TABLE 1.—Continued

 

Study

Spealman

and
Goldberg
(1982)

Species

Squirrel
Monkey

Risner and Beagle

Goldberg
(1983)

Henning-
field,

Miyasato,

and
Jasinski
(1983)

Goldberg
and
Henning-
field
(1983)

Dog

Human

Human

Squirrel
Monkey

Reinforcement
Schedule

Second order FI 1,
2, or 5 min. (FR 10
stimulus) and FI 5
min. schedules
were tested.
Several doses of
nicotine and
cocaine and saline
were tested.

FR 15 followed by
4 min. timeout.
Several doses of
nicotine, cocaine,
and saline were
tested. Progres-
sive ratio schedule
was used.

FR 10 followed by
1 min. timeout.
Several doses of
nicotine and saline
were tested.

FR 10 followed by
1 min. timeout.
Several doses of
nicotine and saline
were tested.

Main Finding

Nicotine and
cocaine main-
tained similar
patterns of
responding on the
schedules. Nico-
tine, but not
cocaine S-A,
decreased to
saline-like rates
when animals were
pretreated with
mecamylamine.

Nicotine and
cocaine main-
tained qualita-
tively similar
patterns of
responding and
were reinforcers
relative to saline.
Mecamylamine
pretreatment
reduced nicotine
but not cocaine
S-A.

Number of nico-
tine injections
generally ex-
ceeded number of
saline injections
and were inversely
related to nicotine
dose. Post-session
cigarette smoking
was suppressed
by nicotine.

Patterns of
responding were
qualitatively
similar in both
species. Number
of nicotine injec-
tions exceeded
number of saline
injections in 3 of
4 human and 3 of
4 monkey subjects.

Comment

Nicotine’s rein-
forcing efficacy
was comparable to
that of cocaine.

Cocaine main-
tained substan-
tially greater
response rates
than nicotine.

Nicotine produced
subjective effects
similar to those
produced by intra-
venous cocaine
and had both rein-
forcing and
punishing effects.

In both the
human and mon-
key subjects,
there was evidence
that nicotine func-
tioned with both
reinforcing and
punishing
properties.

 

151
support to the initiation of tobacco use may be even greater than with
ilicit drugs, because family members, other social models, and advertis-
ing often tolerate, approve, or promote tobacco use while disapproving
the use of some nonprescription drugs (24) Also, as is the case with
addictive drugs, an accelerated pattern of development of tobacco use
has been observed, which is followed by relatively stable drug intake.
Initially, the level of consumption increases gradually from the first day
of use until some point, perhaps several years later, when it becomes
relatively stable over time. Although many factors can operate to pro-
duce such a biphasic pattern of intake, it is generally assumed that
tolerance and learning factors account for the gradual acceleration and
that a level of optimum drug effect combined with toxicity and adverse
effects at higher doses takes over to produce the stabilization phenome-
non. A preliminary survey, conducted at Johns Hopkins University,
indicates that nicotine, whether administered as cigarette smoke or
smokeless tobacco, does not differ from other drugs in this regard. That
is, tobacco users tend to begin smoking a few cigarettes a day or con-
sume a portion of a container of smokeless tobacco each day and gradu-
ally increase consumption levels over a period of months or even years
before they stabilize the amount they finally use (personal communica-
tion, J.E. Henningfield).

Patterns of Tobacco Self-Administration Are Orderly

Daily patterns of cigarette smoking are orderly. Addicted smokers
tend to smoke their first cigarette within 30 minutes of waking from a
night of sleep and find it difficult to abstain from tobacco use for more
than a few hours (25). If smoking behavior is relatively unconstrained,
regular patterns develop that closely resemble those of psychomotor
stimulant self-administration in animals (20). Similar orderly patterns
of tobacco self-administration are evident with cigarette smoking by
humans. Several studies have demonstrated that across successive
puffs on a cigarette, puff duration decreases and interpuff intervals
tend to increase (26,27,28,29), although these changes are multifactor-
ially determined (30). Anecdotal reports by smokeless tobacco users
suggest that while consumption patterns are necessarily different (e.g.,
some keep a plug in their mouth almost continually during their waking
hours) they are no less regular and orderly.

Tobacco Self-Administration Varies as a Function of Nicotine Dose
The effective dose of a substance may be varied by changing the
quantity of drug per unit (the unit dose), by pretreating the individual
(animal or human) with either an agonist or antagonist, or by altering
the rate of elimination of the substance. Studies that involve these three
manipulations have been done extensively with other drugs and more
recently with nicotine. The results across study, drug, and species are
remarkably similar. For general reviews of human and animal studies

152
see Griffiths, Bigelow, and Henningfield (20) and Henningfield, Lukas,
and Bigelow (31). See Gritz (32) and Henningfield (33) for recent reviews
of the nicotine-specific literature. Over a wide range of dose levels, fre-
quency of self-administration is inversely related to dose but drug in-
take is directly related to dose, reflecting partial compensatory changes
(26,32). Pretreatment with other agonists (or forms of nicotine) reduces
drug taking, e.g., decreases cigarette smoking, (34) and reduces pre-
ferred nicotine concentration of tobacco smoke (35). Pretreatment with
antagonists initially increases drug self-administration. For example,
the centrally and peripherally acting ganglionic blocker, mecamyla-
mine, but not the peripherally acting blocker, pentolinium, increases
subsequent smoking rates and increases preferred nicotine concentra-
tions of tobacco smoke (36,37). In addition, altering the elimination rate
of nicotine alters the amount of nicotine that is self-administered in the
form of tobacco smoke (38).

