Ref. Ares(2014)1336783 - 29/04/2014
Reducing the dependence potential of manufactured cigarettes by reducing their
nicotine content to levels that cannot cause or sustain addiction
Geoff Ferris Wayne
Report to World Health Organization/ SacTob
Oct 16, 2013
DRAFT
I.
Introduction
II.
Tobacco addictiveness model
III.
Establishing a threshold for addiction
IV.
Feasibility of nicotine reduction
V.
Potential behavioral and population outcomes
VI.
Policy approaches to nicotine reduction
VII.
Conclusions
VIII.
Recommendations
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I.
Introduction
Nearly two decades ago
, Benowitz and Henningfield (1994) proposed a gradual
reduction of nicotine in cigarettes as a potential strategy for harm reduction. A number
of health scientists have since concluded that such an approach could have a significant
and positive impact on public health
(Benowitz and Henningfield 2013; Gray et al. 2005;
Hatsukami et al. 2013a; Henningfield et al. 1998; Smith et al. 2013; Tengs et al. 2005;
Zeller et al. 2009). The goals of a nicotine reduction policy are to reduce pharmacologic
addiction in smokers, making it easier for them to quit, or encouraging them to transition
to less harmful sources of nicotine, while preventing novice smokers from transitioning
from experimental or occasional smoking to cigarette addiction
(Benowitz and
Henningfield 2013; Henningfield et al. 1998). This strategy is consistent with Article 9 of
the Framework Convention on Tobacco Control (FCTC), which addresses the need to
develop guidelines for regulating the contents and emissions of tobacco products
(World Health Organization 2003; World Health Organization 2012).
A nicotine reduction strategy is premised on the assumption that nicotine is primarily
responsible for supporting cigarette use, and that a threshold level of nicotine can be
identified below which the acquisition and maintenance of cigarette dependence will be
substantially reduced
(Henningfield et al. 1998). Thus, there are both theoretical and
practical questions which must be addressed in evaluating the likely outcomes of this
approach: the role of nicotine in initiating and sustaining tobacco addiction, the amount
of nicotine necessary for addiction, differences due to the chemical form or delivery
mechanisms of nicotine, the degree of variation in response to nicotine among
individuals or key populations such as children and those with mental illness, processes
for reducing nicotine in tobacco and their potential effects, behavioral responses to
reduced nicotine cigarettes such as compensatory or increased smoking in nicotine
addicted smokers, and relative toxicity of reduced nicotine cigarettes.
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An early obstacle to evaluating the potential outcomes of a nicotine reduction strategy
was the lack of an existing science base. For example, an initial concern was the
potential for reduced nicotine products to increase the toxicity of cigarette use as a
result of more intense or more frequent smoking
(Jarvis and Bates 1999; Shatenstein
1999). More recent clinical studies appear to address this concern, demonstrating
substantial reductions in smoking and reduced exposure to toxins with little
compensation even at very low doses of nicotine
(Benowitz et al. 2012; Benowitz et al.
2007; Hatsukami et al. 2010a). This report will review the state of the science with
respect to tobacco and nicotine addiction
(section II), the concept of a threshold for
nicotine addiction
(section III), and the practical feasibility of reducing nicotine in
cigarettes below the threshold for addiction
(section IV).
Environmental factors are also known to affect adoption and use of tobacco products,
and would likely play a critical role in the outcome of a nicotine reduction strategy.
Factors to be considered include the relative availability of alternate sources of nicotine,
the degree of regulation of alternative products, potential growth of illicit sales of high
nicotine cigarettes, availability of treatment for dependence, education of smokers and
potential smokers regarding use, withdrawal, and treatment, and public support for
regulation of nicotine. For example, lack of accessibility or appeal of less toxic nicotine
delivery systems and treatment medications are more likely to spur illicit sales or drive
smokers to other potentially harmful tobacco product
(Henningfield et al. 2004b). This
report will review population outcomes that may be anticipated as a result of a nicotine
reduction strategy
(section V), and policy approaches necessary to support this
strategy and minimize unintended or negative health consequences to nicotine
reduction
(section VI).
The Institute of Medicine report “Clearing the Smoke”
(Stratton et al. 2001) provides a
useful framework for assessing tobacco product harm in relation both to a product’s
toxicity as well as those factors that encourage experimentation and use (see also
(Hatsukami et al. 2012; Zeller et al. 2009). Cigarettes and other burned tobacco are not
only highly toxic in comparison to alternatives such as medicinal nicotine, but have
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unmatched potential for harm due to their greater availability, addictiveness, and
appeal. A nicotine reduction strategy could substantially reduce population harm, even
in the absence of reducing toxicity, by decreasing incentives to begin or continue use of
these deadly products
(Zeller et al. 2009). This report assesses the likelihood of such an
outcome based on the available science base, and identifies those areas in which
additional research is needed
(section VII).
II.
Tobacco addictiveness model
Early efforts to reduce the disease burden of smoking relied on product-driven
reductions in cigarette smoke delivery. This was achieved primarily through the
introduction of filter ventilation to dilute the smoke, alongside use of expanded tobacco
and other product changes
(Hoffmann and Hoffmann 1997). However, smokers simply
compensated for reduced delivery by altering their smoking behavior, puffing longer and
more frequently, or increasing the number of cigarettes smoked per day, maintaining
their exposure to both nicotine and toxins
(Benowitz et al. 2005; National Cancer
Institute 2001).
In a historical analysis
, Parascandola (2011) observed that the failure of past tobacco
harm reduction efforts resulted from an incomplete understanding within the public
health community of the factors controlling smoking behavior, and in particular, the role
of nicotine in driving that behavior. A nicotine reduction strategy follows directly from
the assumption that nicotine is the primary psychoactive drug in tobacco and the key to
ongoing tobacco use. However, the state of the science on nicotine addiction and
tobacco use is evolving. Anticipating the consequences of product regulation—both
intended and unintended-- requires a clear and complete understanding of nicotine and
tobacco dependence.
II.a. Nicotine addiction
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Nicotine is a highly addictive and potent drug, generating psychoactive and rewarding
effects at acutely administered doses of less than 1 mg
(Benowitz 2008). Low doses of
nicotine produce central or peripheral nervous system stimulation, arousal, enhanced
mood, and increase in heart rate or blood pressure, while high doses may result in
bradycardia, hypotension, and depressed mental status. Nicotine also improves motor
reflex and cognitive performance including attention and memory
(Heishman et al.
2010). Tolerance to the behavioral and cardiovascular effects of nicotine develops
rapidly with repeated exposure. Thus, the pharmacologic basis of nicotine addiction
combines positive reinforcements (arousal, mood, performance) alongside the
avoidance of withdrawal symptoms that arise in the absence of nicotine
(Benowitz 2008;
DiFranza et al. 2010a).
The addiction potential of a nicotine delivery system varies as a function of its dosing
mechanism, including the speed with which it can deliver nicotine and the ease with
which nicotine can be extracted
(Henningfield et al. 2011; Wayne and Carpenter 2009).
Cigarettes provide a particularly effective form of delivery. When an individual inhales
smoke from a cigarette, nicotine from the tobacco is carried in smoke particles into the
lungs, where it is rapidly absorbed and carried to the brain. Nicotine diffuses readily into
brain tissue, binding to nicotinic cholinergic receptors (nAChRs). The gradual absence
of nicotine following extinction of smoking results in subnormal release of dopamine and
other neurotransmitters, experienced as malaise and inability to experience pleasure.
Other symptoms of nicotine withdrawal include irritability, restlessness, anxiety, difficulty
concentrating, decreased heart rate, increased appetite, and inability to sleep
(Benowitz
2008).
Cigarette addiction is maintained through repeated behaviors. The first cigarette of the
day produces substantial pharmacologic effect and enhanced mood. With subsequent
smoking, there is an accumulation of nicotine in the body, resulting in a greater level of
tolerance, and withdrawal symptoms become more pronounced between successive
cigarettes. Most smokers tend to take in the same amount of nicotine from day to day.
Smokers adjust their smoking behavior to compensate for changes in the availability of
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nicotine or in the rate of elimination of nicotine from the body in order to regulate the
body levels of nicotine
(Benowitz 2008).
Compulsion is a core feature of tobacco addiction, characterized by wanting, craving or
needing to smoke that recurs after each cigarette
(DiFranza et al. 2010b). When defined
to include withdrawal symptoms, compulsion has 99% sensitivity in identifying which
novice smokers will progress to established smoking
(DiFranza et al. 2007a; DiFranza
et al. 2007b; Wellman et al. 2004).
II.b. Individual variability in response to nicotine
Most tobacco use begins in adolescence. While many youth try cigarette smoking, only
20–25% of those who experiment with cigarettes become addicted adult smokers
(Institute of Medicine 1994). Genetic vulnerability to nicotine dependence may explain
the transition to tobacco use for some. Twin studies indicate greater than 50%
heritability in prevalence of cigarette smoking, number of cigarettes smoked per day,
ability to quit smoking, and nature of withdrawal symptoms experienced at quitting
(Lessov-Schlaggar et al. 2008). Other risk factors for smoking include peer and parental
influence and individual personality traits such as depression or anxiety
(Institute of
Medicine 1994).
Early exposure to nicotine is associated with more severe nicotine dependence and
increased smoking behaviors among adult smokers
(Benowitz and Henningfield 1994;
Breslau and Peterson 1996; Cui et al. 2006; Lando et al. 1999; Taioli and Wynder
1991). These findings mirror animal studies, in which exposure during adolescence
produces both increased reward and higher levels of self-administration
(Adriani et al.
2002; Adriani et al. 2003; Kota et al. 2008; Levin et al. 2007; Trauth et al. 1999; Trauth
et al. 2000; Vastola et al. 2002). These findings suggest that the developing brain may
be more susceptible to permanent changes caused by nicotine exposure that support
addiction
(Benowitz 2008; Hatsukami et al. 2010b).
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A high (approximately fourfold) individual variability has been observed in rate of
metabolism of nicotine
(Hatsukami et al. 2010b; Hukkanen et al. 2005). Women
metabolize nicotine faster than men
(Benowitz 2008; Benowitz et al. 2006b), which
could contribute to a higher level of addiction. Women have greater sensitivity to
nicotine than men
(Sofuoglu and Mooney 2009), and more difficulty quitting smoking
(Eissenberg et al. 1999; Fant et al. 1996; Gritz et al. 1996; Perkins et al. 1999; Wetter et
al. 1999) . 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 and regulation of nicotine intake
(Bevins and Caggiula 2009;
Carpenter et al. 2005; Perkins et al. 2006; Perkins et al. 1997).
Individuals with psychiatric and/or substance abuse disorders have much higher rates of
nicotine dependence, smoke more cigarettes per day, and have more difficulty quitting
(Lasser et al. 2000; Lawrence et al. 2010; McClave et al. 2010; Williams and Ziedonis
2004; Ziedonis et al. 2008). Nicotine use may function as a form of self-medication for
some disorders
(Schroeder and Morris 2010), particularly schizophrenia, where nicotine
can improve deficient sensory gating
(Leonard and Adams 2006; Leonard et al. 2001),
and depression, where nicotine may desensitize nicotinic receptors in a manner
functionally similar to many antidepressant drugs
(Mineur and Picciotto 2009; Mineur
and Picciotto 2010). In addition, smoking (but not nicotine) inhibits brain monoamine
oxidase, which could contribute to antidepressant actions
(Lewis et al. 2007). Smokers
with mental illness constitute more than a third of all smokers and more than half of
nicotine-dependent smokers
(Grant et al. 2004; Lasser et al. 2000; Lawrence and
Mitrou 2009).
A subset of light or occasional smokers consumes five or fewer cigarettes per day or
nondaily, and appears to smoke primarily for the positive reinforcing effects of nicotine
(Benowitz 2008). These smokers use cigarettes primarily in association with specific
activities, such as after meals or with alcohol, and less in response to negative affect,
and may be more reactive to smoking cues
(Watson et al. 2010). Although they
experience minimal or no withdrawal symptoms, many of these occasional smokers
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have difficulty quitting, suggesting dependence but in a form distinct from that of
everyday smokers.
II.c. Tobacco delivered nicotine
Tobacco smoke is a complex mixture containing several thousand individual
compounds
(Hoffmann and Hoffmann 1997; Wayne and Carpenter 2009), that may
contribute to a cigarette’s addictive properties either independently
(Plescia et al. 2013)
or in combination with nicotine
(Talhout et al. 2007; Villegier et al. 2007).
Nicotine in its unprotonated or free-base form may be readily absorbed through the oral
mucosa and upper respiratory tract, as in the case of smokeless tobaccos or cigars.
When inhaled in this form, nicotine is characterized by a stinging sensation or “bite” in
the upper respiratory tract, which may be considered too irritating or unpalatable to be
acceptable to smokers. Alternately, in cigarette smoke, a large percentage of nicotine
remains in the protonated or bound form, where nicotine is more easily inhaled and
carried deep within the respiratory tract. However, bound nicotine may not be absorbed
as quickly or readily, and it does not provide the same sensory stimulus of unprotonated
nicotine
(Pankow 2001; Wayne and Carpenter 2009).
Modern cigarette construction seeks to provide an ideal balance between efficiency and
palatability of nicotine delivery. For example, high ammonia content tobacco can
increase the proportion of unprotonated nicotine in cigarette smoke, supporting more
rapid or efficient absorption of nicotine
(Henningfield et al. 2004a). Sugars or other
additives may then be employed to offset the harshness of unprotonated nicotine and
facilitate deeper inhalation
(Wayne and Carpenter 2009).
The sensory characteristics (taste, aroma, tracheobronchial sensations) of tobacco
smoke provide direct cues for the smoker, guiding smoking behaviors at the level of the
individual puff
(Carpenter et al. 2007; Rose 2006). Motoric components of cigarette use
(handling, puffing, inhaling) are not capable of eliciting a significant degree of
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satisfaction among smokers in the absence of sensory components, as indicated by
smoking studies conducted using unlit cigarettes
(Breland et al. 2002). On the other
hand, variations in sensory components such as taste and impact may have significant
effects on measures of smoking reward
(Perkins et al. 2001b; Rose 2006). For
example, attenuating olfactory and taste cues diminishes both enjoyment and
behaviorally reinforcing effects of cigarette smoke, particularly among female smokers
(Rose 2006; Rose and Behm 2004b).
Nicotine plays a central role in the sensory composition of cigarette smoke. Nicotine-
containing cigarettes are consistently rated as stronger than denicotinized cigarettes in
terms of perceived respiratory tract sensations
(Rose and Behm 2004a; Rose and
Behm 2004b). Nicotine aerosol inhalation elicits strong irritant effects
(Lee et al. 1993)
and even IV nicotine infusions can elicit respiratory tract sensations
(Henningfield and
Goldberg 1983; Rose et al. 2000).
Some balance of smoke constituents is necessary to offset the excessive harshness of
nicotine and make tobacco smoke palatable. “Tar” is a common measure of the total
particulates in smoke excluding nicotine; the ratio of tar/nicotine has been found to be a
key determinant of the overall harshness of smoke
(Rose 2006; Rose et al. 1999).
Alternately, some tobacco constituents may provide additional stimulus either alongside
of or in place of nicotine
(Wayne and Carpenter 2009). Menthol is a common tobacco
additive with strong sensory stimulant properties, and has been used to compensate for
reduced nicotine in extremely low delivery products
(Celebucki et al. 2005; Ferris
Wayne and Connolly 2004). Menthol may also attenuate some of the irritant effects of
nicotine by virtue of its local anesthetic properties
(Galeotti et al. 2001), and increases
the permeability of biological membranes
(Shojaei et al. 1999), which could conceivably
influence nicotine absorption.
Some non-nicotine smoke components may have direct pharmacologic effects on the
brain or interact with nicotine’s reinforcing effects
. Brody et al. (2009) demonstrated
significant α4β2* nAChR occupancy from smoking a denicotinized cigarette, suggesting
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that even in the absence of nicotine, tobacco smoke may produce measurable
pharmacologic effects. Various minor tobacco alkaloids are reinforcing either on their
own (nornicotine) or by potentiating the effects of nicotine (anabasine, nornicotine,
anatabine, cotinine and myosmine)
(Bardo et al. 1999; Clemens et al. 2009).
