both nonsmokers and smokers after smoking one or two cigarettes. In
addition, digital blood flow and finger and toe temperature fall (139,
151).

The acute cardiovascular responses to tobacco and nicotine have
been summarized in the Surgeon General's reports on the health
consequences of smoking (136, 138). These reports list the following
acute changes from smoking: increased (1) heart rate, (2) blood
pressure, (3) cardiac output, (4) stroke volume, (5) velocity of
contraction of the heart, (6) myocardial contractile force, (7) coronary
blood flow, (8) myocardial oxygen consumption, (9) arrhythmia
induction, and (10) electrocardiographic changes. These effects are
assumed to be due to catecholamine release from the adrenal medulla,
chromaffin tissue, or sympathetic nerve endings, and are similar to
those obtained by sympathetic stimulation. They are to a considerable
extent mediated by sympathetic excitation (139). These diverse
cardiovascular changes may be a significant component in shifting the
arousal continuum toward an optimum level for smokers. However,
there are no controlled experiments that definitely rule them in or out
as contributors to the reinforcing properties of cigarettes.

Maintenance of the Smoking Habit

The biological factors which can be implicated in the maintenance of
smoking have, by no means, been thoroughly investigated. A great
deal is known about the harm&l biological consequences of smoking,
but very little about the beneficial effects. It is evident that some
component or components in tobacco and tobacco smoke must be
reinforcing, but these have not been unequivocally identified. As noted
earlier, the possible candidates for reinforcing agents can be seen in
the two tables (Tables 1 and 2) from Schmeltz and Hoffman (118). The
leading contender is nicotine because it is clearly a powerful
pharmacological substance and is administered in ways consistent with
its action as a reinforcer. There are, however, some inconsistencies in
the literature. Yanagita (1%`) has reported low levels of nicotine self-
administration in monkeys and rats respectively, while Russell, et al.
(111) report a lack of evidence for self-administration in man, as well
as in other animals. The present discussion focuses upon tolerance to
tobacco and its constituents, the metabolism and fate of the
constituents, and their physiological effects as they relate to the
maintenance of the smoking habit.

Tolerance

By definition, tolerance is manifested by a decreasing response to
repeated administration of the same dose of a drug, or by the
requirement for increasing doses in order to elicit the same response.
Martin (81), Jaffe and Sharpless (61), and others have proposed models

15-13


which imply that dependence and tolerance are based upon identical
mechanisms. It is difficult to think of an example of a drug to which
dependence occurs that does not also involve tolerance. On the other
hand, tolerance may occur without dependence (e.g., phenothiazine,
antihistamines).

Three kinds of tolerance are apt to occur with tobacco use as with
other types of drug use: drug dispositional or metabolic tolerance,
tissue or pharmacodynamic tolerance, and behavioral tolerance. The
first refers to methods that the body uses to eliminate or to deactivate
the drug. For most chemicals derived from tobacco, the liver is the
organ most heavily responsible for detoxifying or transforming them
into inactive and eliminable forms. The kidney is also important,
especially for alkaloids whose water solubility varies with the pH of
the solution. The second kind of tolerance refers to changes in the
ability of receptors to be activated by the drug at its final site of
action. The third type refers to the way in which the subject using the
drug changes his behavior to adapt to the effects which the drug
repeatedly produces.

Of the compounds contained in tobacco and tobacco smoke (118),
three are of primary biological importance: tar, carbon monoxide, and
nicotine. There is evidence that tolerance can develop to the effects of
each of these, although their interaction has scarcely been studied.
While there is evidence that tolerance may develop to other compo-
nents such as acetone and phenol, it is unclear how much they
contribute to the pharmacological actions of cigarettes.

Stolerman, et al. (126) examined the interaction between pairs of
injections of nicotine which varied both in dose and in interval. Two
measures of spontaneous locomotor activity of rats in a T-maze were
taken: rears and entries. After a single treatment with nicotine, acute
tolerance developed as indicated by a shift of the dose-response curve.
The dose of nicotine required to produce a given decrement in activity
was multiplied by a factor of about 2.4 when a delay of 2 hours was
taken between the two injections. When the initial dose was varied, it
was found that there was an optimal level for producing tolerance.
Higher doses were less effective. An explanation for the relative
ineffectiveness of the higher doses in producing tolerance is not
available. A general debilitating effect of pretreatment with large
doses does not seem to explain it, as rats given a saline challenge
exhibited normal motor activity. Perhaps the debilitating effects of a
large pretreatment dose and a challenge somehow summa .e.

15-14


Carbon Mono*

Levels of carbon monoxide achieved in the human body following
cigarette smoking increase levels of carboxyhemoglobin. These chroni-
cally high levels of carboxyhemoglobin found in smokers can induce
polycythemia by increasing hemoglobin levels. These compensatory
changes enable the smoker to tolerate increased carbon monoxide
levels and to cope with the oxygen deficit produced by cigarettes.

Tar

Tar is defined as the total particulate matter (TPM) collected by a
Cambridge filter after subtracting moisture and nicotine. The
polycyclic aromatic hydrocarbons are generally blamed for a substan-
tial portion of the carcinogenic activity of tar. They are also powerful
enzyme inducers and are undoubtedly responsible for much of the
tolerance to themselves and a variety of other compounds produced by
smoking. The tar content of cigarette smoke for all brands is
determined yearly by the Federal Trade Commission which publishes a
listing, along with nicotine content. Tar and nicotine tend to co-vary
and thus their effects may be confounded. Obviously, tar is obtained in
the smoke from pipes and cigars but not from chewing tobacco and
snuff. The latter do not deliver pyrolysis products, such as carbon
monoxide, and may thus be somewhat safer. Because the hepatic
microsomal enzyme formation is induced by a number of carcinogens
in the tar fraction of cigarette smoke, including benzopyrene (96),
smokers are rendered tolerant to both the therapeutic and toxic effects
of a wide variety of drugs (1.29). Even the enzymes in platelets are
activated (53).

