The Health Cdnsequences Of Smoking NICOTINE ADDICTION a report of the Surgeon General 1988 US. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health &vke Cmlen for Disease Control Cenlw for Healfh Plomofkn and Educatkn Offke on Smoldng and Health Rockvllk, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washingtoa, D.C. 20402 The Honorable James Wright Speaker of the House of Representatives Washington, D.C. 20515 Dear Hf. Speaker: I am pleased to transmit to the Congress the 1987 Surgeon General's Report on the health consequences of smoking, as mandated by Section B(a) of the Public Health Cigarette Smoking Act of 1969. The Act requires the Secretary of Health and Human Services to transmit a" annual report to Congress on the health consequences of smoking and such recommendations for legislation as the Secretary may deem appropriate. This report, entitled The Health Consequences of Smoking: Nicotine Addiction, examines the scientific evidence that cigarettes and other forms of tobacco are addicting. The issue of tobacco addiction has been addressed in previous Surgeon General's Reports and in the medical literature beginning in the early 1900s. Because of the recent expansion of research in this area, a thorough review of this topic is warranted. Despite the significant health risks of tobacco use outlined in previous reports, many smokers have great difficulty in quitting. This report concludes that such difficulty is in large part due to the addicting properties of nicotine, which is present in all forms of tobacco. The report further concludes that the processes that determine tobacco addiction are similar to those that determine addiction to other drugs such as heroin and cocaine. Through such understanding, health-care providers may be better able to assist tobacco users in quitting. Private health organizations, health-care providers, community groups. and government agencies should initiate or strengthen programs to inform the public of the addicting nature of tobacco use. A warning label on the addicting nature of tobacco use should be rotated with other health warnings now required on cigarette and smokeless tobacco packages and advertisements. Preventing the initiation of tobacco use must be a priority because of the difficulty in overcoming "icocine addiction once it is firmly established. Because most cases of nicotine addiction begin during childhood and adolescence, school curricula on the prevention of drug use should also include tobacco. Cigarette smoking, the chief avoidable cause of premature death in this country, is responsible for mare than 300,000 premature deaths each year. The disease impact of smoking justifies placing the problem of tobacco use at the top of the public health agenda. The conclusions of this report provide another compelling reason for strengthening our efforts to reduce tobacco use in our society. Sincerely, f$&--- `4.y Otis R. Bane", Y.D. %YPZt*ry Enclosure The Honorable George Bush President of the Senate Washington, D.C. 20515 Deer Hr. Presfdent: I am pleased to transmit t" the Congress the 1987 Surgeon General's Report an the health consequences of smoking, as mandated by Section g(a) of. the Public Health Cigarette Smoking Act of 1969. The Act requires the Secretary of Health and Human Services to transmit an annual report t" Congress on the health consequences of smoking end such recommendations for legislation as the Secretary may deem appropriate. This report, entitled The Health Consequences of Smoking: Nicotine Addiction, examines the scientific evidence that cirarettes and other forma of tobacco are addicting. The issue of tobacco addrction has been addressed in previous Surgeon General's Reports end in the medical literature beginning in the early 1900s. Because of the recent expansion of research in this area, a thorough revi.& of this topic is warranted. Despite the significant health risks of tobacco "se outlined in previous reports, many smokers have great difficulty in quitting. This report concludes that such difficulty is in large part due t" the addicting properties of nicotine, which is present i" all forms of tobacco. The report further concludes that the processes that determine tobacco addiction are similar to those that determine addiction to other drugs such as heroin and cocaine. Through such understanding, health-care providers may be better able to assist tobacco users in quitting, Private health organizations, health-care providers, community groups. and government agencies should initiate or strengthen programs to inform the public of the addicting nature of tobacco use. A vaming label on the addicting "ature of tobacco use should be rotated vith other health warnings now required on cigarette and swkelesa tobacco packages and advertisements. Preventing the initiation of tobacco use must be a priority because of the difficulty in overcoming "icotfne addiction once it is firmly established. Because m"st cases of nicotine addiction begin during childhood and adolescence, school curricula on the prevention of drug use should also include tobacco. Cigarette smoking, the chief avoidable cause of premature death in this country, is responsible for more than 300,000 premature deaths each year. The disease impact of smoking justifies placing the problem of tobacco use at the top of the public health agenda. The conclusions of this report provide another compelling Peas"" for strengthening "UT efforts to reduce tobacco use in our society. Sincerely, C&=5---& Otis R. Boven, H.D. Secretary FOREWORD This 20th Report of the Surgeon General on the health conse- quences of tobacco use provides an additional important piece of evidence concerning the serious health risks associated with using tobacco. The subject of this Report, nicotine addiction, was first mentioned in the 1964 Report of the Advisory Committee to the Surgeon General, which referred to tobacco use as "habituating." In the landmark 1979 Report of the Surgeon General, by which time considerably more research had been conducted, smoking was called "the prototypical substance-abuse dependency." Scientists in the field of drug addiction now agree that nicotine, the principal pharmacologic agent that is common to all forms of t.obacco, is a powerfully addicting drug. Recognizing tobacco use as an addiction is critical both for treating the tobacco user and for understanding why people continue to use tobacco despite the known health risks. Nicotine is a psychoactive drug with actions that reinforce the use of tobacco. Effort,s to reduce tobacco use in our society must address all the major influences that encourage continued use, including social, psychological, and phar- macologic factors. After carefully examining the available evidence, this Report concludes that: o Cigarettes and other forms of t,obacco are addicting. o Nicotine is the drug in tobacco that causes addiction. o The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. We must recognize both the potential for behavioral and pharma- cologic treatment of the addicted tobacco user and the problems of withdrawal. Tobacco use is a disorder which can be remedied through medical attention; therefore, it should be approached by health care providers just as other substance-use disorders are approached: with knowledge, understanding, and persistence. Each health care provider should use every available c!inical opportunity to encourage or assist smokers to quit and to help former smokers to maintain abstinence. To maintain momentum toward a smoke-free society, we also must take steps to prevent young people from beginning to smoke. First, we must insure that every child in every school in this country is educated as to the health risks and the addictive nature of tobacco use. Most jurisdictions require that school curricula include preven- tion of drug use; therefore, education on the prevention of tobacco use should be included in this effort. Second, warning labels regarding the addictive nature of t,obacco use should be required for all tobacco packages and advertisements. Young people in particular may not be aware of the risk of tobacco addiction. Finally, parents and other role models should discourage smoking and other forms of tobacco use among young people. Parents who quit set an example for their children. Smoking continues to be the chief preventable cause of premature death in this country. Nicotine has addictive properties which help to sustain widespread tobacco use. It is gratifying to see the decline in reported smoking prevalence and cigarette consumption in the United States during the past 25 years. However, we cannot expect to see a sustained decline in rates of smoking-related cancers, cardiovascular disease, and pulmonary disease without sustained public health efforts against tobacco use. The Public Health Service is committed to preventing tobacco use among youth and to promoting cessation among existing smokers. We hope that this Report will assist the health care community, voluntary health agencies, and our Nation's schools in working with us to reduce tobacco use in our society. Robert E. Windom, M.D. Assistant Secretary for Health ii PREFACE This Report of the Surgeon General is the U.S. Public Health Service's 20th Report on the health consequences of tobacco use and the 7th issued during my tenure as Surgeon General. Eighteen Reports have been released previously as part of the health consequences of smoking series; a report on the health consequences of using smokeless tobacco was released in 1986. Previous Rep0rt.s have reviewed the medical and scientific evi- dence establishing the health effects of cigarette smoking and other forms of tobacco use. Tens of thousands of studies have documented that smoking causes lung cancer, other cancers, chronic obstructive lung disease, heart disease, complications of pregnancy, and several other adverse health effects. Epidemiologic studies have shown that cigarette smoking is responsible for more than 300,000 deaths each year in the United States. As I stated in the Preface to the 1982 Surgeon General's Report, smoking is the chief avoidable cause of death in our society. From 1964 through 1979, each Surgeon General's Report ad- dressed the major health effects of smoking. The 1979 Report provided the most comprehensive review of these effects. Following the 1979 Report, each subsequent Report has focused on specific populations (women in 1980, workers in 19851, specific diseases (cancer in 1982, cardiovascular disease in 1983, chronic obstructive lung disease in 19841, and specific topics (low-tar. low-nicotine cigarettes in 1981, involuntary smoking in 1986). This Report explores in great detail another specific topic: nicotine addiction. Careful examination of the data makes it clear that cigarettes and other forms of tobacco are addicting. An extensive body of research has shown that nicotine is the drug in tobacco that causes addiction. Moreover, the processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. Actions of Nicotine All tobacco products contain substantial amounts of nicotine. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in . . . 