CliniCal pharmaCology & TherapeuTiCs | VOLUME 83 NUMBER 4 | APRIL 2008
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Clinical Pharmacology of Nicotine: Implications
for Understanding, Preventing, and Treating
understanding the basic and clinical pharmacology of nicotine provides a basis for improved prevention and treatment
of tobacco addiction. nicotine acts on nicotinic cholinergic receptors in the brain to release dopamine and other
neurotransmitters that sustain addiction. neuroadaptation and tolerance involve changes in both nicotinic receptors and
neural plasticity. nicotine addiction can occur in the context of physical dependence characterized by
self-medication to modulate negative affect and/or to relieve withdrawal symptoms, as well as, in light or occasional
smokers, primarily for positive reinforcement in specific situations. nicotine is metabolized primarily by Cyp2a6.
its clearance exhibits considerable individual variability that is determined by genetic, racial, and hormonal (sex)
factors. genetically slow metabolism of nicotine appears to be associated with a lower level of dependence. nicotine
dependence is highly heritable and appears to be influenced by genes coding for some nicotine receptor subtypes, some
neurotransmitter genes, and genes involved in neural connectivity. novel pharmacotherapies for nicotine dependence
include partial agonists for nicotinic receptors and nicotine vaccines. pharmacogenetic studies suggest various candidate
genes and a nicotine metabolism phenotype that influence outcome. human pharmacology studies of nicotine and
smoking behavior also provide a basis for assessing the benefits and risks of long-term nicotine use for harm reduction and
for a potential cigarette regulatory strategy that includes reducing nicotine content of cigarettes to nonaddictive levels.
Although most of the toxicity of smoking is related to other com-
ponents of the cigarette, it is nicotine that causes addiction to
smoking. An understanding of how nicotine produces addiction
and influences smoking behavior provides a necessary basis for
therapeutic advances in smoking cessation interventions. This
paper is intended to provide a state-of-the-art review of prog-
ress in the clinical pharmacology of nicotine and its relevance
to the treatment and prevention of tobacco addiction. Topics of
discussion include the pharmacology and genetics of nicotine
dependence, progress in individualization of smoking cessation
treatment, and the currently controversial public health issues
of harm reduction for smokers who cannot quit and nicotine-
based strategies for regulation of tobacco products to prevent
NicotiNe aNd the global tobacco epidemic
Tobacco addiction produces devastating health consequences,
including premature death in half of lifelong smokers. Cigarette
smoking has declined in the United States from a peak of 42 in
1965 to ~21% at present, but still 45 million adults in the United
States continue to smoke. Smoking remains the most impor-
tant avoidable cause of health disability and premature death.
In developed countries, 12.2% of all-cause mortality can be
attributed to cigarette smoking. Although smoking prevalence
is declining in most developed countries, smoking remains quite
common in developing countries, with rates exceeding 40% in
many. It is estimated that cigarette smoking kills in excess of
5 million people annually around the world at present, with pro-
jections of 10 million premature deaths per year by the year 2020
if current smoking prevalence persists. Mortality from smoking
is such that half of the deaths occur in middle age.
ReceNt obseRvatioNs oN the health coNsequeNces
of tobacco use
That cigarette smoking accelerates cardiovascular disease and
causes chronic obstructive pulmonary disease and cancer is well
1Department of Medicine, University of California, San Francisco, California, USA; 2Department of Psychiatry, University of California, San Francisco, California, USA;
3Department of Biopharmaceutical Sciences, University of California, San Francisco, California, USA. Correspondence: NL Benowitz (firstname.lastname@example.org)
Received 30 October 2007; accepted 3 January 2008; advance online publication 27 February 2008. doi:10.1038/clpt.2008.3
532 VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
known to readers. Less well known, but equally or more impor-
tant, is the increased risk of infectious disease.1 This includes
an increased risk of severe influenza, invasive pneumococcal
disease, and tuberculosis. In some countries, the smoking-
attributable risk of death from tuberculosis far exceeds smoking-
attributable deaths from vascular disease or cancer. Cigarette
smoking is associated with many reproductive complications,
including infertility, spontaneous abortion, low birth weight,
and sudden infant death syndrome. Smoking aggravates heart
failure, such that stopping smoking has an equal or greater mor-
tality benefit than therapy with angiotensin-converting enzyme
inhibitors, β-blockers, or spironolactone. Smoking increases
insulin resistance, is a major risk factor for the development of
diabetes, and among diabetics smoking markedly accelerates
the progression of vascular disease. Smoking increases com-
plications of surgery, including delayed wound healing and an
increased risk of wound and other infections.
Of particular interest to clinical pharmacologists are the
numerous interactions between cigarette smoking and medi-
cations. Cigarette smoking may interact with medications
through effects on drug metabolism or pharmacodynamics. It
is well known that smoking accelerates the metabolism of many
drugs, particularly those metabolized by CYP1A2, including
caffeine, clozapine, olanzapine, tacrine, theophylline, erlotinib,
and others. A recently described example of the clinical conse-
quences of enzyme induction from smoking is that the accel-
erated metabolism of erlotinib most likely explains the poorer
response of smokers compared to nonsmokers with nonsmall
cell lung cancer.2 Cigarette smoking also appears to induce
drug metabolism by CYP2E1 and by some uridine diphosphate
glucuronosyltransferase pathways, the latter resulting in more
rapid glucuronidation of a number of drugs. For example, ciga-
rette smoking is associated with a decreased risk of hematologic
toxicity of irinotecan, a drug widely used for metastatic colon
cancer and other solid tumors.3 Smoking accelerates the metab-
olism of irinotecan to its active metabolite SN-38 and further
accelerates the glucuronidation of SN-38, explaining the reduced
toxicity but also suggesting that smoking could reduce efficacy.