Acetaldehyde is self-administered by animals
(Plescia et al. 2013), and has been shown
to potentiate the reinforcing effects of nicotine, especially in adolescence
(Belluzzi et al.
2005; Cao et al. 2007; Rodd-Henricks et al. 2002; Talhout et al. 2007).
Harman and salsolinol are condensation products of acetaldehyde that inhibit
monoamine oxidase (MAO)
(Talhout et al. 2007). MAO inhibitors increase response
rates substantially when given to rats self-administering nicotine
(Guillem et al. 2005;
Guillem et al. 2008; Villegier et al. 2007) (Guillem et al. 2005; Villégier et al., 2007),
possibly by exerting antidepressant effects on their own, or by potentiating the
reinforcing effects of nicotine by increasing the lifetime of neurotransmitters such as
dopamine after their release is evoked by nicotine
(Rose et al. 2001).
II.d. Dual-reinforcement model of addiction
Although the addictive properties of tobacco are often attributed exclusively to nicotine
(USDHHS 1988) the reinforcing effects of nicotine in the absence of tobacco have not
been conclusively shown using blinded protocols
(Dar and Frenk 2004; Fulton and
Barrett 2008). As with other psychostimulant drugs, nicotine produces unconditioned
effects that increase the ability of non-drug stimuli to serve as conditioned reinforcers,
independently of any direct association between nicotine administration and stimulus
presentation
(Caggiula et al. 2002; Chaudhri et al. 2007; Chaudhri et al. 2006; Olausson
et al. 2003; Olausson et al. 2004; Palmatier et al. 2007a; Palmatier et al. 2007b).
The critical role played by non-drug stimuli has been demonstrated in rodent studies,
where discontinuing environmental stimuli associated with intravenous nicotine injection
decreases self-administration behavior almost as effectively as the removal of nicotine
itself
(Caggiula et al. 2002; Le Foll and Goldberg 2005). In experiments with rats
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(Cohen et al. 2005) and squirrel monkeys
(Le Foll et al. 2007) the response rate
maintained by nicotine-associated light stimuli is equal to the responding maintained by
nicotine. By contrast, the use of behavioral procedures without environmental stimuli
directly paired with nicotine delivery result in very low levels of drug-taking behavior
(Donny et al. 2003).
An emerging hypothesis proposes that nicotine addiction, whether characterized by high
rates of self-administration exhibited in laboratory animals, or by cigarette smoking in
humans, is supported by the reinforcing stimuli that accompany nicotine intake, and the
capacity of nicotine to enhance the reinforcing effects of such stimuli. In this dual-
reinforcement model, nicotine acts first as a primary reinforcer, establishing a
concurrent neutral stimulus as a conditioned reinforcer by association. Secondly,
nicotine acts as a reinforcement enhancer, magnifying the incentive value of the
nicotine-associated, conditioned reinforce
(Caggiula et al. 2009).
As the effects of nicotine become associated with various non-nicotine stimuli, these
stimuli acquire conditional value or serve as cues for future nicotine delivery. As a
result, the conditional stimuli for tobacco can alter behavior in a manner that maintains
smoking or results in lapse/relapse after sustained abstinence. Thus, proximal stimuli
normally associated with smoking, such as a lit cigarette, can induce reports of craving
in smokers but not in non-smokers
(Carter and Tiffany 1999). This hypothesis serves to
explain the importance of sensory stimuli relative to nicotine in determining subjective
responses to tobacco smoke
(Rose 2006; Rose et al. 2000) as well as the reduction in
subjective reports of tobacco craving, desire to smoke, and tobacco withdrawal that are
produced by placebo cigarettes
(Donny et al. 2007).
Rees et al. (2012) observe that sensory cues can be highly characteristic for individual
tobacco products, and suggest that these brand-specific cues may acquire incentive
salience, reinforcing use at the level of brand characteristics. They suggest that the
limited commercial appeal of denicotinized cigarettes such as Quest may be due in part
to disruptions to the established chemosensory cue-nicotine dosing contingency. While
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nicotine administration increases the salience of sensory cues, it does not alter their
palatability (Palmatier et al. 2013). Thus, the incentive amplifying effects of nicotine may
be most effective for familiar sensory stimuli that already have positive associations,
such as flavors like cocoa or menthol.
II.e. Drug expectancy
Drug expectancy plays an important role in smoker response
(Darredeau and Barrett
2010; Juliano et al. 2011; Perkins et al. 2008; Perkins et al. 2004), particularly in women
(Perkins et al. 2006). According to expectancy theory, a smoker will experience urge
reduction in response to smoking a placebo cigarette, if the smoker has the stimulus (or
dose) expectancy that he or she is smoking an active nicotine cigarette and has the
response expectancy that nicotine reduces urges to smoke
(Kirsch and Lynn 1999;
Perkins et al. 2003). The expectation that an individual is receiving nicotine increases
the likeability and clinical efficacy of nicotine replacement products, and this expectation
interacts with pharmacological factors to produce overall subjective and behavioral
responses
(Darredeau and Barrett 2010; Hughes et al. 1989; Perkins et al. 2009a).
In a balanced placebo design, smokers who expect smoking to relieve negative affect
(following an anxious mood induction) experience improved mood, even when they
smoke a placebo cigarette
(Juliano and Brandon 2002). Telling smokers they are
smoking nicotine attenuates urge to smoke in the context of smoking a placebo
cigarette, but has little effect in the context of nicotine administration, indicating that
either nicotine or the belief that one is smoking a nicotine cigarette is sufficient to
attenuate smoking urges, but that dose expectancies are not additive with the effects of
nicotine
(Juliano et al. 2011).
Drug expectancy may be informed by sensory stimuli that indicate to a smoker the
likelihood of a given nicotine dose through conditioned associations. These cues may
be articulated by the smoker as “strength” of the cigarette and reflect some combination
of the nicotine-derived impact and other smoke compounds that interact with oral,
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trigeminal, or other receptors
(Megerdichian et al. 2007; Wayne and Carpenter 2009;
Wayne et al. 2004).
Expectancy effects are also separable from nonpharmacological stimuli. For example,
the same denicotinized cigarettes smoked under different dose expectancy sets
produce different effects
(Darredeau et al. 2013). Nicotine content information plays a
role in smokers' subjective responses to nicotine inhalers, particularly with respect to
craving associated with positive reinforcement (i.e., intention to smoke) though not on
craving associated with negative reinforcement (i.e., withdrawal relief)
(Darredeau and
Barrett 2010; Perkins et al. 2009b). Although smokers have expectancies for
pleasurable effects from smoking, they show reduced expectancy of positive effects
from less familiar formulations
(Perkins et al. 2003).
II.f. Social/ contextual factors
Dependence is not limited to the physiological experience of nicotine exposure, but also
shaped by acquisition practices and consumption behaviors that are product specific,
and set within unique cultural contexts. The social context of tobacco use is clearly
relevant to understand patterns of use of various tobacco products, as is the extent of
external pressure to abstain or qu
it. De Leon et al. (2013) identify the need for tobacco
use measures which account for contextual factors that help to determine smoking
behaviors and dependence. These would include: where it is permissible to use
tobacco products (both legally and in terms of social norms); the cost of tobacco use
both individually and to one's family; and, how stigmatized tobacco use is among
subpopulations (eg, with respect to gender, religious affiliation, and social status).
These factors may prove particularly useful in understanding the process of
experimentation with tobacco prior to transitioning to tobacco dependence, the
processes that lead to the choice to quit, and quitting outcomes.
II.g. Summary of findings on tobacco addictiveness
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1) Tobacco addiction is maintained by nicotine. Cigarettes that do not deliver
nicotine do not sustain addiction.
2) Nicotine addiction is supported both by positive reinforcements (e.g. mood,
performance) and the avoidance of withdrawal symptoms.
3) There is considerable individual variability in response to nicotine. Women differ
from men in metabolism of nicotine and are more responsive to conditioned
cues.
4) Nicotine dependence initiated in adolescence has implications for dependence in
adulthood.
5) Nicotine delivered by tobacco smoke is distinct from other forms of nicotine.
6) Key factors in the determination of addictiveness of tobacco delivered nicotine
include the form of nicotine, ease of inhalation, related sensory stimulus, and the
potential addictive or reinforcing effects of other smoke compounds.
7) Denicotinized tobacco is more successful at reducing craving and producing
pleasure in smokers than nicotine without tobacco.
8) The weight of evidence supports the dual-reinforcement model of addiction, in
which the conditioned stimulus (tobacco smoke) strengthens dependence
beyond that produced by unconditioned nicotine.
9) Drug expectancy alters response to nicotine and non-nicotine cigarettes.
Expectancy may reflect cues housed within the delivery mechanism (sensory
stimuli) as well as information received through advertising, packaging, or other
communication.
10) Development of dependence is informed by social context and environmental
factors that determine product access and appeal.
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III.
Establishing a threshold for addiction
The concept of a nicotine addiction threshold implies that there is a minimum amount of
nicotine intake required for acquisition and maintenance of nicotine addiction. In their
original proposal,
Benowitz and Henningfield (1994) proposed 5 mg/day (associated
with plasma cotinine levels of approximately 50-70 ng/ml/day) as an estimate of the
addiction threshold for nicotine. This estimate was based on observational data from
experienced smokers, rather than empirical studies that manipulated nicotine exposure,
and was intended primarily as a starting point for more critical research and discussion.
Since this initial proposal, the widespread clinical availability of denicotinized cigarettes
has led to a significant body of research exploring the effects of reduced nicotine
exposure on smoking behaviors and subjective measures
(Hatsukami et al. 2007;
Hatsukami et al. 2010b). At the same time, growing interest has led to a range of animal
studies on nicotine self-administration and related behaviors
(Caggiula et al. 2009;
Donny et al. 2012; Palmatier et al. 2012; Smith et al. 2013). These studies provide
insight regarding the potential reinforcing effects of cigarettes at extremely low levels of
nicotine.
III.a. Nicotine self-administration
Henningfield and colleagues
(Henningfield and Goldberg 1983; Henningfield et al. 1983)
conducted early studies of intravenous (IV) nicotine self-administration by smokers.
Although nicotine responses tended to be more regularly spaced than responses to
saline, the overall response rates for nicotine did not reliably exceed those for saline.
Therefore, the evidence for nicotine serving as a reinforcer was unclear. In a 2004
study, IV nicotine (.75, 1.5, and 3 mg/injection) and saline were available concurrently
for abstinent male cigarette smokers during 3-hour sessions. Smokers preferred
nicotine injections compared with saline administration for all 3 nicotine doses
(Harvey
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et al. 2004). These doses were higher than the usual nicotine intake of a smoker, which
is on average 1–2 cigarettes/hour or 1–4 mg nicotine/hour
(Benowitz and Jacob 1990).
A more recent study examined self-administration of nicotine using doses within the
range of average intake by smokers
(Sofuoglu et al. 2008). A choice procedure was
used in which male and female smokers were able to select among various IV nicotine
doses (0.1, 0.4, 0.7 mg) or saline, where the 0.1 mg dose represented approximately
half the amount of nicotine inhaled from a typical cigarette puff. Both the 0.4 and 0.7
mg, but not the 0.1 mg, doses were preferred over placebo. These findings provide a
preliminary estimate for the reinforcing threshold of nicotine in smokers as between 0.1
and 0.4 mg.
The findings are consistent with research on discrimination, which indicates that
threshold levels for nicotine discrimination are well below the typical nicotine delivery of
most cigarette brands, and does not differ between smokers and non-smokers, with
median thresholds of 3 μg/kg vs 2 μg/kg, respectively (i.e. around .23 and .15 mg)
(Perkins et al. 2001b). However, as noted by
Hatsukami et al. (2010b), a more than
hundred fold variability of nicotine discrimination is reported among individuals.
Animal studies of nicotine self-administration are more numerous than human studies
and support similar conclusions with respect to a nicotine threshold.
Smith et al. (2013)
reported significant decreases in nicotine self-administration among rats when nicotine
dose was reduced to 3.75 µg/kg/infusion or below. In contrast, doses at or above 7.5
µg/kg/infusion produced similar or greater rates of self-administration relative to
maintenance at 60 µg/kg. In this study nicotine was administered alongside a cocktail
of other tobacco constituents, in order to more accurately mirror the effects of tobacco
use.
Donny et al. (2012) examined dose–response curves across a range of studies both for
acquisition and maintenance of nicotine self-administration. They placed the peak of
the acquisition curve at around 20–30 µg/kg, with similar results observed over several
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Nicotine reduction
17
species, including rats, dogs, monkeys, and humans
(Harvey et al. 2004; Matta et al.
2007). At lower unit doses (3.75–10 µg/kg) mean response rates increased with dose,
showing considerable individual variability in response rates in this range, and a lower
proportion of subjects acquiring nicotine self-administration compared to saline control
(Cox et al. 1984; Shram et al. 2008b).
During maintenance of nicotine self-administration, the peak of the dose-response curve
was typically found between 10–30 µg/kg
(Brower et al. 2002; Corrigall and Coen 1989;
DeNoble and Mele 2006; Donny et al. 1995; Shoaib et al. 1997; Watkins et al. 1999).
Again, nicotine self-administration decreased and variability increased when unit doses
less than 10 µg/kg were substituted. The authors observed that the threshold reinforcing
dose at the low end of the dose range was rarely determined. However, doses as low
as 3 µg/kg have been shown to maintain nicotine self-administration rates above those
for saline in both limited and extended access studies
(Brower et al. 2002; Corrigall and
Coen 1989; Cox et al. 1984; Shoaib et al. 1997; Watkins et al. 1999).
The findings suggest that a nicotine reinforcement threshold for maintenance of nicotine
self-administration in adult animals might lie between 3 and 7.5 μg/kg nicotine (0.23 and
.56 mg), consistent with although marginally higher than those indicated by human
studies. However, the number and range of doses has been small in most studies,
limiting accuracy. Moreover, some studies manipulated doses between subjects, which
would not be analogous to the within-subject change in doses that would occur following
the implementation of a nicotine reduction policy
(Donny et al. 2012)
Research conducted on nicotine self-administration has relied for the most part on rapid
infusions of high unit doses of nicotine (15-30 µg/kg/infusion
). Sorge and Clarke (2009)
compared self-administration of nicotine in rats across a range of infusion durations (3,
30, 60, and 120 s) and found that slow infusions were preferred over fast infusions, and
were self-administered at doses as low as 3 µg/kg. Their findings demonstrated that
slower self-administration procedure differed pharmacologically from the traditional
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procedure, and suggest that administration parameters (i.e. time course of dose
delivery) could play a critical role in determining a nicotine reinforcement threshold.
III.b. Acquisition of nicotine dependence
The dose of nicotine necessary for maintenance of smoking may differ from that needed
for acquisition of dependence
(Hatsukami et al. 2013a). Despite a lack of available data
directly addressing the question,
Donny et al. (2012) conclude based on cross-study
comparison that the threshold for maintenance is likely lower than that for acquisition.
This conclusion would be consistent with the observation that pre-exposure to nicotine
can increase acquisition of nicotine self-administration
(Adriani et al. 2003; Hanson et
al. 1979; Shoaib et al. 1997).
Acquisition of dependence among adolescents may present a different case to that of
acquisition among adults. As noted previously, adolescent rats and mice appear to be
more vulnerable than adults to the reinforcing effects of nicotine
(Kota et al. 2008; Kota
et al. 2007; Vastola et al. 2002), demonstrating faster acquisition of nicotine self-
administration and higher baseline rates compared to adults
(Adriani et al. 2002; Chen
et al. 2007; Levin et al. 2007; Levin et al. 2003). However, conflicting evidence suggests
that adult male rats are more likely than rats in early adolescence to acquire nicotine
self-administration at a low dose of nicotine
(Shram et al. 2008a; Shram et al. 2008b;
Shram et al. 2008c).
Cross-sectional and longitudinal studies indicate that youth who smoke on a less than
daily basis report onset of dependence symptoms
(Caraballo et al. 2009; DiFranza et al.
2007b; DiFranza et al. 2002; Gervais et al. 2006; Kandel et al. 2007; O'Loughlin et al.
2003) In behavioral studies, adolescent smokers appear to self-administer
physiologically active doses of nicotine, despite lower volume puffs relative to adults
(Aung et al. 2004; Corrigall et al. 2001; Kassel et al. 2007b; Wood et al. 2004).