111 the blood are similar in magnitude in people using different forms of tobacco. Once in the blood stream, nicotine is rapidly distributed throughout the body. Nicotine is a powerful pharmacologic agent that acts in a variety of ways at different sites in the body. After reaching the blood stream, nicotine ent,ers the brain, interacts with specific receptors in brain tissue. and initiates metabolic and electrical activity in the brain. In addition, nicotine causes skeletal muscle relaxation and has cardiovascular and endocrine (i.e., hormonal) effects. Human and animal studies have shown that nicotine is the agent in tobacco that leads to addiction. The diversity and strength of its actions on the body are consistent with its role in causing addiction. Tobacco Use as an Addiction Standard definitions of drug addiction have been adopted by various organizations including the World Health Organization and the American Psychiatric Association. Although these definitions are not identical, they have in common several criteria for establish- ing a drug as addicting. The central element among all forms of drug addiction is that the user's behavior is largely controlled by a psychoactive substance (i.e., a substance that produces transient alterations in mood that are primarily mediated by effects in the brain). There is often compul- sive use of the drug despite damage to the individual or to society, and drug-seeking behavior can take precedence over other important priorities. The drug is "reinforcing"-that is, the pharmacologic activity of the drug is sufficiently rewarding to maintain self- administration. "Tolerance" is another aspect of drug addiction whereby a given dose of a drug produces less effect or increasing doses are required to achieve a specified intensity of response. Physical dependence on the drug can also occur, and is characterized by a withdrawal syndrome that usually accompanies drug absti- nence. After cessation of drug use, there is a strong tendency to relapse. This Report demonstrates in detail that tobacco use and nicotine in particular meet all these criteria. The evidence for these findings is derived from animal studies as well as human observations. Leading national and international organizations, including the World Health Organization and the American Psychiatric Associa- tion, have recognized chronic tobacco use as a drug addiction. Some people may have difficulty in accepting the notion that tobacco is addicting because it is a legal product. The word "addiction" is strongly associated with illegal drugs such as cocaine and heroin. However, as this Report shows, the processes that determine tobacco addiction are similar to those that determine addiction to other drugs, including illegal drugs. In addition, some smokers may not believe that tobacco is addicting because of a reluctance to admit that one's behavior is largely controlled by a drug. On the other hand, most smokers admit that they would like to quit but have been unable to do so. Smokers who have repeatedly failed in their attempts to quit probably realize that smoking is more than just a simple habit. Many smokers have quit on their own ("spontaneous remission") and some smokers smoke only occasionally. However, spontaneous remission and occasional use also occur with the illicit drugs of addiction, and in no way disqualify a drug from being classified as addicting. Most narcotics users, for example, never progress beyond occasional use, and of those who do, approximately 30 percent spontaneously remit. Moreover, it seems plausible that spontaneous remitters are largely those who have either learned to deliver effective treatments to themselves or for whom environmental circumstances have fortuitously changed in such a way as to support drug cessation and abstinence. Treatment Like other addictions, tobacco use can be effectively treated. A wide variety of behavioral interventions have been used for many years, including aversion procedures (e.g., satiation, rapid smoking), relaxation training, coping skills training, stimulus control, and nicotine fading. In recognition of the important role that nicotine plays in maintaining tobacco use, nicotine replacement therapy is now available. Nicotine polacrilex gum has been shown in controlled trials to relieve withdrawal symptoms. In addition, some (but not all) studies have shown that nicotine gum, as an adjunct to behavioral interventions, increases smoking abstinence rates. In recent years, multicomponent interventions have been applied successfully to the treatment of tobacco addiction. Public Health Strategies The conclusion that cigarettes and other forms of tobacco are addicting has important implications for health professionals, educa- tors, and policy-makers. In treating the tobacco user, health profes- sionals must address the tenacious hold that nicotine has on the body. More effective interventions must be developed to counteract both the psychological and pharmacologic addictions that accompa- ny tobacco use. More research is needed to evaluate how best to treat those with the strongest dependence on the drug. Treatment of tobacco addiction should be more widely available and should be V considered at least as favorably by third-party payors as treatment of alcoholism and illicit drug addiction. The challenge to health professionals is complicated by the array of new nicotine delivery systems that are being developed and introduced in the marketplace. Some of these products are produced by tobacco manufacturers; others may be marketed as devices to aid in smoking cessation. These new products may be more toxic and more addicting than the products currently on the market. New nicotine delivery systems should be evaluated for their toxic and addictive effects; products intended for use in smoking cessation also should be evaluated for efficacy. Public information campaigns should be developed to increase community awareness of the addictive nature of tobacco use. A health warning on addiction should be rotated with the other warnings now required on cigarette and smokeless tobacco packages and advertisements. Prevention of tobacco use should be included along with prevention of illicit drug use in comprehensive school health education curricula. Many children and adolescents who are experimenting with cigarettes and other forms of tobacco state that they do not intend to use tobacco in later years. They are unaware of, or underestimate, the strength of tobacco addiction. Because this addiction almost always begins during childhood or adolescence, children need to be warned as early as possible, and repeatedly warned through their teenage years, about the dangers of exposing themselves to nicotine. This Report shows conclusively that cigarettes and other forms of tobacco are addicting in the same sense as are drugs such as heroin and cocaine. Most adults view illegal drugs with scorn and express disapproval (if not outrage) at their sale and use. This Nation has mobilized enormous resources to wage a war on drugs - illicit drugs. We should also give priority to the one addiction that is killing more than 300,000 Americans each year. We as citizens, in concert with our elected officials, civic leaders, and public health officers, should establish appropriate public policies for how tobacco products are sold and distributed in our society. With the evidence that tobacco is addicting, is it appropriate for tobacco products to be sold through vending machines, which are easily accessible to children? Is it appropriate for free samples of tobacco products to be sent through the mail or distributed on public property, where verification of age is difficult if not impossible? Should the sale of tobacco be treated less seriously than the sale of alcoholic beverages, for which a specific license is required (and revoked for repeated sales to minors)? In the face of overwhelming evidence that tobacco is addicting, policy-makers should address these questions without delay. To vi achieve our goal of a smoke-free society, we must give this problem the serious attention it deserves. C. Everett Koop, M.D., Sc.D. Surgeon General vii ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Ronald M. Davis, M.D., Director. The Manag- ing Editors were Thomas E. Novotny, M.D., and William R. Lynn, Office on Smoking and Health. Scientific editors were Neal L. Benowitz, M.D., Professor of Medicine, Chief, Division of Clinical Pharmacology and Experimen- tal Therapeutics, San Francisco General Hospital, University of California, San Francisco, California; Neil E. Grunberg, Ph.D., Department of Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Jack E. Henningfield, Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland; and Harry A. Lando, Ph.D., Professor, Department of Psychology, Iowa State University, Ames, Iowa. The following individuals prepared draft chapters or portions of the Report. David B. Abrams, Ph.D., Assistant Professor of Psychiatry and Human Behavior, Brown University Program in Medicine, The Miriam Hospital, Center for Health Promotion, Providence, Rhode Island Timothy B. Baker, Ph.D., Department of Psychology, University of Wisconsin, Madison, Wisconsin Neal L. Benowitz, M.D., Professor of Medicine, Chief, Division of Clinical Pharmacology and Experimental Therapeutics, San Fran- cisco General Hospital, University of California, San Francisco, California Thomas H. Brandon, M.S., Department of Psychology, University of Wisconsin, Madison, Wisconsin Richard F. Catalano, Ph.D., Research Assistant Professor, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington Larry D. Chait, Ph.D., Research Associate (Assistant Professor), Department of Psychiatry, University of Chicago, Chicago, Illinois Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera- peutics, McGill University, Montreal, Quebec, Canada ix Richard R. Clayton, Ph.D., Professor, Department of Sociology, University of Kentucky, Lexington, Kentucky Allan C. Collins, Ph.D., Institute for Behavioral Genetics, School of Pharmacy, University of Colorado, Boulder, Colorado Thomas M. Cooper, D.D.S., Professor, Department of Community Dentistry, University of Kentucky, Lexington, Kentucky Lori A. Crane, M.P.H., Division of Cancer Control, Jonsson Compre- hensive Cancer Center, University of California, Los Angeles, California Susan Curry, Ph.D., Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, Washington D. Layten Davis, Ph.D., Director, Tobacco and Health Research Institute, University of Kentucky, Lexington, Kentucky Ronald M. Davis, M.D., Director, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland Edward F. Domino, M.D., Professor, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan John L. Egle, Jr., Ph.D., Department of Pharmacology/Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia Joan Ershler, Ph.D., Research Associate, Mt. Sinai Medical Center, Milwaukee, Wisconsin Raymond Fleming, Ph.D., Assistant Professor, University of Wiscon- sin-Milwaukee, Mt. Sinai Medical Center, Milwaukee, Wisconsin Kathleen A. Fletcher, Ph.D., M.P.H., Consultant, The University of Texas Health Science Center, Houston, Texas Paul J. Fudala, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland C. Gary Gairola, Ph.D., University of Kentucky, Tobacco and Health Research Institute, Lexington, Kentucky David Gilbert, Ph.D., Department of Psychology, Southern Illinois University, Carbondale, Illinois Lewayne D. Gilchrist, Ph.D., Research Associate Professor, School of Social Work, University of Washington, Seattle, Washington Donna M. Goldberg, M.A., Annapolis, Maryland Steven R. Goldberg, Ph.D., Preclinical Pharmacology Research Branch, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland John Grabowski, Ph.D., Department of Psychiatry and Behavioral Science, The University of Texas Health Science Center, Houston, Texas Neil E. Grunberg, Ph.D., Department of Medical Psychology, Uni- formed Services University of the Health Sciences, Bethesda, Maryland X Dorothy K. Hatsukami, Ph.D., Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota J. David Hawkins, Ph.D., Professor, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington Jack E. Henningfield, Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Cen- ter, National Institute on Drug Abuse, Baltimore, Maryland. Ronald I. Herning, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Matthew Owen Howard, M.S., M.S.W., Research Assistant, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington John R. Hughes, M.D., Departments of Psychiatry, Psychology, and Family Practice, University of Vermont, Burlington, Vermont Edgar T. Iwamoto, Ph.D., Department of Pharmacology, College of Medicine, University of Kentucky, Lexington, Kentucky Murray E. Jarvik, M.D., Ph.D., The Neuropsychiatric Institute and Hospital, School of Medicine, University of California, Los An- geles, Veterans' Administration Medical Center, Brentwood Divi- sion, Los Angeles, California Robert C. Klesges, Ph.D., Associate Professor, Center for Applied Psychological Research, Department of Psychology, Memphis State University, Memphis, Tennessee Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco Use, Addiction Research Foundation, Professor of Psychology and of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontario, Canada Howard Leventhal, Ph.D., Professor and Chairman, Department of Psychology, University of Wisconsin, Madison, Wisconsin Edythe D. London, Ph.D., Chief, Neuropharmacology Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Scott E. Lukas, Ph.D., Assistant Professor of Psychiatry (Pharmacol- ogy), Harvard Medical School, Department of Psychiatry, Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, Massachusetts Alfred C. Marcus, Ph.D., Associate Director, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California Andrew W. Meyers, Ph.D., Professor, Center for Applied Psychologi- cal Research, Department of Psychology, Memphis State Universi- ty, Memphis, Tennessee Thomas E. Novotny, M.D., Medical Epidemiologist, Office on Smok- ing and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland xi Carol Tracy Orleans, Ph.D., Senior Investigator, Behavioral Medi- cine and Director of Smoking Cessation Services, Division of Cancer Control, Fox Chase Cancer Center, Philadelphia, Pennsyl- vania John P. Pierce, MSc., Ph.D., Chief, Epidemiology