system. Smoking-induced reduction in skin blood flow also can be
antagonized by a vascular vasopressin antagonist, which suggests a
role for vasopressin in mediating some cardiovascular responses (2).

The cardiovascular effects of oral snuff have been examined system-
atically in only one study (13). Changes in heart rate and blood pressure
that are similar in magnitude to those of cigarette smoking were ob-
served. However, the time course appears to be slower than the
response to cigarette smoking, with maximum effects observed at 5 to
10 minutes after a dose of oral tobacco. Similar findings, along with in-
creased myocardial contractility and coronary, femoral, and renal blood
flow, were also noted in anesthetized dogs after the administration of
oral tobacco (13). Thus it appears that single doses of smokeless tobac-
co can produce hemodynamic effects that are similar to those of
cigarette smoking. Whether such changes are sustained throughout the
day with repeated daily doses remains to be established.

Central Nervous System

Although smokers give different explanations for why they smoke,
most agree that smoking produces arousal, particularly with the first
few cigarettes of the day, as well as relaxation, especially in stressful
situations (14). Desynchronization, decreased alpha and theta activity,
and increased alpha frequency that is consistent with arousal are the
usual electroencephalographic responses to cigarette smoking (15,16).
These effects are blocked by mecamylamine, a centrally active nicotinic
receptor antagonist, which indicates a role for nicotinic cholinergic
receptor activation (17). Tobacco abstinence is associated with effects
that are opposite those of smoking, namely, increased alpha power and
reduced alpha frequency (15,18).

Endocrine System

Cigarette smoking and nicotine have been reported to increase circu-
lating levels of catecholamines, vasopressin, growth hormone, cortisol,
ACTH, and endorphins (3, 19,20).

Nicotine inhibits the synthesis of prostacyclin in rabbit aorta and
human peripheral veins and the hypoxia-induced release of prostacyclin
from rabbit hearts (21). Cigarette smoking has been reported to decrease
the urinary excretion of prostacyclin metabolites in humans, which sup-
ports the prediction from animal studies (22). Prostacyclin has anti-
aggregatory and vasodilating actions that are believed to play a homeo-
static role in preventing vascular thrombosis.

Nicotine, Smokeless Tobacco, and Human Diseases

As attested to in the Surgeon General’s reports since 1964, smoking
is a major risk factor for coronary and peripheral vascular disease,
cancer, chronic obstructive lung disease, peptic ulcer disease, and repro-

176
ductive disturbances, including prematurity. Tobacco smoke is a com-
plex mixture of chemicals, including carbon monoxide, many of which
are believed to contribute to human disease. Smokeless tobacco
likewise exposes users to a number of chemicals, particularly nicotine.
Nicotine may play a contributory or supportive role in the pathogenesis
of many smoking-related diseases. That nicotine causes human disease
de novo has not been proven; however, its potential health conse-
quences deserve serious consideration. More direct data on its causal
role are needed.

Coronary and Peripheral Vascular Disease

Nicotine may contribute to atherosclerotic disease by actions on lipid
metabolism, coagulation, and hemodynamic effects. Compared to non-
smokers, cigarette smokers have elevated levels of low density (LDL)
and very low density lipoproteins (VLDL) and reduced levels of high
density lipoproteins (HDL). This profile is associated with an increased
risk of atherosclerosis (23). It is hypothesized that nicotine, by releasing
free fatty acids, increases the synthesis of triglycerides and VLDL by
the liver, which in turn results in decreased HDL production.

In most studies, the blood of smokers is shown to coagulate more
easily (24), platelets are found to be more reactive, and platelet survival
is shortened when compared to nonsmokers (25). Thrombosis is believed
to play a role that promotes the growth of vascular endothelial cells that
contribute to the atherosclerotic plaque. The importance of nicotine as a
determinant of platelet hyperreactivity is supported by a study that
shows an apparent relationship between nicotine concentrations after
smoking different brands of cigarettes and platelet aggregation
response (26). Nicotine may affect platelets by releasing epinephrine,
which is known to enhance platelet reactivity; by inhibiting prosta-
cyclin, an antiaggregatory hormone that is secreted by endothelial cells;
or perhaps directly. Finally, by increasing the heart rate and cardiac
output, nicotine increases blood turbulence and may promote endo-
thelial injury. Although several potential mechanisms for promoting
atherogenesis have been considered, nicotine has not yet been demon-
strated to accelerate atherosclerosis in experimental animals.