The phenomenon of tolerance to the effects of tobacco products has
been clearly demonstrated in both humans and animals. As might be
expected, most of the emphasis has focused upon nicotine, but carbon
monoxide and tar components also play an important role. As with all
other drugs, tolerance varies with subjects and functions. Certain
invertebrate forms which feed on the tobacco plant have a high
genetically determined tolerance. It is reasonable to assume that even
in humans some of the variance in response to tobacco is innately
determined and may account for some of the high concordance in
smoking behavior seen in identical twins. Other forms of tolerance are
clearly the result of experience and develop after exposure to tobacco
products. Much more research needs to be done to determine the
degree of tolerance which develops in different physiological and
psychological functions after tobacco use. For example, it is evident
that even in heavy smokers of long duration the heart rate speeds up
after each cigarette. On the other hand, nausea and vomiting diminish
and disappear with continuing moderate use of cigarettes. It would be
very informative indeed to know what changes take place at the

15-15


putative sites of action of nicotine with chronic use. Do nicotinic
synapses at ganglia change in the same way as nicotinic synapses in
the brain? Do carbon monoxide and tar constituents have any action on
these components or on enzyme systems elsewhere in the body?
Answers to these questions will enable us to understand better the
physiological basis of the smoking habit.

Tolerance to the effects of cigarette smoke was noted in dogs given
cigarette smoke via tracheostomy (44). At the beginning of the study
the smoke was aversive, but with the passage of time, animals
exhibited tail wagging and improved cooperation. In a careful study,
Stolerman, et al. (127) showed the development of both acute and
chronic tolerance in rats. Nicotine administered intraperitoneally to
experimentally naive rats depressed activity in a Y-shaped runway in a
dose-related manner. After a single intraperitoneal dose of nicotine,
acute tolerance to the depressant action of a second dose developed
with a definite time course. This became maximal after 2 hours and
wore off after about 8 hours. Repeated intraperitoneal doses of
nicotine (three times daily for 8 days) elicited chronic tolerance which
persisted for at least 90 days after the end of regular treatment with
the drug. Tolerance was also produced when nicotine was administered
in rats' drinking water and through reservoirs implanted subcutane-
ously. It appears, then, that tolerance to nicotine in rats can develop
quickly, may be easily measured, and persists for prolonged periods
after withdrawal. In these experiments, rapid withdrawal of nicotine
did not produce the signs of illness which morphine withdrawal
regularly produced. The existence of prolonged tolerance to nicotine in
rats suggests that the same phenomenon might exist in man. If
tolerance to the unpleasant effects of nicotine, such as nausea,
developed more rapidly and persisted longer, it might facilitate relapse
to tobacco use.

Metabolism
Nicotine

Tne metabolic fate of 1 mg of nicotine base injected intravenously in
humans (actually as nicotine hydrogen tartrate) was intensively
investigated by Beckett, et al (7'). They found that smokers excrete
nicotine significantly faster than nonsmokers. None of the smokers
reported any nausea from the nicotine injections, but this was reported
in varying degrees by all nonsmokers. Haines, et al. (4.2) reported that
the plasma concentrations of nicotine were actually higher in smokers
than in nonsmokers 1 minute after smoking, but these results were
confounded by the fact that nonsmokers were instructed to smoke
cigarettes. Obviously smokers were able to inhale more effectively
than nonsmokers, in part because they had acquired tolerance to the
aversive effects of cigarette smoke on the respiratory passages.
Indeed, some of the tolerance that smokers show to cigarette smoke

15-16


may be correlated with diminished function of the respiratory
epithelium and possible depression of taste and smell (?`O). The
proposition that heavy smokers adjust their plasma nicotine levels is
compatible with the observation that regular smokers commonly
consume about 20 to 30 cigarettes during the smoking day (approxi-
mately one every 30 to 40 minutes) and that the biological half life of
nicotine in humans is approximately 20 to 30 minutes (57, 111). While
studies with intravenous nicotine (80) show changes in smoking rate
apparently due to nicotine concentration in the blood, studies using
nicotine gum (73) did not show the same effects as intravenous
nicotine. It is postulated that the nicotine derived from the gum is
absorbed in the intestine and sent to the liver directly via the portal
and is there metabolized; therefore less nicotine enters the systemic
circulation. Most investigations of smoking rates indicate that much
more than plasma nicotine level regulation is involved.

Carbon Mommid

The metabolism of carbon monoxide involves both the exhalation of
the substance from the lungs and a compensatory increased hematocrit
to increase oxygen capacity. The former is s!owed by the high affinity
of carbon monoxide for hemoglobin, and the latter's rate is limited by
the process of hematopoiesis. Carboxyhemoglobin has a half life in the
body of at least 3 to 4 hours (137). It is not known whether the
metabolism of carbon monoxide plays a physiological role in the
maintenance of the smoking habit.