Expectancies play a significant role in smoking behavior and motivations to smoke
among adolescents. Specifically, stronger expectancies about the ability of cigarettes to
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19
reduce negative affect predict smoking escalation, though as expectancies become
stronger with increased smoking experience, their effect stabilizes
(Heinz et al. 2010;
Wahl et al. 2005).
In a study comparing high yield vs. denicotinized cigarettes, smoking resulted in a
reduction of negative affect regardless of the nicotine content of the cigarette smoked.
This effect was moderated by affect-related expectancies, such that participants who
smoked a high-yield cigarette and held strong expectancies for smoking to alleviate
negative affect experienced the greatest reductions in negative affect. No change in
affect was measured among nonsmoking adolescents
(Kassel et al. 2007a).
Importantly, onset of smoking and subsequent exposure to nicotine at adolescence,
even at levels below that of daily reinforcement, may serve to lower the threshold for
nicotine dependence in adulthood, despite highly attenuated rewarding or reinforcing
effects
(Breslau and Peterson 1996; Chen et al. 2007; Cui et al. 2006).
III.c. Reinforcing effects of low nicotine cigarettes
Evidence from clinical studies demonstrates that denicotinized tobacco can provide a
significant degree of subjective satisfaction and immediate craving reduction
(Baldinger
et al. 1995; Barrett 2010; Buchhalter et al. 2001; Butschky et al. 1995; Donny et al.
2007; Gross et al. 1997; Pickworth et al. 1999; Rose et al. 2000; Westman et al. 1996)
although ratings may be reliant on smokers level of dependence
(Brauer et al. 2001) .
Craving suppression appears to be a particularly robust effect that is less sensitive to
extinction procedures
(Donny et al. 2007). Nicotine-containing and denicotinized smoke
suppress craving and ad-libitum smoking equally; by contrast, IV nicotine has only a
small effect in suppressing ad libitum smoking
(Dallery et al. 2003; Rose et al. 2003).
Low levels of nicotine present in denicotinized cigarettes may be sufficient to maintain
smoking behavior. Brain imaging studies show that smoking a single very low nicotine
cigarette results in significant (23%) occupancy of α4β2 nicotinic receptors, which are
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20
considered the primary receptor subtype mediating nicotine's reinforcing and other
behavioral effects
(Brody et al. 2009). The effects of nicotine at low levels may be
further reinforced by non-nicotine aspects of tobacco. In a 2010 study, use of
denicotinized tobacco was associated with increased feelings of relaxation relative to
nicotine, suggesting that non-nicotine factors may be partially or even largely
responsible for the calming effects of tobacco smoking
(Barrett 2010).
Other processes may exist whereby dependency on cigarettes could be generated even
with extremely low intake of nicotine, for example, through receptor desensitization,
which can occur with chronic exposure to even very low levels of nicotine
(Grady et al.
1994) Desensitization of receptors mediates nicotine's acute reinforcing effects
(Lu et al.
1999; Picciotto et al. 2008).
Environment is also likely to play a role in smoker behavior. For example
, Donny and
Jones (2009) found that denicotinized cigarettes maintained their reinforcing properties
throughout a 9-day outpatient assessment period, whereas in a similar inpatient study
(Donny et al., 2007), both motivation to smoke and number of denicotinized cigarettes
smoked declined somewhat over time. They hypothesized that extinction may proceed
more slowly in a naturalistic setting, possibly because of the presence of numerous
stimuli associated with smoking
(Bouton 2004).
III.d. Addiction threshold versus reinforcement threshold
There are no universally accepted definitions of nicotine or tobacco addiction. The
World Health Organization defines drug dependence in terms of compulsion, that is, a
behavioral pattern in which use of the drug is given priority over other behaviors to an
extent that is considered detrimental to the individual or to others
(World Health
Organization 1992.). The 1988 Surgeon General report The Health Consequences of
Smoking: Nicotine Addiction
(USDHHS 1988) adds to the requirement of compulsion
that the drug produce psychoactive effects, and that the drug-taking behavior be clearly
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21
reinforced by the effects of the drug. Although these additional criteria are exhibited in
most cigarette smokers, they are not universal in all smokers
(Benowitz 2008)
Diagnostic criteria widely used for identification of nicotine addiction include the DSM-IV
scale, which was developed to assess general drug dependence, and the Fagerström
Test of Nicotine Dependence (FTND), used to assess tolerance and severity of
dependence. A number of concerns have been raised regarding the validity of these
instruments as measures of addiction. The scales correlate poorly with each other, and
neither has consistently predicted other indices of smoking behavior or treatment
outcomes of smokers
(Hendricks et al. 2008; Hughes et al. 2011; Hughes et al. 2004;
Moolchan et al. 2002). These scales may also be insensitive to assessing smokers who
are in the early stages of nicotine use, having been developed and validated in adult
end-stage smokers
(Colby et al. 2000; Rose and Dierker 2010).
DiFranza et al. (2010a) argue that diagnostic criteria for addiction should, at the very
least, be able to differentiate between individuals who are and are not able to abstain
when they decide they want to do so. The authors propose self-assessment of addiction
as the gold standard, noting that self-assessed addiction correlates very highly with self-
rated difficulty quitting (r = .89), and correlates better than the DSM-IV with cigarettes
smoked per day and time to the first morning cigarette
(Hughes et al. 2004). Self-
assessment may also prove more adept at identifying emerging dependence in children
than other diagnostic measures. In one study
(Rubinstein et al. 2011) adolescent self-
assessment of addiction predicted neurophysiological responses to smoking more
successfully than the FTND.
Sofuoglu and LeSage (2012) have identified the lack of a consensus on valid methods
for assessment of nicotine addiction as a significant challenge to nicotine reduction
strategies. The authors propose that the concept of a reinforcement threshold, while at
times used interchangeably with addiction threshold, is not synonymous, and may be
preferable as a policy basis for establishing a threshold level for nicotine. The
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Nicotine reduction
22
reinforcement threshold would be defined as the lowest nicotine dose that would
increase or maintain nicotine self-administration behaviors (i.e. tobacco use).
The authors identify a number of practical advantages. First, the nicotine reinforcement
threshold is more clearly defined and easier to measure than an addiction threshold. A
drug is considered to be reinforcing if it is self-administered to a greater extent than a
vehicle or placebo
(Audrain-McGovern et al. 2009). Second, because dependence
does not occur if a drug is not reinforcing, the nicotine reinforcement threshold is likely
to be lower than the nicotine addiction threshold and may be a more sensitive index for
predicting tobacco use below the threshold for addiction
(Audrain-McGovern et al. 2009;
Glautier 2004).Third, measures of the reinforcement threshold can be accomplished
with short-term studies examining self-administration both in humans and non-humans,
and may be easily adapted to assess individual differences (e.g., age, sex, genetic
factors) and environmental factors (e.g., stress, peer influence)
(Comer et al. 2008).
III.e. Threshold for conditioned stimulus
Given the importance of conditioned stimuli in reinforcing smoking behavior, and the
primary role of nicotine in enhancing salience, it may be useful to consider whether a
separate nicotine threshold exists for the acquisition of reinforcing properties in non-
nicotine stimuli.
Rats trained on a 0.4 mg/kg nicotine dose readily acquire conditioned responding for an
unconditioned reward
(Besheer et al. 2004; Bevins and Palmatier 2004; Wilkinson et al.
2006) Separate groups assigned to 0.1, 0.2, or 0.4 mg/kg nicotine training dose all show
similar acquisition of conditioned responding, though the higher nicotine groups show
greater resistance to extinction
(Murray and Bevins 2007). The similar acquisition rate
across groups might suggest that 0.1 mg/kg nicotine is as salient as the higher nicotine
doses. A non-salience explanation involves the rich schedule of sucrose deliveries in
nicotine sessions; that is, less nicotine was necessary to prompt conditioned responding
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Nicotine reduction
23
due to the high number of nicotine-sucrose pairings
(Besheer et al. 2004; Wilkinson et
al. 2006).
Palmatier et al. (2008) compared the effects of a lower (0.03 mg/kg) and higher nicotine
dose (0.09 mg/kg), reasoning that the new conditioned properties of an associated
stimulus should be based in part on the strength or intensity of the primary reinforcer.
They concluded that the conditional reinforcing properties acquired by the stimulus were
a direct function of increased dose.
This implies that stimulus control of tobacco seeking behavior will be most potent in
subjects exposed to high levels of nicotine, and are likely to be much reduced in the
context of very low nicotine. However, the strength of conditional stimuli will also be
driven by how frequently the stimuli is paired with nicotine, how correlated with nicotine,
and how closely related in time and space. Thus, as suggested in the earlier studies
(Murray and Bevins 2007), given enough pairings, even a nicotine dose that would
otherwise have been a weaker conditional stimulus could come to be a strong
conditioned exciter.
III.f. Summary of findings on threshold for addiction
1) Threshold reinforcement studies show strong agreement across both animals
and humans. Taken together, these studies provide a preliminary estimate for
the reinforcing threshold for nicotine of between 0.1 and 0.5 mg.
2) The threshold for reinforcement is lower when using a self-administration
mechanism that more accurately models cigarette nicotine delivery.
3) The threshold for discrimination of nicotine in humans is approximately 0.2 mg,
though there is high individual variability.
4) Among adults, the threshold for maintenance appears to be lower than the
threshold for acquisition of reinforcing behavior.
5) Acquisition of nicotine use among adolescents may differ from adults.
Adolescent smokers have low daily rates of cigarette use, but appear to self-
Nicotine reduction
24
administer physiologically active doses of nicotine. Expectations of negative
affect reduction are a primary motivation for smoking among adolescents.
6) Denicotinized cigarettes (with nicotine yields of 0.05-0.1 mg) can provide a
significant degree of subjective satisfaction and immediate craving reduction.
7) Low levels of nicotine present in denicotinized cigarettes may be sufficient to
maintain smoking behavior. Alternately, responses to denicotinized cigarettes
may reflect conditioned reinforcing effects, or imply that some non-nicotine
constituents demonstrate primary effects.
8) The goal of reducing nicotine below the threshold for addiction relies to a
significant degree on a reliable measure of addiction. There is no readily
accepted measure of addiction applicable to the establishment of a nicotine
threshold. Common measures of dependence do not apply to all smokers and
may fail to capture adolescent smoking.
9) Among the alternate definitions proposed are self-assessment of addiction
(DiFranza) and the reinforcement threshold (Sofuoglu and LeSage).
10) A high nicotine dose provides a stronger conditioned reinforcing effect; however,
even a weak nicotine dose may be sufficient for conditioned reinforcement,
particularly in the context of many highly correlated pairings (as in the case of
long-term smoking).
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Nicotine reduction
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IV.
Feasibility of nicotine reduction
Most studies examining the behavioral effects of nicotine reduction have relied on
commercially available low-nicotine products, including so-called denicotinized
cigarettes such as Quest. These studies provide valuable insight into the behavioral
responses of smokers. However, they do not necessarily reflect the market of
commercial products that are likely to be available within the context of mandated
nicotine reduction.
Internal tobacco industry documents, although potentially less reliable than published
clinical studies, may provide insight into the commercial manipulation of cigarette-
delivered nicotine and the range of product approaches that are likely to be employed
by tobacco manufacturers
(Panzano et al. 2010; Wayne and Carpenter 2009).
IV.a. Cigarette nicotine delivery
Tobacco manufacturers have used brain imaging to determine effective ranges of
cigarette nicotine delivery under controlled smoking conditions
(Panzano et al. 2010). A
study comparing a no nicotine, low nicotine (0.14 mg) and high nicotine (1.34 mg)
delivery cigarette observed statistically significant amplitude decreases only in the high
nicotine condition (p<0.05)
(Gullotta 1981). A similar study compared six styles of
cigarettes ranging from .12 mg to 1.1 mg of nicotine. The electrophysiological effect of
smoking the 0.12 mg cigarette was indistinguishable from a nicotine-free cigarette, while
the cigarettes of 0.21 mg or greater demonstrated measurable effects
(Gullotta 1990).
A theoretical best-fit curve relating latency of measured brain response to cigarette-
delivered nicotine indicated that latency decrease, as a function of nicotine
concentration, was largest up to 0.4 mg per cigarette, and that no further latency shifts
occurred beyond approximately 1.4 mg per cigarette. This implies that reductions in
smoke nicotine at and below the 0.4 mg level are likely to have the greatest overall
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Nicotine reduction
26
impact on smoker behaviors
(Gullotta 1982). Latency effects during controlled versus
ad-lib smoking were compared using commercial cigarettes ranging in delivery from
0.11 to 1.04 mg nicotine/cig. Smokers were able to achieve measured CNS effects
comparable to that of full flavor cigarettes through compensation even with the lowest
(0.11 mg) nicotine delivery
(Gullotta 1982).
A study examined whether the effects of a higher nicotine delivery cigarette (0.9 mg)
could be replicated by having subjects smoke three lower delivery cigarettes (0.3 mg
nicotine). Latency effects were successfully mimicked by the three low delivery
cigarettes, whereas the amplitude effects required a single, relatively large intake of
nicotine over a short time interval. When three 0.1 mg nicotine cigarettes were
compared to a single 0.3 mg cigarette, the latency effects were no longer similar
(p<0.05). The authors concluded that the neurophysiological effects of nicotine exhibit
“a threshold […] somewhere between 0.1 and 0.3 mg”’-- a result consistent with findings
described in
section III.a (Gullotta 1982).
IV.b. Methods for reducing nicotine in tobacco
Concentration of nicotine in tobacco is a significant correlate to smoke nicotine yield
(Connolly et al. 2007), and can be readily altered and controlled by manufacturers
(Dunsby and Bero 2004; Hurt and Robertson 1998; Slade et al. 1995; Wayne and
Carpenter 2009).
Tobacco types, grades, and stalk positions can produce significant variations in nicotine
concentration. Blending of different tobaccos enables manufacturers to balance
tobacco characteristics as well as to adjust for natural variations in tobacco nicotine
content in order to meet production standards for specific brands and styles
(British
American Tobacco 1972). Differences of a factor of 10 are possible across tobacco
types, and factors of 5 or 6 are common (e.g. 1% nicotine content by weight oriental
tobacco, compared with 5% by weight in burley tobaccos)
(British American Tobacco
1969). Product differences driven by tobacco selection are not limited to nicotine but
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Nicotine reduction
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include sugar and ammonia content, aroma and taste characteristics, and relative
harshness and irritation
(British American Tobacco 1969; Browne 1990).
Extremely high and low nicotine strains of tobacco were developed for research
purposes with the assistance of public research agencies in both the U.S. and Canada
(Cohen 1971; Gibb 1974; Johnson 1977; Kentucky Tobacco Research Board 1977). In
one example, Brown & Williamson compared 3 strains of burley that contained
approximately 1/20, 1⁄2, and 9/10 of normal levels of nicotine, demonstrating that
nicotine in the smoke was proportional to nicotine in tobacco
(Smith 1972). In other
cases, microbial bacteria were used to actively degrade nicotine while leaving other
components of leaf intact
(Geiss 1972; Geiss 1975). Acceptability of tobacco derived
from this process was equal to that of untreated tobacco
(Gravely 1973).
The earliest tobacco processing involved steam extraction of burley tobacco and stems
to reduce the irritation commonly associated with their high nicotine content. Later,
ammonia or similar compounds were incorporated into the extraction process
(Rickett
1980; York 1977) Treatment of tobacco disassociates the nicotine salts naturally
present in tobacco into free nicotine and the free acid. In the case of heat or steam
treatment, the free nicotine is driven from the tobacco
(Ashburn 1961). In other cases
the treatment enables free nicotine to be more easily extracted by means of a solvent
(such as freon), after which the denicotinized extract may or may not be returned.
Extraction processes can support significant reductions in smoke nicotine delivery, while
also demonstrating significant effects on subjective or sensory characteristics of smoke
(Green 1979).
Research conducted by Philip Morris on nicotine reduction prior to development of the
denicotinized brand Next included genetic modification, enzymatic processes, and
nicotine extracted tobacco
(Dunsby and Bero 2004). While none completely eliminated
nicotine, reductions were achieved in the range of 80–98%. Quest cigarettes, produced
by Vector Tobacco beginning in 2003, were produced from genetically modified
tobacco.