There has been debate over the degree to which smokers regulate
their nicotine intake, i.e., the “‘titration’’ hypothesis. It is now generally
agreed that smokers do not precisely titrate their nicotine intake any
more than animals titrate their intake of reinforcing drugs (except
under extremely limited conditions) or humans titrate their intake of
other reinforcing drugs (20). However, when dose manipulations are
observed and objective, sensitive dependent variables are measured in
both animals and humans (26,382,323), most of the studies demonstrate an
increase in smoking as cigarette nicotine content falls below accus-
tomed levels and a decrease in smoking when cigarette nicotine content
is unusually high (32). Kozlowski and his coworkers describe these find-
ings in terms of a “boundry’’ model of dose compensation (39).

Tolerance of Nicotine Develops With Repeated Use (Neuroadaptation)

The administration of most drugs of abuse results in neuroadaptation
as measured by tolerance to the repeated administration of the drug
and a subsequent rebound (withdrawal) when drug administration is
terminated (3). Tolerance to drug effects is determined either by the
diminished response to repeated doses of a drug or the requirement of
increasing doses to achieve the same drug effect. Tolerance to the
behavioral and physiologic effects of nicotine has been studied for
decades (33). As is the case with other drugs of abuse, a variety of
mechanisms accounts for tolerance to many of nicotine’s effects, includ-
ing metabolic (40), behavioral (41-43), and physiologic tolerance (44-46).
More recently, studies have shown that the effects of nicotine that are
suspected to be critical to the addiction process also show tolerance
with repeated dosing (47,48).

Physiologic dependence on drugs is determined by showing that ter-
mination of drug administration produces a syndrome of effects that is
generally opposite to those produced by drug administration. This syn-
drome is reversible, at least in its early stages, by administration of the

153
drug. Prolonged drug abstinence (detoxification) results in ultimate
return to baseline (normal) values of behavioral and physiologic func-
tions. It is now clear that repeated tobacco administration produces
physiologic dependence that is specifically due to nicotine administra-
tion. Recent data that confirm this fact are reviewed in the section on
Dependence Potential of Nicotine.

Nicotine Produces Therapeutic Effects

Most drugs of abuse have specific therapeutic applications; nicotine
is no exception (48-50). The degree to which the therapeutic effects of
nicotine depend upon the individual’s history of nicotine use, as opposed
to the possibility that nicotine is efficacious for preexisting conditions,
remains to be investigated. Similar issues are true for other drugs of
abuse as well. Pomerleau and his coworkers (51) have studied a variety
of mechanisms by which the possibly weak, initial reinforcing effects of
nicotine can be greatly strengthened by subtle effects on mood, cogni-
tion, and normal physiologic and behavioral functioning. For instance,
as will be described below, nicotine may produce a small, but important,
enhancement of work performance. These effects appear to be mediated
by the effects of nicotine on hormonal release and regulation. The
following is a brief summary of some of the effects of nicotine, con-
sidered therapeutic by tobacco users, that have been investigated.

Several studies have shown that nicotine enhances performance on a
variety of cognitive tasks that involve speed, reaction time, vigilance,
and concentration (52-55). These effects are strongest in cigarette
smokers who are deprived of cigarettes. However, such performance
enhancement was also evident after the administration of nicotine to
nonsmokers and was produced by increasing the nicotine dose in per-
sons who were already smoking. Nicotine may also be a useful mood
regulator by virtue of its release of norepinephrine from the adrenal
medulla (56). Norepinephrine release is also stimulated by excitement,
exercise, sex, antidepressant drugs, and other drugs of abuse, sug-
gesting that cigarette smoking may function pharmacologically to
alleviate boredom and stress. Finally, as an anoretic (57-60), nicotine ap-
pears to function in three ways: by decreasing the efficiency with which
food is metabolized (61,62); by reducing the appetite for foods that con-
tain simple carbohydrates (sweets) (63); and by reducing the eating that
may occur in times of stress (64). Nicotine may also function as an anxio-
lytic by reducing responsiveness to stressful stimuli and enhancing
mood (56). In addition, nicotine reduces aggressive responses in experi-
mental situations (65).

A well-documented therapeutic role for nicotine as a drug is evident in
the treatment of tobacco abstinence for many individuals following
dependent patterns of tobacco use, e.g., as assessed by the Fagerstrom
Tolerance Questionnaire (25). This test provides both scientific and prac-
tical evidence of the role of nicotine in tobacco dependence. It is well

154
established that abstinence from tobacco in heavy cigarette smokers
produces signs and symptoms of rebound that can be reversed by
resumed tobacco use and at least. partially reversed by other forms of
nicotine administration (66). For example, nicotine gum treatment for
cigarette smoking is efficacious, although a variety of factors limit suc-
cess rates (34).* This drug substitution strategy is analogous to those
obtained when intravenous opioid users are treated with other opioids
given via other routes. For example, methadone administration may
reverse signs and symptoms of opioid withdrawal, while leaving the pa-
tient feeling partially treated yet likely to relapse if not provided with
an adjunctive behavioral treatment (67).

