Addicted to Nicotine
A National Research Forum

Section I: History and Pharmacology
Jack E. Henningfield, Ph.D., Chair

PHARMACOLOGY OF NICOTINE

Jack E. Henningfield, Ph.D.
The Johns Hopkins University School of Medicine; and
Pinney Associates

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.

Recommended Reading

Heishman, S.J.; Kozlowski, L.T.; and Henningfield, J.E. Nicotine Addiction: Implications for public health policy. J Soc Issues 53(1):13-33,1997.

Henningfield, J.E. Nicotine medications for smoking cessation. N. Eng J Med 333:1196-1203,1995.

Henningfield, J.E.; Schuh, L.M.; and Jarvik, M.E. Pathophysiology of tobacco dependence. In: Bloom, F.E., and Kupfer, D.J. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press,Ltd., 1995.

Henningfield, J.E., and Slade, J. Tobacco-dependence medications: Public health and regulatory issues. Food Drug Law J 53(Suppl):July/August 1998, in press.

Slade, J., and Henningfield, J.E. Tobacco product regulation: Context and issues. Food Drug Law J 53(Suppl):July/August 1998, in press.