[Federal Register: August 11, 1995 (Volume 60, Number 155)]
[Notices]
[Page 41539-41568]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]

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[[Page 41539]]

B. NICOTINE IS ADDICTIVE

1. Major Public Health Groups and Leading Experts Concur
    Until the 1980's, nicotine was not widely appreciated to be an
addictive drug. Within the past 15 years, however, broad international
agreement has developed within the scientific community that nicotine
in tobacco is a highly addictive or dependence-producing substance. The
terms ``addictive'' and ``dependence-producing'' are generally used
interchangeably; both terms refer to the persistent and repetitive
intake of psychoactive substances despite evidence of harm and a desire
to quit.<SUP>31 Some scientific organizations have replaced the term
``addictive'' with ``dependence-producing'' to shift the focus to
dependent patterns of behavior and away from the moral and social
issues associated with addiction.<SUP>32 Both terms are equally
relevant for purposes of understanding the drug effects of nicotine,
and in this section, the terms will be used interchangeably. The
current broad recognition that nicotine is an addictive substance has
been due to: (1) an evolution in the understanding of the science of
addiction (e.g., the recognition that a substance does not have to be
intoxicating when used at addictive levels); <SUP>33 (2)
epidemiological evidence establishing the high percentage of tobacco

[[Page 41540]]
users who display the clinical symptoms of addiction; and (3) the
accumulation of evidence in the last two decades demonstrating, in both
laboratory animals and humans, that nicotine is a psychoactive drug
that produces pharmacological effects similar to those seen with other
addictive substances.

    \31\ Surgeon General's Report. 1988. Nicotine Addiction. Page 7.
    \32\ Id. at p. 11.
    \33\ 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. (Hereafter cited as Surgeon General's Report. 1964.
Smoking and Health.) The 1964 Surgeon General's Report considered
nicotine to be ``habituating'' rather than addictive because it did
not appear to produce intoxication or cause physical dependence, and
its users did not tend to increase the dose. These were considered
to be the features of addictive drugs.
    At that time, cocaine and amphetamines were also regarded as not
causing physical dependence. See:
    Wesson DR, Smith DE. Cocaine: Its Use for Central Nervous System
Stimulation Including Recreational and Medical Uses. In: Cocaine:
1977. NIDA Research Monograph. DHEW Publication Number (ADM) 77-471.
Department of Health, Education, and Welfare. Rockville, MD. 1977.
Page 145.
    Winkler A. The Etiology of Opioid Dependence. In: Opioid
Dependence: Mechanisms and Treatment. Winkler A (ed). 1980. Plenum
Press. New York, NY. Page 26.
    Winkler A. The Problems of Drug Dependence. In: Opioid
Dependence, supra, at p. 13.
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    Scientists' understanding of addiction has evolved over the past 30
years. Earlier definitions of addiction suggested that addiction was
predominately the result of weakness in the personality of the user
rather than the result of the pharmacological effects of the addicting
substance.<SUP>34 More recently, animal and human research has revealed
the pharmacological basis of addiction.<SUP>35 It has been shown that
addictive substances produce

[[Page 41541]]
definable chemical effects in the brain that reinforce continued use of
these substances and cause physiological and/or psychological
dependence on these substances.<SUP>36 The contemporary understanding
of addiction also places a major emphasis on the intrinsic
pharmacological ability of a substance to cause compulsive, regular use
and on the inability of users to stop using the substance, even when
they are strongly motivated to do so.<SUP>37

    \34\ See: The Committee on Nomenclature and Statistics of the
American Psychiatric Association. 1952. Diagnostic and Statistical
Manual, Mental Disorders with Special Supplement on Plans for
Revision. American Psychiatric Association. Washington, DC. Page 39.
    Surgeon General's Report. 1964. Smoking and Health. Page 351.
    Surgeon General's Report. 1988. Nicotine Addiction. Page 248.
    \35\ See: Hanson HM, Ivester CA, Morton BR. Nicotine self-
administration in rats. In: Cigarette Smoking as a Dependence
Process, NIDA Research Monograph 23. U.S. Department of Health,
Education, and Welfare. 1979. Pages 70-90.
    Goldberg SR, Spealman RD, Goldberg DM. Persistent behavior at
high rates maintained by intravenous self-administration of
nicotine. Science. 1981;214:573-575.
    Griffiths RR, Henningfield JE, Bigelow GE. Human cigarette
smoking: manipulation of number of puffs per bout, interbout
interval and nicotine dose. J Pharmacol Exp Ther. 1981;220(2):256-
265.
    Griffiths RR, Henningfield JE. Pharmacology of cigarette smoking
behavior. Trends Pharmacol Sci. 1982;3:260-263.
    Henningfield JE, Goldberg SR. Nicotine as a reinforcer in human
subjects and laboratory animals. Pharmacol Biochem Behav.
1983;19(6):989-992.
    \36\ Surgeon General's Report. 1988. Nicotine Addiction. Pages
170-279.
    \37\ See: American Psychiatric Association. 1994. Diagnostic and
Statistical Manual of Mental Disorders (Fourth Edition). American
Psychiatric Association. Washington, DC. Page 176. (Hereafter cited
as American Psychiatric Association. 1994. DSM IV.)
    World Health Organization. 1992. The ICD-10 Classification of
Mental and Behavioural Disorders: Clinical Descriptions and
Diagnostic Guidelines. World Health Organization. Geneva,
Switzerland. Page 76. (Hereafter cited as World Heath Organization.
1992. ICD-10.)
    Surgeon General's Report. 1988. Nicotine Addiction. Pages 248-
250.
---------------------------------------------------------------------------

    In 1986, the Office of the U.S. Surgeon General issued a report
concluding that nicotine in smokeless tobacco is addictive.<SUP>38 In
1988, the Surgeon General issued an additional report concluding that
nicotine in cigarettes and other forms of tobacco is addictive.<SUP>39

    \38\ U.S. Department of Health and Human Services. The Health
Consequences of Using Smokeless Tobacco: A Report of the Advisory
Committee to the Surgeon General, 1986. U.S. Department of Health
and Human Services, Public Health Service, Bethesda, MD. NIH
Publication No. 86-2874, April 1986. Pages 144-145, 166. (Hereafter
cited as Surgeon General's Report. 1986. Smokeless Tobacco.)
    \39\ Surgeon General's Report. 1988. Nicotine Addiction. Page 9.
---------------------------------------------------------------------------