Although the euphoriant properties of drugs can stand apart from
collateral therapeutic actions (as is the case with morphine, am-
phetamine, and alcohol), attention to such drug effects may enhance the
efficacy of treatment. Because nicotine, in the form of tobacco, is widely
available, is relatively inexpensive, and is in a convenient form for
precise dose regulation, it provides an ideal means of self-medication.
These effects may contribute to the abuse liability of tobacco and are of
demonstrable significance in the treatment of tobacco addiction (51).

Similar Strategies Are Involved in the Treatment of
Tobacco Addiction and Other Forms of Drug Addiction

If tobacco use is a form of drug addiction, then strategies of treat-
ment of other forms of drug addiction should be applicable. Most avail-
able information and existing strategies for treatments of tobacco use
are based on nonpharmacologic approaches. Such approaches have
been no more useful in the treatment of tobacco dependence than in the
treatment of dependence of opioids, stimulants, sedatives, or alcohol.
On the contrary, experience in the treatment of drug addiction
disorders makes clear the importance of addressing the pharmacologic
components of the addiction (67). This conclusion is strengthened by the
observation that persons being treated for opioid addiction regard
tobacco to be as necessary as methadone (68) and that persons success-
fully treated for other kinds of drug addiction are unable to give up
tobacco (69). This provides the support for the fundamental premise
that tobacco addiction generally constitutes an independent health-
impairing disorder. Specific treatment implications relating to cigarette
smoking as a form of drug abuse are considered below.

To the extent that tobacco use is similar to other forms of drug abuse,
treatment strategies that are used for drug abusers may be applied to
the treatment of cigarette smoking. Although it is not the purpose of
this chapter to describe in detail the treatment for cigarette smoking, a

* These therapeutic effects are produced by nicotine chewing gum, an orally administered form of nicotine that is
approved by the Food and Dru Administration (FDA). The gum is obtainabie in the United States by prescrip-
tion only and is commonly used by physicians to help individuals quit smoking.

155
few commonalities, as well as differences, are worth mentioning. Four
basic pharmacologic treatments for drug abuse provide the advantage
of licit administration of an agent controlled by a certified clinician.
These involve substitution therapy (e.g., methadone for opiate depen-
dence) in which a more manageable form of the drug is provided accord-
ing to a prearranged maintenance protocol; blockade therapy (e.g.,
naltrexone for opiate dependence) in which the effects of the abused
drug are blocked by pretreatment with an antagonist; and nonspecific
supportive therapy in which the patient is treated symptomatically, ex-
emplified by the temporary use of benzodiazepines during alcohol
detoxification (67). All three approaches have been used in the treat-
ment of cigarette smoking with varying degrees of success (48). A
fourth strategy of pretreating the patient with a drug that results in
adverse side effects when the subsequent abused drug is taken (e.g,
treatment of alcoholism with disulfiram) has not been systematically
explored with tobacco.

The most recent, widely used treatment for cigarette smoking, and
the first of those recognized as efficacious by the FDA, is modeled
directly after the treatment of heroin addiction by methadone substitu-
tion. This treatment is nicotine gum substitution (70). It is a practical
application of the postulate that tobacco use is basically a form of drug
addiction on nicotine. This recognition is especially relevant here,
because smokeless tobacco is an oral form of nicotine. All of the relevant
therapeutic data support the premise that compulsive tobacco use en-
tails nicotine addiction, which in the form of tobacco exposes the user to
health hazards, and that therapeutic strategies paralleling those for
other forms of drug abuse are effective in treatment. Differences appear
to be principally related to the social tolerance of tobacco addiction,
relative to other forms of drug addiction, which contribute to greater
difficulty in treating this form of drug abuse.

Summary of Commonalities Between Tobacco and
Prototypic Addictive Drugs

The preceding review has shown that tobacco shares many points in
common with prototypic addictive drugs. These similarities provide a
strong conceptual basis for the categorization of tobacco as an addictive
drug. The behavioral process is orderly, tobacco self-administration
results in the delivery of a centrally active drug (nicotine), and the drug
appears to be the major determinant in the control of the compulsive
behavior of tobacco self-administration. These findings are consistent
with those expected with animal and human subjects, as determined
across a broad range of studies of drugs of abuse (20).

In summary, tobacco, opium, and coca produce different effects but
share a number of important similarities. Whereas large doses of
opioids can produce a debilitating sedation, high doses of coca alkaloids
(cocaine HCI) produce levels of behavioral excitation that are not nor-

156
mally produced by tobacco; but the intake of all of these substances
leads to compulsive use. Compulsive use and the other commonalities
described in the preceding subsections provide compelling evidence
that tobacco use can be a form of drug dependence or addiction. The
next major question is what element(s) of tobacco are critical to control-
ling the behavior of the user. The conceptual leap from habitual
behavior to drug abuse and addiction can be made only on the basis of
evidence that a specific psychoactive drug is critical to the behavior.
The next section on the abuse liability and dependence potential of
nicotine will address this question.