Tar

Some examples of the effects of induction of microsomal enzymes are
cited by Hunter and Chasseaud (54). Aryl hydrocarbon hydroxylase is
regularly induced by smoking. Benzopyrene hydroxylase and aminozao
dye N-methylase were higher in the placentae of pregnant smoking
women than in those of nonsmokers. Since tar induces the enzymes of
its own metabolism, the smokers might be expected to continue to
smoke so as to maintain the levels of tar in the blood, thereby
maintaining the action of tar on the metabolism of toxic substances, as
discussed above. Metabolism of benzodiazepines, propoxyphene, penta-
zoeine and phenacetin is increased in smokers. Xanthines such as
theophylline are also metabolized more quickly in smokers (105) and,
by inference, so should caffeine be metabolized more quickly. Perhaps
this is why heavy smokers drink more coffee than nonsmokers (9).

Dependence

Dependence may play an extremely important biological role in the
maintenance of the smoking habit (147). The characterization of
tobacco use as a dependence process raises the issue of tobacco

15-17


withdrawal. Thus, the subject of dependence is deferred to the section   '
on cessation of the smoking habit to be discussed in conjunction with
the acute effects of cessation and the abstinence syndrome.

Physiological Effects of Tobacco and Its Constituents in the
Maintenance of Smoking

Although a great deal has been written in previous editions of the
Surgeon General's Report on the untoward effects of smoking, very
little has been said about the factors that might be responsible for the
establishment and maintenance of the habit. In the past 15 years the
public has been exposed to ample warnings about the dangers of
smoking; nonetheless the incidence of smoking remains high. There-
fore, it is important to consider both the evidence and hypotheses about
why smoking is such a tenacious habit. The actions of cigarette smoke
and its components upon the central nervous system, cardiovascular
system, and endocrine system might give us a clue to the strength and
persistence of the habit.

Central Nervous Sy&m

In their study of smokers, deprived smokers, and nonsmokers, Knott
and Venables (72) showed that the deprived smoker is characterized by
a "state of cortical hypoexcitation and that tobacco smoking increased
cortical excitation to the level of the nonsmoker." Citing the findings
that tobacco smoking improves efficiency, prevents deterioration of
reaction time (35), and improves learning (1, 3, 17), they suggest "that
individuals smoke to achieve this specific psychological state of
increased vigilance and attention associated with alpha frequency."

Nelsen, et al. (95) studied the effects of nicotine administered (100
pg/kg) subcutaneously to rats. The rats had electrodes placed in the
reticular formation which, when stimulated, blocked visual learning
tasks. The nicotine attenuated the electrical stimulation and increased
learning. The suggestion is made that the nicotine-induced limbic
system activation antagonized the behavioral disruption.

In Carruthers' attempt to isolate the "rewarding centers" (16), he
used a &blocker, oxprenolol, to decrease epinephrine and norepineph-
rine associated with anxiety and smoking. The secondary effects of
increased heart rate, blood pressure, and free fatty acids were blocked
along with the systemic increase in catecholamines, and yet the
satisfaction subjectively evaluated was unchanged. His conclusion was
that there may be a hypothalamic norepinephrine release leading to
pleasure. It is not clear whether the oxprenolol crosses the blood-brain
barrier. The more conservative conclusion would be that heart rate,
blood pressure, and free fatty acid increases might not be involved in
the pleasure associated with smoking.

15-18


In addition to the learning studies mentioned above, recent studies
add the following data. Stevens (124) studied 115 males on four
learning tasks. His conclusion was that those who smoked more than 12
cigarettes per day did significantly less well than the nonsmokers and
light smokers. Andersson and Hockey (2) showed that, in two groups of
24 female students who were habitual smokers, the group in a control,
no-smoking condition showed immediate serial recall equivalent to that
of the group allowed to smoke one cigarette. The group not smoking
did perform better in incidental memory, such as remembering in
which corner the words were presented. This suggested that the
cigarette increased attentional selectivity during increased arousal.
Elgerot (28) used three complex and two simple tests to determine
differences between a &hour abstaining group and the same group
after smoking freely. In the nonsmoking condition, they improved on
complex tests but were unchanged with respect to simple tests. The
interpretation is baaed on the performance-arousal curve: "According
to the Yerkes-Dodson law, the optimal level for arousal is lower for
complex than for simpler tests," The conclusion is that the combination
of the task and the cigarette led to an arousal level too great for the
complex tests. An alternative hypothesis is that the smokers were
under-aroused and that the abstainers were anxious enough, but not
too anxious. The second explanation would account for the finding, but
it is not consistent with other authors. Elgerot (28) cites the following
effects in habitual smokers: (1) decreased hand-steadiness (M), (2)
improved simple and choice reaction times (93), (3) improved driving
tasks demanding sustained performance (48), and (4) impaired short-
term memory but favorable effects on consolidation (1). Some of these
changes in arousal levels and functioning capacities may be of benefit
to the smoker and may reinforce maintenance of the smoking habit.

Other effects of smoking on the nervous system may be positively
reinforcing. Decreased acetylcholine axonal transport and synthesis in
neurons (49) may lead to decreased GI motility and augment the
sympathetic response in calming digestion. Other investigators have
shown no basic differences in the basic taste sensations between
smokers and nonsmokers (83).

Cardiovascular System

The most commonly reported acute changes in the cardiovascular
system are the following: increase in plasma cateeholamines (4, 78),
increased heart rate (4, 5, 7'8), increased blood pressure (4, 5),
vasoconstriction (&3,94), and increased carboxyhemoglobin (4,98). It is
conceivable that cardiovascular changes are associated with pleasant
emotional experiences, although Carruther's (16) P-blocking experi-
ment would not support this possibility. Possibly decreased peripheral
blood flow (43) is a heat-conserving mechanism which may drive

15-19


individuals to smoke. The increased viscosity of the blood due to
increased hematocrit (140) is of unknown benefit on a chronic basis.