The enzyme-inducing effects of cigarette smoke are thought to
be primarily related to effects of polycyclic aromatic hydrocar-
bons and other combustion products, although nicotine per se
appears to induce the metabolism of CYP2E1. In contrast to
the usual induction of metabolism seen in smokers, smoking
appears to inhibit the metabolism of nicotine, and nicotine has
been shown in vitro to inhibit CYP2A6 activity. Smoking pro-
duces an unusual sort of drug interaction with inhaled drugs
such as insulin. Smoking is known to enhance pulmonary per-
meability to a variety of chemicals, including drugs. Inhaled
insulin levels peak earlier and reach higher levels in smokers
compared to nonsmokers.4
Several pharmacodynamic interactions arise from the cardio-
vascular effects of nicotine and cigarette smoke. The relevant
cardiovascular effects include constriction of skin and coronary
blood vessels, increase in heart rate and myocardial contractil-
ity, induction of a hypercoagulable state, and impaired oxygen
release to body tissues (the latter due to the effects of carbon
monoxide in smoke).5 By reducing the blood flow to the skin
and subcutaneous tissue, cigarette smoking slows absorption of
insulin from subcutaneous sites. In patients with angina pecto-
ris, the frequency of angina and the duration of exercise before
the development of chest pain or electrocardiographic changes
are improved less by β-blockers or calcium channel blockers
in smokers compared to nonsmokers. Cigarette smoking and
oral contraceptives interact synergistically to increase the risk
of stroke and premature myocardial infarction in women due
to induction of a hypercoagulable state. Cigarette smoking
enhances the procoagulant effects of estrogens. For this reason,
oral contraceptives are relatively contraindicated in women who
NicotiNe phaRmacology aNd tobacco addictioN
Quitting smoking at any age leads to a significant reduction in
the risks associated with smoking. The vast majority of smok-
ers in the United States would like to quit. Approximately 40%
of smokers attempt to quit each year, but <10% of these remain
abstinent. Tobacco addiction is best considered as a chronic dis-
ease, with most smokers requiring repeated quit attempts before
achieving permanent abstinence. Tobacco addiction is main-
tained by nicotine dependence. Cigarettes that do not deliver
nicotine do not sustain addiction. Understanding nicotine
dependence is key to successfully treating tobacco addiction.
An understanding of the neural basis for nicotine addiction is
useful in considering research on the clinical pharmacology
of nicotine. When a person inhales smoke from a cigarette,
nicotine is distilled from the tobacco and is carried in smoke
particles into the lungs, where it is absorbed rapidly into the pul-
monary venous circulation. It then enters the arterial circulation
and moves quickly to the brain. Nicotine diffuses readily into
brain tissue, where it binds to nicotinic cholinergic receptors
(nAChRs), which are ligand-gated ion channels. When a cho-
linergic agonist binds to the outside of the channel, the channel
opens allowing the entry of cations, including sodium and cal-
cium. These cations further activate voltage-dependent calcium
channels, allowing further calcium entry.
The nAChR complex is composed of five subunits. There
is much diversity of nAChRs with nine α-subunit isoforms,
α-2–α-10, and three β-subunit isoforms, β-2–β-4, identified
in brain tissues.6 The most abundant nAChRs are the α-4 and
β-2–containing receptors, accounting for 90% of high affinity
nicotine binding in the rat brain. The presence of the β-2 subunit
is critical for dopamine release and for the behavioral effects
of nicotine, including self-administration. The α-4 subunit is
an important determinant of sensitivity to nicotine. The α-3
β-4 subtype is believed to mediate the cardiovascular effects of
nicotine. α-7 Homomeric receptors are thought to be involved
in rapid synaptic transmission and may play a role in learning
and sensory gating.
Nicotinic receptor activation works, at least in part and pos-
sibly in the main, by facilitating the release of neurotransmit-
ters. Most of this release is believed to occur via modulation by
CliniCal pharmaCology & TherapeuTiCs | VOLUME 83 NUMBER 4 | APRIL 2008
presynaptic nAChRs. Dopamine release is critical to the rein-
forcing effects of nicotine and other drugs of abuse. Chemically
or anatomically lesioning dopamine neurons in the brain pre-
vents nicotine self-administration in rats. Other neurotrans-
mitters, including norepinephrine, acetylcholine, serotonin,
γ-aminobutyric acid (GABA), glutamate, and endorphins
are released as well, mediating various behaviors of nicotine
(Figure 1). Nicotine releases dopamine in the mesolimbic area,
the corpus striatum, and the prefrontal cortex. Of particular
importance are the dopaminergic neurons in the ventral teg-
mental area of the midbrain and the release of dopamine in the
shell of the nucleus accumbens, as this pathway appears to be
critical for drug-induced reward. Activation of dopaminergic
neurons in the ventral tegmental area is enhanced by excit-
atory glutaminergic and inhibited by GABA-ergic projections
that are also stimulated by nicotine. Thus, the overall effect of
nicotine on dopamine release is dependent on the interplay of
direct effects of nicotine and modulatory effects of glutamate
and GABA. Dopamine release signals a pleasurable experience.
When intracranial self-administration is used as a model for
brain reward in rats, nicotine acutely lowers the threshold for
self-administration, consistent with greater reward.
Chronic nicotine exposure results in neuroadaptation, that
is, the development of tolerance. Neuroadaptation is associated
with an increased number of brain nicotinic cholinergic recep-
tors. Chronic exposure to nicotine also results in changes in
gene expression and protein synthesis, with generation of new
synaptic connections, analogous to other forms of learning.7
When a person stops smoking, the absence of nicotine results
in subnormal release of dopamine and other neurotransmitters.
Thus, nicotine withdrawal results in the state of deficient dop-
amine responses to novel stimuli in general and a state of mal-
aise and inability to experience pleasure. Nicotine withdrawal
symptoms include irritability, restlessness, anxiety, problems of
getting along with friends and family, difficulties concentrat-
ing, increased hunger and eating, constipation, and craving for
tobacco. The state of malaise and inability to experience pleasure
associated with nicotine withdrawal has been termed “hedonic
dysregulation.” Hedonic dysregulation may explain craving, and
its rapid reversal by nicotine readministration may explain why
even a single cigarette can easily result in a return to compulsive
tobacco use. The neural plasticity changes described previously
are likely to be long lasting and may explain persistent craving
and the risk of relapse to smoking months or even years after
Addiction to tobacco is multifactorial, including a desire for
the direct pharmacologic actions of nicotine, relief of withdrawal
symptoms, and learned associations. Smokers describe a variety
of reasons for smoking, including pleasure, arousal, enhanced
vigilance, improved performance, relief of anxiety or depres-
sion, reduced hunger, and control of body weight. Consistent
with reports of arousal, electroencephalographic desynchroni-
zation with an upward shift in the dominant α-frequency and
a decreased total α- and θ-power follows cigarette smoking or
administration of nicotine.
In addition, environmental cues—such as the smell of a ciga-
rette, observing friends who are smoking, a meal, cup of coffee,
talking on the phone, or an alcoholic beverage—often trigger an
urge to smoke. Functional imaging studies indicate that expo-
sure to drug-associated cues activates cortical regions of the
brain, including the insula. Smokers who suffer damage to the
insula (e.g., due to brain trauma) are more likely to quit smoking
soon after the injury, are more likely to remain abstinent, and are
less likely to experience conscious urges to smoke, compared to
nonsmokers with brain injury that does not affect the insula.8
Smoking and depression are strongly linked. Smokers are more
likely than nonsmokers to have a history of major depression.
When smokers with a history of depression do quit, depressed
mood is more apt to be a prominent withdrawal symptom.