Experimental Studies of the Abuse Liability and
Physical Dependence Potential of Nicotine

The comparison of tobacco to prototypic addictive drugs is the basis
for concluding that compulsive tobacco use is a form of drug
dependence behavior in which nicotine plays an important role. To test
this hypothesis further, it should be possible to show that nicotine is an
abusable substance even in the absence of the many stimuli associated
with cigarette smoking. This can be done by evaluating nicotine in ac-
cordance with methods and criteria that have been used to assess any
substance that is suspected of causing abuse and physical dependence.
One-half century of research at the NIDA Addiction Research Center,
and research in other laboratories, has produced valid and reliable ex-
perimental methods to evaluate a substance’s potential to cause abuse
and to produce physical dependence. The methods are empirically based
on generally accepted examples of drug addiction, most notably opioid
dependence (e.g., morphine) and, to a lesser degree, psychomotor
stimulant dependence (e.g., cocaine) and sedative dependence (e.g., bar-
biturates and alcohol), These methods encompass standards for assess-
ing the two dimensions of drug addiction—abuse liability and physical
dependence potential. The evidence that is related to the abuse liability
and physical dependence potential of nicotine is presented below.

Abuse Liability of Nicotine

Abuse liability refers to drug effects that contribute to compulsive
self-administration, often in the face of excessive financial cost, physical
and social dysfunction, and the exclusion of more socially acceptable
behaviors (5,6). In other words, it entails those effects of a substance
that contribute to diminution of voluntary control over the use of the
substance by the individual.

Objective methods to assess abuse liability are available and have
been used to assess diverse agents (5). These methods have been readily
adapted to studies of nicotine abuse liability, with consideration given
to the fact that nicotine has more rapid effects than many other drugs of
abuse.

157
The hypothesis is that nicotine is psychoactive and serves as a
euphoriant and reinforcer. Psychoactivity and euphoria are determined
by assessing the pharmacodynamic subjective effects of single doses of
the drug (‘‘single-dose”’ or ‘‘abuse liability” studies) and are validated
by observed behavioral and physiologic responses. Reinforcing efficacy
is determined by assessing the ability of the drug to strengthen and
maintain orderly patterns of behavior when the subject is permitted ac-
cess to the drug {i.e., the prototypic ‘‘self-administration’’ study).

Pharmacodynamic Effects of Nicotine. In human studies of nicotine
related psychoactivity, volunteers are given a range of doses of the test
compound and placebo under double-blind conditions. Persons with
histories of drug abuse are used because they can accurately discriminate
compounds with a potential for abuse and can compare the effects of the
compounds to those of abuse drugs (5). In one study, three doses of
nicotine were given both intravenously and in the form of tobacco smoke
under controlled conditions (71). Nicotine produced a similar profile of ef-
fects (figure 1). Self-reported (subjective), observer-reported (behavioral),
and physiologic variables were measured before, during, and after drug
administration. In brief, nicotine was shown to be psychoactive, as
evidenced by the reliable discrimination of nicotine from placebo. Self-
reported effects of nicotine peaked within 1 minute after administration
(by either route) and dissipated within a few minutes: peak and duration
of response were directly related to the dose.

The two hallmark indicators of euphoria in such studies are the Lik-
ing Scale (Single Dose Questionnaire) and the Morphine Benzedrine
Group (MBG) Scale (Addiction Research Center Inventory [ARCTI)) (5).
Responses on the 5-point Liking Scale, which asked how much the drug
was liked (0 = ‘‘not at all,” 4 = ‘“‘an awful lot’’) are presented in figure 2.
Nicotine produced responses on the Liking Scale similar to those of
morphine and d-amphetamine. MBG Scale scores of the ARCI were con-
sistent with the Liking Scale data, confirming that nicotine, given by
both routes of administration, was a euphoriant. In another comparison
between drugs, subjects more frequently identified nicotine injections
as cocaine.

Similar results for intravenous and inhaled nicotine were also obtained
on several physiologic measures, including pupil diameter, blood
pressure, and skin temperature. These data confirmed that nicotine,
given in either tobacco smoke or intravenously, was the critical pharma-
cologic compound accounting for these effects of tobacco smoke. A sub-
sequent study showed that nicotine’s subjective and physiologic effects
could be partially blocked by pretreating the subjects with the antago-
nist mecamylamine (18). Results of studies with animals also indicate
that nicotine produces discriminable effects, and the data suggest that
animals identify nicotine as being more similar to cocaine than to
placebo or pentobarbital, but not identical to cocaine (17).

158
FIGURE 1.—This figure is a summary of the data from a study of the
liability of nicotine delivered as tobacco smoke (filled symbols-IN) or
intravenous injections (open symbols-IV). Dose is presented on the hori-
zontal axes. Even with a controlled smoking procedure, nicotine dose
administration via cigarette smoke is more variable (producing flatter
dose-response functions) than when given intravenously. Also, important
effects of nicotine are covert though reliable and orderly (e.g., relaxed feel-
ings, symptom scores). The finding that a low dose of tobacco smoke was
more effective in reducing desire to smoke than a low dose of intravenous
nicotine is consistent with the fact that satisfaction from smoking is also
due to stimuli provided by the cigarette and the smoke.

