences exist in the issues that surface when treating adolescents or elderly persons. Research also shows that treatments that are effective for one route of tobacco administration do not generalize to others. It is important to learn more about the specific needs of these different populations of tobacco users in order to develop effective treatments.

What We Know

Gender. Men are more likely to quit tobacco use than women, and they experience greater confidence in their ability to quit. Women may also have a higher relapse rate than men. The reasons for these differences are not entirely clear. However, some evidence shows that women respond differently to the effects of nicotine and nicotine abstinence compared with men, and therefore, their treatment needs may differ. For example, studies show that women are less sensitive to nicotine and therefore may experience fewer beneficial effects from nicotine replacement therapy (NRT). Some evidence suggests that the sensory aspects of smoking may be more important to women. Women are also more likely than men to smoke to reduce stress, and women experience greater weight concerns, and weight gain, after cessation. Furthermore, the menstrual cycle phase may contribute to differences in the experience of craving for cigarettes.
Age. The rate of smoking at both ends of the age spectrum tends to be lower than the middle part of the age spectrum. However, treatment of individuals at these ends cannot be neglected. The rate of smoking among adolescents is increasing, and smoking that begins in adolescence is likely to continue into adulthood. Also, negative physical consequences from smoking are experienced even among the young. For elderly persons, quitting is important because the beneficial effects from smoking cessation can still be experienced in spite of many years of smoking. Unfortunately, research in these areas is lacking.
Research on adolescent smoking cessation is limited, and treatment success rates tend to be low. Treatment issues that need to be addressed with adolescent smokers include physical dependence on tobacco products. The type of withdrawal symptoms experienced by adolescents are reported to be similar to those observed among adults; a substantial percent of adolescents who are daily smokers report experiencing these symptoms. Other issues involve the high occurrence of comorbid disorders, including alcohol and other drug use among adolescents. Many adolescents have concerns regarding peer acceptance, must deal with the role of cigarette smoking as part of their self-image, and experience difficulties in coping with the stresses in their lives. In addition, sustaining the motivation to remain abstinent after quitting is another prominent issue among this population. These findings indicate that adolescents may require medications to treat the physical dependence on nicotine, but more importantly, cessation treatment must have strong motivational and behavioral components.

Elderly individuals may also require tailored treatments. Many elderly people have smoked for a long time, tend to be highly addicted, and have tried quitting but have been unsuccessful. Few clinical trials have been conducted with this population. Assessment of the nicotine patch use has shown that few experienced side effects, success rates were comparable to those found in younger adult populations, and more advice led to better treatment rates.
Route of Administration. Much of the treatment focus has been on cigarette smoking. The development of treatment methods is crucial for individuals who self-administer tobacco by methods other than inhalation. There are several reasons why this area needs attention. First, individuals who use tobacco through other routes, such as oral spit tobacco, constitute a significant number of individuals. Second, these individuals experience negative health consequences, including an addiction to nicotine. Third, effective methods observed for cigarette smokers may not generalize to other populations of tobacco users. For example, with spit tobacco users, nicotine replacements have been observed to reduce withdrawal signs and symptoms, but not to enhance tobacco abstinence rates, as observed with cigarette smokers. The interaction between intensity of treatment and the use of NRT may differ among spit tobacco users compared with cigarette smokers. For example, nicotine gum in conjunction with minimal treatment results in poorer treatment outcome compared with placebo gum with minimal treatment. Replacement of sensory aspects of tobacco use may not be as important with smokeless tobacco users as with cigarette smokers.
In summary, differences observed across gender, age and route of administration indicate that distinct areas need to be emphasized and addressed in treatment, with particular attention paid to differences in response to medications.

What We Need to Know More About

General Issues

How do gender, age, and different routes of tobacco administration affect the pharmacologic, physical, and psychological response to nicotine? What are the implications of these potential differences with regard to treatment, including the use of nicotine replacement or other medications?
What are good assessment tools for these different special populations?
What are the primary and population-specific issues that need to be addressed in treating these special populations, and how can we address them?
Does the importance of sensory aspects of tobacco use differ across genders, age groups, and routes of tobacco administration?
Does the interaction of pharmacologic and behavioral treatments differ across genders, age groups, and routes of tobacco use? Do certain populations require different emphasis on these types of treatments?
Do differences exist in the obstacles toward success, relapse patterns, and relapse situations and factors that facilitate abstinence across genders, age groups, and routes of tobacco use? Are there differences in the recovery process?

Age

How can we motivate adolescents and elderly individuals to quit or seek treatment, and how can we sustain this motivation? What are the various avenues for intervention?
What are other important strategies to have in place that incorporate the developmental issues experienced by adolescents to enhance treatment success among them?
Can we intervene with adolescents at an earlier stage in the progression to nicotine dependence? Would reduction in exposure to nicotine be considered a feasible outcome variable, especially since many adolescents fail at quitting?

Gender

What are the hormonal effects on nicotine sensitivity? Do hormones affect reactions to stress? Are some phases of the menstrual cycle more likely to lead to relapse compared with others? What is the effect of nicotine among postmenopausal women? What is the impact of pregnancy, as a result of the hormonal changes, on the pharmacology of the drug?

Routes of Administration

What is the interplay among cigarette, cigar, and oral tobacco use during attempts at abstinence?
Are there effective methods to reduce tobacco use and toxic exposure to tobacco products that may facilitate abstinence among users who do not want to quit?