Nicotine may play a role in causing acute coronary events. Myocar-
dial infarction can occur with one or more of three precipitants: throm-
bosis, excessive oxygen and substrate demand, and coronary spasm.
Nicotine can promote thrombosis as discussed previously. Nicotine in-
creases the heart rate and blood pressure and, therefore, myocardial ox-
ygen consumption. Coronary blood flow increases in a healthy person to
meet the increased demand. In the presence of coronary heart disease,
ischemia may develop and myocardial dysfunction may occur. Nicotine
may induce coronary spasm by sympathomimetic actions or by the
inhibition of prostacyclin. Coronary spasm has recently been reported
to occur during cigarette smoking (27). All of the above may contribute

177
to the precipitation of acute myocardial infarction in a person with pre-
existing coronary atherosclerosis.

Cigarette smoke exposure decreases the ventricular fibrillation
threshold after experimental myocardial infarction in dogs (28). How
much of this effect is due to nicotine and how much is due to carbon
monoxide have not been established. Sudden cardiac death in smokers
might result from ischemia, as discussed above, combined with the
arrhythmogenic effect of increased circulating catecholamines.

Hypertension

Cigarette smoking has not been associated with an increased
prevalence of hypertension. However, a recent preliminary report sug-
gested higher blood pressure in young men who used smokeless tobacco
compared to cigarette smokers or nonsmokers (29). Smokers who have
essential hypertension experience an accelerated progression of
vascular and renal disease. Nicotine may contribute to such a process
by producing vasoconstriction or enhancing coagulation. There also
may be other interactions with hypertensive disease. For example, a pa-
tient with a pheochromocytoma developed paroxysmal hypertension
and angina pectoris following the use of oral snuff (30). In a controlled
situation, blood pressure was recorded to increase from 110/70 to
300/103 with a heart rate increase from 70 to 110 within 10 minutes
after the use of oral snuff. Rechallenge after surgery for the pheochro-
mocytoma revealed only the usual blood pressure increase.

Peptic Ulcer Disease

Smoking is strongly related to the prevalence of peptic ulcer disease,
and failure to stop smoking is the major predictor of failure to respond
to ulcer therapy (31). Smoking decreases pancreatic fluid and bicar-
bonate secretion that result in greater and more prolonged acidity of
gastric fluid of the duodenal bulb (32). Similar effects after the infusion
of nicotine have been reported in animals (33). The swallowing of tobac-
co juice that contains large concentrations of nicotine may conceivably
have local effects and therefore elicit added concern for the use of
smokeless tobacco.

Pregnancy

Smoking is a major risk factor for low birth weight and, conse-
quently, fetal morbidity and mortality (34). Tobacco smoke may influ-
ence the fetus either through alterations in maternal physiology that
limit the nutrient flow to the fetus or by the transplacental passage of
smoke components that have direct effects on the fetus. The factors
that are considered most likely to affect the fetus are carbon monoxide
and nicotine. Carbon monoxide inhalation has been shown to increase
carboxyhemoglobin in both maternal and fetal blood that possibly
limits oxygen supply to the fetus (35). However, while newborn infants

178
of smoking mothers have higher concentrations of carboxyhemo-
globin than do neonates of nonsmokers, there are only trivial differ-
ences in hemoglobin concentrations, hematocrit, and various charac-
teristics of hemoglobin (36). Thus it is difficult to explain an adverse
effect that is based on chronic hypoxia due to carbon monoxide in
tobacco smoke. It is more likely that nicotine is important in causing
adverse effects.

The effects of nicotine on the fetus may include a reduction of uterine
blood flow or a direct effect on fetal function (37,38). The presence of
nicotine and its principal metabolites has been demonstrated in the um-
bilical cord blood and urine of newborn infants of smoking mothers, as
well as in amniotic fluid, indicating transplacental passage (39).