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IV.c. Denicotinized or reduced nicotine cigarettes
Although in principle it should be possible to make tobacco cigarettes that are
completely free of nicotine, in most cases the term “denicotinized” indicates tobacco
with low nicotine concentration. Generally these cigarettes contain 1 mg nicotine or
less, and when smoked on a standard smoking machine, produced nicotine yields
(0.05-0.1 mg) equivalent to approximately 5% to 10% of the nicotine yield of standard
commercial brands
(Benowitz and Henningfield 2013).
The main technical challenge of the denicotinized cigarette is not reducing nicotine but
maintaining smoke sensory characteristics and appeal. The earliest nicotine extracted
tobaccos, relying on techniques such as solvent or steam extraction, were perceived as
“stinging” and “numbing” with extremely low acceptability regardless of tobacco type
and despite use of flavorings
(Kassman 1986). The differences were not simply due to
lack of nicotine, since adding back extracted nicotine in test cigarettes did not restore
the cigarettes to the taste of unextracted cigarettes. Analysis identified other tobacco
materials that were removed incidentally in the extraction process, including waxes,
heavy hydrocarbons, and essential oils, which when added back after extraction
improved subjectives. These findings underscored the importance of elements other
than nicotine to product acceptance
(Kassman 1986; Philip Morris 1995a).
For the brand Next, Philip Morris employed the supercritical extraction technique used
to decaffeinate coffee as a means to remove nicotine from tobacco
(Dunsby and Bero
2004). Despite ongoing efforts to improve selectivity and limit the underlying effects of
extraction, the process altered taste characteristics of the tobacco, leading to
exploration of many post-extraction flavoring and casing systems
(Houghton 1990). The
most successful were menthol-based prototypes that covered much of the unusual taste
while also providing some of the impact lost through the removal of nicotine
(Ferris
Wayne and Connolly 2004; Gullotta 1991).
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An extended test of the Next prototype conducted among an internal expert panel found
that although extracted cigarettes could be appealing initially, continued smoking
through a pack of extracted cigarettes led to increasingly poor acceptability ratings.
When nicotine was added back to the extracted cigarette the level of acceptability did
not fall over time
(Philip Morris 1995b). Alternately, a consumer study conducted among
interested smokers found liking ratings for the extracted cigarette improved over time
within a cohort of highly motivated smokers, indicating that smokers may be able to
adjust expectations under some conditions
(Philip Morris 1995a).
IV.d. Free-base nicotine in low delivery cigarettes
Pankow (2001) and others
(Ferris Wayne et al. 2006; Henningfield et al. 2004a) have
identified the fraction of free-base nicotine in tobacco smoke as critical both to the rate
of transfer of nicotine from tobacco to smoke and from smoke to nicotine receptors in
the back of the throat and lungs. Standard measures of smoke nicotine delivery do not
differentiate between forms of nicotine
(Ashley et al. 2009) However, internal industry
documents suggest that comparisons of free-base nicotine delivery may provide a more
accurate measure of subjective response to products, particularly in low yield brands
(Ferris Wayne et al., 2006; Wayne and Carpenter, 2009).
Products which appear to differ significantly by total smoke nicotine can resemble each
other in terms of free nicotine delivery. Brown & Williamson compared smoke yields of
Marlboro (1.15 mg nicotine) and the high impact, low yield product Merit (0.64 mg) and
found essentially the same free nicotine (~0.3 mg) from each brand. The authors
concluded that a person smoking both products would have difficulty differentiating
between them physiologically
(Gregory 1980). Similarly, although Marlboro had less
smoke nicotine than Winston, it had a higher level of weaker bases, such as pyrazines.
These weaker bases “accounted for the pH being slightly higher” of Marlboro –
supporting equivalent levels of volatile or “free” nicotine – despite the fact that nicotine
was not as high
(Shannon; Dube; Walker; Reynolds 1992)
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Limited published measures of free-base nicotine in cigarette smoke suggest that
differences in commercial brands differ from those identified by standard smoking
protocols
(Pankow et al. 2003; Watson et al. 2004) Ranges of free-base nicotine are
similar across nicotine delivery categories of full-flavored, light, and ultralight cigarette
brands. The degree of filter ventilation increases the proportion of free-base nicotine in
mainstream smoke, suggesting that, even without compensatory behavior, a ventilated
cigarette will deliver a greater proportion of total nicotine in free-base form
(Watson et
al. 2004).
IV.e. Products that support compensatory smoking
Smokers will adjust their smoking behavior when switched from regular to light (or low-
yield) cigarettes so as to maintain their desired nicotine intake
(Baldinger et al. 1995;
Benowitz et al. 2005; National Cancer Institute 2001). Unlike conventional low-yield
cigarettes, reduced nicotine cigarettes do not rely on ventilation for reduced smoke
yields, and do not appear to support compensation as easily
(Benowitz et al. 2007;
Hatsukami et al. 2010a; Rose and Behm 2004a).
Rose and Behm (2004a) compared
smoking of a cigarette with smoke yields of .2 mg nicotine/ 14 mg tar to a commercial,
highly ventilated low-yield cigarette (.2 mg nicotine/ 1 mg tar) in a single session ad-lib
crossover study, finding substantial compensation for the commercial low-nicotine
cigarette but no appreciable compensation with the low–nicotine content cigarette.
Benowitz et al. (2006a) compared smoking behavior versus usual brand for cigarettes
with adjusted nicotine content ranging from 1 to 12 mg nicotine. The study found strong
compensatory behavior for cigarettes with moderate levels of nicotine, but minimal
compensation and significant reduction in nicotine exposure for cigarettes with 1, 2 and
4 mg nicotine (0.1, 0.2, 0.3 mg nicotine yields). The lowest nicotine cigarette had an
average nicotine intake of .26 mg, compared to 1.47 mg nicotine for usual brand. A
longer term study using the same range of nicotine content (1 to 12 mg), but decreased
at monthly intervals over six months found similar results, with a high level of
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compensation for the 12 mg cigarette, but only a small degree of compensation at the
lowest nicotine content levels
(Benowitz et al. 2012).
Hatsukami et al. (2010a) assigned smokers to either 0.3 mg nicotine yield cigarettes,
0.05 mg nicotine yield cigarettes, or 4 mg nicotine lozenges in a six-week switching
study. Among those smoking 0.3 mg cigarettes, the number of cigarettes smoked per
day increased significantly at each of the first 5 weeks of treatment compared to usual
brand, while among those assigned 0.05 mg cigarettes, number of cigarettes smoked
per day (relative to baseline) decreased significantly.
These studies suggest that for cigarettes with reduced nicotine content, there may be a
threshold below which compensation is less likely to occur. This threshold appears to
be in the range of approximately 0.05- 0.1 mg smoke nicotine yield. At less extreme
levels of reduced nicotine (0.2-0.3 mg), compensatory behaviors are significantly
increased.
A similar threshold may exist for commercial, ventilated low yield cigarettes. In a ten
week progressive tapering study using commercially available cigarettes,
Benowitz et
al. (2009) found that forced switching from regular cigarettes to popular low yield
cigarettes with machine-determined yields of ≥0.6 mg nicotine resulted in complete or
nearly complete compensation, with no reduction in exposure to nicotine or tobacco
smoke toxins. When switched to ultralow yield cigarettes in the 0.1 to 0.2 mg nicotine
yield range, exposure to nicotine and tobacco smoke toxins were substantially though
not entirely decreased (about 40%, versus a 90% reduction in nominal yields).
IV.f. Product formulation and approaches to nicotine reduction
Formulation differences play a key role in product abuse liability and in determination of
a threshold for reinforcement. For example, oral smokeless tobacco products appear to
support somewhat lower risk of addiction than cigarettes
(Hatsukami et al. 2004;
Henningfield et al. 1997), and the risk of developing addiction to nicotine replacement
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Nicotine reduction
32
medications appears to be small
(Henningfield et al. 2009; USDHHS 1988) even though
the absolute nicotine delivery may not differ. Currently, most manufactured cigarettes
contain 10–15 mg of nicotine per cigarette, of which approximately 10% is delivered in
smoke. This supports a typical systemic intake of 1–2 mg of nicotine per cigarette
(Benowitz and Henningfield 2013). A threshold level for nicotine set at the low range of
0.1-0.2 mg per cigarette would on its face require an overall reduction in nicotine intake
on the order of 90%.
Various approaches could be considered to achieve such a reduction. A decrease in
the nicotine concentration in tobacco could be used to limit total nicotine content per
cigarette to a level at or below the intake threshold. This approach would ensure per
cigarette nicotine consumption remained below the stated threshold regardless of
behavioral changes by the smoker (i.e. increased frequency or volume puffs) or
manipulation of the form of nicotine delivery, although it would not prevent an increase
in number of cigarettes smoked as a means of obtaining more nicotine. Construction of
such a cigarette would pose a likely technical challenge, as it would require a reduction
in tobacco nicotine content approximately ten times that found in the commercial
denicotinized brands Next and Quest. This reduction would likely result in significant
changes in the sensory or taste profiles of the tobacco. No studies have been
conducted on the likely behavioral effects of cigarettes constructed at this range of
nicotine content.
Alternately, a reduction in nicotine concentration of tobacco could be used to limit
nicotine content to a level such that machine measured smoke yields are likely to
remain at or below the nicotine threshold. This approach would more closely resemble
the commercial products Next and Quest, with smoke nicotine yields of less than 0.1 mg
and total nicotine content of tobacco less than 1 mg. The development of saleable
brands at this range of nicotine provides strong evidence of the technical feasibility of
this approach. The majority of behavioral research on nicotine reduction has been
conducted with cigarettes in this range of nicotine.
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33
A third alternative would to meet a threshold for smoke nicotine yields through product
parameters other than reduced nicotine concentration, or in combination with reduced
nicotine tobacco. This approach could include extreme levels of filter ventilation, high
levels of expanded tobacco, and reduced tobacco content. Again, the technical
feasibility of this approach has been demonstrated commercially, at the extreme ends of
the ultralight category, i.e. those with approximately .1 mg nicotine/1 mg tar yields under
machine smoking conditions. Cigarettes following this approach would likely maintain
nicotine/tar levels similar to or greater than that of current commercial cigarettes, in
contrast to cigarettes with reduced nicotine concentration that would produce smoke
with extremely low nicotine/tar ratios. They would potentially support high levels of
compensation, through behavioral manipulation such as covering vent holes and
altering puffing behavior.
With any of the alternatives outlined above, physical or chemical parameters of cigarette
construction could be manipulated to alter the basic formulation of the cigarette. For
example, new filters could be employed to alter the form of nicotine (through use of an
acid or base) or to change the size distribution of aerosol particles that determine
deposition and absorption of nicotine and other constituents
(Wayne and Carpenter
2009; Wayne et al. 2004; Wayne et al. 2008). Chemical factors such as tobacco
processing, use of additives, or construction parameters including length, width,
moisture, and packing density could be used to alter combustion or pyrolysis conditions,
to change the balance of smoke composition and sensory characteristics, or introduce
new compounds with unique behavioral or sensory effects or that interact with or alter
nicotine
(Carpenter et al. 2007; Megerdichian et al. 2007; Wayne and Carpenter 2009).
Thus, regardless of approach, considerable attention must be paid to product factors
other than nicotine delivery.
IV.g. Summary of findings on feasibility of nicotine reduction
Nicotine reduction
34
1) Cigarettes may be pharmacologically active above a certain threshold of smoke
nicotine yield, whereas below this threshold (somewhere between 0.1 and 0.3
mg) they are no longer as effective.
2) A single intake of nicotine from a single cigarette over a short time period is more
effective than a series of smaller intakes across many cigarettes, particularly at
lower levels of nicotine.
3) Reduction of the total nicotine concentration of tobacco is a common practice
within the tobacco industry. A wide range of techniques have been employed
including tobacco type and leaf selection, genetic selection, microbial or
enzymatic treatment, and selective extraction of nicotine.
4) Both selective extraction and genetic modification have proven capable of
producing tobaccos with nicotine reduced by 80-95%.
5) Reduced nicotine tobacco has different sensory characteristics to that of
unmodified tobacco. This is due in part to the absence of nicotine, but also to
loss of incidental compounds such as waxes, hydrocarbons, and essential oils.
6) Total nicotine intake is only one measure of the overall sensory and
pharmacological effects of nicotine, and does not differentiate between forms of
nicotine. Free-base nicotine is primarily responsible for the sensory impact of
nicotine and may be a more accurate measure of subjective or physiological
effects, particularly in low or reduced nicotine products.
7) For cigarettes with reduced nicotine content, there may be a threshold below
which compensation is less likely to occur. This threshold appears to be in the
range of approximately 0.05-0.1 mg nicotine yield. At less extreme levels of
reduced nicotine (0.2-0.3 mg), compensatory behaviors are significantly
increased.
8) Similar findings are reported for switching studies using denicotinized cigarettes
(0.05 mg nicotine), and extremely low nicotine conventional cigarettes (.1-.2 mg
nicotine), despite differences in construction and greater available nicotine in rod.
9) Reduction of tobacco nicotine content in cigarettes below the 0.1 mg threshold
would require a tenfold reduction beyond that of current denicotinized products.
The feasibility and behavioral responses to such a product remain unexplored.
Nicotine reduction
35
10) The majority of behavioral research has been conducted with cigarettes made
with reduced nicotine tobaccos with machine measured smoke yields near the
0.1 mg nicotine threshold.
11) Physical or chemical parameters of cigarette construction can be manipulated to
alter the basic formulation of the cigarette such as size distribution of particles,
combustion and pyrolysis, and introduction of new compounds. Attention must
be paid to product factors other than nicotine delivery.
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Nicotine reduction
36
V.
Potential behavioral and population outcomes
Denicotinized cigarettes can reduce smoking of conventional cigarettes by providing a
temporary behavioral substitute for conventional cigarettes, and by removing the
primary reinforcing effects of nicotine, generating less craving on a continuing basis
(Becker et al. 2008). Evidence presented in the previous sections indicates that, while
smokers prefer nicotine-containing cigarettes, reduced nicotine cigarettes are capable
of providing subjective satisfaction and immediate craving reduction. Some individuals
may still continue to smoke following mandated nicotine reduction, whether due to the
strong substitution effects reported above, or because the nicotine content in cigarettes
remains above their individual threshold for reinforcement
(Hatsukami et al. 2010b;
Rose 2008).
Behavioral models apply the available evidence on individual level effects of reduced
nicotine cigarettes to predict potential population outcomes. However, studies on the
acquisition of reduced nicotine cigarette use among non-smoking populations, and on
the long-term effects of reduced nicotine cigarette use, remain limited.
V.a. Potential effects on cigarette consumption
Research in behavioral economics has proven its utility in understanding smoker
consumption behavior. For example,
DeGrandpre et al. (1992) applied demand curve
analysis in a meta-analysis of 17 studies examining the effects of nicotine yield on
smoking behavior. They found a strong relationship between consumption and nicotine
yield suggesting that decreasing the smoker's usual nicotine yield spurred increased
smoking behavior.
Within-subjects use of nicotine-containing and denicotinized cigarettes indicates similar
elasticities, as increases in unit price cause similar reductions in self-administration.
However, when both cigarette types are concurrently available at the same range of unit
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Nicotine reduction
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prices, the nicotine-containing cigarettes are reliably preferred. This demonstrates that
the act of smoking possesses reinforcing value in regular smokers regardless of
nicotine content, and that denicotinized cigarettes can serve as an effective behavioral
economic substitute for nicotine-containing cigarettes
(Shahan et al. 2001; Shahan et al.
1999).
Increasing unit price for nicotine-containing cigarettes, while holding denicotinized
cigarette unit price constant, increases consumption of denicotinized cigarettes. The
same holds when nicotine gum is used in place of denicotinized cigarettes
(Shahan et
al. 2000) However, when both alternatives are made available, consumption of nicotine
gum diminishes while consumption of denicotinized cigarettes does not
(Johnson et al.
2004). Increased price of both denicotinized cigarettes and nicotine cigarettes results in
increased gum consumption. These findings suggest that the availability of alternative
nicotine-substitutes such as nicotine medications, oral tobaccos, or nicotine-containing
electronic cigarettes may have direct effects on self-administration of cigarettes,
regardless of cigarette nicotine content.