GROUP MEANS: 3 MINUTES POST DRUG

10r 1Or 30
ro6
| ¢ SELF-REPORT No change dua 10 drug SELF-REPORT Fee! drug [ SELF-REPORT Symptoms of drug

1

 

One

a cs oa +

ror OBSERVED No change due tc drug Cr OBSERVED Drug effect 30r OBSERVED: Signs ot drug
t '

 

 

 

 

» | &
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ool 2 | 8 a0
a a
ain 14K Zain 4K oi 2914 ai tain 2a
Placebo: Thy sv 30w Pcombo TSiv Siw sow Proceso: Biv 1S sore

Self-Administration of Nicotine. The second abuse liability dimension
uses the ‘‘self-administration” procedure to examine the conditions
under which a subject will voluntarily take the drug. Self-administration
studies determine whether the drug serves as a biologically effective,
positive reinforcer (or reward). Variants of these strategies are con-
ducted in both animal and human subjects, thereby providing a means
of establishing the biologic generality of the phenomena, while control-
ling the possible confounding influence of personality, social, or cultural
variables. A high degree of concordance between findings from animal

1459
FIGURE 2.—This figure presents data from a series of abuse liability
studies conducted at the Addiction Research Center. The findings that
Liking Scale scores are directly related to dose and exceed placebo
values are important in identifying dependence-producing drugs. Intra-
venous nicotine produced the same elevated dose-response function as
highly addictive narcotics (e.g., morphine) and a prototypic stimulant
(d-amphetamine). These data are also consistent with the lower abuse
liability of chlordiazepoxide and almost negligible abuse liability of
zomepirac. Administration of intravenous cocaine results in a function
similar to that shown for intravenous nicotine, except that the cocaine
dose levels must be increased by a factor of 5 to 10.

 

 

 

 

 

 

 

 

 

 

MORPHINE BUPRENORPHINE PENTAZOCINE
(SC) (SL) (1M) e
bo nt P+T
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Nn
WW
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L i _i L i L _i_. li 1 4 i
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P 120. 240 P 50 100 200 P 200 400 800

DRUG DOSE (mg)

and human studies has been established over a wide range of drugs (20).
Therefore, this section focuses on the results of studies using human
volunteers.

The methods developed in animal studies can be used to assess
whether the pharmacologic activity of a drug maintains self-administra-

160
FIGURE 3.—This figure shows the patterns of nicotine self-
administration that occurred when volunteer cigarette smokers were
given the opportunity to take injections of nicotine, but not smoke
cigarettes, during 3-hour tests. The amount of nicotine available was
roughly comparable to that obtained by smoking cigarettes. The sub-
jects smoked less following sessions in which they took nicotine than
following sessions in which only saline (the placebo) was available.

LV. NICOTINE INJECTIONS

 

 

 

 

 

 

SUBJECT ug/kg
BE L 1 1 J i | 2/7
KO, 1 1 1 1 1 2/
SKuwu \ L \ 1 122
KUL1 Lo bo tt tt \ ii 41 22
PEwt uw 14 l Lit | dy Ut 4 Lt 18
LAeittitiy i pty py bbe tt 18
KE Yeeipt ps pi lb 43

 

t-——_—————-3 HOURS -———————_j

tion paralleling drug seeking and drug taking by individuals in the
natural environment or ‘‘real world.’’ The strategy is particularly useful
in studies of nicotine, because it precludes confounding by other stimuli
that are associated with tobacco smoke inhalation (e.g., the tobacco
brand, smell of the smoke, and lighting-up rituals).

In one such study, tobacco-deprived volunteers were tested during
3-hour sessions in which 90 presses on a lever resulted in either a nico-
tine or placebo injection (72). All six subject$ voluntarily self-
administered nicotine (figure 3). Patterns of self-administration (injec-
tions) were similar to those observed when human subjects smoke
cigarettes and when rhesus monkeys take intravenous amphetamine in-
jections in comparable experimental situations (20).

One subject, who lacked a history of drug abuse, exhibited an acquisi-
tion pattern of nicotine self-administration that developed gradually
over several sessions. The pattern was a prototypic example of drug

161
abuse development. Double-blind substitution of saline for nicotine
resulted in cessation of the self-injection behavior of subject KO (figure
3). Subjects who were given access to both nicotine and placebo concur-
rently (by pressing alternate levers) chose nicotine, confirming that
nicotine had come to serve as a positive reinforcer (73). These data indi-
cate that the pharmacologic activity of nicotine was critical to the
maintenance of the behavior.

Nicotine self-administration has been studied in a variety of non-
human species under a variety of experimental conditions (74). As noted
earlier, recent results confirm that nicotine can function as an effective
reinforcer although the conditions under which it serves as a reinforcer
for animals are more restricted than those for morphine or cocaine (21).
Nicotine self-administration via cigarette smoke or smokeless tobacco
may provide ideal confluences of conditions for the establishment and
maintenance of nicotine dependence in humans (33) with the presence of
immediate and abundant peripheral taste and olfactory stimuli (75).

Implications of Pharmacodynamic and Self-Administration Studies.
The results of the pharmacodynamic and self-administration studies
provide direct evidence that nicotine itself, and apart from its being pre-
sented in combination with all of the orosensory properties of tobacco
smoke, is an abusable drug. That is, nicotine meets the criteria of being
psychoactive: it serves as a euphoriant and as a reinforcer. These find-
ings strongly suggest that nicotine parallels other drugs (e.g., morphine
in opium use, cocaine in coca leaf use, and ethanol in alcoholic beverage
consumption) in its ability to maintain self-administration. The find-
ings are of sufficient strength that the relevant public health implica-
tions have already been incorporated into issues of public health policy
by the former Director of the National Institute on Drug Abuse, Dr. W.
Pollin (76), the U.S. Public Health Service (77), and the former Secretary
of the Department of Health and Human Services, Mrs. M. Heckler (78).