    The landmark 1988 report by the Surgeon General (``the 1988
report'') noted that the

[[Page 41542]]
main features of the definitions of addiction used by groups throughout
the world are highly consistent. The 1988 report adopted a set of
criteria based on the common criteria of these definitions. The primary
criteria for drug dependence relied on in the Surgeon General's Report
were:
    1. highly controlled or compulsive use (even despite a desire, or
repeated attempts, to quit);
    2. psychoactive (mood altering) effects produced by the action of
the drug substance on the brain; and
    3. drug-motivated behavior caused by ``reinforcing'' effects of the
psychoactive substance.<SUP>40

    \40\ Id. at p. 7.
---------------------------------------------------------------------------

    The 1988 report identified the following additional criteria for
identifying drug dependence:
    <bullet> repetitive and stereotyped patterns of use;
    <bullet> persistent use despite adverse physical, social or
psychological effects;
    <bullet> quitting episodes followed by relapse;
    <bullet> recurrent cravings for the drug, especially during
abstinence;
    <bullet> development of tolerance (diminished responsiveness to the
drug's effects, sometimes accompanied by increased intake);
    <bullet> withdrawal symptoms that can motivate further use of the
drug; and
    <bullet> pleasant (euphoriant) effects produced by the drug.<SUP>41

    \41\ Id. at pp. 7-8.
---------------------------------------------------------------------------

    The 1988 report exhaustively reviewed the available data on the
effects of nicotine on the body, the metabolism of nicotine within the
body, the dependence-producing properties of

[[Page 41543]]
nicotine, tobacco use compared to other drug dependencies, the
pharmacological effects of nicotine that promote tobacco use, and
treatment of tobacco dependence. Applying the criteria for drug
dependence listed above to these data, the 1988 Surgeon General's
Report concluded that:
    1. Cigarettes and other forms of tobacco are addicting;
    2. Nicotine is the drug in tobacco that causes addiction; and
    3. The pharmacological and behavioral processes that determine
tobacco addiction are similar to those that determine addiction to
drugs such as heroin and cocaine.<SUP>42

    \42\ Id. at pp. 6-9.
---------------------------------------------------------------------------

    Major public health organizations and leading experts have
concluded that nicotine is an addictive or dependence-producing
substance.
    <bullet> The World Health Organization, the American Medical
Association, the American Psychiatric Association, the American
Psychological Association, the Royal Society of Canada, and the Medical
Research Council in the United Kingdom have all recognized that
nicotine is an addictive or dependence-producing drug.<SUP>43

    \43\ See: World Health Organization. 1974. World Health
Organization Technical Report Series No. 551. WHO Expert Committee
on Drug Dependence, Twentieth Report. World Health Organization.
Geneva, Switzerland. Pages 15-16.
    World Health Organization. 1992. ICD-10. Page 324.
    American Medical Association. 1993 AMA Policy Compendium. Ethyl
alcohol and nicotine as addictive drugs. American Medical
Association. 1993.
    American Psychiatric Association. 1980. Quick Reference to the
Diagnostic Criteria from DSM-III. American Psychiatric Association.
Washington, DC. Page 99.
    American Psychological Association. Statement of the American
Psychological Association before the U.S. House of Representatives,
Committee on Energy and Commerce, Subcommittee on Health and the
Environment on the subject of The 1988 Surgeon General's Report, The
Health Consequences of Smoking: Nicotine Addiction. July 29, 1988.
Page 1.
    Royal Society of Canada. Tobacco, Nicotine, and Addiction: A
Committee Report. Prepared at the request of The Royal Society of
Canada for The Health Protection Branch, Health and Welfare Canada.
August 31, 1989. Pages 8-9.
    Medical Research Council. The Basis of Drug Dependence. MRC
Field Review. Medical Research Council. 1994. Page 11.

[[Page 41544]]

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    <bullet> On August 2, 1994, FDA's Drug Abuse Advisory Committee, an
independent group composed primarily of experts on addiction science,
concluded that cigarettes and other forms of tobacco are addicting, and
that nicotine is the drug in tobacco that causes addiction. The FDA
advisory committee also concluded that all currently marketed
cigarettes contained addicting levels of nicotine.
    <bullet> In a 1991 survey, the vast majority of scientists funded
by the tobacco industry stated that they believed that cigarette
smoking is addictive.<SUP>44 According to this report, among the
principal investigators of research projects funded by the tobacco
industry in 1989, 83.3% strongly agreed and 15.3% agreed somewhat that
cigarette smoking is addictive.<SUP>45

    \44\ Cummings KM, Sciandra R, Gingrass A, Davis R. What
scientists funded by the tobacco industry believe about the hazards
of cigarette smoking. Am. J of Pub Health. 1991;81(7)894.
    \45\ Id. at p. 895.
---------------------------------------------------------------------------

    Furthermore, the medical community has, since the early 1980's,
come to recognize that nicotine addiction is a clinical disorder. The
Diagnostic and Statistical Manual of Mental Disorders (DSM), published
by the American Psychiatric Association, and the International
Statistical Classification of Disease and Related Health Problems
(ICD), published by the

[[Page 41545]]
World Health Organization, use very similar criteria to identify
dependence.<SUP>46 Like the criteria specified by the U.S. Surgeon
General, these criteria emphasize the ability of a substance to produce
compulsive use, withdrawal and/or tolerance, inability to control or
terminate drug use despite efforts to quit or reduce use, and continued
use despite harmful effects. (See Appendix 1 for a description and
history of the criteria for identifying addiction.)

    \46\ The most recent version of DSM (DSM-IV) defines ``substance
dependence'' as substance use that produces three or more of the
following symptoms in users:
    <bullet> marked tolerance;
    <bullet> a withdrawal syndrome and/or the substance is taken to
relieve or avoid withdrawal symptoms;
    <bullet> the substance is often taken in larger amounts over a
longer period of time than intended;
    <bullet> persistent desire or unsuccessful efforts to cut down
or control substance use;
    <bullet> a great deal of time spent in activities necessary to
obtain the substance, use the substance (e.g., chain smoking), or
recover from its effects;
    <bullet> important social, occupational, or recreational
activities are given up or reduced because of substance use; and
    <bullet> use is continued despite knowledge of having a
persistent or recurrent physical or psychological problem that is
likely to have been caused or exacerbated by the substance.
    DSM-IV explains how the following criteria are apparent in
nicotine dependence: tolerance, withdrawal, desire to quit, great
deal of time using, and continued use despite medical problems.
American Psychiatric Association. 1994. DSM IV. Pages 181, 243.
    ``Dependence syndrome'' is characterized under the ICD-10 as a
cluster of effects after repeated use of a substance resulting in
three or more of the following symptoms:
    <bullet> a strong desire or sense of compulsion to take the
substance;
    <bullet> an impaired capacity to control substance-taking
behavior in terms of its onset, termination, or levels of use;
    <bullet> substance use with the intention of relieving
withdrawal symptoms and with awareness that this strategy is
effective;
    <bullet> a physiological withdrawal state;
    <bullet> evidence of tolerance such that the increased doses of
the substance are required in order to achieve effects originally
produced by lower doses;
    <bullet> progressive neglect of alternative pleasures or
interests in favor of the substance; and
    <bullet> persisting with substance use despite clear evidence of
overtly harmful consequences.
    World Health Organization. 1992. ICD-10. Pages 75-76, 321.
---------------------------------------------------------------------------