V.b. Potential effects on topography and smoking behavior
Switching to cigarettes with reduced nicotine content can elicit modest withdrawal
symptoms due to decreases in nicotine intake
(Benowitz et al. 2009; Benowitz et al.
2007; Hatsukami et al. 2010a; West et al. 1984; Zacny and Stitzer 1988). These
findings raise the possibility that withdrawal symptoms might motivate increases in
smoking behaviors.
There is little evidence of compensatory smoking behavior for reduced nicotine
cigarettes at levels of 0.05-0.1 mg nicotine yield, as indicated earlier (see
section IV.e.).
Strasser et al. (2007) found an increase in total puff volume in participants smoking
reduced nicotine (Quest 3) cigarettes (0.05 mg yield). However, participants in the study
were only evaluated in response to their first use of the study cigarettes. Studies over
several days or weeks using reduced nicotine cigarettes consistently find no increase in
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Nicotine reduction
38
compensatory smoking. In fact, a decrease in smoking may occur over time, as would
be expected during behavioral extinction.
Smoking behaviors measured across a nine-day assessment found initial differences in
puff volume, which dissipated as the study progressed, suggesting that puffing behavior
may be only temporarily disrupted by the switch to reduced nicotine cigarettes
(Donny
and Jones 2009). In another 11-day assessment, subjects exposed to reduced nicotine
cigarettes showed a reduction in ad lib smoking compared to nicotine-containing
condition
(Donny et al. 2007). Hatsukami et al. (2010) showed a similar reduction over
a six-week treatment period. In a six-month tapering study conducted by
Benowitz et al.
(2012), cigarette consumption remained unchanged from baseline through week 14,
when nicotine content stepped to 4 mg. From this point to the end of the study (week
26), cigarette consumption decreased significantly by 4 cigarettes per day. Nicotine
intake compared to usual brand, as measured by plasma cotinine, had declined to 30%
of baseline.
In a self-administration study with rats, dose reduction did not elicit withdrawal among
the subjects as a group, though it elicited withdrawal among some individuals, and
severity of withdrawal was not a determinant of individual differences in compensation
(Harris et al. 2011). These findings complement a previous report that a large but partial
reduction in brain nicotine levels achieved via administration of nicotine-specific
antibodies was not sufficient to elicit withdrawal in rats dependent on a chronic nicotine
infusion
(Roiko et al. 2009). The data suggest that withdrawal is not a prominent
adverse consequence of reductions in nicotine intake for most individuals, and that
significant compensatory smoking behavior in the form of greater intensity of smoking or
increased number of cigarettes per day is not a likely outcome at very low (0.1 mg)
levels of nicotine exposure.
V.c. Potential effects on abstinence and quitting
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Nicotine reduction
39
Studies in both laboratory and outpatient research settings demonstrate that use of
reduced nicotine cigarettes over a period of 1–2 weeks weakens the reinforcing effects
of smoking
(Donny et al. 2007; Rose and Behm 2004a). In clinical trials conducted over
periods of six weeks or more
(Benowitz et al. 2009; Benowitz et al. 2012; Hatsukami et
al. 2010a) smokers consistently report lower levels of dependence following use of
reduced nicotine cigarettes.
Reduced nicotine cigarettes may provide a coping mechanism to get through the initial
stages of abstinence by replacing some of the conditioned rituals associated with
smoking, such as the hand-to-mouth action, the tactile action of puffing on a cigarette
and the sensation of smoke in the mouth and throat
(Walker et al. 2012). Among
smokers seeking to quit, continuous abstinence at week 6 for smokers switched to a 0.3
mg cigarette was 13.5%, and for those assigned a 0.05 mg cigarette was 30.2%. This
suggests that a nicotine reduction policy may be more likely to help smokers achieve
abstinence when they make an active quit attempt
(Hatsukami et al. 2010a).
Reduced nicotine cigarettes may support quitting not only in smokers seeking
treatment, but among smokers who have not previously expressed interest in quitting.
Benowitz et al. (2007) found that 4 weeks after the end of a 6-week progressive
reduction in nicotine content of cigarettes, 25% of enrolled subjects had stopped
smoking. A similarly designed study reported 10% of enrolled subjects had quit
smoking in the period following progressive reduction again among smokers who had
not previously expressed interest in quitting—again among smokers who had not
previously expressed interest in quitting
(Benowitz et al. 2009). The six month
progressive reduction reported a 4% quit rate after completion
(Benowitz et al. 2012).
The effects of reduced nicotine cigarettes on quitting may be increased with the
additional availability of nicotine-based treatment. When smokers were switched to
reduced nicotine cigarettes (0.05-0.09 mg nicotine yield) with and without nicotine patch
for a six-week period, the group without patch smoked significantly more cigarettes per
day versus those assigned patch, and showed greater withdrawal symptoms, although
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Nicotine reduction
40
craving scores were not different between the two groups. At 36 week follow up, 18%
of smokers who had used the reduced nicotine cigarettes alone remained abstinent,
compared to 20% of smokers using reduced nicotine/patch combination
(Hatsukami et
al. 2013b). In another study, those assigned a nicotine patch alongside reduced nicotine
cigarettes showed a greater decrease in the number of cigarettes smoked, greater
decrease in total volume of cigarette smoke inhaled, and greater withdrawal relief
(Donny and Jones 2009).
Walker et al. (2012) conducted a randomized control trial in which use of denicotinized
cigarettes was paired to usual Quitline care. An increase in quit rates over usual
Quitline care was found, with a positive impact on time to relapse and high participant
acceptability. The trial provided strong evidence for the combined use of reduced
nicotine cigarettes alongside nicotine replacement therapy (NRT) and behavioral
support as an effective smoking cessation strategy.
V.d. Potential effects on acquisition of cigarette use
The available literature provides no quantified estimates of the potential impact of a
reduced nicotine policy on smoking initiation. Studies cited in
section III.b suggest that
expectancies regarding the ability of cigarettes to reduce negative affect play a primary
role in acquisition of smoking among adolescents
(Heinz et al. 2010; Wahl et al. 2005)
and that substitution of denicotinized cigarettes reduces negative affect comparable to
that of a nicotine-containing cigarette among adolescent smokers. On the other hand,
no change in affect was measured among nonsmoking adolescents with use of reduced
nicotine cigarette
(Kassel et al. 2007a). This suggests that nonsmoking adolescents are
unlikely to proceed to more escalated smoking behavior in the absence of acute
nicotine effects. Establishment of a threshold for reduction of negative affect in
nonsmoking adolescents would provide further confirmation.
Effects on the likely acquisition of reduced nicotine cigarette use among adult
nonsmokers have not been separately explored. Self-administration of a nicotine nasal
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Nicotine reduction
41
spray has been shown to be similar between dependent and nondependent smokers,
and to be greater in both groups than in ex-smokers or nonsmokers. In nonsmokers,
self-administration is related directly to pleasurable effects but inversely to aversive
effects
(Perkins et al. 2001a). Both positive and negative reinforcement expectancies
change significantly following initiation of smoking
(Doran et al. 2011). Reduced nicotine
exposure in adolescence is likely to reduce vulnerability to nicotine dependence in
adulthood (
section II.b.) More research on the effects of reduced nicotine cigarette use
among nonsmokers and non-dependent smokers is needed.
V.e. Potential unintended behavioral consequences
Low level nicotine exposure in adolescents experimenting with reduced nicotine
cigarettes could potentially increase risk of addiction to other drugs of abuse
(Hatsukami
et al. 2010b). In animal studies, very brief exposure to intravenous nicotine doses (only
two infusions of 0.03 mg/kg daily for 4 days) in adolescent rats sensitized them to the
reinforcing effects of cocaine, suggesting a potential adverse consequence of very
limited nicotine exposure in adolescence
(McQuown et al. 2007). This daily dose is
comparable in humans to the nicotine intake from four standard cigarettes
(approximately 4.2 mg), or approximately 40 reduced nicotine cigarettes..
Reduced nicotine cigarettes could potentially serve as starter products for other higher
nicotine products, in a manner similar to that previously demonstrated among
smokeless tobacco products with low levels of free-base nicotine (Connolly 1995). Dual
use of reduced nicotine cigarettes in conjunction with other tobacco products with higher
nicotine content, such as oral tobacco or small cigars, could also lead to greater
exposure to toxicants
(Hatsukami et al. 2010b).
V.f. Potential population differences
As observed in
section II.b., non-nicotine smoking factors may be especially important
for tobacco dependence in women. Women are less responsive than men to
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Nicotine reduction
42
manipulations of nicotine exposure, and more responsive than men to manipulations of
non-nicotine components of cigarette smoking, such as sensory cues
(Perkins et al.
2009a; Perkins et al. 1999; Perkins et al. 2006). At least some of this difference
precedes the onset of dependence due to chronic nicotine exposure via smoking
(Perkins et al. 2009a). Reduced nicotine cigarettes support craving relief among
women more than men
(Barrett 2010) produce positive subjective effects (satisfaction,
relaxation, reduced anxiousness), and reduce smoking intentions among women more
than men
(Barrett and Darredeau 2012).
These findings suggest that women may be at greater risk to maintain long-term use of
reduced nicotine tobacco than men. On the other hand, in a cessation study, tapered
use of reduced nicotine cigarettes in combination with nicotine replacement therapy had
a greater effect on continuous abstinence at 4 weeks for women than for men
(Becker
et al. 2008).
Walker et al. (2012) observed no difference by gender in the effect of the
paired Quitline intervention.
The potential adverse effects of nicotine reduction among those with severe psychiatric
disorders remain a concern. A recent study explored the effects of reduced nicotine
cigarettes among smokers with schizophrenia
(Tidey et al. 2013). Denicotinized
cigarettes reduced cigarette craving, nicotine withdrawal symptoms, smoking withdrawal
symptoms, and usual-brand smoking, and were well tolerated, with no indication that
the reduction in nicotine affected psychiatric symptoms. However, the cigarettes
substituted for nicotine containing cigarettes less effectively for smokers with
schizophrenia than control smokers, suggesting that long-term use of reduced nicotine
cigarettes among those with schizophrenia may be less likely given the presence of
nicotine-containing alternatives. Further studies with reduced nicotine among
individuals with depression or other serious mental health disorders are warranted.
V.g. Potential health effects
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Nicotine reduction
43
Hatsukami et al. (2010a) reported significant reductions in toxicant exposure following
switching to reduced nicotine cigarettes, including tobacco-specific nitrosamines
(TSNA), acrolein, and benzene, although no measured reduction was found in exposure
to polycyclic aromatic hydrocarbons. The reductions in TSNA were consistent with
reduced levels measured in the tobacco, while other toxicant differences were believed
to reflect reductions in smoking behavior. These findings support the conclusion that a
reduced nicotine policy may support reduced health risks not only among those who
quit or fail to acquire tobacco dependence, but potentially among those who continue
use of tobacco products despite reduced nicotine
(Joel et al. 2012).
The likely reduction in nicotine intake is another potential health benefit to be
considered
(Joel et al. 2012; Rose and Behm 2004a). Although non-nicotine
components of tobacco are the primary causes of tobacco-related disease, nicotine has
a number of effects which may be contributors to development of cardiovascular
disease, including vasoconstriction, promotion of thrombosis and atherosclerosis, and
impairment of insulin sensitivity
(Assali et al. 1999; Benowitz 1988). Nicotine may also
promote arteriogenesis
(Heeschen et al. 2003), which could increase the blood supply
to tumors and may inhibit apoptosis
(Suzuki et al. 2003), promoting carcinogenisis.
Alternately
, Girdhar et al. (2008) postulate based on in-vivo research that nicotine may
moderate the risk of cardiovascular disease caused by non-nicotine smoke components
by reducing platelet activation. In this case, reductions in cigarette nicotine content
could increase risks for cardiovascular disease. The authors observe that use of pure
nicotine as a tobacco substitute has no record of harm, suggesting that the direct health
effects of nicotine use are minimal.
No significant difference in adverse health events were identified between those
assigned a reduced nicotine cigarette and those assigned NRT only in the Quitline
intervention conducted in New Zealand
(Walker et al. 2012). The weight of evidence
suggests that similar or reduced health risks are the most likely outcome of switching to
reduced nicotine cigarettes, but more studies are needed in this area.
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Nicotine reduction
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V.h. Potential illicit sales of nicotine-containing cigarettes
A number of studies describe the importance of smuggling to cigarette manufacturers
as a means of promoting products in low and middle income countries
(Lee et al. 2012;
Legresley et al. 2008). Most illicit cigarette sales are supply driven, and remain
commonplace even where prices and excises remain low
(Joossens and Raw 2003)
High rates of smuggling are generally on the order of 10-15%
(Joossens and Raw 2008;
Mecredy et al. 2013; Pavananunt 2011).
No published studies quantify the likelihood of illicit sales of higher nicotine cigarettes
within the context of a reduced nicotine market.
Givel (2011) describes the outcome of
a sales ban enacted in 2004 to end tobacco consumption in Bhutan, with only small
quantities of tobacco for personal consumption permitted for import. Smuggling and
black market sales increased in the years following the ban, sufficient to support a
smoking rate of 10% among Bhutanese men.
In the case of a nicotine reduction policy, both the appeal of reduced nicotine cigarettes,
and the availability and appeal of alternative forms of nicotine, are likely to have a
significant effect on the extent of illicit tobacco sales
(Borland 2013). A recent study in
Canada found that contraband cigarettes had less rated appeal among youth compared
to leading brands, suggesting that the availability of contraband cigarettes could
potentially have a greater impact among addicted smokers versus novice or
experimenting users
(Czoli and Hammond 2013). Availability of contraband cigarettes
have been associated with reduced likelihood of cessation and reduced attempts to quit
(Hyland et al. 2005; Hyland et al. 2006; Licht et al. 2011).
V.i. Models of population effects
Tengs et al. (2005) simulated the population effects of a reduced nicotine mandate
within the U.S. over a 6-year period. Assuming an 80% decline in smoking prevalence,
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Nicotine reduction
45
a 10% increase in the mortality of current smokers due to compensation, and 10% of
smokers assumed to enter the black market annually, their model estimated a
cumulative gain of 157 million quality-adjusted life years (QALY) over 50 years. They
then varied the model parameters in a number of ways, concluding that as long as
smoking cessation increased by 10% or more, smoking relapse and initiation decreased
by 10% or more, and compensation increased smoker mortality by no more than 80%, a
net gain in QALYs was likely. Significantly, over a range of plausible estimates (0-50%
of all smokers), QALYs were uniformly gained rather than lost regardless of the extent
of black market entry.
Another simulated model estimated health outcomes assuming that nicotine reduction
would reduce the probability of initiating smoking for every age and gender, that the
probability of cessation would increase, and that former smokers would have a
decreased probability of relapse. Alternately, it considered the possibility that promotion
of reduced nicotine cigarettes as “safer” could worsen all three outcomes. Outcome
estimates were created for behavior change probability values in increments of 10%
from −80% to +80%. The study concluded that a 60% reduction in smoking behaviors
(initiation, use, relapse) would offset any plausible increase (50% or less) in harm
resulting from compensatory smoking or other unintended health consequences among
those who continue to smoke. A modest 20% reduction in initiation, use, and relapse,
coupled with a 20% reduction in disease risk among continuing smokers, supported a
cumulative gain of 165 million QALY. A significant 80% reduction in initiation, use, and
relapse, with no change in disease risk among those continuing to smoke, resulted in an
estimated gain of 281 million QALY
(Ahmad and Billimek 2005).
A commissioned study modeled the potential effects within Canada of a nicotine
reduction policy across tobacco products
(IEC; Industrial Economics 2013). The study
inputs were based on a literature review as well as interviews with health experts.
Consideration was given to outcomes on smoking initiation and cessation, black market
increases, substitution of other tobacco products for cigarettes, and potential
compensatory behavior. Estimates of the impact on initiation and cessation in the
Nicotine reduction
46
absence of second-order impacts (black market, substitution, compensation) reduced
costs of tobacco-related illness by 19% after 30 years. Assuming an increase in black
market share from 15% to 50%, the benefits decreased 40%. Mortality benefits of a
nicotine standard were driven primarily by the impact on cessation, while the morbidity
benefits were driven primarily by the impact on initiation.
V.j. Summary of findings regarding potential outcomes of nicotine reduction
1) The act of smoking possesses reinforcing value in addicted smokers regardless
of nicotine content. Denicotinized cigarettes can serve as an effective behavioral
economic substitute for nicotine-containing cigarettes.