Physical Dependence Potential of Nicotine

Physical dependence potential (also referred to as physiological
dependence potential) pertains to the direct physiologic effects that are
produced by the repeated administration of a drug that results in neuro-
adaptation (3,4). Neuroadaptation is characterized by demonstrated
tolerance to the effects of the drug and the occurrence of physiologic
withdrawal signs following the termination of drug administration.

Physical dependence potential studies are conducted according to
standardized tests, using methods such as the substitution approach in
which an active drug is removed and replaced with either a placebo or
another form of the drug (5). Although many studies on the effects of
tobacco abstinence on mood, behavior, and physiologic functions have
been conducted, until recently, the classic ‘direct addiction” or
“substitution” methodologies had not been used to study the physical
dependence potential of nicotine (79).

162
The absence of such studies and the fact that many critical markers of
tobacco abstinence are not overt or easily measured (e.g., change in
affect, EEG, and cognitive performance impairment) have led to ques-
tions about the severity of the tobacco withdrawal syndrome (33).
However, as shown below, abstinence from chronic tobacco or oral nico-
tine use is followed by a syndrome of behavioral and physiologic
changes that are orderly, replicable, specific to nicotine, and of func-
tional consequence in relapse to tobacco following abstinence. The
apparent absence of withdrawal symptoms among some people is not
inconsistent with the finding that nicotine has the potential to produce
physical dependence. As is true for users of opiates (e.g., heroin), the
magnitude of the withdrawal syndrome is related to a variety of factors
such as dosage and individual predispositions (80).

Definition of Tobacco Withdrawal. There are abundant data indicat-
ing neuroadaptation to tobacco use, showing that this adaptation is at
least partially nicotine specific and that termination of chronic tobacco
use produces a behavioral and physiologic rebound or withdrawal syn-
drome (33). This has been stated in the Diagnostic and Statistical
Manual (DSM) of the American Psychiatric Association (APA) as
follows (81):

Tobacco Withdrawal (APA, DSM, III, 1980). The essential feature
is a characteristic withdrawal syndrome due to recent cessation of or
reduction in tobacco use that has been at least moderate in duration
and amount. The syndrome includes craving for tobacco, irritability,
anxiety, difficulty concentrating, restlessness, headache, drowsiness,
and gastrointestinal disturbances. It is assumed that this syndrome
is caused by nicotine withdrawal, since nicotine is the major pharma-
cologically active ingredient in tobacco.

Withdrawal does not occur with all smokers; but in many heavy
cigarette smokers, changes in mood and performance that are prob-
ably related to withdrawal can be detected within two hours after the
last cigarette. The sense of craving appears to reach a peak within the
first 24 hours after the last cigarette, thereafter gradually declining
over a few days to several weeks. In any given case it is difficult to dis-
tinguish between a withdrawal effect and the emergence of pychologi-
cal traits that were suppressed, controlled, or altered by the effects of
nicotine.

This definition by the American Psychiatric Association represents a
reasonable consensus from various reviews of the literature on cigarette
smoking and physiologic dependence on tobacco (3,13,382,82,83), It is
based on experimental data and clinical observations from cigarette
smoking treatment studies demonstrating that certain signs and symp-
toms are of unusually high prevalence during the first few days of absti-
nence. Decreased heart rate and blood pressure have been studied
experimentally (84), as well as changes in cortical EEG potentials (85,86),

163
changes in urine catecholamine excretion (87), and weight gain (57).
Other possible concomitants of tobacco withdrawal reported clinically
include headaches, gastrointestinal disturbances, insomnia, and fatigue
(82,87). A variety of behavioral effects occurs when tobacco or nicotine
administration is abruptly terminated in human and animal subjects,
including increased irritability, aggressiveness, and anxiety; perfor-
mance also is impaired in various psychomotor and learning tests such
as simulated driving, vigilance, and paired-associate learning (88-90).
Self-reported desire to smoke cigarettes (“‘craving”’) increases sharply for
about 1 day following abstinence, then gradually declines over the course
of about 1 week toa lesser level (91). Most of these signs and symptoms of
withdrawal subside over 1 to 2 weeks; however, some former tobacco
users report that the desire to smoke may recur for many years and may
be evoked by specific environmental stimuli that were previously
associated with smoking, such as after meals or in selected social situa-
tions. This, too, parallels the powerful conditioning phenomena that are
reported to be associated with other drugs of abuse (92).

Evidence of Tobacco Withdrawal Symptoms. There is compelling evi-
dence that acute tobacco abstinence produces a rebound (withdrawal)
syndrome. This evidence comes from studies of two laboratories in which
increases in low-frequency EEG bands and decreases in cortical activity
were observed during the first day of tobacco abstinence (85,86). These
effects were immediately reversed when the subjects were allowed to
smoke two cigarettes.

In a study of self-reported withdrawal symptomatology, 40 partici-
pants completed four 25-item questionnaire forms daily for 2 weeks (93).
Subjects were divided into two groups: totally abstinent and partially
abstinent whose smoking levels were maintained at an average of 60 per-
cent. Four symptom clusters emerged: (1) drowsiness in both groups
declined over the first week and then increased over the second week,
forming a U-shaped function; (2) physical symptoms (e.g., headaches and
gastrointestinal disturbances) in both groups declined rapidly the first
week and then remained stable across the second week; (3) psychological
symptoms (e.g., anxiety and irritability) in both groups paralleled physi-
cal symptoms; and (4) craving symptoms in the totally abstinent group
closely paralleled physical and psychological symptoms, whereas craving
levels of the partially abstinent subjects remained elevated across the 2
weeks. The finding that partial abstinence is accompanied by persistent
craving symptomatology is similar to the results of studies on the treat-
ment of illicit opioid dependence with methadone. In these studies, low-
dose methadone maintenance is associated with a persistent opioid crav-
ing (94).