    Nicotine has been recognized as dependence-producing under the DSM
criteria since 1980. The most recent version of DSM (DSM-IV) recognizes
two substance use disorders

[[Page 41546]]
associated with nicotine: nicotine dependence and nicotine
withdrawal.<SUP>47

    \47\ See American Psychiatric Association. 1994. DSM IV, note ,
supra, at p. 99. An individual is classified as having physiologic
(in addition to psychological) dependence on a substance under DSM-
IV if there is evidence of tolerance to or withdrawal from the
substance. Id.
---------------------------------------------------------------------------

    The ICD has included tobacco as a dependence-producing substance
since 1992. Previously, the ICD recognized the existence of tobacco
dependence, but tobacco was treated separately from other addictive
drugs because tobacco differed in its psychotoxic effects<SUP>48 when
used at usual doses. With the publication of ICD-10 in 1992, however,
tobacco was included with the other addictive drugs.<SUP>49

    \48\ World Health Organization. 1978. Mental Disorders: Glossary
and Guide to Their Classification in Accordance with the Ninth
Revision of the International Classification of Diseases. World
Health Organization. Geneva, Switzerland. Page 43.
    \49\ World Health Organization. 1992. ICD-10. Page 75.

[[Page 41547]]

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2. Epidemiological Data Establishes That Tobacco Users Display the
Clinical Symptoms of Addiction

a. Studies Documenting Symptoms of Addiction in Smokers
    Population studies of smokers conducted in recent years clearly
demonstrate that nicotine produces regular, compulsive use, that such
use is persistent despite both attempts to quit and an appreciation of
cigarette's harmful effects, and that abstinence from nicotine produces
withdrawal symptoms:
    Regular, compulsive use:
    <bullet> 87% of people who smoke cigarettes smoke every day;
<SUP>50 and

    \50\ Centers for Disease Control. 1991 National Health Interview
Survey. Atlanta, GA. U.S. Department of Health and Human Services,
1991.
---------------------------------------------------------------------------

    <bullet> Nearly two-thirds of smokers have their first cigarette
within the first half-hour after they wake up.<SUP>51

    \51\ Centers for Disease Control. 1987 National Health Interview
Survey. Atlanta, GA. U.S. Department of Health and Human Services,
1987.
---------------------------------------------------------------------------

    Use persists despite attempts to quit or reduce use:
    <bullet> In one study, 84.3% of those who smoked a pack or more per
day had unsuccessfully tried to reduce the number of cigarettes
smoked.<SUP>52

    \52\ Henningfield JE, Clayton R, Pollin W. Involvement of
tobacco in alcoholism and illicit drug use. British Journal of
Addiction. 1990;85:280.
---------------------------------------------------------------------------

    <bullet> A smoker who makes a serious attempt to stop smoking has a
less than 5% chance of being off cigarettes a year later; <SUP>53

    \53\ Sachs DPL, Leischow SJ. Pharmacologic Approaches to Smoking
Cessation. Clinics in Chest Medicine. 1991;12(4):788.
---------------------------------------------------------------------------

    <bullet> Each year in the United States, 15 million people try to
quit smoking, but less than 3%

[[Page 41548]]
have long-term success; <SUP>54

    \54\  Centers for Disease Control. Morbidity and Mortality
Weekly Report. ``Cigarette Smoking Among Adults-United States,
1993.'' December 23, 1994. Page 927.
---------------------------------------------------------------------------

    <bullet> In one study, 70% of current smokers reported they would
``like to completely stop smoking; <SUP>55 and

    \55\ Id.
---------------------------------------------------------------------------

    <bullet> 83% to 87% of cigarette smokers who smoke more than 26
cigarettes a day believe they are addicted.<SUP>56

    \56\ Substance Abuse and Mental Health Services Administration.
1991/1992 National Household Survey on Drug Abuse. U.S. Department
of Health and Human Services.
---------------------------------------------------------------------------

    Use persists despite harmful consequences:
    <bullet> In one survey, 90% of smokers agreed with the general
proposition that smoking is harmful to health, 65% believed that
smoking had already affected their health, and 77% believed that they
could avoid or decrease serious health problems by quitting smoking;
<SUP>57

    \57\ Thomas RM, Larsen MD. Smoking prevalence, beliefs, and
activities by gender and other demographic indicators. Princeton,
NJ. The Gallup Organization, Inc. 1993.
---------------------------------------------------------------------------

    <bullet> Almost half of the smokers who undergo surgery for lung
cancer resume smoking; <SUP>58 and

    \58\ Davison G, Duffy M. Smoking habits of long term survivors
of surgery for lung cancer. Thorax. 1982;37:331-333.
---------------------------------------------------------------------------

    <bullet> Even after smokers have had their larynxes removed, 40%
try smoking again.<SUP>59

    \59\ West R, Himbury S. Smoking habits after laryngectomy. Br
Med J. 1985;291:514-515.