2) The availability of alternative nicotine-substitutes such as nicotine medications,
oral tobaccos, or nicotine containing electronic cigarettes may have direct effects
on self-administration of cigarettes, whether or not the cigarettes themselves
contain nicotine.
3) Withdrawal is not a prominent adverse consequence of reductions in nicotine
intake for most individuals, and significant compensatory smoking behavior in the
form of greater intensity of smoking or increased number of cigarettes per day is
not a likely outcome at very low (<.1 mg) levels of nicotine exposure.
4) A nicotine reduction policy may be more likely to help smokers achieve
abstinence when they make an active quit attempt. Use of reduce nicotine
cigarettes have improved quit rates across a number of studies.
5) Nonsmoking adolescents are unlikely to proceed to more escalated smoking
behavior in the absence of acute nicotine effects. Establishment of a threshold
for reduction of negative affect in nonsmoking adolescents would provide further
confirmation.
6) The use and effects of reduced nicotine cigarettes among nonsmokers and non-
dependent smokers are underexplored. In nonsmokers, self-administration of
reduced nicotine cigarettes is related directly to pleasurable effects and inversely
to aversive effects.
Nicotine reduction
47
7) Low level nicotine exposure in adolescents could potentially produce risk of
addiction to other drugs of abuse. Low level nicotine products could also serve
as starter products for other forms of tobacco or other forms of nicotine delivery.
8) Women may be more likely than men to sustain long-term use of reduced
nicotine tobacco. Nicotine reduction in schizophrenics had no aversive effects on
mental health symptoms; more studies are needed in other at-risk populations.
9) Reduced nicotine may support reduced health risks not only among those who
quit or fail to acquire tobacco dependence, but potentially among those who
continue use of tobacco products despite reduced nicotine. However, more
studies are needed.
10) Illicit tobacco sales may potentially undermine the health goals of a nicotine
reduction policy. Although no formal estimates have been attempted, both the
appeal of reduced nicotine cigarettes and the availability and appeal of
alternative forms of nicotine are likely to have a significant effect on the extent of
illicit tobacco sales.
11) Various model estimates have been created to describe the likely effects of a
nicotine reduction policy. All indicate a significantly positive effect on health
outcomes.
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VI.
Policy approaches to nicotine reduction
A number of authors propose nicotine reduction of cigarettes in the context of a harm
reduction model in which safer products are made more appealing relative to more toxic
products (Arnott 2013, Borland 2013, Hatsukami 2013; Britton and McNeil 2013; McNeil
et al 2012; Houezec et al., 2011; Hall and West, 2008) This underscores the critical
importance of the regulatory framework within which a nicotine reduction policy would
take place, as well as the resulting commercial marketplace in which smokers and
nonsmokers develop and sustain tobacco or nicotine use behaviors, and the social
environment that influences and supports these behaviors.
VI.a. Comprehensive nicotine regulation
The effects of a cigarette nicotine reduction policy would depend to a significant degree
on the availability, toxicity, and appeal of alternative nicotine delivery systems, including
other forms of (combustible or noncombustible) tobacco, medicinal nicotine, and non-
tobacco commercial nicotine products
(Hatsukami et al. 2010b). It follows that a
successful nicotine reduction policy must take place within the context of
comprehensive regulation of all tobacco and nicotine containing products
(Gray et al.
2005; Hatsukami et al. 2013a; Le Houezec et al. 2011; McNeill et al. 2012; Zeller et al.
2009).
A single institution with authority over tobacco and nicotine regulation would enable
coordination of approaches for different products
(Le Houezec et al. 2011). This
institution would be responsible for formulating decisions about how tobacco and
nicotine products would be regulated, setting performance standards, authorizing health
or other product claims, evaluating products in market, and their population effects.
Access to a comprehensive surveillance system would be critical in order to be able to
respond quickly to any unanticipated changes in nicotine use or health outcomes
(Hatsukami et al. 2013a; Le Houezec et al. 2011).
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The overarching goals of comprehensive nicotine regulation would be to minimize use
of the most toxic nicotine-containing products, to encourage the development of new
and improved nicotine delivery systems as alternatives to more toxic products, and to
continue to monitor and regulate less toxic products for their health effects
(Benowitz
and Henningfield 2013; Gray et al. 2005; Le Houezec et al. 2011) Policy approaches
could be considered to incentivize smokers to adopt less hazardous forms of
tobacco/nicotine use, including restrictions on access, marketing, and use, as well as
differential taxation, such that taxes on cigarettes and combusted tobacco are much
higher than those on cleaner nicotine delivery products
(Benowitz and Henningfield
2013; McNeill et al. 2012; O'Connor 2012).
VI.b. Performance standards
Performance standards are necessary to ensure successful implementation of a
reduced nicotine policy
(Hatsukami 2013; O'Connor 2012). A number of approaches
could be considered for determining product nicotine standards: for example, restriction
of delivered or inhaled nicotine, or of individual doses of nicotine defined at the level of a
single puff. However, focus on the total nicotine available in the unburned cigarette is
the most promising approach, given that it is both more easily measured and less
subject to behavioral manipulation and individual variability (
section IV.f.)
The evidence presented in this report suggests that reduction of nicotine in cigarettes to
less than 1 mg nicotine content may be sufficient to reduce dependence in some
proportion of the smoking population, with minimal adverse effects. This evidence is
drawn from studies using cigarettes constructed with very low nicotine tobacco and
design parameters similar to those of standard conventional cigarettes. It is possible
and even likely that performance standards which focus exclusively on nicotine content
of tobacco would encourage development of cigarettes that contain little tobacco
nicotine but which are otherwise quite different in form and function from conventional
cigarettes. Examples might include products that release nicotine in a more readily
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available (free-base) form, that alter the particle formation or deposition of nicotine, that
release the full amount of nicotine within a single dose, that encourage and enable use
of multiple cigarettes to maintain dose, or that use nicotine analogs and other
pharmacologically active compounds to enhance or replace the effects of nicotine.
Performance standards must be responsive to the changing marketplace
(Hatsukami et
al. 2013a; Hatsukami et al. 2012; O'Connor 2012; Parascandola 2011). Initial standards
should require that products match product parameters of conventional cigarettes
across a range of basic physical characteristics including tobacco weight, length,
circumference, filter, paper, and ventilation
(Wayne and Connolly 2009). New products
and technologies must be carefully evaluated and commercial introduction permitted
only once products have sufficiently demonstrated reduced risk, addictiveness, and
appeal
(Carter et al. 2009; Hatsukami et al. 2013a; Hatsukami et al. 2012; Henningfield
et al. 2011).
Global standards for addiction and harm should ultimately be set through FCTC
processes
(McNeill et al. 2012). These global standards could also support further
product standards, such as restriction on toxicants (e.g. nitrosamines), physical design
parameters that enable or support compensation (e.g. ventilation), flavorants, or other
factors that increase product appeal (e.g. menthol). In each case the effects of these
standards would need to be carefully evaluated
(Hatsukami 2013; Hatsukami et al.
2012; McNeill et al. 2012; O'Connor 2012).
VI.c. Gradual versus sudden reduction
In their original proposa
l, Benowitz and Henningfield (1994) called for a reduction in
nicotine levels over a period of 10–15 years, as a means to minimize potential
withdrawal among other practical concerns. However, a more gradual reduction in
nicotine could have negative health consequences
(Hatsukami et al. 2010b). First, it
would keep individuals for an extended period at doses of nicotine that maintain
smoking behavior. Second, it is possible that a marketwide, gradual shift in nicotine
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51
levels would alter smokers’ relationship to nicotine in unanticipated ways, potentially
adjusting the threshold for addiction in the process
(Smith et al. 2013). For example,
early work on nicotine self-administration found that rats switched to saline extinguished
more slowly if they received an intermediate dose reduction prior to saline substitution
(Cox et al. 1984).
No studies have yet been conducted that model the effects of a reduction in nicotine
over the course of years. However, progressive reduction in nicotine has been
considered over a span of weeks or months, demonstrating that gradual declines in
nicotine consumption may be administered without significant compensation. Further,
once tapering is completed, nicotine intake remains below baseline, suggesting reduced
level of nicotine dependence
(Benowitz et al. 2009; Benowitz et al. 2012; Benowitz et al.
2007). A strong association exists between magnitude of daily smoking reduction and
nicotine dependence, supporting the concept that gradual reductions in intake may
reduce nicotine dependence
(Mooney et al. 2011). A recent literature review concludes
that progressive reduction in the level of nicotine in cigarette tobacco can reduce the
level of nicotine dependence in smokers, with minimal compensatory smoking (at levels
of smoke nicotine <.1 mg) and without adverse effects
(Walker et al. 2009).
Evidence suggests that even immediate reductions in nicotine may be successful in
decreasing smoking rates as well as dependence
(Donny et al. 2007; Hatsukami et al.
2010a). Smokers switched abruptly from own cigarettes to reduced nicotine content
cigarettes for a period of six weeks showed reduced exposure, decreased consumption,
and higher rates of cessation
(Hatsukami et al. 2010a). Similarly, cigarette consumption
declined immediately and motivation to smoke decreased in an 11-day switching study
(Donny et al. 2007).
Both gradual and immediate reductions in nicotine at low doses result in similar self-
administration behavior in rats, with no compensatory behavior in either group
(Smith et
al. 2013) A meta-analysis of the effect on quit rates of an intermediate reduction in
consumption prior to quitting found no difference between reducing cigarettes smoked
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before quit day, and quitting abruptly with no prior reduction
(Lindson-Hawley et al.
2012). Taken together, these studies suggest that cigarette nicotine dose reduction may
be implemented quickly without significant adverse effects among smokers.
VI.d. Alternative forms of nicotine
Some cigarette smokers, when faced with reduced nicotine, are likely to switch to other
products seeking more nicotine. The appeal of alternative tobacco products, such as
oral and smokeless tobacco, waterpipes, pipes, and cigars, may increase in relation to
their ability to substitute for conventional cigarettes more effectively than do the reduced
nicotine cigarettes (see
section V.a.). Combusted tobacco is significantly more harmful
than noncombusted tobacco, which is itself more harmful than clean nicotine products
such as nicotine patch or gum
(Stratton et al. 2001). Given this continuum of harm, it
may be advisable to mandate nicotine reductions not only in cigarettes, but across all
combusted tobacco products, minimizing the risk of switching to the most harmful
products
(O'Connor 2012).
Pharmaceutical products for dispensing nicotine, while much safer than tobacco
products, are made unappealing by design in order to avoid abuse liability, and are not
intended for long term use
(Carter et al. 2009; Henningfield et al. 2011). Although these
products may help a smoker through withdrawal more easily, they do not produce
sufficient positive reward, particularly in the form of fast and effective nicotine delivery,
necessary to provide a reasonable alternative to tobacco products
(Rooke et al. 2013).
Electronic cigarettes were designed with the express purpose of replicating the act of
smoking, without use of tobacco
(Cahn and Siegel 2011; O'Connor 2012). These (or
similar) products may present a more viable alternative to cigarettes
(Le Houezec and
Aubin 2013), and a rapid body of evidence is accumulating on their use and acceptance
(Cahn and Siegel 2011; Dawkins and Corcoran 2013; Dawkins et al. 2013a; Dawkins et
al. 2013b). Electronic cigarettes produce a vapor of nicotine in combination with other
constituents, usually including glycerin or propylene glycol. Currently they are used
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53
primarily for smoking cessation, although for a longer duration than nicotine
replacement therapy
(Dawkins et al. 2013b). Users believe them to be safer than
smoking
(Dawkins et al. 2013b).
Electronic cigarettes deliver nicotine more effectively and more rapidly than a nicotine
inhaler
(Eissenberg 2010) though somewhat less effectively than a conventional
cigarette
(Cahn and Siegel 2011; Eissenberg 2010). They produce sizeable craving
reduction which is attributable at least in part to physical sensory characteristics of the
cigarette independent of nicotine delivery
(Bullen et al. 2010; Cahn and Siegel 2011). At
least some electronic cigarettes demonstrate reliable blood nicotine delivery (mean of
6.77 ng/ml 10 min after 10 puffs, mean maximum of 13.91 ng/ml by the end of the ad lib
puffing period). They are capable of reductions in tobacco-related withdrawal
symptoms and urge to smoke, provide direct positive effects, and low adverse effects
(Dawkins and Corcoran 2013).
VI.e. Cessation and behavioral treatment
As nicotine is reduced to nonaddictive levels, there will likely be a sharp increase in the
number of smokers who want to quit
(Benowitz and Henningfield 2013; Henningfield et
al. 1998). Many will visit physicians seeking nicotine replacement or behavioral therapy
to aid cessation or relief from withdrawal symptoms. Effective and affordable treatment
offered by health care professionals will be invaluable in ensuring the mandate's
success
(Benowitz and Henningfield 2013; O'Connor 2012; Zeller et al. 2009).
Coverage by insurance programs is critical, as are individualized services to special
populations for whom adverse effects may be heightened, such as those with co-morbid
psychiatric disorders
(Henningfield et al. 1998). The broad availability of
pharmacotherapies and treatment may not only reduce the discomfort associated with
reduced nicotine content of cigarettes but may lead to substantial reductions in cigarette
smoking and possibly to eventual cessation of all tobacco and nicotine products for
some or many current smokers.
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VI.f. Surveillance
The public health community has been slow in the past to recognize the potential
limitations of regulatory or harm reduction approaches despite early evidence of their
ineffectiveness
(McNeill et al. 2012; Parascandola 2011). An adequate surveillance
system will enable regulators to monitor the impact of tobacco products on prevalence,
initiation, and harm, and to address unintended outcomes
(Hatsukami et al. 2013a).
Mandatory reporting regulations for all nicotine and tobacco products, as adopted in
Canada and described in Articles 9 and 10 of the FCTC, are a necessary condition of
adequate surveillance, and should include physical design components (tobacco
weight, nicotine concentration, filter ventilation), tobacco and added constituents,
emissions for combustible products, as well as measures of abuse liability
(Carter et al.
2009; Hatsukami et al. 2013a; Hatsukami et al. 2012; McNeill et al. 2012).
Hatsukami et al. (2013a) and others
(Stratton et al. 2001) describe a comprehensive
approach to tobacco product evaluation that can be effectively applied to ongoing
evaluation of reduced nicotine cigarettes. This includes: preclinical tests in animals to
assess abuse liability, acquisition of nicotine self-administration in both adolescent and
adult animals, and neurophysiological changes that affect function resulting from
exposure; human imaging, laboratory, and clinical trial studies that examine the abuse
liability, tobacco use behaviors, toxicant exposure, and potential health risks in general
and vulnerable populations; and assessment of moderating factors including how the
consumer perceives the product and its appeal, and packaging, price, and promotion
(Hatsukami et al. 2013a).
Although biomarker testing in large studies of smokers is promising as an evaluation of
disease risk, this approach may not be feasible in many countries where resources are
unavailable
(McNeill et al. 2012). The complexity of tobacco products, and knowledge
required to assess toxicology, abuse liability, and outcomes may be an additional
barr
ier. McNeill et al. (2012) identify the need for a global data repository to facilitate
implementation of tobacco product regulation and surveillance worldwide. The
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repository would ease the burden on regulators by collecting and analyzing data,
making global comparisons, and relaying information to national regulators with
recommendations in an easily understandable form.
VI.g. Consumer education and beliefs
The effects of a reduced nicotine policy will depend in part on how effectively risks are
communicated, as well as the relative appeal of reduced nicotine and other tobacco or
nicotine products. Beliefs about the increased safety of reduced nicotine products could
reduce likelihood of quitting or switching to safer alternatives, and could encourage
greater experimentation with cigarettes.
Limited evidence suggests that smokers believe reduced nicotine cigarettes to be less
harmful. A 2006 study
(Shadel et al. 2006) evaluated beliefs following exposure to a
single print advertisement of a nicotine free product (Quest). Smokers made a number
of false inferences about the product: that it was lower in tar, healthier, and less likely to
cause cancer. The denicotinized Philip Morris brand Next was developed in response to
focus group interest in no-nicotine products, based on perceptions that the product
would be healthier, as well as facilitate quitting
(Dunsby and Bero 2004).