An important series of studies on the dependence potential of nicotine
has recently been completed at the University of Minnesota (95,96,97).
The goals of these studies were to determine reliable and valid indicators

164
of tobacco withdrawal by examining physical, subjective, and behav-
ioral reactions to tobacco deprivation. The first three studies of this
series evaluated the dependence potential of tobacco and established a
reliable battery of measures. In a residential study, 27 smokers resided
for 7 days on a research ward (95). Following baseline, they were assigned
to abstain from smoking or to continue smoking for 4 days. Physiologic,
subjective, and behavioral measures were obtained and analyzed. The
second study was conducted on a nonresidential basis to assess tobacco
withdrawal in the nonlaboratory environment (96). In this study, signs
and symptoms of tobacco withdrawal were measured in 100 smokers.
Following baseline measurements, subjects were randomly assigned to
either nicotine or placebo gum, to be chewed at each subject’s own rate.
The subjects returned on three different occasions for assessment. The
third study assessed the reliability of the tobacco withdrawal syndrome
within subjects (97). This study employed a modified, within-subject ex-
perimental design; baseline smoking, tobacco deprivation, return to
baseline smoking, and tobacco deprivation were assessed in each sub-
ject.

The results of all three studies demonstrated that the syndrome of
withdrawal that occurs reliably and consistently in chronic smokers
after tobacco deprivation includes decreased heart rate, increased
caloric intake/eating, an increased number of awakenings during sleep,
an increased desire to smoke cigarettes, and increased confusion. Other
changes that were found, but not consistently, included increased irri-
tability and decreased vigor. A prospective examination of data from
both residential and nonresidential studies revealed that there were no
statistically significant differences between men and women in either
number or severity of tobacco withdrawal symptoms (98).

A subsequent study was designed to assess the relationship between
tobacco withdrawal symptoms and pre- and post-cigarette blood nico-
tine levels, pre-cigarette cotinine levels, change in nicotine level from
pre- to post-cigarette, half-life of nicotine, and total smoke exposure (99).
Twenty subjects were required to smoke cigarettes for 3 days using a
portable recorder that allowed measurements of smoking topography
in a nonlaboratory environment. Blood samples were drawn to deter-
mine blood nicotine and cotinine levels. Subjects abstained from
cigarettes for the next 4 days. A battery of tests to measure tobacco
withdrawal symptoms was administered. In general, results showed an
inconsistent relationship between measures of nicotine intake and
tobacco withdrawal. The most consistent finding was the relationship
of the desire to smoke cigarettes to blood nicotine and cotinine levels
and change in nicotine from pre- and post-cigarette; that is, the higher
the nicotine and cotinine level and “nicotine boost,”’ the greater the
desire for cigarettes during abstinence.

The three initial studies that were conducted at the University of
Minnesota (95,96,97) systematically examined the physiologic depen-

165
dence produced by chronic tobacco use. This work represents a major
advance in furthering the understanding of tobacco dependence. The
NIDA Addiction Research Center is also nearing the completion of a
series of studies on the physical dependence potential of tobacco and
the degree to which oral nicotine treats the abstinence syndrome. Pre-
liminary data analysis confirms the findings from the Minnesota
studies.

Implications of Physical Dependence Potential Studies. These recent
studies confirm and extend the findings of earlier investigations that
demonstrated that nicotine had the potential to produce physiologic
dependence. It is now known that the syndrome is orderly and is due to
the administration and withdrawal of nicotine. The overt signs are more
subtle than those marking opioid and sedative withdrawal, but these
signs are not necessarily less important to the individual. For instance,
withdrawal effects such as mood changes, performance deficits, and
weight gain may be of considerable importance to the normal function-
ing of the individual. It is anticipated that just as detoxification and
treatment of opioid and sedative dependence have benefited from im-
proved understanding of these syndromes of withdrawal, so also may
detoxification and treatment of tobacco withdrawal benefit.

Evidence That Orally Delivered Nicotine (Including
Via Smokeless Tobacco) Has a Liability for Abuse and a
Potential to Produce Physical Dependence

As previously indicated, moist snuff contains as much as 15.1 mg
nicotine per gram; plug tobacco contains 17.2 mg per gram (100,101).
Lower-nicotine-containing brands exist. However, marketing efforts
encourage (and users demonstrate) graduation to the higher-nicotine-
containing products (1). These levels of nicotine are substantial, since
the relative potency of nicotine is 5 to 10 times greater than that of co-
caine in producing discriminable subjective effects (1 to 2 mg of nicotine
given intravenously, orally, or inhaled produces reliable behavioral and
physiologic effects).

Two studies have confirmed that typical patterns of smokeless tobac-
co use result in the delivery of quantities of nicotine that produce
plasma nicotine elevations comparable to those produced when ciga-
rettes are smoked (102,103). These studies also found that smokeless
tobacco use reflected several of the indices of abuse liability and
physical dependence potential. Smokeless tobacco users self-
administered substantial quantities of nicotine; the patterns of
smokeless tobacco use were orderly and stable; and subjective and
behavioral effects may be produced from such use. More recently, a new
form of smokeless tobacco, moist brown tobacco in tea bag-like
pouches, was also shown to deliver pharmacologically active quantities
of nicotine to the central nervous system (104).