Endocrinological System

Although there has been much recent research on endocrine effects of
smoking, the role these play in the smoking habit has scarcely been
examined. With the development of more refined and more economical
techniques for measuring hormones and their actions, we can expect an
acceleration of research in this area.

Hayward and Pavasuthipaisit (IS) administered IV nicotine to
monkeys, causing an increase of arginine vasopressin (AVP) without
changes in plasma osmolarity. Husain, et al. (55) and Robinson (109)
also demonstrated the release of AVP plus neurophysins in humans.

Cryer, et al. (22) demonstrated that growth hormones and cortisol
are released by smoking and are unaffected by P-blockers. Both are
involved in protein and carbohydrate metabolism. Perhaps their effect
on plasma glucose helps reinforce the smoking habit. Similar results
were found by others (100,141,149).

Perhaps a factor involved in maintenance of smoking is the
increased lipolysis due to release of catecholamines and glucocorto-
coids. A common reason given for returning to smoking is weight gain
(150).

Other endocrinological effects of nicotine include increased gastric
HCl secretion (24, 89), decreased pancreatic bicarbonates and water
secretion secondary to inhibition of secretin (II, 12, 13, 25), changes in
placental hormones (21, 122)~ alteration in prostaglandin formation
(144), and delayed LH surge in female rats (85). Also, it is known that
in smokers there is decreased sperm quality and distribution (117).
Smokers and nonsmokers do not seem to vary in LH, TSH, T4, and
FSH (149), however.

Cessation of the Smoking Habit
Early Effects of Cessation

Cessation of smoking is associated with alterations in CNS, cardiovas-
cular, and other physiological functions. Whether these are true
"withdrawal" phenomena characterized by a rebound or merely a
return to normal levels still remains to be determined. It is evident,
however, that significant changes do occur.

A number of physiological changes have been observed on withdraw-
al from tobacco. Decreases in heart rate and diastolic blood pressure
are observed as early as 6 hours after withdrawal (91). These changes
persist for at least 3 days (?I), (146) and perhaps for 30 (37). Decreased
excretion of both adrenaline and norepinephrine (92) and various
metabolic changes have also been observed (37).

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These metabolic and peripheral effects, which are often associated
with decreased arousal, have been supported by EEG studies showing
increases in low-frequency activity (135) and alterations in cortical
alpha frequencies (72). Ulett and Itil (135) recorded cortical EEG from
heavy smokers (one pack of cigarettes per day) in an attempt to detect
EEG changes associated with acute withdrawal. Baseline EEG
measurements were obtained while the smokers engaged in their
normal smoking pattern and were compared with data from the same
individuals after they were deprived of tobacco for 24 hours. It was
found that there was a significant increase in the low-frequency EEG
bands (3-5-7 cycles&c) during deprivation. This effect was readily
reversed after the subjects smoked two cigarettes within a 5-minute
period.

In a similar study, Knott and Venables (72) did a computer analysis
of cortical alpha activity in male nonsmokers, smokers asked to abstain
for a 13- to &hour period, and smokers who continued their normal
pattern of smoking. Analysis of variance of pre-smoking alpha activity
indicated the mean alpha frequency of the subjects in the deprived
group was significantly lower (9.3 Hz) than in the nonsmoking group
(10 Hz) and nondeprived group (9.9 Hz). When the deprived group
smoked two cigarettes, the alpha frequency increased to the levels of
the nonsmoker and smoker control groups. Thus, there is evidence for a
rebound effect and a true withdrawal reaction. The data are
interpreted as indicating that deprived smokers are in a state of
cortical "hype-excitation," and that smoking has the effect of
increasing excitability to levels comparable to those found in non-
smoking and nondeprived groups. Since all groups were equal on
measures of extroversion, the authors hypothesize. that they have
described a true "smoking factor" rather than a difference due to
personality. Alternatively, one could conclude from the same data that
the results obtained are due to the removal of an arousal-producing
drug from a group of people who are ordinarily hypo-aroused.

Numerous other physiological changes have been noted to occur
after cessation of smoking. Ejrup (27) reports that weight gain is a
common sequela to cessation. Although not generally observed, he
reported that, in a number of patients, blisters in the mouth occurred
along with constipation upon cessation of smoking. If the patients
resumed smoking, the blisters disappeared.

Krumholz, et al. (74 have measured changes in cardiopulmonary
function at rest and during exercise 3 and 6 weeks after cessation of
smoking. All subjects had smoked more than one pack of cigarettes a
day for at least 5 years. Changes during exercise were measured on the
standard bicycle-ergometer test. Following 3 weeks of abstinence,
heart rate, oxygen debt, and ratio of oxygen debt to total increase in
oxygen uptake during exercise were significantly reduced. In addition,
expiratory peak flow and DL were significantly increased. Pulmonary

15-21


compliance increased after 3 weeks and continued to do so at 6 weeks.
At 6 weeks, maximum voluntary ventilation and inspiratory reserve
volume were increased and functional residual capacity was decreased.

Glauser and colleagues (37, 38) studied seven subjects before and 1
month after cessation of smoking. The following measures were found
to have changed significantly: (1) body weight increased from a mean
of 133 to 195 pounds, (2) body surface area increased from 2.03 to 2.05
m, (3) heart rate decreased from 60 to 5'7 beats per minute, (4) sugar
levels (30 seconds after eating) fell from 13'7 to I23 mg percent, (5)
protein-bound iodine decreased from 5.1 to 4.6 pg percent, (6) serum
calcium decreased from 10.2 to 9.7 mg percent, and (7) oxygen
consumption decreased from 233 to 260 ml of oxygen/min. The authors
concluded that the metabolic change that follows cessation of smoking
may be one important variable that causes an increase in weight.