Smokers express doubt about health claims for reduced exposure products, about
whether they would actually switch to such a product, and whether they would taste as
good as conventional cigarettes
(Parascandola et al. 2009). These and other
responses are likely to be affected by ongoing marketing and communication efforts by
manufacturers, public health communication strategies in support of nicotine reduction,
and the relative availability and public knowledge of other tobacco or nicotine products.
Education of smokers and nonsmokers about the health risks of tobacco in the absence
of nicotine, the relative harm of available products, and opportunities for treatment are
critical. Marketing of tobacco and nicotine products will need to be strongly regulated
(Hatsukami et al. 2013a; McNeill et al. 2012)
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VI.h. Public support for reduced nicotine policy
Recent studies in the U.S. demonstrate strong public support for mandated nicotine
reduction. In a survey of 511 nonsmokers and 510 smokers, nearly 2 in 3 (65%)
supported reducing nicotine in cigarettes to nonaddictive levels, including 73% of
nonsmokers and 58% of smokers. More than 3 in 4 persons (77%), including 81% of
nonsmokers and 74% of smokers, supported the reduction of nicotine if it could cause
fewer children to become addicted to cigarettes. Nonsmokers were significantly more
likely than smokers to support reducing nicotine in cigarettes under both conditions
(Connolly et al. 2012). Another survey found that 67% of smokers would support an
FDA regulation that made cigarettes less addictive if “nicotine was made easily
available in non-cigarette form.”
(Fix et al. 2011) A third cross-sectional survey of adults
(n=2649), found that nearly half supported nicotine reduction, including 46% of never
smokers, 49% of former smokers, and 46% of current smokers. Among smokers,
support was highest among those who intended to quit in the next 6 months
(Pearson et
al. 2013). This survey was the only one to include a neutral response option, and nearly
27% of respondents chose this option, which may explain the higher levels of
agreement in the other surveys.
VI.i. Unintended market consequences
Reduced access to nicotine containing cigarettes may increase the demand for
contraband cigarettes among addicted smokers
(Benowitz and Henningfield 2013).
Minimizing the impact of illicit cigarette sales will require effective surveillance strategies
(Hatsukami et al. 2013a) as well as policies that limit the scale of the contraband market
(Joossens and Raw 2008). Most smuggling worldwide is large-scale and organized,
consisting of containers of cigarettes supplied by tobacco manufacturers and exported
to countries where they have no legal market
(Joossens and Raw 2003; Joossens and
Raw 2008) Thus, successful efforts to control smuggling have relied on making
manufacturers liable for the safe transport of cigarettes to their legitimate end market.
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Chain of custody markings would require manufacturers to print legibly, on all packages
of tobacco products, a unique serial number to identify the manufacturer and the date
and location of manufacture, and another identifier to show the chain of custody—
wholesaler, exporter, distributor, and end market. Other successful anti-smuggling
measures include scanners for container detection, prominent fiscal marks on packs,
increased punishment, more customs officers, and parliamentary hearings to expose
tobacco industry export practices. These approaches have resulted in a reduction in
cigarette smuggling from around 15% to 1–2% in Spain and Italy, and significant
reductions in the United Kingdom
(Joossens and Raw 2008). By contrast, voluntary
approaches have had no measurable effect.
Besides large scale, organized smuggling, other types of illegal trade could include
bootlegged or counterfeit products. These products could potentially consist of
extremely low grade tobaccos with high levels of toxins ,or have other unanticipated
risks, thus presenting a serious health problem within some subset of smokers. As
noted by
Benowitz and Henningfield (2013), it is difficult to imagine growth of a
bootlegged cigarette industry, operating outside of regulatory control, sufficient in scale
to rival the present cigarette market.
Unregulated combustible tobaccos, such as roll-your-own tobacco, could become a
substitute for manufactured cigarettes. Other possibilities include significant dual use of
reduced nicotine cigarettes in conjunction with nicotine delivery devices, use of pH
modification or additives to increase the impact and pharmacology of manufactured
products, and significant unanticipated behavioral changes in use of reduced nicotine
products as a result of long-term use. Availability of more appealing alternative nicotine
products is likely to function as a check on these unintended market outcomes
(Benowitz and Henningfield 2013; Hatsukami et al. 2013a).
VI.j. Summary of findings regarding policy approaches to nicotine reduction
Nicotine reduction
58
1) Comprehensive, coordinated regulation of all tobacco and nicotine containing
products is necessary for successful implementation of a nicotine reduction
policy.
2) Regulating the total nicotine available in the unburned cigarette is the most
promising approach to nicotine reduction, given that it is both more easily
measured and less subject to behavioral manipulation and variability.
3) Performance standards which focus exclusively on nicotine content of tobacco
would encourage development of cigarettes that contain relatively little tobacco
nicotine but which are otherwise quite different in form and function from
conventional cigarettes.
4) New products and technologies must be carefully evaluated and commercial
introduction permitted only once products have sufficiently demonstrated reduced
risk, addictiveness, and appeal.
5) Gradual nicotine reduction over a time course of years may have unintended
consequences, which have yet to be studied. Progressive nicotine reduction
conducted over a time course of months, as well as immediate nicotine
reduction, shows no adverse effects or evidence of compensatory smoking.
6) Smokers are likely to switch to alternative products. The most promising of these
are electronic cigarettes or other nicotine devices that provide both nicotine and
sensory characteristics like a cigarette, but in the absence of tobacco.
7) Increased availability of behavioral counseling and pharmacotherapies to assist
smokers with significant withdrawal symptoms or for those who wish to quit are
necessary to support nicotine reduction.
8) An adequate surveillance system is needed to enable regulators to monitor the
impact of tobacco and nicotine containing products on prevalence, initiation,
harm, and to address unintended outcomes. Efforts may be necessary to assist
countries that are unable to support a large-scale surveillance system.
9) Beliefs about the increased safety of reduced nicotine products could reduce
likelihood of quitting or switching to safer alternatives. Public health
communication strategies and regulation of marketing are critical.
Nicotine reduction
59
10) Public support for nicotine reduction of cigarettes is high, particularly in the
context of making other forms of nicotine available for consumption.
11) Successful efforts to control smuggling have relied on making manufacturers
liable for the safe transport of cigarettes to their legitimate end market.
12) Heath threats may be posed by smaller scale contraband cigarettes, unregulated
tobacco, dual use, and modifications to reduced nicotine cigarettes intended to
increase or replace the effectiveness of nicotine.
Nicotine reduction
60
VII.
Conclusions
Although the science on nicotine reduction and use of reduced nicotine cigarettes
remains limited, the level of agreement among available studies is striking. Findings
from animal and human studies are broadly comparable, identifying similar thresholds
for self-administration, effects of both sensory stimuli and broad classes of tobacco
compounds (MAO, alkaloids) on nicotine reinforcement, importance of acquisition of
dependence in adolescence versus adulthood, and a relative lack of withdrawal or
adverse effects in the context of progressive reduction in nicotine.
Assessing the weight of the evidence presented above, the most likely consequences of
mandated nicotine reduction include:
a reduction in acquisition of smoking and progression to addiction among novice
smokers
a reduction in smoking among some proportion of addicted smokers as a result
of behavioral extinction
an increase in quitting and a reduction in the number of smokers who relapse
from quitting
an increase in use and availability of alternative forms of nicotine, including oral
or smokeless tobacco products, nicotine aerosol or vapor products, and
medicinal nicotine
a reduction in health risks for most smokers, reflecting reduced consumption,
reduced exposure to tobacco smoke, and reduced toxicants in tobacco (e.g.
TSNAs, nicotine).
Possible consequences of mandated nicotine reduction, for which there is currently too
little information to make a judgment include:
an increase among some proportion of smokers in use and availability of black
market cigarettes with high nicotine content
Nicotine reduction
61
an increase among some proportion of smokers in dual use of nicotine containing
products and cigarettes
changes in the design or construction of reduced nicotine products, whether by
manufacturers or by smokers, that alter the delivery characteristics of the
product, with unanticipated effects on toxicity, addiction, and appeal
increased use of nicotine containing products among nonsmokers and those who
would not have smoked, due to greater availability, appeal, and lower perceived
risk of these products
greater long-term use of reduced nicotine cigarettes among women than men
Other potential but less likely outcomes of mandated nicotine reduction based on the
current evidence include:
increased smoking behavior (puffing or cigarettes per day) among some
proportion of smokers as a compensatory response to lack of nicotine
increased risk of cardiovascular disease among continuing smokers as a result
of exposure to tobacco smoke in the absence of nicotine
increased use of other drugs of abuse potentiated by exposure to reduced
nicotine cigarettes
a significant black market of high nicotine cigarettes replacing or supplanting the
regulated cigarette market
Nicotine reduction
62
VIII.
Recommendations
A nicotine reduction policy is technically feasible, is supported by smokers and
nonsmokers, and is likely to have a significant positive impact on population
health.
Mandated nicotine reduction should take place alongside comprehensive
regulation of all nicotine and tobacco containing products. Comprehensive
regulation should support the use of products which demonstrate less toxicity,
such as medicinal nicotine or nicotine delivery devices, and should reduce
availability and appeal of more toxic products.
There is strong agreement regarding the identification of a threshold for
reinforcement of nicotine in cigarettes at around 0.1- 0.2 mg of delivered nicotine.
This level is at or below the self-administration level of nicotine in human
smokers (between 0.1- 0.4 mg) and animals (between ~0.2- 0.5 mg); at or below
the threshold for discrimination of nicotine in both smokers and nonsmokers; and
is consistent with internal studies of threshold for latency effects of cigarette
nicotine yield conducted by manufacturers (between 0.1- 0.3 mg).
Mandated nicotine reduction over a relatively short time course shows little
adverse withdrawal or behavioral effects. A more gradual reduction may have
unintended behavioral and health consequences. Availability of effective and
affordable treatment and of alternative forms of nicotine will help dependent
smokers who experience adverse effects.
Anticipation of population outcomes is limited in a number of key areas.
Research needs include: further establishment of the likely use and effects of
reduced nicotine cigarettes in nonsmoking adolescents, nonsmoking adults, and
nondependent smokers; further studies among at risk populations such as those
with moderate and severe depression; further studies on the comparative health
effects of reduced nicotine versus nicotine containing cigarettes; and studies on
long-term use of reduced nicotine cigarettes.
Nicotine reduction
63
IX.
Citations
Adriani W, Macri S, Pacifici R, Laviola G (2002) Peculiar vulnerability to nicotine oral
self-administration in mice during early adolescence. Neuropsychopharmacology
: official publication of the American College of Neuropsychopharmacology
27(2):212-24 doi:10.1016/S0893-133X(02)00295-6
Adriani W, et al. (2003) Evidence for enhanced neurobehavioral vulnerability to nicotine
during periadolescence in rats. The Journal of neuroscience : the official journal
of the Society for Neuroscience 23(11):4712-6
Ahmad S, Billimek J (2005) Estimating the health impacts of tobacco harm reduction
policies: a simulation modeling approach. Risk analysis : an official publication of
the Society for Risk Analysis 25(4):801-12 doi:10.1111/j.1539-
6924.2005.00647.x
Ashburn G (1961) Vapor-phase removal of nicotine from smoke. RJ Reynolds
Ashley DL, Pankow JF, Tavakoli AD, Watson CH (2009) Approaches, challenges, and
experience in assessing free nicotine. Handbook of experimental
pharmacology(192):437-56 doi:10.1007/978-3-540-69248-5_15
Assali AR, Beigel Y, Schreibman R, Shafer Z, Fainaru M (1999) Weight gain and insulin
resistance during nicotine replacement therapy. Clinical cardiology 22(5):357-60
Audrain-McGovern J, Rodriguez D, Epstein LH, Rodgers K, Cuevas J, Wileyto EP
(2009) Young adult smoking: what factors differentiate ex-smokers, smoking
cessation treatment seekers and nontreatment seekers? Addictive behaviors
34(12):1036-41 doi:10.1016/j.addbeh.2009.06.012
Aung AT, Pickworth WB, Moolchan ET (2004) History of marijuana use and tobacco
smoking topography in tobacco-dependent adolescents. Addictive behaviors
29(4):699-706 doi:10.1016/j.addbeh.2004.02.012
Baldinger B, Hasenfratz M, Battig K (1995) Switching to ultralow nicotine cigarettes:
effects of different tar yields and blocking of olfactory cues. Pharmacology,
biochemistry, and behavior 50(2):233-9
Bardo MT, Green TA, Crooks PA, Dwoskin LP (1999) Nornicotine is self-administered
intravenously by rats. Psychopharmacology 146(3):290-6
Barrett SP (2010) The effects of nicotine, denicotinized tobacco, and nicotine-containing
tobacco on cigarette craving, withdrawal, and self-administration in male and
female smokers. Behavioural pharmacology 21(2):144-52
doi:10.1097/FBP.0b013e328337be68
Nicotine reduction
64
Barrett SP, Darredeau C (2012) The acute effects of nicotine on the subjective and
behavioural responses to denicotinized tobacco in dependent smokers.
Behavioural pharmacology 23(3):221-7 doi:10.1097/FBP.0b013e328353431c
Becker KM, Rose JE, Albino AP (2008) A randomized trial of nicotine replacement
therapy in combination with reduced-nicotine cigarettes for smoking cessation.
Nicotine & tobacco research : official journal of the Society for Research on
Nicotine and Tobacco 10(7):1139-48 doi:10.1080/14622200802123294
Belluzzi JD, Wang R, Leslie FM (2005) Acetaldehyde enhances acquisition of nicotine
self-administration in adolescent rats. Neuropsychopharmacology : official
publication of the American College of Neuropsychopharmacology 30(4):705-12
doi:10.1038/sj.npp.1300586
Benowitz NL (1988) Toxicity of nicotine: implications with regard to nicotine replacement
therapy. Progress in clinical and biological research 261:187-217
Benowitz NL (2008) Clinical pharmacology of nicotine: implications for understanding,
preventing, and treating tobacco addiction. Clinical pharmacology and
therapeutics 83(4):531-41 doi:10.1038/clpt.2008.3
Benowitz NL, et al. (2009) Progressive commercial cigarette yield reduction:
biochemical exposure and behavioral assessment. Cancer epidemiology,
biomarkers & prevention : a publication of the American Association for Cancer
Research, cosponsored by the American Society of Preventive Oncology
18(3):876-83 doi:10.1158/1055-9965.EPI-08-0731
Benowitz NL, et al. (2012) Smoking behavior and exposure to tobacco toxicants during
6 months of smoking progressively reduced nicotine content cigarettes. Cancer
epidemiology, biomarkers & prevention : a publication of the American
Association for Cancer Research, cosponsored by the American Society of
Preventive Oncology 21(5):761-9 doi:10.1158/1055-9965.EPI-11-0644
Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P, 3rd (2007) Nicotine
and carcinogen exposure with smoking of progressively reduced nicotine content
cigarette. Cancer epidemiology, biomarkers & prevention : a publication of the
American Association for Cancer Research, cosponsored by the American
Society of Preventive Oncology 16(11):2479-85 doi:10.1158/1055-9965.EPI-07-
0393
Benowitz NL, Henningfield JE (1994) Establishing a nicotine threshold for addiction. The
implications for tobacco regulation. The New England journal of medicine
331(2):123-5 doi:10.1056/NEJM199407143310212
Benowitz NL, Henningfield JE (2013) Reducing the nicotine content to make cigarettes
less addictive. Tobacco control 22 Suppl 1:i14-7 doi:10.1136/tobaccocontrol-
2012-050860
Nicotine reduction
65
Benowitz NL, Jacob P, 3rd (1990) Intravenous nicotine replacement suppresses
nicotine intake from cigarette smoking. The Journal of pharmacology and
experimental therapeutics 254(3):1000-5
Benowitz NL, et al. (2005) Carcinogen exposure during short-term switching from
regular to "light" cigarettes. Cancer epidemiology, biomarkers & prevention : a
publication of the American Association for Cancer Research, cosponsored by
the American Society of Preventive Oncology 14(6):1376-83 doi:10.1158/1055-
9965.EPI-04-0667
Benowitz NL, Jacob P, 3rd, Herrera B (2006a) Nicotine intake and dose response when
smoking reduced-nicotine content cigarettes. Clinical pharmacology and
therapeutics 80(6):703-14 doi:10.1016/j.clpt.2006.09.007
Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P, 3rd (2006b) Female sex and
oral contraceptive use accelerate nicotine metabolism. Clinical pharmacology
and therapeutics 79(5):480-8 doi:10.1016/j.clpt.2006.01.008
Besheer J, Palmatier MI, Metschke DM, Bevins RA (2004) Nicotine as a signal for the
presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning
preparation in rats. Psychopharmacology 172(1):108-17 doi:10.1007/s00213-
003-1621-9
Bevins RA, Caggiula AR (2009) Nicotine, tobacco use, and the 55th Nebraska
Symposium on Motivation. Nebraska Symposium on Motivation Nebraska
Symposium on Motivation 55:1-3
Bevins RA, Palmatier MI (2004) Extending the role of associative learning processes in
nicotine addiction. Behavioral and cognitive neuroscience reviews 3(3):143-58
doi:10.1177/1534582304272005
Borland R (2013) Minimising the harm from nicotine use: finding the right regulatory
framework. Tobacco control 22 Suppl 1:i6-9 doi:10.1136/tobaccocontrol-2012-
050843
Bouton ME (2004) Context and behavioral processes in extinction. Learning & memory
11(5):485-94 doi:10.1101/lm.78804
Brauer LH, Behm FM, Lane JD, Westman EC, Perkins C, Rose JE (2001) Individual
differences in smoking reward from de-nicotinized cigarettes. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
3(2):101-9 doi:10.1080/14622200110042000
Breland AB, Buchhalter AR, Evans SE, Eissenberg T (2002) Evaluating acute effects of
potential reduced-exposure products for smokers: clinical laboratory
methodology. Nicotine & tobacco research : official journal of the Society for
Research on Nicotine and Tobacco 4 Suppl 2:S131-40
doi:10.1080/1462220021000032780
Nicotine reduction
66
Breslau N, Peterson EL (1996) Smoking cessation in young adults: age at initiation of
cigarette smoking and other suspected influences. American journal of public
health 86(2):214-20
British American Tobacco (1969) Introductory Notes on Leaf Blending. In: Tobacco BA
(ed).