[[Page 41549]]

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    Abstinence produces withdrawal symptoms:
    <bullet> Abstinence from smoking is often accompanied by powerful
cravings for a cigarette; <SUP>60

    \60\ See: Benowitz NL. Cigarette smoking and nicotine addiction.
Medical Clinics of North America. 1992;76(2):423.
    West R, Schneider N. Craving for Cigarettes. British Journal of
Addiction. 1987;82:407.
---------------------------------------------------------------------------

    <bullet> Smokers in a position to compare the effects of nicotine
with the effects of other addictive drugs say they are comparable;
<SUP>61 and

    \61\ Henningfield JE, Miyasato K, Jasinski DR. Abuse liability
and pharmacodynamic characteristics of intravenous and inhaled
nicotine. J Pharmacol Exp Ther. 1985;234(1):4-5.
---------------------------------------------------------------------------

    <bullet> Nicotine replacement therapy significantly reduces
withdrawal symptoms in smokers who are attempting to quit.<SUP>62

    \62\ NDA 20-076 Habitrol (Ciba), NDA 20-150 Nicotrol (Kabi), NDA
19-983 ProStep (Elan), NDA 20-165 Nicoderm (Alza), NDA 20-066
Nicorette (Merrell Dow).
---------------------------------------------------------------------------

    Data from clinical research evaluating nicotine replacement therapy
(nicotine gum and patches) as aids in smoking cessation support the
conclusion that a high proportion of smokers are addicted. The studies,
submitted to the FDA as part of new drug applications for nicotine
replacement products, were conducted in male and female smokers who
smoked about a pack to a pack and a half of cigarettes (about 20 to 30
cigarettes) per day. The subjects were recruited from the general
population by advertisement, from primary health care settings, and
from medically based smoking cessation programs.<SUP>63

    \63\ Id., NDA's for Habitrol (Ciba), ProStep (Elan), and
Nicoderm (Alza).
---------------------------------------------------------------------------

    Participants in these studies clearly demonstrated addiction to
nicotine delivered from cigarettes. All reported symptoms of nicotine
addiction at trial entry, and all suffered withdrawal symptoms after
smoking cessation. These withdrawal symptoms were relieved

[[Page 41550]]
entirely or partly by medical administration of nicotine.
    Smokers using the above nicotine replacement products (in the
dosage range of 14 to 24 mg/nicotine per day) had an initial quit rate
of about 50%, twice that of smokers receiving placebo. This two-fold
difference was maintained throughout a full year of follow-up, and was
associated with reductions in craving, withdrawal symptoms, and the
desire to smoke.<SUP>64 In studies in which nicotine replacement
therapy was provided for a year or more, relapse rates were nearly half
those of studies in which nicotine replacement was halted after a fixed
interval (usually about 6 to 12 weeks).<SUP>65

    \64\ See: Fiore MC, Smith SS, Jorenby DE, Baker TB. The
effectiveness of the nicotine patch for smoking cessation: a meta-
analysis. JAMA. 1994;271(24):1940-47.
    NDA 20-076 Habitrol (Ciba), NDA 20-150 Nicotrol (Kabi), NDA 19-
983 ProStep (Elan), NDA 20-165 Nicoderm (Alza), NDA 20-066 Nicorette
(Merrell Dow).
    \65\ Id.
---------------------------------------------------------------------------

    Data from these studies demonstrate how tenacious nicotine
addiction is, even for adults who express a strong desire to quit
smoking and who receive optimal medical care. Only half of the patients
studied were able to stop smoking for as long as 1 week, and the long-
term failure rate was more than 80% after patients were withdrawn from
nicotine replacement. The fact that nicotine replacement therapy in
smokers reduces relapse rates provides strong evidence that it is the
nicotine in tobacco products that creates and sustains addiction to
cigarettes.

[[Page 41551]]

b. Studies Documenting Symptoms of Addiction in Smokeless Tobacco Users
    Smokeless tobacco users can also develop a dependence on nicotine
similar to that experienced by cigarette smokers.<SUP>66 The Surgeon
General's 1986 report concluded that smokeless tobacco is
addictive.<SUP>67 This is not surprising, since smokeless tobacco users
can absorb at least as much nicotine as smokers.<SUP>68 The 1986 report
states that:

    \66\ Benowitz NL. Pharmacology of smokeless tobacco use:
nicotine addiction and nicotine-related health consequences. In:
Smokeless Tobacco or Health, An International Perspective. Smoking
and Tobacco Control, Monograph 2. U.S. Department of Health and
Human Services. Public Health Service. National Institutes of
Health. NIH Publication No. 93-3461. 1993. Page 227.
    \67\ Surgeon General's Report.1986. Smokeless Tobacco. Pages
182-183.
    \68\  Surgeon General's Report. 1994. Preventing Tobacco Use
Among Young People. Page 40.
---------------------------------------------------------------------------

    * * * given the nicotine content of smokeless tobacco, its
ability to produce high and sustained blood levels of nicotine, and
the well-established data implicating nicotine as an addictive
substance, one may deduce that smokeless tobacco is capable of
producing addiction in users.<SUP>69

    \69\ Id. at p. 141.
---------------------------------------------------------------------------

    Studies have shown that smokeless tobacco is associated with
compulsive use, <SUP>70 persistent use despite efforts to quit, <SUP>71
persistent use despite harmful consequences, <SUP>72 and

[[Page 41552]]
withdrawal symptoms when use is discontinued.<SUP>73, <SUP>74

    \70\ See Benowitz, note 66, supra, at p. 223.
    \71\ See: Ary DV, Lichtenstein E, Severson HH, Weissman W,
Seeley JR. An in-depth analysis of male adolescent smokeless tobacco
users: interview with users and their fathers. J. Behavioral
Medicine. 1989;12:449-467.
    Severson HH. Enough snuff: ST cessation from the behavioral,
clinical, and public health perspectives. In: Smokeless Tobacco or
Health, An International Perspective. Smoking and Tobacco Control,
Monograph 2. U.S. Department of Health and Human Services. Public
Health Service. National Institutes of Health. NIH Publication No.
93-3461. 1993. Pages 281-282.
    \72\ Connolly GN, Winn DM, Hecht SS, Henningfield JE, Hoffman D,
Walker B. The re-emergence of smokeless tobacco. N. Engl J. Med.
1986;314(16):1020-1026.
    \73\ Hatsukami D, Gust W, Keenan R. Physiologic and subjective
changes from smokeless tobacco withdrawal. Clin Pharmacol Ther.
1987;41(1):103-107.
    \74\ Id.
    See also Severson, note 71, supra, at p. 282.
---------------------------------------------------------------------------

    Fewer clinical and epidemiological data are available on the
prevalence of addiction among smokeless tobacco users than among
smokers. However, some users of smokeless tobacco products do meet
addiction criteria.<SUP>75 A 1986 report of the Office of the Inspector
General of the Department of Health and Human Services found that 37%
of young users of smokeless tobacco (also called ``spit'' tobacco)
continue use because they are addicted.<SUP>76 In a study involving 675
men enrolled in a cessation program, 68% reported an average of four
unsuccessful attempts to quit.<SUP>77 Other studies of smokeless
tobacco cessation programs reveal that many users continue consuming
the product despite their desire to quit.<SUP>78 Glover reported a 2.3%
quit rate at 6 months and concluded that smokeless tobacco may be more
addicting than cigarette smoking.<SUP>79 Other researchers have found
that over one-third of the current