Branch, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland Ovide F. Pomerleau, Ph.D., Behavioral Medicine Program, Universi- ty of Michigan, Department of Psychiatry, Ann Arbor, Michigan Amelie G. Ramirez, M.P.H., Faculty Associate, The University of Texas Health Science Center, Assistant Professor, Baylor College of Medicine, Houston, Texas Jed E. Rose, Ph.D., Veterans' Administration Medical Center, Wadsworth and Brentwood Divisions, Los Angeles, California J.A. Rosecrans, Ph.D., Department of Pharmacology, Medical Col- lege of Virginia, Virginia Commonwealth University, Richmond, Virginia David P.L. Sachs, M.D., Director, Smoking Cessation Research Institute, Palo Alto, California Mary Anne Salmon, Ph.D., Research Associate, Health Services Research Center, University of North Carolina, Chapel Hill, North Carolina Nina G. Schneider, Ph.D., Associate Research Psychologist, Depart- ment of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Research Psychologist, Psychopharmacology Unit, Vet- erans' Administration Medical Center, Brentwood Division, Los Angeles, California V.J. Schoenbach, Ph.D., Associate Professor, Department of Epide- miology, Research Associate, Health Services Research Center, University of North Carolina, Chapel Hill, North Carolina Saul Shiffman, Ph.D., Associate Professor, Department of Psycholo- gy, University of Pittsburgh, Pittsburgh, Pennsylvania Victor J. Strecher, Ph.D., Research Associate, Health Services Research Center, Assistant Professor, Department of Health Education, University of North Carolina, Chapel Hill, North Carolina David M. Warburton, Professor, Department of Psychology, Univer- sity of Reading, Whiteknights, Reading, United Kingdom Elizabeth A. Wells, Ph.D., Post-Doctoral Fellow, Center for Social Welfare Research, University of Washington, Seattle, Washington Thomas Ashby Wills, Ph.D., Assistant Professor of Psychology, Assistant Professor of Epidemiology and Social Medicine, Depart- ment of Epidemiology and Social Medicine, Ferkauf Graduate School of Psychology and Albert Einstein College of Medicine, Bronx, New York xii Phillip P. Woodson, Dr.sc.nat., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Leo G. Abood, Ph.D., Department of Pharmacology, University of Rochester Medical Center, Rochester, New York John S. Baer, Ph.D., Department of Psychology, University of Washington, Seattle, Washington Timothy B. Baker, Ph.D., Department of Psychology, University of Wisconsin, Madison, Wisconsin Claudia R. Baquet, M.D., M.P.H., Chief, Special Populations Studies Branch, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland Glen Bennett, M.P.H., Field Studies Advisor, Office of Prevention, Education, and Control, National Heart, Lung, and Blood Insti- tute, Bethesda, Maryland George E. Bigelow, Ph.D., Associate Professor of Behavioral Biology, Director, Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Universi- ty School of Medicine, Baltimore, Maryland Clarice Brown, M.S., Data Analyst, Office of Prevention, Education, and Control, National Heart, Lung, and Blood Institute, Bethesda, Maryland David M. Burns, M.D., Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Medical Center, San Diego, California Donald R. Cherek, Ph.D., Department of Psychiatry and Behavioral Sciences, Mental Sciences Institute, The University of Texas Health Science Center, Houston, Texas Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera- peutics, McGill University, Montreal, Quebec, Canada Ro Nemeth-Coslett, Ph.D., Psychologist, Prevention Research Branch, Division of Clinical Research, National Institute on Drug Abuse, Rockville, Maryland Thomas J. Crowley, M.D., University of Colorado Health Sciences Center, Denver, Colorado Joseph W. Cullen, Ph.D., Deputy Director, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland K. Michael Cummings, Ph.D., M.P.H., Research Scientist, Depart- ment of Cancer Control and Epidemiology, Roswell Park Memorial Institute, Buffalo, New York . . x111 Susan Curry, Ph.D., Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, Washington Vincent T. DeVita, Jr., M.D., Director, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Sir Richard Doll, University of Oxford, Oxford, England Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Centers for Disease Control, Hyattsville, Mary- land William H. Foege, M.D., Executive Director, The Carter Center of Emory University, Atlanta, Georgia Richard R. Frecker, M.D., Ph.D., Head, Biomedical Research, Department of Pharmacology, Addiction Research Foundation, Toronto, Ontario, Canada K.H. Ginzel, Ph.D., Professor, Department of Pharmacology and Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas Russell E. Glasgow, Ph.D., Oregon Research Institute, Eugene, Oregon Nancy P. Gordon, Sc.D., Behavioral Scientist, Division of Research, Kaiser Permanente Medical Group, Oakland, California Roland R. Griffiths, The Johns Hopkins University School of Medicine, Baltimore, Maryland Ellen R. Gritz, Ph.D., Director, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California Sharon M. Hall, Ph.D., Professor, Department of Psychiatry, Center for Social and Behavioral Sciences, University of California, San Francisco, California Louis S. Harris, Ph.D., Senior Science Advisor, National Institute on Drug Abuse, Alcohol, Drug Abuse, and Mental Health Administra- tion, Rockville, Maryland Ronald I. Herning, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Insti- tute, Valhalla, New York Leo Hollister, M.D., Medical Director, Harris County Psychiatry Center, Houston, Texas Enid Hunkeler, Senior Investigator, Kaiser Permanente Medical Care Program, Oakland, California Peyton Jacob III, Ph.D., Division of Clinical Pharmacology, San Francisco General Hospital, University of California, San Francis- co, California Jerome Jaffe, M.D., Director, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Murray E. Jarvik, M.D., Ph.D., The Neuropsychiatric Institute and Hospital, School of Medicine, University of California, Los An- xiv geles, and Veterans' Administration Medical Center West LOS Angeles, Brentwood Division, Los Angeles, California Martin Jarvis, M.Phil., Senior Lecturer, Addiction Research Unit, Institute of Psychiatry, London, England Chris-Ellen Johanson, Ph.D., Department of Psychiatry, Pritzker School of Medicine, University of Chicago Drug Abuse Research Center, Chicago, Illinois Reese T. Jones, Ph.D., Department of Psychiatry, University of California School of Medicine, San Francisco, California Kenneth J. Kellar, Ph.D., Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco Use, Addiction Research Foundation, Toronto, Ontario, Canada Richard J. Lamb, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Charles L. LeMaistre, M.D., President, University of Texas Systems Cancer Center, Houston, Texas Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Howard Leventhal, Ph.D., Professor of Psychology, University of Wisconsin, Madison, Wisconsin Edward Lichtenstein, Ph.D., Oregon Research Institute, Eugene, Oregon Donald Ian Macdonald, M.D., Administrator, Alcohol, Drug Abuse, and Mental Health Administration, Rockville, Maryland G. Alan Marlatt, Ph.D., Professor of Psychology, University of Washington, Seattle, Washington William R. Martin, M.D., Chairman, Department of Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky James 0. Mason, M.D., Dr.P.H., Director, Centers for Disease Control, Atlanta, Georgia J. Michael McGinnis, M.D., Deputy Assistant Secretary (Disease Prevention and Health Promotion), Washington, D.C. A. Thomas McLellan, Ph.D., Substance Abuse Treatment Research Center, Philadelphia Veterans' Administration Medical Center and The University of Pennsylvania, Philadelphia, Pennsylvania Nancy K. Mello, Ph.D., Alcohol and Drug Abuse Research Center, McClean Hospital, Belmont, Massachusetts Gregory J. Morosco, Ph.D., M.P.H., Smoking Education Program Coordinator, National Heart, Lung, and Blood Institute, Bethesda, Maryland Joseph P. Mulholland, Ph.D., Bureau of Economics, Federal Trade Commission, Washington, D.C. Herbert W. Nickens, M.D., M.A., Director, Office of Minority Health, Public Health Service, Washington, D.C. xv Richard Peto, M.A., M.Sc., Imperial Cancer Research Fund, Cancer Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, University of Oxford, Oxford, England Roy W. Pickens, Ph.D., Director, Division of Clinical Research, National Institute on Drug Abuse, Rockville, Maryland John P. Pierce, MSc., Ph.D., Chief, Epidemiology Branch, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland John M. Pinney, Executive Director, Institute for the Study of Smoking Behavior and Policy, John F. Kennedy School of Govern- ment, Harvard University, Cambridge, Massachusetts Michael R. Polen, M.A., Research Associate, Division of Research, Kaiser-Permanente Medical Group, Oakland, California William Pollin, M.D., Former Director, National Institute on Drug Abuse, Bethesda, Maryland David C. Ramsey, M.P.H., Health Educator, Division of Health Education, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Everett R. Rhoades, M.D., Assistant Surgeon General and Director, Indian Health Service, Rockville, Maryland M.A.H. Russell, F.R.C.P., Addiction Research Unit, Institute of Psychiatry, University of London, London, England Charles R. Schuster, Ph.D., Director, National Institute on Drug Abuse, Rockville, Maryland Burt Sharpe, M.D., Hennepin County Medical Center, Department of Medicine, Minneapolis, Minnesota Donald R. Shopland, Public Health Advisor, Smoking, Tobacco, and Cancer Program, National Cancer Institute, Bethesda, Maryland Jerome E. Singer, Ph.D., Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland Maxine L. Stitzer, Ph.D., Associate Professor, Behavioral Biology, The Johns Hopkins School of Medicine, Behavioral Pharmacology Research, Francis Scott Key Medical Center, Baltimore, Maryland David N. Sundwall, M.D., Assistant Surgeon General and Adminis- trator, Health Resources and Services Administration, Rockville, Maryland Dennis D. Tolsma, M.P.H., Director, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Frederick L. Trowbridge, M.D., Director, Division of Nutrition, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Frank J. Vocci, Jr., Ph.D., Acting Chief, Drug Abuse Staff, Center for Drug Evaluation and Research, Food and Drug Administration, Washington, DC Ronald W. Wilson, M.A., National Center for Health Statistics, Centers for Disease Control, Hyattsville, Maryland xvi Roy A. Wise, Ph.D., Department of Psychology, Concordia Universi- ty, Montreal, Quebec, Canada Faye Wright, Center for Applied Psychological Research, Depart- ment of Psychology, Memphis State University, Memphis, Tennes- see Ernst L. Wynder, M.D., President, American Health Foundation, New York, New York James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland Tomoji Yanagita, M.D., Ph.D., Preclinical Research Laboratories, Central Institute for Experimental Animals, Kawasaki, Japan Frank E. Young, M.D., Commissioner, Food and Drug Administra- tion, Rockville, Maryland The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Margaret Anglin. Secretary, Office on Smoking and Health, Rock- ville, Maryland Charles Appiah, Project Clerk. Smoking and Health Project,. The Circle, Inc., McLean, Virginia John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Sonia Balakirsky, Secretary, Office on Smoking and Health, Rock- ville, Maryland Carol Bean, Associate Project Director, Smoking and Health Project, The Circle, Inc., McLean, Virginia Tamara Blair, Production Coordinator, Information Management Department, ATLIS Federal Services, Inc., Rockville, Maryland Catherine E. Burckhardt, Editorial Assistant, Office on Smoking and Health, Rockville, Maryland Gayle Christman, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Carol K. Cummings, Secretary, Office on Smoking and Health, Rockville, Maryland Stephanie D. DeVoe, Programmer, Information Systems Depart- ment, ATLIS Federal Services, Inc., Rockville, Maryland Michael C. Fiore, M.D., M.P.H., Medical Epidemiologist, Office on Smoking and Health, Rockville, Maryland David Fry, Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Lynn Funkhauser, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Mary Gardner, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia xvii Amy Garson, M.P.H. student, Office on Smoking and Health, Rockville: Maryland -4rnetta G. Glover, Secretary, Office on Smoking and Health, Rockville, Maryland William Groskopf, Library Acquisitions Specialist, Information Management Department, ATLIS Federal Services, Inc., Rock- ville, Maryland Evridiki Hatziandreu, M.D., M.P.H., Epidemic Intelligence Service Officer, Office on Smoking and Health, Rockville, Maryland Susan A. Hawk, Ed.M., M.S., Chief, Technical Information