Nicotine withdrawal in healthy smokers produces mood dis-
turbances comparable in intensity to those seen in psychiatric
Nicotine pharmacokinetics and pharmacodynamics
Pharmacokinetics and metabolism. Nicotine is a weak base (pKa =
8.0). Absorption through mucous membranes depends on pH.
Chewing tobacco, snuff, and nicotine gum are buffered with
an alkaline pH to facilitate absorption through buccal mucosa.
Smoking is a highly efficient form of drug administration, as
the drug enters the circulation rapidly through the lungs and
moves into the brain within seconds. Inhaled drugs escape
first-pass intestinal and hepatic metabolism. The more rapid
the rate of absorption and entry of a drug into the brain, the
greater the “rush,” and the more reinforcing the drug. Smoking
produces high concentrations of a drug in the brain that are
comparable to those seen after intravenous administration. A
number of substances of abuse, including marijuana, cocaine,
opiates, phencyclidine, and organic solvents, are abused by the
inhalational route, because access to the brain is so rapid. The
smoking process also allows precise dose titration, so a smoker
may obtain desired affects.
Nicotine is rapidly and extensively metabolized by the liver,
primarily by the liver enzyme CYP2A6 (and to a lesser extent
by CYP2B6 and CYP2E1) to the cotinine (Figure 2).10 The
metabolite cotinine is widely used as a quantitative marker for
exposures to nicotine and is useful as diagnostic test for the
Dopamine Pleasure, appetite suppression
Norepinephrine Arousal, appetite suppression
Acetylcholine Arousal, cognitive enhancement
Glutamate Learning, memory enhancement
β-endorphinReduction of anxiety and tension
GABAReduction of anxiety and tension
figure 1 Nicotinic cholinergic receptor activation promotes the release of a
variety of neurotransmitters, which may then mediate various behaviors in
smokers. GABA, γ-aminobutyric acid.
534 VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
structure and function of nicotinic receptors and in intracellular
processes of neuroadaptation, as mentioned previously.
Two issues are particularly relevant in understanding the phar-
macodynamics of nicotine. First, the nicotine dose–response
relationship is complex. Low doses may stimulate neural systems,
whereas higher doses depress them. For example, low doses of
nicotine produce central or peripheral nervous system stimula-
tion with arousal and an increase in heart rate or blood pressure.
At high doses, such as during nicotine intoxication, nicotine
produces ganglionic blockade resulting in bradycardia, hypoten-
sion, and depressed mental status. A second important phar-
macodynamic issue is the development of tolerance. Tolerance
develops rapidly to the dysphoria, nausea, and vomiting that
often occurs when smoking one’s first cigarette. Tolerance to
subjective effects and partial tolerance to the acceleration of
heart rate produced by nicotine develop within the day in many
smokers. Thus within even a single day, because of the develop-
ment of tolerance, the positive rewards of smoking diminish,
and smoking becomes motivated more by relief of withdrawal
symptoms. Tolerance develops to different extents for various
response to nicotine, consistent with different rates of inactiva-
tion of different nicotinic cholinergic receptor subtypes.
Nicotine and the tobacco addiction cycle
Nicotine from tobacco induces stimulation and pleasure and
reduces stress and anxiety in smokers. Smokers come to use
nicotine to modulate the level of arousal and for mood control
in daily life. Neuroadaptation occurs with repetitive exposure
to nicotine, resulting in development of tolerance to many of
the behavioral and cardiovascular effects of nicotine. When a
person stops smoking, nicotine withdrawal symptoms emerge,
as described previously.
Thus, the pharmacologic basis of nicotine addiction can
be seen as a combination of positive reinforcements, such as
use of tobacco and as a measure of compliance with treatments
for smoking cessation. Cotinine is subsequently metabolized
to trans-3′-hydroxycotinine (3HC) exclusively or nearly exclu-
sively by CYP2A6. The ratio of 3HC to cotinine can be used as
a phenotypic marker for CYP2A6 activity and for the rate of
nicotine metabolism.11 The half-life of nicotine averages ~2 h,
while the half-life of cotinine averages ~16 h. Cotinine levels
are fairly stable throughout the day in smokers; and because
the levels of 3HC are formation-limited, the ratio of 3HC/
cotinine are also fairly stable. This ratio can be measured in
blood, saliva, or urine of people while they are using tobacco,
based on their intake of nicotine from tobacco. Nicotine and
cotinine are also metabolized by glucuronidation, thought
to be primarily via UGT 1A4, 1A9, and 2B10 (ref. 10). While
glucuronidation is usually a minor pathway of nicotine metabo-
lism, in people who have low CYP2A6 activity, glucuronidation
can be a major determinant of nicotine clearance.
Considerable genetic polymorphism in CYP2A6 and UGT
activity is associated with wide individual variability and
racial differences in the rate of nicotine metabolism.12,13
Asians and African Americans metabolize nicotine on aver-
age more slowly than do whites or Hispanics. Sex hormones
also substantially affect CYP2A6 activity. The rate of nico-
tine metabolism is faster in women than in men.14 Nicotine
metabolism is faster in women taking estrogen-containing oral
contraceptives and even faster during pregnancy, compared
to other women.
There is considerable peak-to-trough oscillation in blood
levels from cigarette to cigarette. However, consistent with the
half-life of 2 h, nicotine accumulates in the body over 6–9 h of
regular smoking. Thus, smoking results not in intermittent and
transient exposure to nicotine but in an exposure that lasts 24 h a
day. Arteriovenous differences in nicotine concentration during
cigarette smoking are substantial, with arterial levels exceeding
venous levels up to tenfold. The persistence of nicotine in the
brain throughout the day and night results in changes in the
figure 2 Major metabolic pathways of nicotine in humans.
CliniCal pharmaCology & TherapeuTiCs | VOLUME 83 NUMBER 4 | APRIL 2008
response to negative affect. Although withdrawal symptoms may
not be prominent, many light and occasional smokers have dif-
ficulty quitting, representing in some cases a high level of depen-
dence but with different pharmacodynamics than that described
above for the daily addiction cycle in heavier smokers.
iNdividual vaRiability iN addictioN vulNeRability
Most tobacco use begins in childhood or adolescence. Eighty
percent of smokers begin smoking by the age of 18 (ref. 15).
However, while many youth try cigarette smoking, only 20–25%
of those who experiment with cigarettes become addicted adult
smokers. Risk factors for youth smoking include peer and paren-
tal influences; behavioral problems, for example, poor school
performance; personality characteristics such as rebellious-
ness or risk taking, depression and anxiety; and genetic influ-
ences.15 Twin studies provide strong evidence of the presence of
genetic vulnerability for development of nicotine dependence.