[[Page 41553]]
smokeless tobacco users report an unsuccessful attempt to quit, despite
the fact that 92% of those surveyed believed that there are health
risks associated with smokeless tobacco use.<SUP>80

    \75\ Benowitz NL. Pharmacology of Smokeless Tobacco Use:
Nicotine Addiction and Nicotine-Related Health Consequences. In:
Smokeless Tobacco or Health, Smoking and Tobacco Control Monograph
2. U.S. Department of Health and Human Services.1993. Page 224.
    \76\ U.S. Department of Health and Human Services. Spit Tobacco
and Youth. Washington DC. U.S. Department of Health and Human
Services, Office of the Inspector General. 1992. Page 7.
    \77\ See Severson, note 71, supra, at pp. 281-282.
    \78\  See: Glover ED. Conducting smokeless tobacco cessation
clinics. Am. J. Pub. Health. 1986;76(2):207.
    Hatsukami D, Nelson R, Jensen J. Smokeless tobacco: Current
status and future directions. Brit. J. of Addiction. 1991;86:559-
563.
    \79\  See: Glover ED, Glover PN. Smokeless tobacco cessation and
nicotine reduction therapy. In: Smokeless Tobacco or Health, An
International Perspective. Smoking and Tobacco Control, Monograph 2.
U.S. Department of Health and Human Services. Public Health Service.
National Institutes of Health. NIH Publication No. 93-3461. 1993.
Pages 291-295.
    Glover, note 78, supra, at p. 207.
    \80\ See Ary, note 71, supra.
---------------------------------------------------------------------------

    Studies suggest that tolerance to nicotine develops with prolonged
smokeless tobacco use. One study noted that a higher percentage of
older users of smokeless tobacco used brands with a higher nicotine
content compared with younger users.<SUP>81 A World Health Organization
study group reported on another study that showed a positive
relationship between the number of years of smokeless tobacco use, the
number of minutes per day of reported use, and urinary nicotine and
cotinine <SUP>82 levels. These relationships are consistent with the
development of tolerance and physical dependence.<SUP>83

    \81\  Browson RC, DiLorenzo TM, Van Tuinen M, Finger WW.
Patterns of cigarette and smokeless tobacco use among children and
adolescents. Preventive Medicine. 1990;19:170-180.
    \82\ Cotinine is a major metabolite of nicotine and an indicator
of nicotine absorption.
    \83\ World Health Organization. 1988. WHO Technical Report
Series No 773. Smokeless Tobacco Control: Report of a WHO Study
Group. World Health Organization. Geneva, Switzerland. Page 36.
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    Biglan and coworkers demonstrated that nicotine reinforces
smokeless tobacco use. In one study that describes the drug-reinforcing
behavior of the product, smokeless tobacco users were found to titrate
the level of nicotine in their bodies by adjusting use to maintain a
specified level of nicotine. In another study in which men used both
snuff and cigarettes, the subjects smoked more cigarettes when
smokeless tobacco use was restricted, and consumed

[[Page 41554]]
more smokeless tobacco when cigarette use was restricted.<SUP>84

    \84\ See Benowitz, note 66, supra, at pp. 223-224.
---------------------------------------------------------------------------

    Smokeless tobacco users who are addicted experience withdrawal
symptoms similar to those reported by smokers.<SUP>85 One study found
that among daily smokeless tobacco users ages 10 to 22 who had
previously tried to quit, 93.3% experienced at least one symptom of
nicotine withdrawal.<SUP>86 It has been concluded that ``dependence on
smokeless tobacco may be no less tenacious than dependence on
cigarettes.<SUP>87 (See Appendix 1 for a more complete discussion of
the definition of addiction and rates of dependence.)

    \85\ See: Hatsukami, note 73, supra, at pp.103-107.
    Severson, note 71, supra, at p. 282.
    \86\ U.S. Department of Health and Human Services, Public Health
Service, Centers for Disease Control and Prevention. Reasons for
tobacco use and symptoms of nicotine withdrawal among adolescents
and young adult tobacco users--United States, 1993. MMWR.
1994;43(41):745-750.
    \87\ Jarvis MJ. Dependence on smokeless tobacco. In: Smokeless
Tobacco or Health, An International Perspective. Smoking and Tobacco
Control, Monograph 2. U.S. Department of Health and Human Services.
Public Health Service. National Institutes of Health. NIH
Publication No. 93-3461. 1993. Page 243.

[[Page 41555]]

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3. Laboratory Studies Establish That Nicotine Produces Pharmacological
Effects Similar to Those of Other Addictive Substances

    Evidence gathered in the last two decades demonstrates, in both
laboratory animals and humans, that nicotine is a psychoactive drug
that produces pharmacological effects similar to those of other
addictive substances. Many of the advances in the understanding of the
psychopharmacological and addictive aspects of nicotine have come from
recent laboratory studies using both animals and human volunteers.
    Animal studies have the advantage of being able to assess the
pharmacological actions of a potentially addictive substance,
independent of such factors as the taste of the substance, the
personality of the user, or social factors such as peer pressure.
Studies using human volunteers have the advantage of allowing the
subject to directly inform the researcher of the subjective effects of
the drug being studied.
    Two kinds of studies are used to determine whether a substance may
be an addictive drug: ``drug discrimination'' studies and ``self-
administration'' studies. There is a strong correlation between the
results of these studies in animals and humans. Substances that animals
identify as similar to known psychoactive drugs in drug discrimination
studies and substances that animals self-administer in self-
administration studies are highly likely to be addictive in humans.
With very few exceptions, substances that are addictive in humans are
self-administered by animals.<SUP>88

    \88\ Gardner EL. Brain Reward Mechanism. In: Substance Abuse, A
Comprehensive Textbook. 2nd ed. Baltimore, MD: Williams and Wilkins;
1992:70.