Center, Office on Smoking and Health, Rockville, Maryland Patricia E. Healy, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Terri L. Henry, Clerk-Typist, Office on Smoking and Health. Rockville, Maryland Timothy K. Hensley, Technical Publications Writer, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Information Manage- ment Department, ATLIS Federal Services, Inc., Rockville, Mary- land Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Karen Jacob, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Sheila Jones, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Rick Keir, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Julie Kurz, Graphics Specialist, Information Management Depart- ment, ATLIS Federal Services, Inc., Rockville, Maryland Diana Lord, Research Assistant, Department of Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland Gerri E. Mast, Secretary, Center for Health Promotion and Educa- tion, Centers for Disease Control, Atlanta, Georgia Judy J. Mast, Secretary, Center for Health Promotion and Educa- tion, Centers for Disease Control, Atlanta, Georgia Dixie McGough, Program Manager, Information Management De- partment, ATLIS Federal Services, Inc., Rockville, Maryland Paul G. McGovern, Ph.D., Postdoctoral Research Associate, Smoking Research Group, Department of Psychology, Iowa State Universi- ty, Ames, Iowa Dan McLaughlin, Editorial Assistant, Smoking and Health Project, The Circle, Inc., McLean, Virginia . . . xv111 Nancy Miltenberger, Editor. Smoking and Health Project, The Circle, Inc., McLean, Virginia Cathie O'Donnell, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland Russell D. Peek, Library Acquisitions Specialist, Information Man- agement Department, ATLIS Federal Services, Inc., Rockville, Mar.yland Mary B. Pfeiffer, M.L.S., Librarian, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Margaret E. Pickerel, Public Information and Publications Special- ist, Office on Smoking and Health, Rockville, Maryland Renate Phillips, Desktop Publishing/Graphic Artist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Karen Sherman, Production Assistant, Information Management Department, ATLIS Federal Services, Inc., Rockville, Maryland Linda R. Spiegelman. Administrative Officer, Office on Smoking and Health, Rockville, Maryland Tamara Shipp, Publications Assistant, Smoking and Health Project, The Circle, Inc., McLean, Virginia Evelyn L. Swarr, Systems Management Projects Supervisor, Infor- mation Systems Department, ATLIS Federal Services, Inc., Rock- ville, Maryland Patricia Y. Thomas, Secretary, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Daniel R. Tisch, Project Director, Smoking and Health Project, The Circle, Inc., McLean, Virginia Louise G. Wiseman, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland xix TABLE OF CONTENTS Foreword ................................................................. i Preface .................................................................. iii Acknowledgments .................................................... ix I. Introduction, Overview, Summary, and Conclusions . . . . . . . . . . . . . . . . . . ..**............................... 1 II. Nicotine: Pharmacokinetics, Metabolism, and Phar- macodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 III. Nicotine: Sites and Mechanisms of Actions.. ........ .75 IV. Tobacco Use as Drug Dependence ..................... 145 V. Tobacco Use Compared to Other Drug Dependencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 VI. Effects of Nicotine That May Promote Tobacco Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 $11. Treatment of Tobacco Dependence.. . . . . . . . . . . . . . . . . . . .459 Appendix A: Trends in Tobacco Use in the United States . . . . . , . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . .561 Appendix B: Toxicity of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . 619 xxi CHAPTER I INTRODUCTION, OVERVIEW, SUMMARY, AND CONCLUSIONS CONTENTS Introduction ............................................................ 5 Development and Organization of this Report ......... 5 Overview ................................................................ 6 Major Conclusions .................................................... 9 .__- Brief History Relevant to this Report .......................... 9 Chapter Conclusions ............................................... .13 Chapter II: Nicotine: Pharmacokinetics, Metabo- lism, and Pharmacodynamics ........... .13 Chapter III: Nicotine: Sites and Mechanisms of Actions ........................................ ,14 Chapter IV: Tobacco Use as Drug Dependence.. ... .14 Chapter V: Tobacco Use Compared to Other Drug Dependencies ................................. .15 Chapter VI: Effects of Nicotine That May Promote Tobacco Use .................................. .15 Chapter VII: Treatment of Tobacco Dependence .... .15 Appendix A: Trends in Tobacco Use in the United States .......................................... .16 Appendix B: Toxicity of Nicotine ....................... .16 References ............................................................ .18 3 Introduction Development and Organization of this Report This Report was developed by the Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Public Health Service of the U.S. Department of Health and Human Services as part of the Department's responsibility, under Public Law 91-222, to report new and current information on smoking and health to the United States Congress. The scientific content of this Report reflects the contributions of more than 50 scientists representing a wide variety of relevant disciplines. These experts, known for their understanding of and work in specific content areas, prepared manuscripts for incorpora- tion into this Report. The Office on Smoking and Health and its consultants edited and consolidated the individual manuscripts into appropriate chapters. These draft chapters were subjected to an extensive outside peer review (see Acknowledgments for individuals and their affiliations) whereby each chapter was reviewed by up to 11 experts. Based on the comments of these reviewers, the chapters were revised and the entire volume was assembled. This revised edition of the Report was resubjected to review by 20 distinguished scientists inside and outside the Federal Government, both in this country and abroad. Parallel to this review, the entire Report was also submitted for review to 12 institutes and agencies within the U.S. Public Health Service. The comments from the senior scientific reviewers and the agencies were used to prepare the final volume of this Report. This Report contains a Foreword by the Assistant Secretary for Health, a Preface by the Surgeon General of the U.S. Public Health Service, and the following chapters and appendices: Chapter I. Introduction. Overview, Summary, and Conclu- sions Chapter II. Nicotine: Pharmacokinetics, Metabolism, and Pharmacodynamics Chapter III. Nicotine: Sites and Mechanisms of Actions Chapter IV. Tobacco Use as Drug Dependence Chapter V. Tobacco Use Compared to Other Drug Dependencies Chapter VI. Effects of Nicotine That May Promote Tobacco Use Chapter VII. Treatment of Tobacco Dependence Appendix A. Trends in Tobacco Use in the United States Appendix B. Toxicity of Nicotine Overview This Report of the Surgeon General on tobacco and health focuses on the pharmacologic basis of tobacco addiction. Previous Surgeon General's Reports have reviewed the medical and scientific evidence establishing that cigarette smoking and tobacco use in other forms are deleterious to health. Several reports emphasized particular diseases (e.g., 1982 Report on cancer (US DHHS 1982), 1983 Report on cardiovascular disease (US DHHS 1983a), 1984 Report on chronic obstructive lung disease (US DHHS 1984a)); some reports concentrat- ed on specific populations (e.g., 1980 Report on women (US DHHS 1980)); and some reports dealt with particular aspects of smoking (e.g., 1986 Report on involuntary smoking (US DHHS 1986a)). These reports have been important because so many individuals engage in a behavior that causes morbidity and premature mortality. The present Report addresses a central issue of the tobacco and health problem: Why do people smoke and in other ways consume tobacco products? Specifically, this Report reviews the pharmacolog- ic basis of the disease-producing and life-threatening behavior of tobacco use. Psychological and social factors are also important influences on tobacco use, but a detailed review of these factors is beyond the scope of this Report. Reviews of this literature include previous reports of the Surgeon General (US DHEW 1979; US DHHS 1980, 1982, 1983a, 1984a), research monographs from the National Institute on Drug Abuse (NTDA) (Jarvik et al. 1977; Krasnegor 1978, 1979a,b,c; Grabowski and Bell 1983), and articles by scientists who study tobacco use and nicotine (Russell 1971, 1976; Gritz 1980; Henningfield 1984). This Report reviews evidence that tobacco use is addicting and that nicotine is the active pharmacologic agent of tobacco that causes this addictive behavior. Previous Surgeon General's Reports have focused on evidence that cigarette smoking and tobacco use are health hazards. Now that those relationships are well-documented and well-known, this Report addresses addictive properties of cigarette smoking and tobacco use in order to help develop more effective prevention and cessation programs. This Report topic is particularly timely because of recent advances and extensive data gathered in the 1980s relevant to the issue of tobacco addiction. Since the early 1900s scientific literature and historical anecdotes have provided evidence that tobacco use is a form of drug addiction. In the 1970s however, research efforts increased considerably on various aspects of tobacco addiction, including nicotine pharmacokinetics, pharmacodynamics, self-ad- ministration, withdrawal, dependence, and tolerance. In addition, advances in the neurosciences have begun to reveal effects of nicotine in the brain and body that may help to explain why tobacco use is reinforcing and difficult to give up. These issues are addressed 6 in this Report. Finally, recent developments in the use of nicotine replacement in smoking cessation emphasize the importance of pharmacologic aspects of cigarette smoking. Concepts of drug addiction or drug dependence are discussed in detail in Chapters IV and V. It is useful to begin this Report with a brief summary of main points about drug dependence that provide the foundation for the findings of the Report. The terms "drug addiction" and "drug dependence" are scientifi- cally equivalent: both terms refer to the behavior of repetitively ingesting mood-altering substances by individuals. The term "drug dependence" has been increasingly adopted in the scientific and medical literature as a more technical term, whereas the term "drug addiction" continues to be used by NIDA and other organizations when it is important to provide information at a more general level. Throughout this Report, both terms are used and they are used synonymously. The main conclusions of the Report are based upon concepts of drug dependence that have been developed by expert committees of the World Health Organization, as well as in publications of NIDA and the American Psychiatric Association. These concepts were used to develop a set of criteria to determine whether tobacco-delivered nicotine is addicting. The criteria for drug dependence include primary and additional indices and are summarized below. CRITERIA FOR DRUG DEPENDENCE Primary Criteria . Highly controlled or compulsive use . Psychoactive effects . Drug-reinforced behavior Additional Criteria . Addictive behavior often involves: -stereotypic patterns of use -use despite harmful effects -relapse following abstinence -recurrent drug cravings . Dependence-producing drugs often produce: -tolerance -physical dependence -pleasant (euphoriantl ef'fects The primary crit.eria listed above are sufficient to define drug dependence. Highly controlled or compulsive use indicates that drug- seeking and drug-taking behavior is driven by strong, often irresisti- ble urges. It can persist despite a desire to quit or even repeated attempts to quit. Such behavior is also referred to as "habitual" behavior. To distinguish drug dependence from habitual behaviors not involving drugs, it must be demonstrated that a drug with psychoactive (mood-altering) effects in the brain enters the blood stream. Furthermore, drug dependence is defined by the occurrence of drug-motivated behavior; therefore, the psychoactive chemical must be capable of functioning as a reinforcer that can directly strengthen behavior leading to further drug ingestion. Additional criteria are