Genetic determinants of nicotine addiction are discussed in a
The younger a person starts smoking, the more highly depen-
dent he or she is likely to become, making it more difficult to
quit.15 Animal studies suggest that the developing brain is sus-
ceptible to permanent changes due to nicotine, which may lead
to addiction. When pregnant rats are fed nicotine, neuronal
growth and maturation in the fetal brain are impaired. Rats
exposed to nicotine in utero demonstrate cognitive impairments
after birth, and the neural changes due to nicotine are speculated
to affect cardiopulmonary regulation and the greater risk of sud-
den infant death syndrome that is observed in infants of smok-
ers. Nicotine administration to adolescent rats resulted in greater
neurochemical changes and higher nicotine self-administration
as adults, compared to rats that were first exposed as adults,16
consistent with the idea that early exposure to nicotine increases
the severity of dependence.
Racial differences in vulnerability to tobacco addiction and
related disease have been described. African-American smok-
ers appear to be more highly addicted and have higher rates
of lung cancer compared to whites and Hispanics.17,18 Asians
appear to be less highly addicted and have a lower risk of lung
cancer. Interestingly, African Americans smoke fewer cigarettes
than whites, but they take in 30% more nicotine for each ciga-
rette smoked.19 Menthol cigarette smoking is a potential con-
tributor to racial differences in smoking behavior and disease.
African Americans predominantly (~75%) smoke mentholated
cigarettes, while only 20–30% of whites smoke menthol ciga-
rettes. There is evidence that the smoking of menthol cigarettes
makes it harder to quit smoking.20 Menthol could contribute
to addiction by its strong sensory stimulant properties, which
would be expected to strengthen conditioned aspects of smok-
ing. Mentholated cigarette smoking inhibits the metabolism of
nicotine, but the consequences of this addiction with respect
to addiction or health effects is unclear.21 Asians smoke fewer
cigarettes per day on average compared to whites, which may be
related to slower metabolism of nicotine (discussed in greater
detail in a later section).22
enhancement of mood or functioning, as well as the avoidance
of negative consequences of prior drug use—that is, the relief
of withdrawal symptoms—in situations when nicotine is not
available. A daily smoking cycle can be conceived as follows
(Figure 3). The first cigarette of the day produces substantial
pharmacologic effect, primarily arousal, but at the same time
tolerance begins to develop. A second cigarette is smoked later,
at a time when the smoker has learned that there is some regres-
sion of tolerance. With subsequent smoking, there is an accu-
mulation of nicotine in the body, resulting in a greater level of
tolerance, and withdrawal symptoms become more pronounced
between successive cigarettes. Transiently high brain levels of
nicotine after smoking individual cigarettes may partially over-
come tolerance, but the primary (euphoric) effects of nicotine
tend to lessen throughout the day. Overnight abstinence allows
considerable resensitization to the actions of nicotine. Because of
the dose–response and tolerance characteristics, most smokers
tend to take in the same amount of nicotine from day to day to
achieve the desired effects of cigarette smoking. Smokers adjust
their smoking behavior to compensate for changes in the avail-
ability of nicotine or in the rate of elimination of nicotine from
the body in order to regulate the body levels of nicotine.
A subset of smokers are light or occasional smokers. That is
smokers of five or fewer cigarettes per day or nondaily smokers.
These smokers appear to smoke primarily for the positive reinforc-
ing effects of nicotine and experience minimal or no withdrawal
symptoms. Such smokers smoke primarily in association with
specific activities, such as after meals or with alcohol, and less in
0800 hours1800 hours 0400 hours
Plasma nicotine concentration (ng/ml)
figure 3 Model for the nicotine addiction cycle during daily cigarette
smoking. The solid line represents venous plasma concentrations of nicotine
as a cigarette is smoked (systemic dose of nicotine 1 mg) every 40 min
from 0800 to 0900 hours. The upper dashed line indicates the threshold
concentration for nicotine to produce pleasure or arousal. The lower
dashed line indicates the concentrations at which symptoms of abstinence
from nicotine occur. The shaded area represents a zone of nicotine
concentrations (the “neutral” zone) in which the smoker is comfortable
without experiencing either pleasure/arousal or abstinence symptoms.
Note that the threshold levels for both pleasure/arousal and abstinence rise
progressively during smoking owing to neuroadaptation (development of
tolerance). The magnitude of pleasure/arousal is seen to be greatest with
the first cigarette of the day and becomes less intense with subsequent
cigarettes. Late in the day, cigarettes produce little primary pleasure/arousal
but are smoked primarily to relieve abstinence symptoms. Cessation of
smoking overnight allows resensitization of drug response (i.e., loss of
tolerance). Dr Shi Jun performed the mathematical simulations using a
pharmacokinetic–pharmacodynamic model of nicotine tolerance. Reprinted
from Benowitz, N.L. Cigarette smoking and nicotine addiction. Med. Clin.
North Am. 76, 415–437 (1992).
536 VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
and the nicotine intake per cigarette, supporting the idea that
clearance influences smoking behavior.22
Genetic variation of CYP2A6 may influence the risk of
smoking-induced cancer by a mechanism in addition to its
effects on smoking behavior. The tobacco-specific nitrosamine
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is believed
to contribute to lung and possibly pancreatic cancer. This
nitrosamine is activated to a carcinogen in part by CYP2A6.
Therefore, a smoker who is a slow metabolizer would be expected
to both take in less smoke per cigarette and to bioactivate less
of the nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-bu-
tanone taken in compared to a normal metabolizer. A few stud-
ies support this hypothesis, showing that slow metabolizers have
a lower risk of lung cancer compared to normal metabolizers,
although some studies do not confirm this association.25 Genetic
variation of CYP2A6 activity may also explain some racial dif-
ferences in lung cancer risk, such as the lower risk in Asians,
who have lower CYP2A6 activity and slower nicotine clearance
on average, compared to whites.13,22 However, this mechanism
does not seem to hold for African-American smokers, who are
also more likely to be CYP2A6 slow metabolizers but who have
a higher cancer risk compared to whites.18,19
geNetics of NicotiNe addictioN aNd RespoNse
Twin studies indicate a high degree of heritability (≥50%) in the
prevalence of cigarette smoking and the ability to quit smok-
ing (dependence) and in the number of cigarettes smoked per
day.26 Twin studies even demonstrate heritability in the nature
of particular symptoms experienced when a smoker stopped
Numerous studies have attempted to identify genes underlying
nicotine addiction, as summarized in recent reviews.26 Studies
of the genetics of nicotine dependence and smoking behavior
are problematic because complex behaviors such as smoking are
determined by multiple genes, as well as environmental factors,
and because there are many different dependence phenotypes
that may be examined, which may have different genetic under-
pinnings. Family linkage studies and candidate gene association
studies have suggested a number of loci or particular genes that
are associated with smoking behavior, although smoking phe-
notypes vary considerably from study to study. Candidate genes
coding for nicotine receptor subtypes, dopamine receptors or
transporters, GABA receptors, and others have been identified
in various studies as being associated with different aspects of
smoking behavior.27 However, subsequent research has not rep-
licated many of these earlier findings.