166
Reinforcing Properties of Nicotine in the Form of Chewing Gum

There is growing evidence that nicotine is reinforcing and has the
potential to produce dependence even when absorbed through the buc-
cal mucosa (and therefore more slowly) via chewing gum (nicotine pola-
crilex). One recently completed study involved the self-administration
of either a nicotine- or placebo-containing chewing gum by smokers who
had quit smoking (105). When given a choice between placebo and
nicotine chewing gum, subjects preferred nicotine to placebo and self-
administered the nicotine gum throughout each day.* These data are
particularly compelling, because nicotine, in the form of the nicotine
polacrilex, is in an ion-bound complex. In this preparation, the nicotine
is released and absorbed slowly compared to the nicotine in smokeless
tobacco; and the polacrilex form of nicotine administration appears to
be of relatively low abuse liability. This study also demonstrated that
instructions by a physician can alter patterns of gum use and preference
(105). These data, which suggest that instructions can modulate the self-
administration of orally delivered nicotine, are in keeping with the well-
known fact that physicians control their patients’ use of narcotics,
sedatives, and stimulants.

Physical Dependence Potential of Smokeless Tobacco

Hatsukami and coworkers, at the University of Minnesota, studied
neuroadaptation (physiologic dependence) in smokeless tobacco users
(106). All 16 subjects in the study used moist snuff and no other
nicotine-delivering product. Measures of mood, feeling, behavior, and
physiologic function were comparec at baseline and during abstinence.
Subjects showed significant signs and symptoms of nicotine with-
drawal as measured by decreased resting pulse, attenuated orthostatic
pulse changes, and increases in tobacco seeking (‘‘craving”’), eating,
sleep disruptions, and confusion.

A study with nicotine gum showed orally delivered nicotine may
cause physical dependence (107). The subjects that were tested had been
treated for tobacco dependence with nicotine gum that they used on a
daily basis for at least 1 month. Eight subjects were then tested over
the course of 4 weeks. They were given nicotine-containing gum during
the first and fourth weeks; during the second and third weeks, they
received nicotine gum for 1 week and placebo gum for the other. During
the week that placebo gum was presented, seven subjects showed signs
and symptoms of withdrawal, and two subjects relapsed to smoking or
nicotine-containing gum. This study confirms that orally given nicotine
has the potential to produce physical dependence. These findings were
most recently confirmed by another study that showed development of
physical dependence to nicotine gum in patients treated for tobacco
dependence (108).

* Self-administration took place at an average rate of 7.4 pieces compared to an average of 1.2 pieces of placebo
gum per day.

167
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174
PHYSIOLOGIC AND PATHOGENIC EFFECTS OF
NICOTINE AND SMOKELESS TOBACCO

The user of smokeless tobacco is systematically exposed to signifi-
cant amounts of nicotine, a potent multisystem pharmacologic agent.
This chapter addresses the physiologic effects of nicotine upon the car-
diovascular, nervous, and endocrine systems and the possible roles of
nicotine in the pathogenesis of a variety of diseases.

Nicotine is described in pharmacology textbooks as a stimulant of
autonomic ganglia and skeletal neuromuscular junctions (i.e., nicotinic
muscarinic receptors). However, in vivo the actions of nicotine are far
more complex depending on the dose, target organ, prevalent auto-
nomic tone, and previous exposure history (tolerance) (1,2). For pur-
poses of this review, the focus is on the effects of nicotine in humans.
Where human data are lacking and animal studies provide important
information about physiologic effects, those studies are also discussed.

Most data on the actions of nicotine in humans derive from studies of
the effects of cigarette smoking, comparing cigarettes with and without
nicotine, and studies of the effects of intravenous nicotine. These
studies provide the basis for our understanding of the human pharma-
cology of nicotine. However, as noted previously, actions of nicotine
from smokeless tobacco and nicotine via inhalation or intravenous infu-
sion may differ.

Physiologic Effects of Nicotine

Cardiovascular System

The predominant cardiovascular actions of nicotine result from ac-
tivation of the sympathetic nervous system. Smoking a cigarette in-
creases the heart rate (10 to 20 BPM), blood pressure (5 to 10 mmHg),
cardiac stroke volume and output, and coronary blood flow (8-5). Smok-
ing may have different effects in smokers with coronary heart disease.
It may reduce left ventricular contractility and cardiac output (6), ef-
fects that are believed to be related to myocardial ischemia due to
smoking-mediated tachycardia and the effects of carbon monoxide.
Coronary blood flow may also decrease after smoking, which possibly is
related to a nicotine-mediated increase in coronary vascular resistance
(7,8). Smoking, or nicotine intake, causes cutaneous vasoconstriction
that is associated with a decrease in skin temperature, systemic veno-
constriction, and increased muscle blood flow (9-11).

Smoking results in increased circulating concentrations of norepi-
nephrine, consistent with neural adrenergic stimulation, and epinephrine,
indicating adrenal medullary stimulation (8) Circulating free fatty
acids, glycerol, and lactate concentrations increase. Cardiovascular and
metabolic effects are prevented by combined alpha and beta adrenergic
blockade, which indicates that the cardiovascular effects of cigarette
smoking are mediated by activation of the sympathetic nervous

175