often used to help characterize drug dependence. Several are associated with the drug-taking behavior itself': (1) the behavior may develop into regular temporal and physical patterns of use (repetitive and stereotypic); (2) drug use may persist despite adverse physical, psychological, or social conse- quences; (3) quitting episodes are often followed by resumption of drug use (relapse); (4) urges (cravings) to use the drug may be recurrent and persistent, especially during drug abstinence. Similar- ly, several common effects of dependence-producing drugs can strengthen their control over behavior and increase the likelihood of harm by contributing to the regularity and overall level of drug intake: (1) diminished responsiveness (tolerance) to the effects of a drug occurs, and may be accompanied by increased intake over time; (2) abstinence-associated withdrawal reactions (due to physical dependence) can motivate further drug intake; (3) effects that are considered pleasant (euphoriant) to the drug user can be provided by the drug itself. Dependence-producing drugs can also produce effects that individuals find useful. For example, many addicting drugs have therapeutic uses in medical treatments of various disorders. Most medically approved drugs that are addicting, however, are generally only available by prescription. Effects of a drug considered by the individual to be useful can promote initiation of drug use, strengthen the addiction, and contribute to relapse following cessa- tion of use. Tobacco and nicotine are considered in the Report in light of the above criteria. In brief, the organization of the Report is as follows: review of evidence that tobacco use is accompanied by orderly patterns of uptake of nicotine in the body and brain resulting in the development of tolerance (Chapter II); review of how effects of nicotine in the brain and the rest of the body are chemically mediated (Chapter 1111; review of the evidence that tobacco is addicting and that nicotine is an addicting drug (Chapter IV); comparison of tobacco use with other addictions and of nicotine with other addicting drugs (Chapter VI: review of possible effects of nicotine that may promote the use of tobacco and present impedi- ments to quitting smoking (Chapter VII; review of strategies for 8 helping people to achieve and maintain tobacco abstinence (Chapter VII). In addition, appendices are included that summarize informa- tion regarding trends in tobacco use (Appendix A) and information regarding the toxicity of nicotine itself (Appendix BI. A summary of the main findings of the Report follows. Major Conclusions 1. Cigarettes and other forms of tobacco are addicting. 2. Nicotine is the drug in tobacco that causes addiction. 3. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. Brief History Relevant to this Report Tobacco products have been used for centuries. The tobacco plant was native to the New World. The oldest cited evidence of tobacco use appears on a Mayan stone carving dated from 600 to 900 A.D. There are reports of tobacco smoking in Christopher Columbus' diary in 1492; reports of tobacco smoking appear in the logs of other European explorers of the New World in the 16th century. Since the colonial period, tobacco has been an integral part of the American economy (Robert 19491. Tobacco use permeated the New World and quickly spread throughout the rest of the world during the 16th and 17th centuries. As use of tobacco products spread, so did controversy over the effects of these products. Throughout history, while some persons extolled the virtues of tobacco (including numerous alleged medicinal uses), others condemned its use. George Washington is attributed with exhorting the home front during the Revolutionary War, "If you can't send money, send tobacco." In contrast, Dr. Benjamin Rush condemned tobacco use in his 1798 book Essa,vs. The controversy continued into the 19th century with no convincing scientific or medical evidence to support either position (Robert 1949). In 1856-57 the British medical journal Lancet published opinions of 50 physicians on tobacco use. Many opponents attributed in- creased crime, nervous paralysis, loss of intellectual abilities, and visual impairment to tobacco use-all of these claims lacked convincing evidence. In restating the main arguments of the tobacco proponents, the Lancet editors wrote that tobacco use "...must have some good or at least pleasurable effects; that, if its evil effects were 9 so dreadful as stated the human race would have ceased to exist" (Lancet 1857). While the health-promoting and health-damaging effects of tobac- co products were being debated throughout the 17th and 18th centuries, scientists were trying to determine the chief active ingredient in tobacco. In the early 1800s the oily essence of tobacco was discovered by Cerioli and by Vauquelin. This active substance was named "Nicotianine," after Jean Nicot, who sent tobacco seeds from Portugal to the French court at the end of the 16th century. In 1828, Posselt and Reimann at the University of Heidelberg isolated the pure form of Nicotianine and renamed it, "Nikotin." The chemical's empirical formula, C10H,4N2, was determined in the 184Os, and "nicotine" was synthesized in the 1890s (Robert 1949). Since the late 1800s research on the pharmacologic actions of nicotine has contributed substantially to basic information about the nervous system (Kharkevich 1980; Volle 1980). The classic work by Langley and Dickinson (18891 on nicotine's effects in autonomic ganglia led to the postulates that chemicals transmit information between neurons and that there are receptors on cells that respond functionally to stimulation by specific chemicals. As early as the 1920s and 1930s some investigators were concluding that nicotine was responsible for the compulsive use of tobacco products (Arm- strong-Jones 1927; Dorsey 1936; Lewin 1931). Johnston (1942) concluded that, "smoking tobacco is essentially a means of adminis- tering nicotine, just as smoking opium is a means of administering morphine." Throughout the 20th century, research has continued to investi- gate the role of nicotine in tobacco use. The 1964 Report of the Surgeon General's Advisory Committee on Smoking and Health (US PHS 19641 held that: "The habitual use of tobacco is related primarily to psychological and social drives, reinforced and perpetu- ated by the pharmacologic actions of nicotine on the central nervous system. Nicotine-free tobacco or other plant materials do not satisfy the needs of those who acquire the tobacco habit." The 1964 Report, relying upon a distinction (that is no longer made) between "habituating" and "addicting" drugs. asserted that tobacco was habituating and not addicting. The distinction in 1964 between habituating drugs iincluding cocaine and amphetamines) and addict- ing drugs (including opiates and barbiturates) was based on: (1) whether the drug produced clear physical dependence; (2) whether damage was mainly to the individual user (habituating drugs) or to society (addicting drugs); and (3) the strength of the habitual behavior that developed. There was no question at the time of the 1964 Report that nicotine was the critical pharmacologic agent for tobacco use, but its role was then considered to be more similar to cocaine and amphetamines than to opiates and barbiturates. Later 10 in 1964 the World Health Organization dropped this semantic distinction between habituating and addicting drugs because it was recognized that habitual use could be as strongly developed for cocaine as for morphine. that social damage generally accompanied personal damage, and that behavioral characteristics of drug use could be similar for the so-called habituating and addicting drugs. In an effort to shift the focus to dependent patterns of behavior and away from moral and social issues associated with the term addiction, the term dependence was recommended. It is now clear that even by the earlier distinction in nomencla- ture, cigarettes and other forms of tobacco are addicting and actions of nicotine provide the pharmacologic basis of tobacco addiction. The term "dependence producing" may also be used to describe cigarettes and other forms of tobacco use, analogous to actions of other drugs (e.g., opiates, cocaine). Since 1964, considerable additional evidence has been compiled that substantiates these conclusions. The present Report reviews this information and the relevant literature. Previous Surgeon General's Reports provided current reviews of the health consequences of cigarette smoking particularly relevant to public health. For example, despite the accumulating evidence, in the early 1960s there was little recognition by the public of the health hazards of smoking. Each Report examined specific informa- tion considered to be important for public dissemination. A brief review of topics addressed in these reports provides the background for the present Report. In the late 195Os, the U.S. Public Health Service, the National Cancer Institute, the National Heart Institute, the American Cancer Society, and the American Heart Association appointed a study group to examine the available evidence on smoking and health. This study group concluded that excessive cigarette smoking is a causative factor in lung cancer. In 1962, Surgeon General Luther Terry established an advisory committee on smoking and health. This committee released its Report on January 11, 1964, concluding that cigarette smoking is a cause of lung cancer in men and a suspected cause of lung cancer in women, and increased the risk of dying from pulmonary emphysema. The next Report was issued in 1967 (US PHS 1968a) and stated that "the case for cigarette smoking as the principal cause of lung cancer is overwhelming." Further, the 1967 Report concluded that: "There is an increasing convergence of many types of evidence . . . which strongly suggests that cigarette smoking can cause death from coronary heart disease." The 1967 Report also concluded that "Cigarette smoking is the most important of the causes of chronic non-neoplastic bronchopulmonary disease in the United States." The 1968 and 1969 Reports (US PHS 1968b, 1969) strengthened the conclusions reached in 1967. The 1971 Report provided a detailed 11 review of the evidence to date regarding health consequences of smoking (US DHEW 1971). The subsequent reports (1972 to 1976) continued to review the increasing evidence associating cigarette smoking with many health hazards. The 1972 Report also discussed involuntary or passive smoking (US DHEW 1972). The 1973 Report included some data on the health hazards of smoking pipes and cigars (US PHS 1973). The 1975 Report updated information on the health effects of involuntary or passive smoking (US DHEW 1975). The combined 1977-78 Report discussed smoking-related problems unique to women (US DHEW 1978). At the time of its release, the 1979 Report was the most comprehensive review by a Surgeon General's Report of the health consequences of smoking, smoking behavior, and smoking control. In addition to providing a thorough review of the health consequences of smoking, the 1979 Report discussed the health consequences of using forms of tobacco other than cigarettes (pipes, cigars, and smokeless tobacco). Moreover, the 1979 Report expanded the scope of the previous reports and examined behavioral, pharmacologic, and social factors influencing the initiation, maintenance, and cessation of cigarette smoking. Relevant to the topic of the present Report, the 1979 Report concluded that "it is no exaggeration to say that smoking is the prototypical substance-abuse dependency and that improved knowledge of this process holds great promise for preven- tion of risk." Since the release of the 1979 Report, each subsequent Report has focused on a specific population or setting (women in 1980 (US DHHS 19801, the workplace in 1985 (US DHHS 1985)), a specific topic (health effects of low-tar and low-nicotine cigarettes in 1981 (US DHHS 19811, involuntary smoking in 1986 (US DHHS 1986a)), or a specific disease (cancer in 1982 (US DHHS 19821, cardiovascular diseases in 1983 (US DHHS 1983aL chronic obstruc- tive lung disease in 1984 (US DHHS 1984al). In addition to the previous Surgeon General's Reports, several other developments and publications provide relevant background for the present Report. For example, numerous monographs pre- pared in the 1970s by the National Institute on Drug Abuse (NIDA) considered tobacco use as a form of drug dependence. In 1980, the American Psychiatric Association, in its Diagnostic and Statistical Manual of Mental Disorders, included tobacco dependence as a substance abuse disorder and tobacco withdrawal as an organic mental disorder (APA 1980). The 1987 