My&en, et al. (93) have studied chronic smokers who smoked for 5
days, abstained for 5 days, and smoked for 5 additional days. Results
from this group were compared with those from a nonabstaining group
of smokers. A number of physiological differences were noted during
the abstinence period. Adrenaline and noradrenaline excretion levels
decreased, skin temperature increased, heart rate decreased, and hand
steadiness improved.

Accompanying these objective changes in physiology and perfor-
mance are subjectively reported changes in physical symptoms,
arousal, and mood. These have been reported in studies of smokers
sampled while actually undergoing withdrawal (34, 41, US), as well as
in retrospective studies of ex-smokers up to 14 years after cessation
(15,34, 82,103,112, 131,152). Although the specific symptoms reported
in each study differ, as does the percentage of abstinent smokers
reporting each symptom, a consistent pattern of symptoms can still be
discerned. Common among the physical symptoms reported are nausea,
headache, constipation, diarrhea, and increased appetite (41, 92, 146).
Also reported are disturbances of arousal, including drowsiness and
fatigue, as well as insomnia and other sleep disturbances (92, 152).
Inability to concentrate is a common complaint and is consistent with
objective assessments of the concentration of smokers in abstinence
(46). Thus, the objective changes reviewed above appear to be reflected
in the subjective experience and self-reports of deprived smokers.

Long Term Effects of Cessation

Once a smoker gets past the initial 3- to 14day withdrawal effects (45,
59,120), what biological factors tend to encourage the now ex-smoker
to continue abstinence? The factors opposing most ex-smokers'
attempts to refrain seem to win out, since relapse is so frequent. In all
cessation methods described, about two-thirds are able to attain some
degree of abstinence for a short duration, but about half of these
return to smoking in 1 to 2 years (20, 68). Is it the methodology of

15-22


cessation or the post-cessation factors which determine continuation of
abstinence? Kasl (69) claims "there is evidence that smokers who stop
spontaneously have a lower rate of relapse than those who seek help
and participate in some sort of program." The effects of cessation on
the central nervous system, cardiovascular system, and endocrine
system which might encourage continued abstinence will be discussed
along with some of the psychobehavioral components.

Cardiovascular System

When a smoker terminates his intake of tobacco, he reduces his risk in
a number of cardiovascular diseases: coronary heart disease (29,50, 67,
123), cerebrovascular accidents (50), recurrence of myocardial infarc-
tion (29), sudden death from CHD (67, 123), myocardial infarction
(123), and complications of atherosclerosis (101). These reduced risks
are measurable on populations, but what cardiovascular benefits of
cessation exist to individuals? One report says that the subendothelial
edema of small arterioles and vasa vasorum is secondary to the carbon
monoxide of cigarettes and that this, including coronary arteries (5),
tends to return to normal after 5 to 10 years of cessation. This might
reinforce cessation, especially in ex-smokers with angina pectoris or
other ischemic heart disease. Janzon (62), using venous occlusion
plethysmography on the calf, found that after 8 to 9 weeks of cessation
peripheral blood flow increased measurably, whereas the control group
of continuing smokers actually decreased their peripheral blood flow.
It is likely that this improvement of circulation would be accompanied
by a sense of well-being and reinforce abstinence as time progressed.
The decrease in heart rate and blood pressure (52), along with
decreased catecholamines, may be a factor in continuing abstinence.
Related to the cardiovascular benefits of cessation, it was found that
peakexpiratory flow rates of 57 liters/min resulted (go), an increase
which would be positively reinforcing, especially in active ex-smokers.

Endocrinological System

If the metabolic rate declines (52), the major effect would be increased
weight, as has been noted by many (34,37,82,148). This would tend to
reinforce smoking in most people. But there may be some unseen
benefit of decreased metabolism in those who are either able to
maintain their weight or who are not self-conscious of weight gain.

In Pearson's study of theophylline metabolism (lU2), he found that
smokers' half-life of theophylline was 4.2 hours while nonsmokers' was
7.1. Upon cessation, the normalization (toward 7.1) took 3 months to 2
years, implying that there may be induced enzymes in the smoker
which do not readily normalize. This may be indicative of other
metabolite-clearing processes and, because the normalization effect is
gradual, may keep the ex-smoker in a "smoking" state so that he does

15-23


not "miss" this aspect of smoking. Is it possible that this kind of
normalization is responsible for so many returning to smoking after 1
to 2 years (20, 68)? Another possible influence may be in sex hormonal
levels. After 3 months there is improved quality of sperm motility and
density as well as fertility (117).

Other Effects

Pederson and Lefcoe (103) used the Jackson Personality Inventory and
a modification of the Reid-Ware Internal-External Control Scale and
found no difference between smokers and successful ex-smokers. They
point out that ex-smokers have usually tried to stop at least once and
failed, have stopped for health reasons, have experienced cravings and
discomfort, and have used substitutes. The fact that spontaneous
quitters are more successful than those who get help (69) implies that
they are either more strong-willed and independent, primed to give up
the habit because of other negative factors, or less dependent upon
cigarettes. West's description (145) of ex-smokers is that they are more
likely to be male, older, have smoked less before cessation, started
smoking at a later age, have a milieu that is supportive of their
stopping, and have fewer indices of neurosis and few psychosomatic
symptoms. Lebowitz and Burrows (77) discuss the finding that ex-
smokers have higher incidence of diagnosed disease and less incidence
of symptoms when compared to smokers, suggesting that when it
"becomes official" that smoking caused an illness, the smoker will quit
more readily than if his symptoms are unattached to etiology or
specific pathology.