Recent genome-wide association studies point to several genes
that are promising signals for genetic determinants of nicotine
dependence. Bierut, Saccone, and co-workers examined a phe-
notype that is thought to reflect a vulnerability to becoming
dependent on nicotine.28,29 All subjects had to have smoked 100
cigarettes lifetime, and the comparison groups were those who
became dependent upon nicotine vs. those who did not become
dependent. Genotype signals from the genome-wide associa-
tion studies were used to guide a second phase candidate gene
Although there are conflicting findings, a number of studies
find that women have a harder time quitting smoking than do
men. Smoking behavior in women is more highly influenced
by conditioned cues and by negative affect, while men are more
likely to smoke in response to pharmacologic cues, more pre-
cisely regulating their intake of nicotine. As mentioned previ-
ously, women on average metabolize nicotine faster than do
men,14 and being a fast metabolizer could contribute to a higher
level of addiction, based on findings of CYP2A6 genetic stud-
ies to be discussed in the next section. Women have a higher
prevalence of major depressive disorder than men. Given the
strong link between nicotine dependence and depression, this
could be another basis for sex differences and the level of nico-
Other vulnerable populations for nicotine dependence include
people with psychiatric disease and/or substance abuse disor-
ders. Smoking rates in schizophrenic individuals are extraor-
dinarily high (≥80%), and smoking is common in people with
major depression and other mood and anxiety disorders com-
pared to people without psychiatric disease.23 Likewise, smoking
is more common in alcoholics, heroin users, and other illicit
drug abusers. It is estimated that 70% of all cigarettes smoked
in the United States are consumed by people with psychiatric
and/or substance abuse disorders.23 Theories to explain the link
between smoking and schizophrenia include self-medication
with nicotine, particularly via effects on α-7 nicotinic receptors
to improve sensory gating (which is deficient in schizophre-
nics). Nicotine may also be a self-medication for depression,
since nicotine releases many of the same neurotransmitters that
are released by antidepressant drugs. In addition, smoking (but
not nicotine) inhibits brain monoamine oxidase, which could
contribute to antidepressant actions.24
Alcohol, heroin, cocaine, marijuana, and other drugs of abuse
share neural reward mechanisms with nicotine, and the use of
one may sensitize and/or reinforce the use of another. Finally,
there is considerable genetic overlap between smoking and
depression and smoking and alcohol use.
NicotiNe metabolism as a deteRmiNaNt of
tobacco use aNd disease Risk
Insofar as smokers regulate their intake of nicotine to main-
tain particular levels of nicotine in the body throughout the
day, people who metabolize nicotine more quickly would be
expected to take in more cigarette smoke per day compared to
slower metabolizers. This appears to be the case. Genetically
slow metabolizers (e.g., people with variant CYP2A6 genes asso-
ciated with reduced enzyme activity) smoke fewer cigarettes per
day and tend to have higher carbon monoxide levels than do
normal metabolizers.13 In addition, genetically slow metaboli-
zers appear to be less dependent, based on the observation that
the fraction of slow metabolizers in the population of smokers
decreases with increasing age of the smoker cohort, suggesting
that slow metabolizers are more likely to quit. In a population
of Asian and white smokers, the clearance of nicotine assessed
by intravenous infusion of deuterium-labeled nicotine was posi-
tively correlated with the number of cigarettes smoked per day
CliniCal pharmaCology & TherapeuTiCs | VOLUME 83 NUMBER 4 | APRIL 2008
resulting in a net increase in societal use of tobacco. A full dis-
cussion of the pros and cons of harm regulation is beyond the
scope of this article. The subsequent discussion here will examine
pharmacologic aspects of treatment of nicotine dependence, harm
reduction strategies, and potential for nicotine-based regulation
that might prevent tobacco in youth and facilitate quitting smok-
ing in adults.
phaRmacotheRapy of NicotiNe addictioN
mechanism of currently available treatments
A complete review of the pharmacology of drugs used to treat
tobacco dependence is beyond the scope of this article. The
focus here will be on mechanisms of action and the prospects
for future therapies.
Currently, three classes of medications have been approved
for smoking cessation: nicotine replacement products (patch,
gum, spray, inhaler, and lozenge), bupropion and most recently,
varenicline. While not approved by regulatory authorities for
smoking cessation, clinical trials have also demonstrated the
efficacy of nortriptyline and clonidine, which are considered to
be second-line drugs.33 All these drugs have been shown in con-
trolled clinical trials to be effective with odds ratios ranging from
2 to 3 in comparison to placebo treatment. Absolute smoking
cessation rates range from 5 to 35%, depending on the drug and
the intensity of concomitant counseling. Several novel therapies
are under investigation as treatments for smoking cessation.
Nicotine replacement therapy. Nicotine medications act on
nAChRs to mimic or replace the effects of nicotine from
tobacco. Nicotine replacement medications are believed to
facilitate smoking cessation in several ways. The principal
action is the relief of withdrawal symptoms when a person
stops tobacco use. Amelioration of withdrawal symptoms is
observed with relatively low blood levels of nicotine. A sec-
ond mechanism of benefit is positive reinforcement, particu-
larly for the arousal and stress relieving effects. The degree of
positive reinforcement is related to the rapidity of absorption
and the peak nicotine level achieved in arterial blood. Positive
reinforcement is most relevant to rapid-delivery formulations,
such as nicotine nasal spray and, to a lesser extent, nicotine
gum, inhaler, and lozenge. The use of these products allows
smokers to dose themselves with nicotine when they have the
urge to smoke cigarettes. Nicotine patches, on the other hand,
deliver nicotine gradually and produce sustained nicotine
levels throughout the day, thus not providing much positive
A third possible mechanism of benefit is related to the abil-
ity of nicotine medications to desensitize nicotinic receptors.
This desensitization results in a reduced effect of nicotine from
cigarettes, so that when a person lapses to smoking while on
nicotine replacement therapy, the cigarette is less satisfying and
the person is less likely to resume smoking.
Bupropion. Bupropion was marketed as an antidepressant medi-
cation before it was marketed for smoking cessation. The seren-
dipitous observation of spontaneous smoking cessation among
association study, which resulted in several strong genetic asso-
ciations. Most prominent were the α-5, α-3, and β-3 nicotinic
receptor genes, neurexin 1, VPS13A (vacuolar sorting protein),
KCNJ6 (a potassium channel), and the GABA A4 receptor gene.