revised edition of this manual tAPA 1987), in recognition of the role of nicotine, changed "tobacco withdrawal" to "nicotine withdrawal." In 1982, the Director of NIDA testified to Congress that the position of NIDA was that tobacco use could lead to dependence and that nicotine was a prototypic dependence-producing drug. In a 1983 publication, "Why People Smoke Cigarettes," the U.S. Public Health Service supported this position of NIDA regarding tobacco and nicotine (US DHHS 1983133. In the 1984 NIDA Triennial Report to Congress, nicotine was labeled a prototypic dependence-producing drug and the role of nicotine in tobacco use was considered to be analogous to the roles of morphine, cocaine, and ethanol, in the use of opium, coca-derived products, and alcoholic beverages, respectively (US DHHS 1984b3. In 1986, a consensus conference of the National Institutes of Health and the Report of the Advisory Committee to the Surgeon General on the health consequences of using smokeless tobacco concluded that smokeless tobacco can be addicting and that nicotine is a depen- dence-producing (i.e., addicting) drug (US DHHS 1986b). The present Report is the 20th such report issued by the Public Health Service on the health consequences of tobacco use. The deleterious effects of cigarette smoking are now well known. Therefore, this Report focuses on pharmacologic information to help understand why people smoke. Such information will assist health professionals in developing effective strategies to prevent initiation and to promote cessation. The literature reviewed in this Report indicates that tobacco use is an addictive behavior. It is the purpose of this Report to thoroughly review the relevant literature. Chapter Conclusions In addition to the three overall conclusions of this Report, there are many other substantive conclusions. These points are listed under the appropriate Chapter and Appendix headings. Chapter II: Nicotine: Pharmacokinetics, Metabolism, and Phar- macodynamics 1. All tobacco products contain substantial amounts of nicotine and other alkaloids. Tobaccos from low-yield and high-yield cigarettes contain similar amounts of nicotine. 2. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in the blood are similar in magnitude in people using different forms of tobacco. With regular use, levels of nicotine accumulate in the body during the day and persist overnight. Thus, daily tobacco users are exposed to the effects of nicotine for 24 hr each day. 3. Nicotine that enters the blood is rapidly distributed to the brain. As a result, effects of nicotine on the central nervous system occur rapidly after a puff of cigarette smoke or after absorption of nicotine from other routes of administration. 4. Acute and chronic tolerance develops to many effects of nicotine. Such tolerance is consistent with reports that initial 13 use of tobacco products, such as in adolescents first beginning to smoke. is usually accompanied by a number of unpleasant symptoms which disappear following chronic tobacco use. Chapter III: Nicotine: Sites and Mechanisms of Actions 1. Nicotine is a powerful pharmacologic agent that acts in the brain and throughout the body. Actions include electrocortical activation, skeletal muscle relaxation, and cardiovascular and endocrine effects. The many biochemical and electrocortical effects of nicotine may act in concert to reinforce tobacco use. 2. Nicotine acts on specific binding sites or receptors throughout the nervous system. Nicotine readily crosses the blood-brain barrier and accumulates in the brain shortly after it enters the body. Once in the brain, it interacts with specific receptors and alters brain energy metabolism in a pattern consistent with the distribution of specific binding sites for the drug. 3. Nicotine and smoking exert effects on nearly all components of the endocrine and neuroendocrine systems (including catechol- amines, serotonin, corticosteroids, pituitary hormones). Some of these endocrine effects are mediated by actions of nicotine on brain neurotransmitter systems (e.g., hypothalam- ic-pituitary axis). In addition, nicotine has direct peripherally mediated effects (e.g., on the adrenal medulla and the adrenal cortex). Chapter IV: Tobacco Use as Drug Dependence 1. Cigarettes and other forms of tobacco are addicting. Patterns of tobacco use are regular and compulsive, and a withdrawal syndrome usually accompanies tobacco abstinence. 2. Nicotine is the drug in tobacco that causes addiction. Specifi- cally, nicotine is psychoactive ("mood altering") and can provide pleasurable effects. Nicotine can serve as a reinforcer to motivate tobacco-seeking and tobacco-using behavior. Toler- ance develops to actions of nicotine such that repeated use results in diminished effects and can be accompanied by increased intake. Nicotine also causes physical dependence characterized by a withdrawal syndrome that usually accompa- nies nicotine abstinence. 3. The physical characteristics of nicotine delivery systems can affect their toxicity and addictiveness. Therefore, new nicotine delivery systems should be evaluated for their toxic and addictive effects. 14 Chapter V: Tobacco Use Compared to Other Drug Dependen- cies 1. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. 2. Environmental factors including drug-associated stimuli and social pressure are important influences of initiation, patterns of use, quitting, and relapse to use of opioids, alcohol, nicotine, and other addicting drugs. 3. Many persons dependent upon opioids, alcohol, nicotine, or other drugs are able to give up their drug use outside the context of treatment programs; other persons, however, re- quire the assistance of formal cessation programs to achieve lasting drug abstinence. 4. Relapse to drug use often occurs among persons who have achieved abstinence from opioids, alcohol, nicotine, or other drugs. 5. Behavioral and pharmacologic intervention techniques with demonstrated efficacy are available for the treatment of addiction to opioids, alcohol, nicotine, and other drugs. Chapter VI: Effects of Nicotine That May Promote Tobacco Dependence 1. After smoking cigarettes or receiving nicotine, smokers per- form better on some cognitive tasks (including sustained attention and selective attention) than they do when deprived of cigarettes or nicotine. However, smoking and nicotine do not improve general learning. 2. Stress increases cigarette consumption among smokers. Fur- ther, stress has been identified as a risk factor for initiation of smoking in adolescence. 3. In general, cigarette smokers weigh less (approximately 7 lb less on average) than nonsmokers. Many smokers who quit smoking gain weight. 4. Food intake and probably metabolic factors are involved in the inverse relationship between smoking and body weight. There is evidence that nicotine plays an important role in the relationship between smoking and body weight. Chapter VII: Treatment of Tobacco Dependence 1. Tobacco dependence can be treated successfully. 2. Effective interventions include behavioral approaches alone and behavioral approaches with adjunctive pharmacologic treatment. 15 3. Behavioral interventions are most effective when they include multiple components (procedures such as aversive smoking, skills training, group support, and self-reward). Inclusion of too many treatment procedures can lead to less successful out- come. 4. Nicotine replacement can reduce tobacco withdrawal symp- toms and may enhance the efficacy of behavioral treatment. Appendix A: Trends in Tobacco Use in the United States 1. An estimated 32.7 percent of men and 28.3 percent of women smoked cigarettes regularly in 1985. The overall prevalence of smoking in the United States decreased from 36.7 percent in 1976 (52.4 million adults) to 30.4 percent in 1985 (51.1 million adults). 2. In 1985, the mean reported number of cigarettes smoked per day was 21.8 for male smokers and 18.1 for female smokers. 3. Smoking is more common in lower socioeconomic categories (blue-collar workers or unemployed persons, less educated persons, and lower income groups) than in higher socioeconom- ic categories. For example, the prevalence of smoking in 1985 among persons without a high school diploma was 35.4 percent, compared with 16.5 percent among persons with postgraduate college education. 4. An estimated 18.7 percent of high school seniors reported daily use of cigarettes in 1986. The prevalence of daily use of one or more cigarettes among high school seniors declined between 1975 and 1986 by approximately 35 percent. Most of the decline occurred between 1977 and 1981. Since 1976, the smoking prevalence among females has consistently been slightly higher than among males. 5. The use of cigars and pipes has declined 80 percent since 1964. 6. Smokeless tobacco use has increased substantially among young men and has declined among older men since 1975. An estimated 8.2 percent of 17- to 19-year-old men were users of smokeless tobacco products in 1986. Appendix B: Toxicity of Nicotine 1. At high exposure levels, nicotine is a potent and potentially lethal poison. Human poisonings occur primarily as a result of accidental ingestion or skin contact with nicotine-containing insecticides or, in children, after ingestion of tobacco or tobacco juices. 2. Mild nicotine intoxication occurs in first-time smokers, non- smoking workers who harvest tobacco leaves, and people who 16 chew excessive amounts of nicotine polacrilex gum. Tolerance to these effects develops rapidly. 3. Nicotine exposure in long-term tobacco users is substantial, affecting many organ systems (Chapters II and III). Pharmace logic actions of nicotine may contribute to the pathogenesis of smoking-related diseases, although direct causation has not yet been determined. Of particular concern are cardiovascular disease, complications of hypertension, reproductive disorders, cancer, and gastrointestinal disorders, including peptic ulcer disease and gastroesophageal reflux. 4. The risks of short-term nicotine replacement therapy as an aid to smoking cessation in healthy people are acceptable and substantially outweighed by the risks of cigarette smoking. 17 References AMERI(`XN PSYCIII,\TRIC` ASSOCIATION. Diagno,stic und Staf~slic.al Manual of Mental Dtsortlr~ Washington. D.C: American Psychiatric Association, 1980. AMERICAN PSYCHIATRIC ASSOCIATION. nin,onoat;c and Statrstictr/ Manual of Mental D/sortfcv~ Third Editron, Kevijcd. Washington, D.C.: American Psychiatric Association. 1987 ARMSTRONG-JONES, R. Tobacco, its use and abuse. From the nervous and mental aspect. Pro<,titlor:er 118%19. 1927. DORSEY. J.L. Control of the tobacco habit. Arruais ofIntwnaI Medicine 10(4~:628-631, 1936. GRABOWSKI, J.. BELL, C.S. Measltwnzcnt in the Analysis and Treatment ofSmoking Behor,ior. NIDA Researcn Monograph 49. U.S. Department of Health and Human Services. Public Health Service. Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 83.1285. 1983. GRITZ. E.R. Smoking behavior and tobacco abuse. In. Mello. N.K. ted.1 AdLunces in Substance Abusr. Volume 1. Greenwich, Connecticut: JAI Press, 1980, pp. 91-158. HENNINGFIELD, J.E. Behavioral pharmacology of cigarette smoking. In: Thompson, T Dews. P.B., Barrett, J.E. teds.1 ilrlI,trnces in Beha~~wral Pharmacology, Volume 4. Orlando: Academic Press. 1984. pp. 131-210. clARVIK, M.E.. CIJLLEN, J.W., GRITZ, E.R., \`OGT, T M., WEST, L.J. (eds.1 Research on Smokrn~ Beha~~ior. NIDA Research Monograph 17. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Sational Institute on Drug Abuse. DHEW Publication No. IADM, X-581. 1977. .JOHNSTON, L.M Tobacco smoking and nicotine. Lancet 2:`742, 1942. KHARKEVICH, D.A. ted.1 I1ortdbook of E.rper.imrntu/ Pharmacologic. Berlin: Spring- er-\?erlag. 1980. pp. 1-H. KRASNEGOR, N.A. fed.1 Self-AtfnzrnistrutIon of Abused Sabstance.s: Methods fiu Stud,v. NIDX Research Monograph 20 U.S. Department of Health, Education. and Welfare, Public Hea!th Service. Alcohol, Drug Abuse, and Mental Health Administration. National Institute on Drug Abuse. DHEW Publication No. tADMl 78-727, 1978. KRASNEGOR, N.A. ted.1 R~~hac~ioral Analysis and Trrutrnent 01` Substance Abuse. NIDA Research Monograph 2. 5. U.S. Department of Health, Education, and Welfare, Public Hralth Service. Alcohol, Drug Abuse, and Mental Health Administration. National Institute on Drug Abuse. DHEW Publication No. tADMl 79-839. 1979a. KRASNEGOR, N.A. ced.1 The Bc~har~ioral Aspects of Smokrng. NIDA Research >fIonograph 26. U.S. Department ot Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. iADMl 79-888, 197913. KRASNEGOR. NA led.1 (`i,qarrtfr Snrnkin~ ns o Dqxwdc~nw Process. NIDA Research Monograph 23 U.S. Department of Health. Education. and Welfare, Public Health Service. Alcohol, Drug Abuse. and Mental Health Administration. National Institute on Drug Abuse. DHEW Publication No. !ADMl 79-800. 