Another possible effect of cessation may be decreased "chest pain"
in those having gastroesophageal reflex, as discussed by Bennett (10).

By far the the most common, and clinically the most important,
symptom to appear following withdrawal from tobacco is craving for
tobacco. The best estimates indicate that 90 percent of all smokers in
withdrawal will verbalize their need for cigarettes (41). Moreover,
among smokers who have been abstinent for 5 to 9 years, one out of
five report that they continue to have at least an occasional craving for
tobacco (34). The importance of craving lies not in its universality or
persistence, but in its relation to the clinical goal of modifying smoking
behavior. Indeed, the importance of the tobacco withdrawal syndrome
in its entirety is based on its provocative role in causing relapse among
abstinent smokers.

Dependence

As stated earlier, characterizing tobacco use as a dependence process
necessarily raises the issue of tobacco withdrawal. Some authorities
believe an abstinence syndrome is crucial to the definition of drug
dependence. Indeed, some of the initial reluctance to label tobacco as a

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dependence-producing substance rested on doubts concerning the
existence of a tobacco withdrawal syndrome. This was the position
taken by the Surgeon General in 1964, when first alerting the country
to the dangers of tobacco. Since then, there has been an accumulation
of studies which suggest that withdrawal from tobacco does produce a
variety of signs and symptoms which can be characterized as a tobacco
withdrawal syndrome. Although the syndrome is variable and is only
roughly described and understood, its existence is no longer a matter of
great controversy. It is characteristic of withdrawal syndromes that
their severity is dose-dependent (60). Therefore, it is expected that
heavy smokers would report more severe withdrawal symptoms than
light smokers.

The inconsistency of the effect of deprivation is reflected in the
literature. Studies by Myrsten, et al. (92) and Mausner (83) report no
differences in this regard between light and heavy smokers. In
contrast, Burns (15) reports that subjects who suffered withdrawal
symptoms had smoked an average of 6.9 cigarettes/day more than
asymptomatic subjects (p<.Ol). Wynder, et al. (152) report that the
proportion of abstinent smokers reporting more than one withdrawal
symptom increases with baseline consumption.

Another possible confounding factor is that, because smokers can
vary their smoking consumption in other ways-depth of inhalation,
number of puffs, etc.-cigarette consumption may actually be a very
poor measure of dose. Also, differences in nicotine metabolism
introduce variability in dose even among those who consume similar
amounts of nicotine. Thus, estimating a smoker's dose may require
measuring serum levels of nicotine or its metabolites. In the one study
which has approached this problem, Zeidenberg, et al. (154) found
among men a higher and significant correlation between serum
cotinine levels before treatment and self-reported "degree of diffi-
culty" in smoking cessation. There is some indication that the severity
of the abstinence syndrome is dose-dependent, but much ambiguity
remains. Because dose dependency is so characteristic of withdrawal
syndromes from other substances, establishing this effect for tobacco
would be an important step toward an understanding of tobacco
dependency. Further research into the relationship should probably
proceed along the lines followed by Zeidenherg, et al., using serum
wtinine levels rather than cigarette consumption as the independent
variable. Dependent measures should include more refined instruments
than Zeidenberg and his coworkers' estimates of "difficulty" and
should explore both the number of withdrawal symptoms and their
severity.

Two studies have focused upon the diurnal variations in withdrawal
symptoms (79, 87). Data from a study by Meade and Wald (87) show
that craving in abstinent smokers and in "ad lib" smoking have the
same diurnal pattern; that is, the lowest peak occurs when the subject

15-25


wakes up, gradually rising to a peak in the evening, then falling again
at bedtime. Thus, there is a consistent function which describes three
different stages of the habit and its control (unrestricted smoking,
abstinence, and relapse). The meaning of the underlying function has
not been determined. Two different types of explanation are plausible.
One focuses on diurnal variation in the internal environment of the
smoker, suggesting the influence of some metabolic factor with diurnal
variation. The other explanation focuses on the diurnal variation in the
social environment, e.g., the timing of work, meals, social contact,
recreation, and so on, which affects craving for tobacco. Research
which accurately measures craving and relates it to environmental
stimulus events and circadian variations in the internal environment
could help to decide between these explanations. A more comprehen-
sive understanding of how craving varies with stimulus events and
with time of day might prove helpful in designing interventions which
help prepare smokers to cope with their craving.

Time Course and Duration

While the time course of the abstinence syndrome following abrupt
withdrawal from other dependence-producing substances has been
systematically studied (60), assessment of the course of the tobacco
withdrawal syndrome is made difficult by the subtlety and variability
of the symptoms (139).

The onset of the syndrome appears to be rapid. Changes in mood
(115) and performance (93) are evident. Early effects are not easily
distinguishable from the absence of nicotine effects or the effects of
simple frustration. Another study reports data suggesting a decrease
in symptoms over time (41).

After a marked decline in the first week, the tobacco withdrawal
syndrome becomes increasingly less yielding. Estimates of the tobacco
withdrawal syndrome's duration have been made in retrospective
studies which ask ex-smokers to recall how long their discomfort or
"difficulty" lasted. However, these studies produce contradictory
findings. Burns (15) reports a range from 1 to 12 weeks, and Wynder,
et al. (1%) report that most symptoms were gone after 4 weeks. In
contrast, Mausner (83) reports that, of the ex-smokers who ventured
an estimate, fully two-thirds stated that their difficulty had lasted
between 1 month and 5 years. In another retrospective study, 21
percent of the sample of ex-smokers reported at least intermittent
craving for cigarettes 5 to 9 years after cessation (34). Thus, the
duration of the tobacco withdrawal syndrome appears to be extremely
variable, and no definitive estimate is yet available.