Of interest is that some of these genes, such as the neurexin 1
gene, are genes related to cell communication. Other genome-
wide association studies have identified a number of genes
affecting cell adhesion and extracellular matrix molecules that
are common among various addictions, consistent with the idea
that neural plasticity and learning are key determinants of indi-
vidual differences in vulnerability to nicotine, as well as other
Greater than fourfold individual variability has been observed
in the rate of metabolism of nicotine.10 As mentioned earlier,
genetic variation in CYP2A6, the enzyme that primarily metab-
olizes nicotine, has been found to be associated with the level
of nicotine dependence. A large twin study of nicotine pharma-
cokinetics and metabolism has shown that nicotine clearance
is more than 50% heritable.31 Of note, however, is that either
controlling for CYP2A6 variants or deleting subjects who have
CYP2A6 variant alleles from the analysis had only a small
effect on the estimate of heritability. This finding suggests that
genes other than CYP2A6 play an important role in regulat-
ing CYP2A6 activity. The fact that only a small fraction of the
population variance in nicotine clearance is explained by known
CYP2A6 variants has led to the use of phenotypic markers of
nicotine metabolism, such as the 3HC/COT ratio, as discussed
ReduciNg tobacco-iNduced disease
Reducing tobacco-induced disease should be a high priority for
healthcare providers and for public health policy makers and
planners. The most effective ways to reduce disease are to pre-
vent youths from becoming smokers and to get current smokers
to quit. However, even if prevention was to become instantly
and completely effective, promoting quitting remains critical for
reducing tobacco-induced disease in the next 50 years given the
many millions of current smokers around the world.
More controversial is the idea of tobacco harm reduction. Harm
reduction implies reducing the disease burden of smoking in
people who continue to use tobacco products or constituents of
tobacco products, such as nicotine medications.32 The main argu-
ment for tobacco harm reduction is that many smokers are highly
addicted and cannot or choose not to stop smoking because of
their need for nicotine. Switching such individuals to less harm-
ful products that deliver nicotine might substantially reduce the
risk of smoking-related disease. Several arguments against harm
reduction have been raised: (1) providing nicotine, even in a less
harmful product, maintains nicotine addiction; (2) the availabil-
ity of less harmful tobacco products may result in lower concern
about the harmful health effects of smoking and therefore more
people beginning to use or not quitting tobacco product use; and
(3) the use of less harmful tobacco products would allow tobacco
use in general to remain normative in society, thereby undermin-
ing efforts toward a tobacco-free society. There are also concerns
about industry overmarketing potentially less hazardous products,
538 VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
iNdividualizatioN of phaRmacotheRapy
While a number of drugs are effective in enhancing smoking
cessation as discussed above, success rates are still relatively low,
and most smokers require multiple quit attempts before they quit
for good. Tobacco addiction differs in its manifestations from
person to person. There are individual differences in the nature
of reinforcement (i.e., what benefit people say they get from
smoking), in withdrawal symptoms, as well as in conditioned
aspects of smoking. There has been much interest, therefore, in
individualization of smoking cessation pharmacotherapy. The
goal would be to select medications and doses based on individ-
ual characteristics of smokers. An area of much current research
activity in this regard is pharmacogenetics of nicotine addiction
treatment. A number of pharmacogenetic studies have been con-
ducted, focusing primarily on candidate genes related to nicotine
reward and nicotine metabolism pathways.27 For example, vari-
ants in the dopamine D2 receptor, dopamine transporter, dop-
amine β-hydroxylase, and catechol-O- methyltransferase genes
have been reported to affect response to transdermal nicotine
and/or bupropion. Variation in the opiate mu 1 receptor gene
has been reported to influence response to transdermal nicotine,
and variants in the CYP2B6 gene have been found to predict
response to placebo in bupropion clinical trials.36,37 To date,
few of these findings have been replicated, and the fraction of
the total variance in smoking cessation response explained by
single candidate genes appears to be small. Ongoing research is
focusing on looking at multiple genes and looking at gene–gene
interactions as predictors of treatment outcome.
Given the tendency of smokers to regulate their intake of
nicotine, it is logical to consider nicotine metabolism genes,
namely CYP2A6, as potential predictors of response to smoking
cessation treatment. Unfortunately, the prevalence of CYP2A6
gene variants is too low, at least in whites, to be able to detect
significant genetic associations in most studies. An alternative
to CYP2A6 genotyping is the use of the phenotype for the rate
of nicotine metabolism. As mentioned previously, the 3HC/
cotinine ratio is a phenotypic marker of the rate of nicotine
metabolism,11 and this metabolite ratio has been studied as a
predictor of response to pharmacotherapy. In one trial, compar-
ing transdermal nicotine and nicotine nasal spray, the nicotine
metabolite ratio was shown to be a strong predictor of smoking
cessation both at the end of treatment and at 6 months in people
treated with transdermal nicotine but not nicotine nasal spray.38
In smokers treated with transdermal nicotine, slow metabolizers
had a better cessation response and a higher plasma nicotine
concentration while using the patch compared to faster metabo-
lizers, suggesting that higher nicotine levels might be responsible
for better cessation outcome. In contrast, smokers treated with
nicotine nasal spray showed no difference in plasma nicotine
concentration as a function of rate of nicotine metabolism, con-
sistent with the idea that nicotine from the spray is titrated by
the smoker to the desired effect.
Another recent trial examined the association between a nico-
tine metabolite ratio and a response to bupropion treatment.39
Faster metabolism of nicotine was associated with lower success
rate in quitting in the placebo treated group, but among smokers
veterans treated with bupropion for depression led to the explora-
tion of bupropion as a smoking cessation medication. Bupropion
increases brain levels of dopamine and norepinephrine, simulat-
ing the effects of nicotine on these neurotransmitters. Bupropion
also has some nicotine receptor blocking activity, which could
contribute to reduced reinforcement from a cigarette in the case
of a lapse.