Nonnicotine-Related Adverse
Metabolic Consequences

Certain brands of chewing tobacco and snuff contain glycyrrhizinic
acid, which is also an ingredient of licorice. Glycyrrhizinic acid has po-
tent mineralocorticoid hormone activity that can result in potassium
wasting. Two patients who were heavy users of oral smokeless tobacco
developed severe hypokalemia with muscle weakness (and in one case,
evidence of muscle breakdown) that apparently was due to the ingestion
of large amounts of this substance (40). Smokeless tobacco also contains
large amounts of sodium (41) that, if swallowed, may aggravate hyper-
tension or cardiac failure.

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(15) Herning, R.I., Jones, R.T., and Bachman, J. EEG changes during
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(18) Ulett, J., and Itil, T. Quantitative electroencephalogram in smoking
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(19) Sandberg, H., Roman, L., Zavodnick, J., and Kupers, N. The effect of
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(20) Pomerleau, O.F., Fertig, J.B., Seyler, L.E., and Jaffe, J. Neuroendo-
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(21) Wennmalm, A. Nicotine inhibits hypoxia- and arachidonate-induced
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(22) Nadler, J.L., Velasco, J.S., and Horton, R. Cigarette smoking inhibits
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(25) Mustard, J.F., and Murphy, E.A. Effect of smoking on blood coagula-
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CONCLUSIONS

1. The use of smokeless tobacco products can lead to nicotine
dependence or addiction.

2. An examination of the pharmacokinetics of nicotine (i.e., nico-
tine absorption, distribution, and elimination) resulting from
smoking and smokeless tobacco use indicates that the magni-
tude of nicotine exposure is similar for both.

3. Despite the complexities of tobacco smoke self-administration,
systematic analysis has confirmed that the resulting addiction
is similar to that produced and maintained by other addictive
drugs in both humans and animals. Animals can learn to dis-
criminate nicotine from other substances because of its effects
on the central nervous system. These effects are related to the
dose and rate of administration, as is also the case with other
drugs of abuse. :

4. It has been shown that nicotine functions as a reinforcer under a
variety of conditions. It has been confirmed that nicotine can
function in all of the capacities that characterize a drug with a
liability to widespread abuse. Additionally, as is the case with
most other drugs of abuse, nicotine produces effects in the user
that are considered desirable to the user. These effects are
caused by the nicotine and not simply by the vehicle of delivery
(tobacco or tobacco smoke).

5. Nicotine is similar on all critical measures to prototypic drugs of
abuse such as morphine and cocaine. The methods and criteria
used to establish these similarities are identical to those used for
other drugs suspected of having the potential to produce abuse
and physiologic dependence. Specifically, nicotine is psycho-

182
active, producing transient dose-related changes in mood and
feeling. It is a euphoriant that produces dose-related increases in
scores on standard measures of euphoria. It is a reinforcer (or
reward) in both human and animal intravenous self-administration
paradigms, functioning as do other drugs of abuse. Additionally,
nicotine through smoking produces the same effects, and it
causes neuroadaptation leading to tolerance and physiologic
dependence. Taken together, these results confirm the hypothesis
that the role of nicotine in the compulsive use of tobacco is the
same as the role of morphine in the compulsive use of opium
derivatives or of cocaine in the compulsive use of coca deriva-
tives.

_ The evidence that smokeless tobacco is addicting includes the
pharmacologic role of nicotine dose in regulating tobacco intake;
the commonalities between nicotine and other prototypic
dependence-producing substances; the abuse liability and depen-
dence potential of nicotine; and the direct, albeit limited at pres-
ent, evidence that orally delivered nicotine retains the character-
istics of an addictive drug.

. Several other characteristics of tobacco products in general,
including smokeless tobacco, may function to enhance further the
number of persons who are afflicted by nicotine dependence:
nicotine-delivering products are widely available and relatively
inexpensive; and the self-administration of such products is legal,
relatively well tolerated by society, and produces minimal disrup-
tion to cognitive and behavioral performance. Nicotine produces
a variety of individual-specific therapeutic actions such as mood
and performance enhancement; and the brief effects of nicotine
ensure that conditioning occurs, because the behavior is
associated with numerous concomitant environmental stimuli.