Introduction

One way the term "treatment resistance" can be meaningfully applied to tobacco use is when the individual is not aware of the health effects of smoking as a problem. In this scenario, there is little likelihood that any actions will be taken, particularly when the problematic behavior is reinforced by a psychoactive drug. Fifty years ago this type of treatment resistance was probably stronger than today. It therefore seems that information about the negative effects of smoking is needed, first and foremost, as a prerequisite for further actions to be effective.

Tobacco smoking contributes to morbidity and mortality; it is also a dependence disorder by itself, and there can be resistance to giving up a dependence. Resistance can differ in these two different states (e.g., a smoker might want to reduce the risk of mortality but be reluctant to give up nicotine's effects). Such a smoker might want to change to safer tobacco products or to pure nicotine products if the correct information about these alternatives were available.

Many smokers are resistant to treatment even though they are very well informed. Some smokers have tried to give up several times but failed because the abstinence symptoms were too strong. For such smokers, new alternatives to abrupt quitting are very much needed. It may be that after some time they stop listening to quitting advice because of the discomfort quitting can cause. If they believe quitting is not possible, they also may not seek help. One option is for a more intensive quitting treatment. Another option may be a reduction in smoking. The latter will be the focus of this presentation.

What We Know

Nicotine has traditionally been seen as harmful and addictive. It is absolutely clear that nicotine, delivered by cigarettes, can cause dependence. However, nicotine from cigarettes does not contribute much to the total mortality and morbidity of smoking. With pure nicotine products (e.g., gum, patch, etc.), it seems that the harm in terms of physical disease is very minimal, with the possible exception of pregnancy (nicotine can have harmful effects on the fetus).

Yet ironically, nicotine presents an opportunity in combating smoking-related morbidity and mortality. There is a dose-response relationship in most smoking-related illnesses (i.e., the more smoking, the bigger the harm). Therefore, less smoking would result in less harm. Evidence is growing that shows many smokers who find it difficult to give up smoking nevertheless would like to reduce the harm associated with smoking. It is in such situations that nicotine from alternative sources could (a) interest the resistant smoker to take some action and (b) reduce the risk of smoking.

Initial research has provided some encouraging results when quitting-resistant smokers are given an opportunity to reduce cigarette smoking. Not only does the toxic intake from smoking decrease, but also a more favorable risk factor profile for the airways and the cardiovascular system occurs. A reduction in smoking has generally not worked well toward abstinence, and concerns have been raised that reduction undermines a smoker's motivation to give up entirely. That worry has not come true in the initial research. On the contrary, having more control over smoking may increase a smoker's motivation to quit, even among those with little or no interest in doing so.

In summary, the following facts are known:

Most (though not all) smokers are aware of the medical risks and addiction involved in smoking, yet most have not quit.
The harm from smoking is related to exposure.
Although the public believes nicotine to be among the most dangerous of tobacco toxins, in reality, the toxic harm associated with nicotine itself is relatively minimal.

What We Need to Know More About

An important topic to learn more about, in well-controlled trials, is whether a reduction in smoking increases or decreases the number of quit attempts or successful quitting. Even if a smoker's motivation to quit or actual quitting does not change, reduced smoking might still be preferable. For while reduction in smoking does not reduce dependence, it would reduce harm.

Evidence so far suggests that nicotine replacement therapy could be used as an aid in smoking reduction. However, placebo-controlled trials are needed to support this hypothesis.

The best candidates for a reduced-smoking message must also to be discussed (e.g., those who are motivated to quit, or intend to give up soon, probably should not be targeted). It may be safer to address this nonimmediate cessation message to smokers who do not have a current motivation to give up or have been discouraged to give up because of difficulties encountered. We need to find out which category of smokers is interested in reducing smoking. Is it those who smoke little and have a low dependence? Or is it the heavily dependent smokers who are at high risk for diseases? And what sort of comparative risks do each of these face?

Two final questions remain: Does a 50-percent reduction in exposure to tobacco toxins reduce risk by 50 percent? And, is a 50-percent decrease in exposure equally important regardless of baseline smoking (e.g., 40 to 20 versus 10 to 5 cigarettes per day)?

In conclusion, we need to know more about:

Whether reduced smoking affects the resistance and motivation to give up.
Whether nicotine replacement is effective in aiding reduced smoking.
Who are the best candidates for a reduced-smoking approach (e.g., Is reduced smoking more beneficial for heavy smokers?).

Addicted to Nicotine: A National Research Forum

Details

Contact

Meeting Summary

Description

Objectives

Introductions

Section 1 - History and Pharmacology

Introduction

What We Know

What We Need To Know More About

Recommended Reading

Introduction

What We Know

What We Need To Know

Recommended Reading

Section II: Nicotine-Individual Risk Factors for Initiation

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need To Know More About

Recommended Reading

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Section III: Nicotine-Environmental Risk Factors for Initiation

Introduction

What We Know

What We Need to Know More About

Recommended Reading

What We Know

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need To Know More About

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Section IV: Biology of Nicotine Addiction

What We Know

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Introduction

What We Know

What We Need to Know More About

Recommended Reading

Section V: Psychobiology of Nicotine Addiction

Introduction

Effects of Smoking on Performance

What We Know

What We Need To Know More About

Effects of Smoking on Stress

What We Know

What We Need To Know More About

Effects of Smoking on Body Weight

What We Know