Varenicline. Varenicline was synthesized with the goal of devel-
oping a specific antagonist for the α-4 β-2 nAChR.34 Varenicline
is an analog of cytisine, a plant alkaloid that has been reported
to have some benefit in smoking cessation but is thought to
have generally poor oral bioavailability. Varenicline was shown
in in vitro receptor binding studies to have high affinity for the
α-4 β-2 nAChR and very little effect on other nAChR subtypes
or neurotransmitter receptors. Varenicline is a partial agonist
of the α-4 β-2 receptor in vivo, as demonstrated by studies of
dopamine release, measured with microdialysis in the nucleus
accumbens of conscious rats. Nicotine, a full agonist, causes
substantial dopamine release. Varenicline, a partial agonist,
produces less of a response than nicotine (~50%) but at the
same time blocks the effects of any nicotine added to the sys-
tem. Clinical trials have found that varenicline is superior to
bupropion in promoting smoking cessation, and prolonged
administration of varenicline has been shown to reduce relapse
in smokers who had been abstinent 12 weeks after initial
medications in development
Rimonabant is a cannabinoid (CB-1) receptor antagonist that
has been developed for treatment for obesity and the metabolic
syndrome. Clinical studies have also shown rimonabant to be
effective as an aid for smoking cessation.35 Cannabinoid recep-
tors are believed to contribute to the reinforcing effects of nico-
Nicotine vaccines are currently undergoing clinical trials.35
Acute immunization is performed so as to develop antibodies
to nicotine. The antibody binds nicotine and slows its entry into
the brain, thereby reducing the reinforcing effects of cigarette
smoking. The nicotine vaccine is a logical approach to prevent-
ing relapse, which occurs in a large proportion of smokers after
Other potential future medications for smoking cessation
include monoamine oxidase inhibitors (MAO-A and MAO-B),
which inhibit the metabolism of dopamine and therefore
increase dopamine levels in brain, and dopamine receptor D3
receptor antagonists and partial agonists, which modulate activ-
ity of a receptor involved in drug-seeking behaviors.35 Inhibitors
of CYP2A6 activity have also been proposed as smoking cessa-
tion aids working by increasing nicotine levels from tobacco use
and thereby reducing urges to smoke. Methoxsalen and tranyl-
cypromine inhibit CYP2A6 activity and slow nicotine metabo-
lism, but both have significant toxicity making routine clinical
use problematic. Finally, novel selective nicotinic cholinergic
receptor agonists and antagonists, in addition to varenicline, are
in early stages of development.
CliniCal pharmaCology & TherapeuTiCs | VOLUME 83 NUMBER 4 | APRIL 2008
nicotine delivery system with absorption kinetics similar to
those of a cigarette would be an important advancement in pur-
suing harm reduction through nicotine maintenance.
An important question in promoting nicotine maintenance is
the safety of nicotine per se. Without doubt, nicotine medication
is much safer than cigarette smoking, with the latter delivering
not only as much or more nicotine but also thousands of toxic
combustion products to the smoker. However, there are some
concerns involving the safety of nicotine per se, including car-
diovascular disease, cancer, reproductive disorders, and delayed
Nicotine is a sympathomimetic drug that releases cate-
cholamines, increases heart rate and cardiac contractility, con-
stricts cutaneous and coronary blood vessels, and transiently
increases blood pressure.5 Nicotine also reduces sensitivity to
insulin and may aggravate or precipitate diabetes, and nico-
tine may contribute to endothelial dysfunction. These various
effects of nicotine on the cardiovascular system could in theory
promote atherogenesis and precipitate acute ischemic events
in people who have coronary artery disease. This has been of
particular concern in smokers who use nicotine medication
while they are still smoking. However, increased cardiovascular
risk does not appear to be a problem. The dose–response curve
for cardiovascular effects such as heart rate acceleration or the
release of catecholamines is flat, such that adding nicotine medi-
cation to smoking produces no further effect. Clinical trials of
nicotine patches in smokers with cardiovascular disease showed
no increased risk of cardiovascular events compared to placebo.
Furthermore, the experience of men in Sweden with a long his-
tory of snuff use, which delivers nicotine without combustion
products, suggests little or no increase of cardiovascular risk.
Nicotine is not a direct carcinogen, but there are concerns
that it may be a tumor promoter. In animal studies, nicotine can
inhibit apoptosis, resulting in impaired killing of cancer cells.44
Nicotine also promotes angiogenesis in animals, an effect which
could lead to greater tumor invasion and metastasis.45 Whether
nicotine is a cancer promoter in people has not been established,
but the report that smokers who switch to smokeless tobacco
may have an increased risk of lung cancer compared to smo-
kers who quit entirely, raises concern about this possibility.42
Exposure to nitrosamines from smokeless tobacco could also
explain or contribute to such an increase in lung cancer risk.
Adverse reproductive effects of nicotine, particularly the fetal
neuroteratogenic effects, have been mentioned previously. In
general, it is not desirable to use nicotine during pregnancy, but
if the alternative is cigarette smoking, then nicotine is undoubte-
dly less hazardous. Nicotine is a potent cutaneous vasoconstric-
tor and can impair wound healing. However, clinical trials using
nicotine replacement medication to aid cessation in surgical
patients indicate that the overall outcome is much better in indi-
viduals using nicotine therapy who quit smoking compared to
In summary, while nicotine is not entirely benign, the ben-
efit of nicotine maintenance therapy to maintain nonsmoking
appears to far outweigh the risks, and such an approach should be
considered for smokers who cannot otherwise quit smoking.
receiving bupropion, the rate of nicotine metabolism had no
differential effect. This finding is consistent with the idea that
rapid metabolizers of nicotine are generally more dependent and
have a harder time quitting compared to slow metabolizers. The
mechanism of such a relationship has not been proven but might
include more severe withdrawal symptoms or a different type of
nicotine reinforcement related to more rapid loss of tolerance in
fast metabolizers. Future studies are needed to potentially test
the idea of tailoring the type or dose of pharmacotherapy using
phenotypes or genotypes of the rate of nicotine metabolism.
Several types of harm reduction products have been developed or
proposed, including smoking products that purportedly deliver
less of various tobacco toxins, smokeless tobacco (i.e., snuff), and
newer nicotine medications.32 Tobacco products that are smoked
might be engineered to deliver fewer of some smoke toxins, but
the combustion process per se generates a number of important
toxins, such as oxidizing chemicals, particulates, and carbon
monoxide. Because of the generation of these products, which
are thought to play a major role in tobacco-related disease, it is
unlikely that any combusted tobacco products will substantially
reduce risk. Smokeless tobacco delivers similar amounts of nico-
tine as does cigarette smoking, and does not expose the individual
to combustion products, but may deliver tobacco carcinogens,
such as tobacco-specific nitrosamines. Swedish snuff (snus) is
particularly low in tobacco-specific nitrosamines. Swedish snus
appears not be associated with an increased risk in cardiovascu-
lar disease, respiratory disease, and most cancers, although it is
associated with an increased risk in the development of pancre-
atic cancer, as well as reproductive problems in pregnant women
who use snus.40,41 A provocative analysis of the American Cancer
Society Cancer Prevention Study II data, based on a community-
based cohort, found that smokers who had switched from smok-
ing to smokeless tobacco had a higher risk of cancer, including
lung cancer, compared to those who quit smoking entirely.42 This
observation raises concerns that nicotine may be a cancer pro-
moter. On the other hand, lifelong use of nicotine derived from
smokeless tobacco in Sweden does not produce an increased risk
of any cancer other than pancreatic cancer, arguing against a gen-
eral tumor-promoting effect of nicotine.