[[Page 41556]]

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a. Animal studies
    An impressive number of animal studies have demonstrated that
nicotine has pharmacological properties common to many other addictive
drugs. These studies establish that nicotine, like other addictive
drugs, has psychoactive properties that exert control over behavior.
    (i) Drug Discrimination Studies
    Drug discrimination studies are used to evaluate the subjective
effects (discriminative stimulus properties ) of a drug and to make
direct comparisons of these effects to known dependence-producing
drugs.<SUP>89 The ability of a substance to produce discriminative
stimulus effects is one characteristic of an addictive substance. In
drug discrimination studies, animals identify nicotine as having a
highly specific discriminative stimulus profile and some similarity
with the discriminative stimulus effects of cocaine and
amphetamine.<SUP>90 (See

[[Page 41557]]
Appendix 1 for a summary of the studies documenting nicotine's
discriminative stimulus effects and the site of these actions.)

    \89\ Balster RL. Drug abuse potential evaluation in animals. Br
J Addiction. 1991; 86:1549-1588.
    \90\ See: Takada K, Swedberg MDG, Goldberg SR, Katz JL.
Discriminative stimulus effects of intravenous l-nicotine and
nicotine analogs or metabolites in squirrel monkeys.
Psychopharmacology. 1989;99:208-212.
    Pratt JA, Stolerman IP, Garcha HS, Giardini V, Feyerabend C.
Discriminative stimulus properties of nicotine: Further evidence for
mediation at a cholinergic receptor. Psychopharmacology. 1983;81:54-
60.
    Goldberg SR, Risner ME, Stolerman IP, Reavill C, Garcha HS.
Nicotine and some related compounds: effects on schedule-controlled
behaviour and discriminative properties in rats. Psychopharmacology.
1989;97:295-302.
    Chance WT, Murfin D, Krynock GM, Rosecrans JA. A description of
nicotine stimulus and tests of its generalization to amphetamine.
Psychopharmacology. 1977;55:19-26.
    Stolerman IP, Garcha HS, Pratt JA, Kumar R. Role of training
dose in discrimination of nicotine and related compounds by rats.
Psychopharmacology. 1984;84:413-419.
    Stolerman IP. Discriminative stimulus effects of nicotine in
rats trained under different schedules of reinforcement.
Psychopharmacology. 1989;97:131-138.
---------------------------------------------------------------------------

    (ii) Self-Administration
    The self-administration model is widely used to assess a drug's
ability to induce and maintain drug-seeking behavior in animals.<SUP>91
Self-administration studies determine whether animals will press a
lever to give themselves repeated doses of the test substance. The
ability of a substance to cause self-administration in animals
demonstrates that the substance is a positive reinforcer; i.e., that it
induces continued, compulsive use.<SUP>92 As noted above, having a
positive reinforcing effect in animals is one of the key pieces of
predictive evidence that a substance will produce addiction in humans.

    \91\ See: Schuster CR, Thompson T. Self-administration of
behavioral dependence on drugs. Annual Rev of Pharm. 1969;9:483-502.
    Griffiths RR, Bigelow GE, Henningfield JE. Similarities in
animal and human drug-taking behavior. Advances in Substance Abuse.
1980;1:1-90.
    \92\ See: Schuster, note 91, supra, at pp. 483-502.
    Griffiths, note 91, supra, at pp. 1-90.
---------------------------------------------------------------------------

    Like many addictive drugs, such as cocaine, opiates, and hypnotics,
nicotine has now been demonstrated through self-administration studies
to be an effective positive reinforcer in animals.<SUP>93 This property
of nicotine was not consistently demonstrated until the 1980s, when

[[Page 41558]]
it was discovered that the reinforcing efficacy of nicotine is highly
dependent on the schedule by which the drug is made available to the
animals and the specific amount administered.<SUP>94 Intermittent
availability of nicotine, which parallels the pattern of cigarette
smoking, will induce self-administration in animals, while continuous
administration (which was used in the earlier studies) is far less
likely to do so. (See Appendix 1 for a summary of the studies
establishing that nicotine is a positive reinforcer in animal self-
administration studies.)

    \93\ See: Cox BM, Goldstein A, Nelson WT. Nicotine self-
administration in rats. British Journal of Pharmacology. 1984;83:49-
55.
    Goldberg, note 35, supra, at pp. 573-575.
    Slifer BL, Balster RL. Intravenous self-administration of
nicotine: with and without schedule-induction. Pharmacol. Biochem.
Behav. 1985;22:61-69.
    Corrigall WA, Franklin KBJ, Coen KM, Clarke PBS. The mesolimbic
dopaminergic system is implicated in the reinforcing effects of
nicotine. Psychopharmacology. 1992;107:285-289.
    \94\ See: Goldberg, note 35, supra, at pp. 573-575.
    Henningfield, note 35, supra, at pp. 989-992.
---------------------------------------------------------------------------

b. Studies in Human Volunteers
    In addition to the extensive population-based epidemiological
studies described above, a growing body of evidence gathered from
laboratory and clinical settings using human volunteers, is providing
further evidence of the addictive effects of nicotine.

[[Page 41559]]

    (i) Evaluation of Subjective Effects
    In one study, smokers with histories of abuse of other drugs
identified intravenous or inhaled nicotine as being a euphoriant
similar to cocaine or amphetamine.<SUP>95 Using a common measure of the
subjective effects of addictive drugs (the Addiction Research Center
Inventory), nicotine produced a dose-related increase in the
``euphoria'' scale (also known as the morphine-benzedrine group
scale).<SUP>96 This study shows that nicotine produces subjective
effects that are similar to those of other addictive drugs. (See
Appendix 1 for a summary of the studies on the subjective effects of
nicotine.)

    \95\ See: Surgeon General's Report. 1988. Nicotine Addiction.
Pages 177-178.
    Henningfield et al, note 21, supra.
    \96\ Id.
---------------------------------------------------------------------------

    (ii) Self-Administration Studies
    Human self-administration of nicotine has been demonstrated under
controlled laboratory conditions. Smokers were provided the opportunity
to give themselves injections of nicotine in test sessions where they
were not allowed to smoke.<SUP>97 The subjects self-administered
nicotine in a regular, orderly pattern, giving themselves roughly the
same amount of nicotine as they were accustomed to getting from their
cigarette smoking.<SUP>98 (See Appendix 1 for a summary of the studies
establishing that nicotine is a positive reinforcer in

[[Page 41560]]
human self-administration studies.)