1979c. LANCET (Editorial I :%70. .March 15, 1857. LANGLEY. J.N.. DICKINSON. W.L On the local paralysis of the peripheral ganglia and on the connexion of different classes of nerve fibers with them. Proc. Roy11 .`+K~. Londm 46:4'3-431. 1889. LEWIS. L. Phanfostic~a: .\-arrvtrc- and Strmulating Drags. Their Use and Abuse. London: Paul. Trench, Trubner. 1931. ROBERT, J 0. The Stan, of Tobacco in Anrerrca. Chapel Hill: University of North Carolina Press. 1949. 18 RUSSELL, M.A.H. Cigarette smoking. Natural history of a dependence of disorder. British Journal of Medical Psychology 4411):1-16. May 1971. RUSSELL, M.A.H. Tobacco smoking and nicotine dependence. In: Gibbins. R.J.. Israel. Y.. Kalant. H., Popham, R.E.. Schmidt, W , Smart, R.G. teds.1 Research Adcbances in Alcohol and Drug Problems. New York: John Wiley and Sons, 1976. pp. 1-47 U.S DEPARTMENT OF HEALTH AND HUMAN SER\`ICES. The Health C;mse- quences of Smoking for Women. A Report of the Sur~cw CerlwaI. U S. Department of Health and Human Services, Public Health Service, Office of the Sissistant Secretary for Health, Office on Smoking and Health. 1980. U.S. DEPARTMENT OF HEALTH AND HlJhIAS SER\.ICES The Health (hnse- quences ofSmoklng: The Changing Cigarette. A Report of the Surgeon General. L1.S. Department of Health and Human Services, Public Health Service. Office of the Assistant Secretary for Health, Office on Smoking and Health. DHHS Pubiication No. !PHS, 81-50156, 1981. U.S. DEPARTMENT OF HEALTH AND HUM.4S SERVICES. The Health Cor~w quences of Smoking: Cancer. A Report of the Sur;peon (;efrerul. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. ~PHSI 82-50179. 1962. US. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cardiocascular Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. IPHS~ 84-50204, 1983a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Why People Smoke Cigarettes. U.S. Department of Health and Human Services, Public Health Service. 1983b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking. Chronic Obstructilse Lung Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services. Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHSI 8450205. 1984a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Drug 4buse and Drug Abuse Research, Triennial Report to Congress from the Secretup, Department of Health and Human Ser[,ices. U.S. Department of Health and Human Services, Public Health Service, Alcohol. Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. IADMI 85-1372, January 1984b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer and Chronic Lung Disease in the Workplace. A Report of the Surgeon General. IJ.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. tPHS, 8% 50207, 1985. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Inuoluntayv Smoking. A Report of the Surgeon General. US. Depart- ment of Health and Human Services, Public Health Service. Office on Smoking and Health. DHHS Publication No. lCDCi 87-8398, 1986a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Using Smokeless Tobnrcu. .4 Report of the Adc,woyl, Committee to the Surgeon General. U.S. Department of Health and Human Services, Public Health Service. National Institutes of Health. NIH Publication No. 862874, 1986b. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE The Health Consequences of Smoking. A Report of the Surgeotl Gner-ol: 1971. U.S Department of Health, Education, and Welfare, Public Health Service. Health Services and Mental Health Admmistration. DHEW Publication No. `IISMi 71-7.513. 1971. 19 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Conseywtzces of Smoking. A Report of the Surgeon General: 1972. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. lHSM) 72-7516, 1972. US. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Conseyrrences of Smoking, 1975. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control. DHEW Publication NO. (CDCj 77-8704. 1975. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Consequences of Smoking, 1977.1978. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 7950065, 1978. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health: A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066, 1979. U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. U.S. Department of Health, Education. and Welfare, Public Health Service, Center for Disease Control. PHS Publication No. 1103, 1964. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Public Sercice Reuiewt 1967. US. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. PHS Publica- tion No. 1696 Revised, 1968a. US. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, 1968. Supplement to the 1967 Public Health Seruice Review. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. 1696, 1968b. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking 1969. Supplement to the 1967 Public Health Service Review. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. 1969-2, 1969. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. (HSM) 73-8704, 1973. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, 1974. U.S. Department of Health. Education, and Welfare, Public Health Service, Center for Disease Control. DHEW Publication No. (CD0 74-8704, 1974. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Reference Edition: 1976. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control. DHEW Publication No. (CDC) 78-8357, 1976. VOr,LE, R.L. Nicotinic ganglion-stimulating agents. Pharmacologv of Gangglionic Transmission 9:281-307. 1980. 20 CHAPTER II NICOTINE: PHARMACOKINETICS, METABOLISM, AND PHARMACODYNAMICS CONTENTS ___ Introduction ........................................................... 25 ~-~ Nicotine and Other Alkaloids in Various Tobacco Prod- ucts ................................................................... 26 Pharmacokinetics and Metabolism of Nicotine ............ .29 Absorption of Nicotine ..................................... .29 Distribution of Nicotine in Body Tissues ............. ..3 1 Elimination of Nicot.ine 33 ....................................... Pathways of Nicotine Metabolism ................ 34 Rate of Nicotine Metabolism ........................ .37 Renal Excretion ....................................... .37 Nicotine and Cotinine Blood Levels During Tobacco Use .............................................................. 37 Nicotine Levels ........................................... 37 Cotinine Levels ........................................... 38 Intake of Nicotine ............................................. 40 Cigarette Smoking ...................................... .40 Elimination Rate as a Determinant of Nicotine Intake by Cigarette Smoking .................... .40 Biochemical Markers of Nicotine Intake ........ .41 Analytical Methods for Measuring Nicotine and Cotinine in Biological Fluids ............................ .42 Pharmacodynamics of Nicotine ................................. .43 General Considerations ....................................... 43 Dose-Response .................................................. .44 Tolerance ......................................................... 44 Acute Sensitivity .............................................. .46 Human Studies ........................................... 46 Animal Studies ........................................... 46 Mechanisms of Differences in Acute Sensitivity. .............................................. 47 Tachyphylaxis (Acute Tolerance) ......................... .47 Human Studies .......................................... .47 Animal Studies ........................................... 49 Mechanisms of Tachyphylaxis ...................... .49 Chronic Tolerance ............................................. .50 Human Studies. ......................................... .50 23 Animal Studies ........................................... 51 Mechanisms of Chronic Tolerance ................. .53 Pharmacodynamics of Nicotine and Cigarette Smok- ing ............................................................... 55 Constituents of Tobacco Smoke Other Than Nicotine With Potential Behavioral Effects .......................... .56 Minor Tobacco Alkaloids .................................... .56 "Tar" and Selected Constituents of Tobacco Smoke Which Contribute to Taste and Aroma .............. .58 Carbon Monoxide ............................................... 59 Acetaldehyde and Other Smoke Constituents ......... .60 Summary and Conclusions ....................................... .60 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62 24 introduction Chemicals with behavioral and physiological activity are delivered to tobacco users when they smoke a cigarette or use other tobacco products. Whether these chemicals are absorbed in quantities that are of biological significance and whether such absorption is related to the behavior of the tobacco user are critical issues in understand- ing their role in addictive tobacco use. The scientific study of the absorption processes, distribution within the body, and elimination from the body of drugs and chemicals is called pharmacokinetics. The study of drug and other chemical actions on the body, over time, is called pharmacodynamics. Pharmacokinetic and pharmacodynamic studies can be done separately or together. An example of the latter is when a drug is administered and its concentrations in the blood and its behavioral and physiological actions are measured over time. Such studies can reveal relationships among the dose of a drug, levels in the blood, and effects on body functions. The pharmacokinetics and pharmacodynamics of some tobacco smoke constituents, particularly nicotine and carbon monoxide, have been extensively studied. These studies show an orderly relationship between the use of tobacco and the absorption of nicotine. Similarly, the effects on behavioral and physiological functions, although complex, are orderly and related to the pharmacokinetics of nicotine. These data will be reviewed in this Section. Research shows that nicotine is well absorbed from tobacco; that it is distributed rapidly and in biologically active concentrations to body organs, including the brain; and that nicotine is the major cause of the predominant behavioral effects of tobacco and some of its physiologic conse- quences. One effect of nicotine, development of tolerance to its own actions, is similar to that produced by other addicting drugs. Tolerance refers to decreasing responsiveness to a drug or chemical such that larger doses are required to produce the same magnitude of effect. Tolerance to many actions of nicotine occurs in animals and humans. Evidence for tolerance to nicotine and mechanisms of tolerance development will be reviewed in this Chapter (see also Chapter VI). Although nicotine has long been considered as the primary pharmacologic reason for tobacco use, and the source of a number of the physiological effects of tobacco, thousands of other chemicals are present in tobacco. Most of these are delivered in such small quantities that they appear to have little OF no behavioral conse- quence. However, a few chemicals do appear to have behavioral effects and there is a potential for numerous chemical interactions that conceivably could have behavioral consequences. This Chapter will conclude with an examination of tobacco smoke constituents 25 other than nicotine that rnay contribute to behavioral effects of cigarette smoking. The toxicity of nicotine is discussed in detail in Appendix B. Nicotine and Other Alkaloids in Various Tobacco Products Nicotine is a tertiary amine composed of a pyridine and a pgrrolidine ring (Figure 1). Nicotine may exist in two different three- dimensionally structured shapes, called stereoisomers. Tobacco contains only (S)-nicotine (also called l-nicotine), which is the most pharmacoloqicaliy active form. Tobacco smoke also contains the less potent (Rj-nicotine (also called d-nicotine) in quantities up to 10 percent of the total nicotine present (Pool, Godin, Crooks 1985). Presumably some racemization occurs during the combustion pro- cess. The nicotine yield of cigarettes, as determined by standardized smoking machine tests, is available for most brands. However, the amount of nicotine in cigarettes or other tobacco products is not specified by manufacturers. Because tobacco is a plant product, there are differences in the amount of nicotine among and within different types and strains of tobacco, including variations in different parts of the plant, as well as differences related to growing conditions. Table 1 shows concentrations of nicotine and other alkaloids in several different tobacco leaves used in making commercial tobacco prod- ucts. Witliin a tobacco plant, leaves harvested from higher stalk positions have higher concentrations of nicotine than from lower stalk positions; ribs and stems of the leaves have the least (Rath- kamp, Tso, Hoffmann 19731. Combining different varieties of tobacco and different parts of the plant is a way to change the nicotine concentration of commercial tobacco. In a study of amounts of nicotine in the tobacco of 15 American cigarette brands of differing machine-determined yields (Benowitz, Hall et al. 19831, tobacco contained on average 1.5 percent nicotine by weight. Nicotine yield of the cigarettes, as defined by Federal Trade Commission smoking machine tests, was correlated inversely with nicotine concentrations in the tobacco. Thus. tobacco of lower- yield cigarettes tended to have higher concentrations of nicotine than did tobacco of higher-yield cigarettes. However, lower-yield cigarettes also contained less tobacco per cigarette, so the total amount of nicotine contained per cigarette, averaging 8.4 mg, was similar in different brands. Thus, low-yield cigarettes are low yield not because of lower concentrations of nicotine in the tobacco, but because they contain less tobacco and have characteristics which remove tar and nicotine by filtration or dilution of smoke with air. Concentrations of nicotine in commercial tobacco products are summarized in Table 2. 