15-26


Degree of Dqn-iuation

Even with continued use, reduction in the dose of a dependence-
producing substance typically results in the emergence of a withdrawal
syndrome (60). It has been shown that smokers who changed to low-
nicotine cigarettes often report the gamut of acute withdrawal
symptoms described above (32,114). Abrupt and total withdrawal from
tobacco, however, is associated with a withdrawal syndrome that
subsides more quickly and is no worse than that seen in partial
abstinence.

Gradual Reduction and Chronic Withdrawal

Despite the usefulness of gradual withdrawal in other dependency
disorders, and despite the congruence of this method with sound
behavioral principles, there is considerable evidence suggesting that
gradual withdrawal from tobacco is associated with treatment failure
(26, 41, 82, 138). This discrepancy may be explained by the observation
that partial abstinence from smoking leads to more, rather than less,
discomfort in withdrawal. The result is that a partially abstinent
smoker is in a chronic state of withdrawal. Typically, this chronic state
of withdrawal leads to relapse and a return to baseline rates of
smoking (26).

Although this explanation is plausible and fits the data available, it
must be treated with caution pending further research. Since all of the
research relies on smokers who have chosen whether to quit "cold
turkey" or by gradual reduction, there is still the possibility that
smokers in some way predisposed to experience a protracted withdraw-
al syndrome disproportionately choose the gradual reduction method.
What is needed is experimental research in which smokers are
randomly assigned to "cold turkey" or gradual reduction groups and in
which the effects on the course of the abstinence syndrome are
evaluated.

Another direction for new research might be to determine the
threshold for the onset of the abstinence syndrome in gradual
reduction. Perhaps there is some rate or degree of reduction which
would not precipitate withdrawal, so that a smoker cc&d be weaned
from tobacco. In addition to a "rate of reduction" parameter, the onset
of severe withdrawal may also be controlled by the absolute dose as
well. The relationship between degree of tobacco deprivation and the
emergence of withdrawal symptoms deserves further study.

Other Factors Possibly Affecting the Abstinence Syndrome
In addition to the factors already cited, the tobacco withdrawal
syndrome may be affected by a number of other variables whose
influence remains to be determined. One could speculate, for example,
about differences between types of smokers in the severity, pattern,

15-27


I

and course of abstinence. A study by Ikard and Tomkins (56) suggests
that "addictive smokers" experience more severe craving. The smokers
in this study were deprived of tobacco only for three hours, however, so
that the effects of this typology on the clinical abstinence syndrome
are still essentially unknown and deserving of study. Other individual
difference variables also deserve study. For example, smoking history,
especially such variables as previous attempts to quit and the reason
for failure, may affect the withdrawal syndrome. Since the symptoms
of withdrawal are relatively ill-defined, the smoker's expectations and
set are probably related to his experience of abstinence, as is his
motivation to quit (6).

Another major factor whose relationship is potentially important,
but unexpected, is sex. There is fragmentary evidence suggesting that
the abstinence syndrome is more severe in women than in men.
Unfortunately, relevant data are too seldom analyzed for this sex
difference. For example, Guilford (41) reports data separately by sex,
but does not submit it to statistical analysis of the sex difference. Yet,
of 18 major symptoms reported by her subjects in the first 4 days of
abstinence, 15 show some sex difference. Among these 15 symptoms, 13
are more frequently reported by women. The difference is statistically
significant (sign test, N = 15, r<2, p<.OO5). Data reported in a number
of other studies line up in the same direction, though the effect fails to
reach significance in the individual studies (104,231,X2).

It seems likely, then, that women report more abstinence symptoms
than men. The importance of this finding lies in its possible relation to
another sex difference in smoking cessation: it is well established that
women are more likely to fail in smoking cessation efforts. Guilford
(/I), for example, has presented data suggesting that the relationship
between withdrawal symptoms and failure in smoking cessation is
stronger for women than for men. Thus, women experience more
discomfort in withdrawal and are more affected by it in their attempts
to quit smoking. It seems likely that this is at least partly responsible
for their lower rates of successful cessation.

Nor are organismic variables the only variables relevant here. The
method used to achieve cessation may well have an effect on the
subsequent withdrawal syndrome. Environmental factors, such as the
smoker's social environment, are potentially powerful determinants of
the smoker's experience of withdrawal. These and other events, such as
social drinking, may produce conditioned craving and are to be
considered high risk situations for relapse (79). Thus, in addition to the
few factors whose influence on the tobacco withdrawal syndrome is
known, there are many other potentially important variables whose
effects remain to be determined.

15-28


Techniques for Measuring Tobacco Usage

The question of how to measure the use of cigarettes is an important
one when evaluating the various methods of cessation and the benefits
of cessation versus the risks of continuance, and when determining the
validity of the reports of study subjects' compliance. (It may also be
important in "quantifying" risk factors for disease in current smokers,
such as type of cigarette, inhaling pattern, and so forth.) There are
five potential sources of information to determine whether or not a
person has smoked: urine, blood, breath, saliva, and verbal.