    \97\ Henningfield JE, Miyasato K, Jasinski DR. Cigarette smokers
self-administer intravenous nicotine. Pharm Biochem Behav.
1983;19:887-890.
    \98\ Id.
---------------------------------------------------------------------------

c. Studies on Tolerance and Withdrawal
    ``Tolerance'' is produced by a substance when the effects of the
substance, at a given dose, become less intense over time, or when an
increasing dose over time is necessary to cause an effect or response
of a specified intensity. It is well documented that nicotine produces
tolerance in users. For example, novice smokers usually experience
nicotine-related effects such as dizziness, nausea, vomiting, and
headaches.<SUP>99 These effects are not produced in experienced smokers
because they rapidly develop a tolerance to nicotine. Eventually,
smokers increase the amount that they will smoke, always ensuring that
the level of nicotine intake will fall below the level at which they
would suffer undesirable physical effects and above the level at which
they would begin to experience withdrawal symptoms.<SUP>100 Tolerance
to nicotine is not complete, because even the heaviest smokers can
experience symptoms, such as nausea and vomiting, when they suddenly
increase their smoking rates.<SUP>101 Additionally, the amount of
nicotine needed to maintain an addiction may plateau. (See Appendix 1
for a summary of studies demonstrating tolerance to nicotine.)

    \99\ Surgeon General's Report. 1994. Preventing Tobacco Use
Among Young People. Page 138.
    \100\ Rose JE, Behm FM, Levin ED. The role of nicotine dose and
sensory cues in the regulation of smoke intake. Pharm Biochem and
Behav. 1993;44:891-900.
    \101\ See: Danaher BG. Research on rapid smoking: Interim
summary and recommendations. Addictive Behaviors. 1977;2:151-166.
    Surgeon General's Report. 1988. Nicotine Addiction. Page 50.
---------------------------------------------------------------------------

    Clinical studies on nicotine withdrawal have demonstrated that
physiological effects

[[Page 41561]]
occur as a result of tobacco deprivation. These effects include
decreased heart rate, decreased arousal evidenced by diminished
alertness, central nervous system changes, decreases in blood pressure,
and disruptions in sleep patterns.<SUP>102 Studies have also
demonstrated that tobacco withdrawal can cause an increase in weight.
This weight increase may be attributed to increased caloric intake,
decreased metabolism, and decreased energy expenditure following
nicotine withdrawal.<SUP>103

    \102\ See: West RJ, Jarvis MJ, Russell MAH, Caruthers ME,
Feyerabend C. Effect of nicotine replacement on the cigarette
withdrawal syndrome. British Journal of Addiction. 1984;79(2):215-
219.
    Hughes JR, Hatsukami D. Signs and symptoms of tobacco
withdrawal. Arch Gen Psychiatry. 1986;43:289-294.
    \103\ See: Wack JT, Rodin J. Smoking and its effect on body
weight and the systems of caloric regulation. The American Journal
of Clinical Nutrition. 1982;35(2):366-380.
    Glauser SC, Glauser EM, Reidenberg MM, Reisy BF, Tallarida RJ.
Metabolic changes associated with the cessation of cigarette
smoking. Archives of Environmental Health. 1970;20:377-381.
---------------------------------------------------------------------------

    After several weeks of nicotine exposure, users who are deprived of
nicotine for more than a few hours develop withdrawal symptoms. The
most common self-reported withdrawal symptoms in nicotine-deprived
smokers and smokeless tobacco users are increased irritability,
anxiety, difficulty concentrating, restlessness, impatience, and
insomnia.<SUP>104 Withdrawal symptoms after quitting tobacco use can
persist for months.<SUP>105 Although nicotine withdrawal is not as
severe as withdrawal from heroin or alcohol, it is comparable to
withdrawal from other stimulants such as cocaine, and can be highly
disruptive to personal

[[Page 41562]]
life.<SUP>106

    \104\ See Hughes, note 102, supra, at pp. 289-294.
    \105\ Ryan FJ. Cold Turkey in Greenfield, Iowa: A Follow-up
Study. In: Dunn WL, ed. Smoking Behavior: Motives and Incentives.
Washington, DC: VH Winston & Sons; 1973:231- 234.
    \106\ Benowitz NL. Cigarette smoking and nicotine addiction.
Medical Clinics of N. America. 1992;76(2):415- 437.

[[Page 41563]]

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4. Nicotine's Sensory Effects Are Secondary to its Psychoactive Effects

    Nicotine is an irritant to the throat and upper respiratory
system.<SUP>107 Its effects in the throat contribute to the harshness
of tobacco smoke reported by smokers.<SUP>108 Many beginning smokers
report that the taste of cigarettes is unpleasant.<SUP>109 Despite
these facts, those who continue to smoke report that they enjoy the
taste of commercial tobacco products.<SUP>110 In some studies, low-
nicotine or nicotine-free products that replicate the taste, flavor, or
throat and chest sensations of cigarette smoking can, in the very short
term, reduce certain nicotine withdrawal symptoms, including craving
for cigarettes.<SUP>111 Significantly, however, many of the positively
perceived aspects of the harsh taste and flavor of commercial tobacco
products are due to ``secondary reinforcement.'' This is a phenomenon
by which smokers associate the irritant effects of nicotine in the
mouth and throat with desired psychoactive effects that occur
immediately thereafter.<SUP>112 These irritant effects are then judged
favorably, because they are

[[Page 41564]]
associated with the delivery of the psychoactive properties of
nicotine. The conditioning process is similar to that which occurs for
other dependence-producing drugs in which effects that are disliked
upon initial exposure come to be associated with desired psychoactive
effects.<SUP>113 Experienced smokers can use the irritant effects of
nicotine to assess how much nicotine they are delivering to themselves
while they are smoking.<SUP>114

    \107\ See Rose, note 100, supra.
    \108\ Rose JE, Sampson A, Levin ED, Henningfield JE.
Mecamylamine Increases Nicotine Preference and Attenuates Nicotine
Discrimination. Pharm Biochem and Behav. 1989;32:933-938.
    \109\ Surgeon General's Report. 1994. Preventing Tobacco Use
Among Young People. Page 138.
    \110\ Id.
    \111\ See: Rose JE, Behm F. Refined cigarette smoke as a method
for reducing nicotine intake. Pharmacology Biochemistry and
Behavior. 1987;28:305-310.
    Levin ED, Rose JE, Behm F. Development of a citric acid aerosol
as a smoking cessation aid. Drug and Alcohol Dependence.
1990;25:273-279.
    Rose JE, Behm FM. Inhalation of vapor from black pepper extract
reduces smoking withdrawal symptoms. Drug and Alcohol Dependence.
1994;34:225-229.
    \112\ See: Rose, note 100, supra.
    Levin ED, Behm F, Rose JE. The use of flavor in cigarette
substitutes. Drug and Alcohol Dependence. 1990;26:115-160.
    Rose JE, Tashkin DP, Ertle A, Zinser MC, Lafer R. Sensory
blockade of smoking satisfaction. Pharmacology Biochemistry and
Behavior. 1985;23:289-293.
    \113\ Surgeon General's Report. 1988. Nicotine Addiction. Pages
264-265, 309.
    \114\ See Rose, note 100, supra.
---------------------------------------------------------------------------