26 NICOTINE NORNICOTINE N'-NITROSONORNICOTINE NICOTINE N-OXIDE (OXYNlCOTINEl ANATAGINE ANABASINE N'-METHYLANATABINE N`-METHYLANABASINE NIMTYRINE NORNICOTYRINE COTININE 6'.OXOANABASINE ANABASEINE 2.3'.DIPYPIDYL METANICOTINE PSEUDCOXYNICOTINE FIGURE L-Chemical structures of nicotine and minor tobacco alkaloids sOL'K(`E IRIP IY*:i Although the major alkaloid in t.obacco is nicotine, there are other alkaloids in tobacco which may be of pharmacologic importance. These include nornicotine, anabasine, myosmine, nicotyrine, and anatabine (Figure 1). These substances make up 8 to 12 percent of the total alkaloid content of tobacco products (Table 1) (Piade and Hoffmann 1980). In some varieties of tobacco, nornicotine concentra- tions exceed those of nicotine (Schmeltz and Hoffmann 1977). Typical quantities of the minor alkaloids in the smoke of one cigarette are: nornicotine (27 to 88 pg), cotinine (9 to 50 pg), anabasine (3 to 12 pgl, anatabine (4 to 14 pg). myosmine (9 pg), and 2,3' dipyridyl (7 to 27 pg). N'-methylanabasine, nicotyrine, nornicoty- rine, and nicotine-N'-oxide have also been identified in cigarette smoke (Schmeltz and Hoffmann 1977). Puffing characteristics, especially puff frequency, influence the delivery of the component alkaloids (Bush, Griinwald, Davis 1972). 27 TABLE l.-Alkaloid content of various tobaccos (mg/kg, dry basis) Dar-k commercial tobacco Anstabme 360 3x0 570 600 Anabasine 140 150 99 150 cotlnlne 195 140 90 40 M\oam,ne 45 50 60 30 2.3 -Dlpwld~l 1w 110 30 10 TABLE 2.-Nicotine content of various tobacco products Nornicotine and anabasine have pharmacologic activity qualita- tively similar to that of nicotine, with potencies of 20 to 75 percent compared with that of nicotine, depending on the test system and the animal (Clark, Rand, Vanov 1965). In addition to direct activity, some of the minor alkaloids may influence the effects of nicotine. For example, nicotyrine inhibits the metabolism of nicotine in animals (Stalhandske and Slanina 1982). The pharmacology of the minor tobacco alkaloids is discussed in more detail in the last section of this Chapter. 28 Pharmacokinetics and Metabolism of Nicotine Absorption of Nicotine Nicotine is distilled from burning tobacco and is carried proximal- ly on tar droplets (mass median diameter 0.3 to 0.5 urn) and probably also in the vapor phase (Eudy et al. 19851, which are inhaled. Absorption of nicotine across biological membranes depends on pH (Armitage and Turner 1970; Schievelbein et al. 1973). Nicotine is a weak base with a pKa (index of ionic dissociation) of 8.0 (aqueous solution, 25oC). This means that at pH 8.0, 50 percent of nicotine is ionized and 50 percent is nonionized. In its ionized state, such as in acidic environments, nicotine does not rapidly cross membranes. The pH of tobacco smoke is important in determining absorption of nicotine from different sites within the body. The pH of individual puffs of cigarettes made of flue-cured tobacco, the predominant tobacco in most American cigarettes, is acidic and decreases progres- sively with sequential puffs from pH 6.0 to 5.5 (Brunnemann and Hoffmann 1974). At these pHs, the nicotine is almost completely ionized. As a consequence, there is little buccal absorption of nicotine from cigarette smoke, even when it is held in the mouth (Gori, Benowitz, Lynch 1986). The smoke from air-cured tobaccos, the predominant tobacco in pipes, cigars, and in a few European cigarettes, is alkaline with progressive puffs increasing its pH from 6.5 to 7.5 or higher (Brunneman and Hoffmann 1974). At alkaline pH, nicotine is largely nonionized and readily crosses membranes. Nicotine from products delivering smoke of alkaline pH is well absorbed through the mouth (Armitage et al. 1978; Russell, Raw, Jarvis 1980). When tobacco smoke reaches the small airways and alveoli of the lung, the nicotine is rapidly absorbed. The rapid absorption of nicotine from cigarette smoke through the lung occurs because of the huge surface area of the alveoli and small airways and because of dissolution of nicotine at physiological pH (approximately 7.4), which facilitates transfer across cell membranes. Concentrations of nic- otine in blood rise quickly during cigarette smoking and peak at its completion (Figure 2). Armitage and coworkers (19751, measuring exhalation of radiolabeled nicotine, found that four cigarette smok- ers absorbed 82 to 92 percent of the nicotine in mainstream smoke, another smoker presumed to be a noninhaler absorbed 29 percent, and three nonsmokers (who were instructed to smoke as deeply as possible) absorbed 30 to 66 percent. Chewing tobacco, snuff, and nicotine polacrilex gum are of alkaline pH as a result of tobacco selection and/or buffering with additives by the manufacturer. The alkaline pH facilitates absorp- tion of nicotine through mucous membranes. The rate of nicotine absorption from smokeless tobacco depends on the product and the 29 M Cigarettes A-----A Oral snuff O--Q Chewing tobacco F--O Nicotine gum N=lo -10 0 30 60 90 120 Minutes FIGURE 2.-Blood nicotine concentrations during and after smoking cigarettes (1 l/3 cigarettes), using oral snuff (2.5 g), using chewing tobacco (average, 7.9 g), and chewing nicotine gum (two 2-mg pieces) `0, `I<(`?: Ht.ni.x!:, ,` /h`,,' !,.`A' /PI, 1 . :11,1 1, 10 I, SW ,I 11, ,111 :! 1$11,,1 o, 13, c,~z,w,~P, da>. blood ..1,11~1~?, nrrr <1?llrrlK ,.1-l !W11111~ !I ? 11?\1 .l.!>l~l:ilA x IL,i'i'!`.' SOL'K(`E Rrnm\,t/ ir;~i( .l,ic ,h l'lhl 39 throughout the day than in nicotine concentrations. As expected, there is a gradual increase in cotinine levels during the day, peaking at the end of smoking and persisting in high concentrations overnight. Intake of Nicotine Cigarette Smoking Nicotine intake from single cigarettes has been measured by spiking cigarettes with "C-labeled nicotine (Armitage et al. 1975). That study of eight subjects, each smoking a single filter-tipped cigarette, indicated an intake range of 0.36 to 2.62 mg. Intake was higher in smokers than in nonsmokers. Intake of nicotine from smoking a single cigarette or with daily cigarette smoking has been estimated by methods similar to those used in drug bioavailability studies (Benowitz and Jacob 1984; Feyerabend, Ings, Russell 1985). Metabolic clearance of nicotine was determined after i.v. injection. Metabolic clearance data were then used in conjunction with blood and urinary concentrations of nicotine measured during a period of smoking to determine the intake of nicotine. In five subjects, average intake of nicotine per cigarette was 1.06 mg (range, 0.58 to 1.49 mg) (Feyerabend, Ings, Russell 19851. In 22 cigarette smokers, 13 men and 9 women who smoked an average of 36 cigarettes/day (range 20 to 621, the average daily intake was 37.6 mg, with a range from 10.5 to 78.6 mg (Benowitz and Jacob 1984). Nicotine intake per cigarette averaged 1.0 mg (range 0.37 to 1.56 mg). Intake per cigarette did not correlate with yields obtained by smoking machine using standard Federal Trade Commission methods. This is because smoking machines smoke cigarettes in a uniform way, using a fixed puff volume (35 mL1, flow rate (over 2 secl, and interval (every minute). Smokers smoke cigarettes differently, changing their puffing behav- ior to obtain the desired amount of tobacco smoke and nicotine. Elimination Rate as a Determinant of Nicotine Intake by Cigarette Smoking There is considerable evidence that smokers adjust their smoking behavior to try to regulate or maintain a particular level of nicotine in the body (Gritz 1980; Russell 1976). For example, when the availability of cigarettes is restricted, habitual smokers can increase intake of nicotine per cigarette 300 percent compared with the intake of unrestrict,ed smoking (Benowitz, Jacob, Koslowski et al. 1986). Techniques for measuring daily intake of nicotine (Benowitz and Jacob 1984) have been applied to study the influence of elimination on nicotine intake. The rate of renal elimination of nicotine was manipulated by administration of ammonium chloride or sodium 40 bicarbonate to acidify or alkalinize the urine: respectively (Benowitz and Jacob 1985). Compared with daily excretion during placebo treatment (3.9 mg nicotine/day), acid loading increased (to 12 mglday) and alkaline loading decreased (to 0.9 mglday) daily excretion of nicotine. The total intake of nicotine averaged 38 mg/day. Average blood nicotine concentrations were similar in placebo and bicarbonate treatment conditions but were 15 percent lower during ammonium chloride treatment. Daily intake of nicotine was 18 percent higher during acid loading, indicating compensation for increased urinary loss. The compensatory increase in nicotine consumption was only partial, replacing about half of the excess urinary nicotine loss. Bicarbonate treatment had no effect on nicotine consumption, consistent with the small magnitude of effect on excretions of nicotine in comparison to total daily intake. These results seem compatible with the suggestion of Schachter (1978) that emotional stress, which results in more acidic urine, might accelerate nicotine elimination from the body and thereby increase cigarette smoking. But caution must be exercised in applying these findings to usual smoking situations. These studies were performed under conditions of extreme urinary acidification or alkalinization, so that the changes in renal clearance would be maximized, Even with extreme differences in urinary pH, differ- ences in overall nicotine elimination rate and smoking behavior were modest. This is because renal excretion is a minor pathway for elimination of nicotine; most is metabolized. Smaller changes in urinary pH, such as occur spontaneously throughout the day or that might be related to stressful events, would not be expected to substantially influence nicotine elimination or smoking behavior. Biochemical Markers of Nicotine Intake Absorption of nicotine from tobacco smoke provides a means of verification and quantitation of tobacco consumption. The general strategy is to measure concentrations of nicotine, its metabolites (such as cotinine), or other chemicals associated with tobacco smoke in biological fluids such as blood, urine, or saliva. Different measures vary in sensitivity, specificity, and difficulty of analysis. Different investigators have used blood or urinary nicotine concentrations, blood or salivary or urinary cotinine concentrations, expired carbon monoxide or carboxyhemoglobin concentrations, or plasma or sali- vary thiocyanate (a metabolite of hydrogen cyanide, a vapor phase constituent) concentrations as measures of tobacco smoke consump- tion. Relationships among daily intake of nicotine, daily exposure to nicotine (that is, blood concentrations of nicotine integrated over 24 hr), various parameters of cigarette consumption, and different measures of nicotine intake have been examined experimentally 41 during ad libitum cigarette smoking on a research ward (Benowitz and Jacob 1984). The best biochemical correlate to nicotine intake and exposure in this study was a random blood nicotine concentra- tion measured at 4 p.m. This level did not depend on when the last cigarette was smoked. This finding is consistent with the observation that nicotine levels accumulate throughout the day and plateau in the early afternoon (see Figure 5). At steady state, with regular smoking throughout the day, there should be a reasonably good correlation between nicotin