Since nicotine underlies addiction and sustains cigarette smok-
ing, it is logical to consider nicotine maintenance as a potential
alternative to tobacco use for smokers who cannot quit. The
administration of nicotine replacement therapy in smokers has
been shown to reduce smoking rates and among those who
reduce their smoking to promote smoking cessation.43 However,
the currently available nicotine delivery systems deliver nicotine
into the blood stream much more slowly than does cigarette
smoking, so for most smokers nicotine medications are not sat-
isfactory substitutes for smoking. Since the rate of absorption is
a determinant of the intensity of pharmacologic effect, nicotine
medications are not perceived to be as satisfying as smoking a
cigarette. The development of a consumer-acceptable inhaled
540 VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
occasionally by youth without the risk of subsequently becoming
addicted adult smokers.
One concern with such a nicotine-reduction strategy is that
smokers will smoke more cigarettes and/or smoke the cigarettes
more intensively to compensate for lower nicotine levels, thereby
increasing their exposure to smoke carcinogens and other toxins.
Such compensation has been observed with currently marketed
low-yield cigarettes, such that smokers of low-yield cigarettes
have similar levels of nicotine and carcinogen intake as smokers
of regular cigarettes.49 It should be recognized, however, that
current low-yield cigarettes are low yield not because nicotine
content is reduced but because of engineering characteristics
such as ventilation and rapid burn time. The proposed reduced
nicotine content cigarettes would actually contain less nicotine
in the tobacco rod.
The feasibility of nicotine reduction has been examined in a
study of 20 subjects exposed to gradual reduction of nicotine
content, going from effective delivers of 1 mg to 0.1 mg nico-
tine.50 In this study, a progressive decline in nicotine intake,
as evidenced by decreased cotinine concentrations, with no
increase in cigarette consumption or carcinogen exposure or at-
risk biomarkers, was observed. This would suggest that compen-
sation will not be a significant problem for this type of reduced
nicotine cigarette. In this study, when tapering research ciga-
rettes was completed, smokers returned to smoking the usual
brand of cigarette, but nicotine intake remained below baseline
for 4 weeks, suggesting that the level of nicotine dependence had
been lowered. Twenty-five percent of the subjects spontaneously
quit smoking. This small study suggests that nicotine reduction
is feasible and may be safe and supports the conduct of large
studies to confirm the observations.
Tengs et al.51 performed a computer simulation of a nationally
mandated nicotine- reduction policy. This simulation predicted
that a progressive decrease in the nicotine content of cigarettes
over 6 years would result in a decline in smoking prevalence
from 23 to 5% of the U.S. population, with a cumulative gain of
157 million quality-adjusted life years. Tengs concluded “Policy
makers would be hard-pressed to identify another domestic
public health intervention, short of historical sanitation efforts,
that has offered this magnitude of benefit to the population.”
Thus, nicotine-based regulation holds considerable potential
for reducing the impact of nicotine addiction and its associated
The intent of this review is to update readers on the clinical
pharmacology of nicotine, including how nicotine contributes to
tobacco addiction, the bases for individual differences in vulner-
ability and underlying genetic determinants of nicotine addic-
tion, and progress in pharmacotherapy of nicotine dependence,
as well as how nicotine pharmacology might be incorporated
into decisions about harm reduction and federal regulatory
strategies. Research on the clinical pharmacology of nicotine
holds great promise for advancing the treatment and prevention
of tobacco addiction, with the potential of stemming one of the
most profound epidemics of modern times.
Comprehensive analyses on how public health might reduce
tobacco-related disease, such as those conducted by the Institute
of Medicine, conclude that federal regulation is necessary for
optimal control of the tobacco problem.32,46 Comprehensive
federal regulation would include regulating nicotine delivery
products (both tobacco and medications), potentially reduced
exposure products with claims to less harm, advertising, mar-
keting to youth, and population surveillance of tobacco use and
its health effects. Proposals for giving regulatory authority to
the Food and Drug Administration or to a comparable federal
agency have been considered by the United States Congress.46
Federal regulations of tobacco as currently proposed would
include the authority for the agency to limit the content of vari-
ous tobacco toxins to meet particular safety standards. Nicotine
is included among those toxins. Nicotine is toxic primarily
because it causes addiction and by causing addiction thereby
undermines rational decision making in deciding whether or
not to use tobacco.
In order to make cigarettes less addictive, a nicotine-reduction
strategy, involving a progressive reduction of the nicotine con-
tent of cigarette tobacco over time, was proposed by Benowitz
and Henningfield in 1994 and supported in concept by the
American Medical Association in 1998.47,48 This type of strategy
would involve gradually reducing nicotine content of cigarettes
over a number of years. Smokers would be gradually weaned
from nicotine dependence and would be expected to have an
easier time quitting smoking (Figure 4). Nicotine in medication
form would be made readily available to those smokers who
become uncomfortable due to inadequate nicotine delivery from
cigarettes. Ultimately, the nicotine content of cigarettes would
be decreased to the point where cigarettes might be smoked
05 10 1520
figure 4 Reducing the nicotine content of cigarettes as a possible regulatory
strategy for reducing the addictiveness of tobacco and therefore to reduce
tobacco use and associated harms. The proposal is to mandate the gradual
reduction in the nicotine content of all cigarettes over a number of years. At
the same time, pure nicotine products would be made readily available to
allow smokers to manage their dependence on nicotine that is no longer
satisfied by smoking. Eventually cigarettes would become nonaddicting, so
that young people who experiment with smoking for psychosocial reasons
would not become addicted adult smokers. Formerly addicted smokers
would either quit smoking, facilitated by a progressive decline in their level
of nicotine dependence, or continue to take pure nicotine as a maintenance
therapy, but with markedly reduced adverse health consequence compared
CliniCal pharmaCology & TherapeuTiCs | VOLUME 83 NUMBER 4 | APRIL 2008
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The author’s effort was supported by Public Health Service grants DA11170,
DA02277, and DA12393 awarded by the National institute on Drug Abuse
and the Flight Attendants Medical Research Institute. Many of the studies
described in this paper were carried out at the General Clinical Research
Center at San Francisco General Hospital with support of the Division of
Research Resources NIH RR00083. Marc Olmsted provided editorial assistance.
coNflict of iNteRest
The author is a paid consultant for several pharmaceutical companies that
develop and/or market medications to aid smoking cessation, and has been
a paid expert witness in litigation against tobacco companies.
© 2008 American Society for Clinical Pharmacology and Therapeutics
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