    Data indicate that long-term smoking is continued not because of
the taste characteristics of tobacco but because of other factors,
specifically the pharmacological effects of nicotine.<SUP>115 Evidence
gathered from nicotine replacement products supports this position. As
noted, two nicotine dosage forms are on the market for treatment of
nicotine withdrawal as an aid to smoking cessation (nicotine polacrilex
gum and nicotine transdermal patches). FDA is reviewing a New Drug
Application (NDA) for a third dosage form, an aqueous nicotine nasal
spray. The nicotine nasal spray was the subject of an August 1994 FDA
Drug Abuse Advisory Committee meeting because of its possible addiction
liability. Among subjects who used the spray for a year during one of
the trials, several reported that they felt dependent on the spray,
displayed withdrawal symptoms upon stopping the spray,

[[Page 41565]]
and sometimes used the spray in larger quantities and more frequently
than was required by the study protocol--all despite the fact that use
of the spray was unpleasant and caused nasal ulcers and other medical
problems for some participants.<SUP>116

    \115\ See: Rose, Tashkin, et al, note 112, supra.
    Rose, note 100, supra.
    \116\ E. Douglas Kramer, M.D. Testimony before the Drug Abuse
Advisory Committee. August 1, 1994. Drug Abuse Advisory Committee
Meeting Transcript. Pages 58-63. Nicotine nasal spray is unique
among nicotine replacement therapies in that it produces peak blood
levels of nicotine almost as quickly as inhalation of cigarette
smoke.
---------------------------------------------------------------------------

    The ability of nicotine nasal spray to produce some of the classic
characteristics of addiction to nicotine supports the position that
tobacco users seek nicotine primarily for its systemic pharmacological
effects, and not for its acute sensory effects. The spray vehicle and
dispensing system of the nicotine nasal spray are rudimentary; it is
merely nicotine in water forced through an aspirator to make a nasal
mist. In contrast to cigarette smoke, aqueous nicotine spray does not
provide the user any pleasing sensory characteristics. In fact, the
spray can be irritating and unpleasant to use, can impart a very
unpleasant taste if it runs down the nose and into the throat, and
excessive use can cause ulcerations of the nasal mucosa.
Notwithstanding the unpleasantness of the nicotine delivery mechanism,
and the presence of painful ulcerations that were further aggravated by
continued use of the spray, the spray was used to maintain nicotine
dependence for many of the participants in its clinical trials.<SUP>117

    \117\ FDA Drug Abuse Advisory Committee Background Information.
August 1, 1994. Joint Abuse Liability Review of Nicotine Nasal
Spray.
---------------------------------------------------------------------------

    The dependence upon nicotine nasal spray illustrates a physical
need for nicotine's pharmacological effects, not merely in the absence
of any pleasurable sensory effects that may be associated with nicotine
in cigarette smoke, but even in the face of rather unpleasant

[[Page 41566]]
and even painful sensations. This provides strong evidence that
nicotine is sought by tobacco users who are dependent upon it for
reasons other than its pleasurable, acute sensory effects in the mouth,
nose, and throat.

[[Page 41567]]

5. Other Factors Associated with Tobacco Use Are Secondary

    There are other factors that play a role in the decisions to begin
and continue the use of tobacco.<SUP>118 For example, social and
psychological factors play a role in the initiation of smoking and, to
a lesser extent, the maintenance of tobacco use.<SUP>119 In particular,
parents, peers, and older siblings greatly influence the likelihood
that a young person will smoke cigarettes.<SUP>120 There is also
evidence that adolescents begin to smoke because it promotes
sociability, plays a part in establishing friendships, and because it
makes them feel mature.<SUP>121 Tobacco advertising also plays a role
in the decision to start using tobacco.<SUP>122 It is recognized

[[Page 41568]]
that many of the mannerisms and processes associated with smoking may,
in the perception of the smoker, become pleasurably linked with tobacco
use. These mannerisms or processes may deliver some element of pleasure
to the smoker, independent of the inhalation of tobacco smoke.<SUP>123

    \118\ Tate JC, Pomerleau CS, Pomerleau OF. Pharmacological and
non-pharmacological smoking motives: a replication and extension.
Addiction. 1994;89:322.
    \119\ See: Surgeon General's Report. 1994. Preventing Tobacco
Use Among Young People. Pages 124-140.
    Stepney R. Smoking behaviour: A psychology of the cigarette
habit. Br J Dis Chest. 1980;74:325-344.
    \120\ See: Bewley BR, Bland JM, Harris R. Factors associated
with the starting of cigarette smoking by primary school children.
Brit J Prev Soc Med. 1974;28:37-44.
    Murray M, Cracknell A. Adolescents' views on smoking. J
Psychosom Res.1980;24:248-249.
    Banks MH, Bewley BR, Bland JM, Dean JR, Pollard V. Long-term
study of smoking by secondary schoolchildren. Arch Disease in
Childhood. 1978;53:14-16.
    \121\ See: Bewley, note 120, supra.
    Bewley BR, Bland JM. Academic performance and social factors
related to cigarette smoking by schoolchildren. Brit J Prev Soc Med.
1977;31:18-24.
    Surgeon General's Report. 1994. Preventing Tobacco Use Among
Young People. Page 124.
    \122\ See: Surgeon General's Report. 1994. Preventing Tobacco
Use Among Young People. Pages 191-192.
    Cocores JA. Smokeless Tobacco. In: Cocores JA, ed. The Clinical
Management of Nicotine Dependence. New York, NY: Springer-Verlag;
1991:49.
    \123\ Christen AG, Glover ED. Psychological satisfactions
derived from smoking cigarettes in fifty-seven dental patients. J
Drug Educ. 1983;13(1):95-102.
---------------------------------------------------------------------------

    It is widely accepted, however, by medical and public health groups
that the maintenance of tobacco use is due primarily to the addictive
properties of nicotine and not solely to these social and psychological
factors.