. All commonly marketed and consumed smokeless tobacco prod-
ucts contain substantial quantities of nicotine; the nicotine is
delivered to the central nervous system in addicting quantities
when used in the fashion that each form is commonly used (or as
recommended in smokeless tobacco marketing campaigns).

. Since the exposure to nicotine from smokeless tobacco is similar
in magnitude to nicotine exposure from cigarette smoking, the
health consequences of smoking that are caused by nicotine also
would be expected to be hazards of smokeless tobacco use. Areas
of particular concern in which nicotine may play a contributory or
supportive role in the pathogenesis of disease include coronary
artery and peripheral vascular disease, hypertension, peptic ulcer
disease, and fetal mortality and morbidity.

183
RESEARCH NEEDS

Available data clearly support the view that nicotine produces behav-
ioral and physiologic dependence and has effects on all critical dimen-
sions exemplified by a drug with a profile of high abuse liability. Never-
theless, the resolution of several questions is essential. These questions
revolve around the relationships between the several forms of tobacco
use. They parallel and have commonalities with important issues in other
forms of drug abuse (e.g., cocaine). There are several major research areas
that could provide data of potential public health significance.

The first area of research is the relationship between the rate of nico-
tine administration and abuse liability. Existing data suggest that the
slowest commercially available nicotine-releasing preparation, nicotine
gum, has a lower abuse liability than the fastest commercially available
nicotine-releasing pyeparation, cigarettes. These facts further suggest
the possibility that there might be quantifiable differences in abuse
liability among tobacco product forms.

The second area of research importance involves the relationship be-
tween the initiation of one form of tobacco use, e.g., smokeless tobacco,
and the use of other forms of tobacco, e.g., cigarettes. The relationships
between common forms of tobacco use, the extent to which they are
interchangeable, and the possibility that the use of one form of tobacco
leads to the use of another need examination.

A third area of specific importance relates to the extent to which
tobacco use, with its implicit acceptance, encourages other drug use. A
related question is the extent to which exposure to drug effects, both
neurologic and behavioral, modifies subsequent drug responses or
establishes the conditions for other equally harmful drugs to become
reinforcers, These issues follow from the observations that cigarette use
is a major correlate (possibly a ‘‘stepping stone”’) of other kinds of drug
dependence and that regular tobacco use generally leads to other forms
of drug addiction.

A fourth area of research is prevention and treatment. Recent sur-
veys indicate that youth attribute negligible risk to smokeless tobacco
products, suggesting the possible need for education-based prevention
approaches. Regarding treatment, it is plausible that nicotine gum
treatment could be of even greater relative utility for smokeless tobacco
users than for cigarette smokers because of the more similar pharmaco-
kinetic profiles of smokeless tobacco- and gum-delivered nicotine com-
pared to cigarette smoke-delivered nicotine.

The absorption and distribution characteristics of nicotine with the
use of smokeless tobacco may differ from those of cigarette smoking.
The pharmacodynamic and pharmacologic consequences of such dif-
ferences may be important but require additional future research. Fur-
ther studies to define more precisely the role of nicotine and of
smokeless tobacco in the causation of diseases other than those that

184
involve the oral cavity are clearly needed. Specifically, research is
needed to:

Determine nicotine blood levels and time course in various popula-
tions of smokeless tobacco users, including established users.

Determine the cardiovascular, hormonal, and metabolic effects of
smokeless tobacco when used in a regular fashion throughout the
day.

Determine the influence of the rate of absorption of nicotine on the
effects from smoking cigarettes and the use of smokeless tobacco.

Using experimental studies, determine the effects of smokeless
tobacco in users of different ages and high-risk status (i.e., patients
with hypertension, coronary heart disease, peripheral vascular
disease, and peptic ulcer).

Using epidemiologic studies, determine the risk potential of the
regular use of smokeless tobacco on the development of diseases
such as coronary heart disease, peptic ulcer, and complications of

pregnancy.

185