In the urine, one can assay for the constituents of the cigarette smoke
itself or for excretion products that are associated with the physiologi-
cal effects. Using the Goldbaun and Womanski method, Prado and
associates (107) measured nicotine excretion in smokers averaging 20
cigarettes/day and found nicotine in the urine in concentrations
varying directly with number of cigarettes and inversely with pH of
the urine. When deprived of cigarettes for 12 hours, there was no
nicotine found in the urine. Trojnar (133) compared the urine
quantities of adrenaline, norepinephrine, vanilinomandelic acid (a
derivative of epinephrine and norepinephrine via monoamine oxidase
and catecholamine-o-methyl transferase), and 5hydrosyindolacetic
acid in nonsmokers and those who had quit for at least 6 months. The
nonsmokers' and quitters' levels were indistinguishable until the ex-
smokers smoked an average of 14 cigarettes. Urine metabolite levels,
with the exception of norepinephrine, rose when measured on the
second day, (EPI 2.64 g/day, VMA 1.31 g/day, SHIAA 2.4 g/day). In a
second study, Trojnar (1.5'2) found that all four values were increased in
smokers over nonsmokers without any discontinuance.

A potential problem in measuring the physiological metabolites
associated with smoking is in false positives. This can occur when a
subject may have experienced severe anxiety, with increased catechol-
amines, but did not smoke. The urine nicotine level would seem to be
more specific, but both methods would have to be used every 12 hours
or less to be accurate.

Blood

One constituent found in blood is carbon monoxide, combined to form
carboxyhemoglobin (COHb). Sillett, et al. (121) describe the simplicity
of using the I.L. 182 CO-Oximeter and the potential for giving subjects
quick feedback on their performance. They also say it is possible to
detect when those who switch from cigarettes to cigars continue to
inhale. Turner (134) points out that the average nonsmoker's blood in
London has 1.3 percent COHb and that 2 percent is used as a
suggestion that smoking has resumed. As cities vary in CO in the air,

15-29


I

standards would have to be set depending on locale. When Ohlin, et al.
(97) confronted 32 patients at an antismoking clinic with their elevated
COHb levels, 13 immediately changed their report, admitting recidi-
vism. When considering COHb, one must take environmental and
occupation sources of CO into account. Although COHb increases
proportionally with number of cigarettes (125) and varies with nicotine
content (III), discretion is necessary in using data.

Serum cotinine levels may be a reliable tool in determining cessation,
according to Zeidenberg, et al. (154). With a half-life of 30 hours, as
opposed to nicotine's 30 minutes, and the relative constancy of the
cotinine levels in regular smokers, it is possible in this way to evaluate
long-range abstinence.

Breath

The determination of mean alveolar CO partial pressure described by
Rawbone, et al. (108) makes it possible to determine the carboxyhemo-
globin levels of the blood with a correlation of r =.96. Also, by
subtracting expired CO from inspired, it is possible to determine if a
smoker is an inhaler. Vogt, et al. (I&?) used expired CO and serum
thiocyanate to assess exposure to cigarettes. Smokers had higher levels
of both (CO 8 ppm, SCN-190 Fmol/l)-three times greater in those
smoking more than a pack a day than in nonsmokers. The correlation
between smoking and each variable separately was less than the two
combined (CO = .4'76; SCN = .479; both = .571). The researchers were
99 percent accurate in separating "typical" smoking habits from
nonsmokers' habits and hypothesized the possibility of grading
intermediate levels for exposure to smoke. No mention was made of
environmental or occupational sources of CO or CN.

Saliva

The presence of nicotine in saliva can be determined by gas
chromatography and an alkali flame ionization detector (i.e., nitrogen
detector) (31), but it is difficult to distinguish a pattern of smoking.
Nonsmokers separated from smokers can be distinguished from
nonsmokers who smoke passively. While this is a sensitive method of
measurement, the presence of nicotine in saliva does not prove direct
use of tobacco. Using this method, it may be possible to determine a
maximal level attainable by passive smoking and use that value as a
cut-off in determining probable usage.

Tenovuo and Maezkinen (230) measured thiocyanate and ionizable
iodine in saliva with the following results:

Thiocyanate (mgjliter)
Males          Females

Smokers          210 + 75          124246

15-30


Nonsmokers         91244          62232

Ionizable Iodine
Males          Females

Smokers
Nonsmokers

7.22.9          10.12 3.6
13.429.7       139+8.0

Although controls using the same subjects, both smoking and
abstaining, were not employed, this technique can adequately separate
the values of smokers' and nonsmokers' thiocyanate, especially for
males. It should be noted, however; that the overlap between smokers
and nonsmokers is considerable and that Vogt found no correlation
between the tar content of cigarettes and the thiocyanate levels in
saliva.

Verbal

Although there are several biological assays measuring use of
-cigarettes, McMahan, et al. (86) propose using the verbal report of the
subject, confirmed by an appropriate associate of the subject. They
point out that the correlation between reports of the subject and the
associate about the subject's smoking behavior is re.86. While the
correlation indicating that the subject and associate agree is encourag-
ing, that may be all this study says. A smoker who does not want the
researcher to know his smoking habit accurately will probably either
not allow the associate to see him in his true habit or will encourage
the associate to "interpret" his smoking pattern along the lines he
wishes to portray. Other methods may be used, such as a lie detector,
but unfortunately they are beatable.

The only "fool-proof" method of determining use is to observe the
subject at all times. Even here the degree of inhalation cannot be
accurately determined. Since this approach is highly impractical,
biological tests must be employed, and understanding of the potential
source of inaccuracy must be considered before drawing firm
conclusions. Based on the above descriptions, it would seem that the
most practical method would be measurement of nicotine, cotinine, and
thiocyanate in the urine. If none of these is found in the urine, the
conclusion is that the subject has not smoked (or has borrowed urine).
If some nicotine is found in the urine, could it have been from passive
smoking? One should note, too, that quantitative analysis of nicotine in
body fluids will take on increasing significance, since tar and nicotine
levels are being decreased in cigarettes, and researchers will need to
know not only whether a subject smoked, but how much.

15-31


I

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