British American Tobacco (1972) Research and Development Department: Progress in
1972 - Plans for 1973. In: Tobacco BA (ed).
Brody AL, et al. (2009) Brain nicotinic acetylcholine receptor occupancy: effect of
smoking a denicotinized cigarette. The international journal of
neuropsychopharmacology / official scientific journal of the Collegium
Internationale Neuropsychopharmacologicum 12(3):305-16
doi:10.1017/S146114570800922X
Brower VG, Fu Y, Matta SG, Sharp BM (2002) Rat strain differences in nicotine self-
administration using an unlimited access paradigm. Brain research 930(1-2):12-
20
Browne CL (1990) The Design of Cigarettes. Hoechst Celanese
Buchhalter AR, Schrinel L, Eissenberg T (2001) Withdrawal-suppressing effects of a
novel smoking system: comparison with own brand, not own brand, and de-
nicotinized cigarettes. Nicotine & tobacco research : official journal of the Society
for Research on Nicotine and Tobacco 3(2):111-8
doi:10.1080/14622200110042636
Bullen C, McRobbie H, Thornley S, Glover M, Lin R, Laugesen M (2010) Effect of an
electronic nicotine delivery device (e cigarette) on desire to smoke and
withdrawal, user preferences and nicotine delivery: randomised cross-over trial.
Tobacco control 19(2):98-103 doi:10.1136/tc.2009.031567
Butschky MF, Bailey D, Henningfield JE, Pickworth WB (1995) Smoking without nicotine
delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacology,
biochemistry, and behavior 50(1):91-6
Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF (2002)
Importance of nonpharmacological factors in nicotine self-administration.
Physiology & behavior 77(4-5):683-7
Caggiula AR, Donny EC, Palmatier MI, Liu X, Chaudhri N, Sved AF (2009) The role of
nicotine in smoking: a dual-reinforcement model. Nebraska Symposium on
Motivation Nebraska Symposium on Motivation 55:91-109
Cahn Z, Siegel M (2011) Electronic cigarettes as a harm reduction strategy for tobacco
control: a step forward or a repeat of past mistakes? Journal of public health
policy 32(1):16-31 doi:10.1057/jphp.2010.41
Nicotine reduction
67
Cao J, Belluzzi JD, Loughlin SE, Keyler DE, Pentel PR, Leslie FM (2007) Acetaldehyde,
a major constituent of tobacco smoke, enhances behavioral, endocrine, and
neuronal responses to nicotine in adolescent and adult rats.
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 32(9):2025-35 doi:10.1038/sj.npp.1301327
Caraballo RS, Novak SP, Asman K (2009) Linking quantity and frequency profiles of
cigarette smoking to the presence of nicotine dependence symptoms among
adolescent smokers: findings from the 2004 National Youth Tobacco Survey.
Nicotine & tobacco research : official journal of the Society for Research on
Nicotine and Tobacco 11(1):49-57 doi:10.1093/ntr/ntn008
Carpenter CM, Wayne GF, Connolly GN (2005) Designing cigarettes for women: new
findings from the tobacco industry documents. Addiction 100(6):837-51
doi:10.1111/j.1360-0443.2005.01072.x
Carpenter CM, Wayne GF, Connolly GN (2007) The role of sensory perception in the
development and targeting of tobacco products. Addiction 102(1):136-47
doi:10.1111/j.1360-0443.2006.01649.x
Carter BL, Tiffany ST (1999) Cue-reactivity and the future of addiction research.
Addiction 94(3):349-51
Carter LP, Stitzer ML, Henningfield JE, O'Connor RJ, Cummings KM, Hatsukami DK
(2009) Abuse liability assessment of tobacco products including potential
reduced exposure products. Cancer epidemiology, biomarkers & prevention : a
publication of the American Association for Cancer Research, cosponsored by
the American Society of Preventive Oncology 18(12):3241-62 doi:10.1158/1055-
9965.EPI-09-0948
Celebucki CC, Wayne GF, Connolly GN, Pankow JF, Chang EI (2005) Characterization
of measured menthol in 48 U.S. cigarette sub-brands. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
7(4):523-31 doi:10.1080/14622200500186270
Chaudhri N, et al. (2007) Self-administered and noncontingent nicotine enhance
reinforced operant responding in rats: impact of nicotine dose and reinforcement
schedule. Psychopharmacology 190(3):353-62 doi:10.1007/s00213-006-0454-8
Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF (2006) Complex
interactions between nicotine and nonpharmacological stimuli reveal multiple
roles for nicotine in reinforcement. Psychopharmacology 184(3-4):353-66
doi:10.1007/s00213-005-0178-1
Chen H, Matta SG, Sharp BM (2007) Acquisition of nicotine self-administration in
adolescent rats given prolonged access to the drug. Neuropsychopharmacology :
official publication of the American College of Neuropsychopharmacology
32(3):700-9 doi:10.1038/sj.npp.1301135
Nicotine reduction
68
Clemens KJ, Caille S, Stinus L, Cador M (2009) The addition of five minor tobacco
alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous
self-administration in rats. The international journal of neuropsychopharmacology
/ official scientific journal of the Collegium Internationale
Neuropsychopharmacologicum 12(10):1355-66
doi:10.1017/S1461145709000273
Cohen C, Perrault G, Griebel G, Soubrie P (2005) Nicotine-associated cues maintain
nicotine-seeking behavior in rats several weeks after nicotine withdrawal:
reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716).
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 30(1):145-55 doi:10.1038/sj.npp.1300541
Cohen N (1971) Minutes of Meeting on May 6 1971. In: Rothmans (ed). British
American Tobacco
Colby SM, Tiffany ST, Shiffman S, Niaura RS (2000) Measuring nicotine dependence
among youth: a review of available approaches and instruments. Drug and
alcohol dependence 59 Suppl 1:S23-39
Comer SD, Ashworth JB, Foltin RW, Johanson CE, Zacny JP, Walsh SL (2008) The
role of human drug self-administration procedures in the development of
medications. Drug and alcohol dependence 96(1-2):1-15
doi:10.1016/j.drugalcdep.2008.03.001
Connolly GN, Alpert HR, Wayne GF, Koh H (2007) Trends in nicotine yield in smoke
and its relationship with design characteristics among popular US cigarette
brands, 1997-2005. Tobacco control 16(5):e5 doi:10.1136/tc.2006.019695
Connolly GN, Behm I, Healton CG, Alpert HR (2012) Public attitudes regarding banning
of cigarettes and regulation of nicotine. American journal of public health
102(4):e1-2 doi:10.2105/AJPH.2011.300583
Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a
limited-access schedule. Psychopharmacology 99(4):473-8
Corrigall WA, Zack M, Eissenberg T, Belsito L, Scher R (2001) Acute subjective and
physiological responses to smoking in adolescents. Addiction 96(10):1409-17
doi:10.1080/09652140120075143
Cox BM, Goldstein A, Nelson WT (1984) Nicotine self-administration in rats. British
journal of pharmacology 83(1):49-55
Cui Y, Wen W, Moriarty CJ, Levine RS (2006) Risk factors and their effects on the
dynamic process of smoking relapse among veteran smokers. Behaviour
research and therapy 44(7):967-81 doi:10.1016/j.brat.2005.07.006
Czoli CD, Hammond D (2013) Cigarette Packaging: Youth Perceptions of "Natural"
Cigarettes, Filter References, and Contraband Tobacco. The Journal of
Nicotine reduction
69
adolescent health : official publication of the Society for Adolescent Medicine
doi:10.1016/j.jadohealth.2013.07.016
Dallery J, Houtsmuller EJ, Pickworth WB, Stitzer ML (2003) Effects of cigarette nicotine
content and smoking pace on subsequent craving and smoking.
Psychopharmacology 165(2):172-80 doi:10.1007/s00213-002-1242-8
Dar R, Frenk H (2004) Do smokers self-administer pure nicotine? A review of the
evidence. Psychopharmacology 173(1-2):18-26 doi:10.1007/s00213-004-1781-2
Darredeau C, Barrett SP (2010) The role of nicotine content information in smokers'
subjective responses to nicotine and placebo inhalers. Human
psychopharmacology 25(7-8):577-81 doi:10.1002/hup.1159
Darredeau C, Stewart SH, Barrett SP (2013) The effects of nicotine content information
on subjective and behavioural responses to nicotine-containing and denicotinized
cigarettes. Behavioural pharmacology 24(4):291-7
doi:10.1097/FBP.0b013e3283635fd9
Dawkins L, Corcoran O (2013) Acute electronic cigarette use: nicotine delivery and
subjective effects in regular users. Psychopharmacology doi:10.1007/s00213-
013-3249-8
Dawkins L, Turner J, Crowe E (2013a) Nicotine derived from the electronic cigarette
improves time-based prospective memory in abstinent smokers.
Psychopharmacology 227(3):377-84 doi:10.1007/s00213-013-2983-2
Dawkins L, Turner J, Roberts A, Soar K (2013b) 'Vaping' profiles and preferences: an
online survey of electronic cigarette users. Addiction 108(6):1115-25
doi:10.1111/add.12150
De Leon E, Smith KC, Cohen JE (2013) Dependence measures for non-cigarette
tobacco products within the context of the global epidemic: a systematic review.
Tobacco control doi:10.1136/tobaccocontrol-2012-050641
DeGrandpre RJ, Bickel WK, Hughes JR, Higgins ST (1992) Behavioral economics of
drug self-administration. III. A reanalysis of the nicotine regulation hypothesis.
Psychopharmacology 108(1-2):1-10
DeNoble VJ, Mele PC (2006) Intravenous nicotine self-administration in rats: effects of
mecamylamine, hexamethonium and naloxone. Psychopharmacology 184(3-
4):266-72 doi:10.1007/s00213-005-0054-z
DiFranza J, et al. (2010a) A systematic review of the Diagnostic and Statistical Manual
diagnostic criteria for nicotine dependence. Addictive behaviors 35(5):373-82
doi:10.1016/j.addbeh.2009.12.013
DiFranza JR, et al. (2007a) Symptoms of tobacco dependence after brief intermittent
use: the Development and Assessment of Nicotine Dependence in Youth-2
Nicotine reduction
70
study. Archives of pediatrics & adolescent medicine 161(7):704-10
doi:10.1001/archpedi.161.7.704
DiFranza JR, et al. (2007b) Susceptibility to nicotine dependence: the Development and
Assessment of Nicotine Dependence in Youth 2 study. Pediatrics 120(4):e974-83
doi:10.1542/peds.2007-0027
DiFranza JR, et al. (2002) Development of symptoms of tobacco dependence in youths:
30 month follow up data from the DANDY study. Tobacco control 11(3):228-35
DiFranza JR, Ursprung WW, Carson A (2010b) New insights into the compulsion to use
tobacco from an adolescent case-series. Journal of adolescence 33(1):209-14
doi:10.1016/j.adolescence.2009.03.009
Donny EC, Caggiula AR, Knopf S, Brown C (1995) Nicotine self-administration in rats.
Psychopharmacology 122(4):390-94
Donny EC, et al. (2003) Operant responding for a visual reinforcer in rats is enhanced
by noncontingent nicotine: implications for nicotine self-administration and
reinforcement. Psychopharmacology 169(1):68-76 doi:10.1007/s00213-003-
1473-3
Donny EC, Houtsmuller E, Stitzer ML (2007) Smoking in the absence of nicotine:
behavioral, subjective and physiological effects over 11 days. Addiction
102(2):324-34 doi:10.1111/j.1360-0443.2006.01670.x
Donny EC, Jones M (2009) Prolonged exposure to denicotinized cigarettes with or
without transdermal nicotine. Drug and alcohol dependence 104(1-2):23-33
doi:10.1016/j.drugalcdep.2009.01.021
Donny EC, et al. (2012) Impact of tobacco regulation on animal research: new
perspectives and opportunities. Nicotine & tobacco research : official journal of
the Society for Research on Nicotine and Tobacco 14(11):1319-38
doi:10.1093/ntr/nts162
Doran N, Schweizer CA, Myers MG (2011) Do expectancies for reinforcement from
smoking change after smoking initiation? Psychology of addictive behaviors :
journal of the Society of Psychologists in Addictive Behaviors 25(1):101-7
doi:10.1037/a0020361
Dunsby J, Bero L (2004) A nicotine delivery device without the nicotine? Tobacco
industry development of low nicotine cigarettes. Tobacco control 13(4):362-9
doi:10.1136/tc.2004.007914
Eissenberg T (2010) Electronic nicotine delivery devices: ineffective nicotine delivery
and craving suppression after acute administration. Tobacco control 19(1):87-8
doi:10.1136/tc.2009.033498
Eissenberg T, Adams C, Riggins EC, 3rd, Likness M (1999) Smokers' sex and the
effects of tobacco cigarettes: subject-rated and physiological measures. Nicotine
Nicotine reduction
71
& tobacco research : official journal of the Society for Research on Nicotine and
Tobacco 1(4):317-24
Fant RV, Everson D, Dayton G, Pickworth WB, Henningfield JE (1996) Nicotine
dependence in women. Journal of the American Medical Women's Association
51(1-2):19-20, 22-4, 28
Ferris Wayne G, Connolly GN (2004) Application, function, and effects of menthol in
cigarettes: a survey of tobacco industry documents. Nicotine & tobacco research
: official journal of the Society for Research on Nicotine and Tobacco 6 Suppl
1:S43-54 doi:10.1080/14622203310001649513
Ferris Wayne G, Connolly GN, Henningfield JE (2006) Brand differences of free-base
nicotine delivery in cigarette smoke: the view of the tobacco industry documents.
Tobacco control 15(3):189-98 doi:10.1136/tc.2005.013805
Fix BV, O'Connor RJ, Fong GT, Borland R, Cummings KM, Hyland A (2011) Smokers'
reactions to FDA regulation of tobacco products: findings from the 2009 ITC
United States survey. BMC public health 11:941 doi:10.1186/1471-2458-11-941
Fulton HG, Barrett SP (2008) A demonstration of intravenous nicotine self-
administration in humans? Neuropsychopharmacology : official publication of the
American College of Neuropsychopharmacology 33(8):2042-3; author reply 2044
doi:10.1038/sj.npp.1301545
Galeotti N, Ghelardini C, Mannelli L, Mazzanti G, Baghiroli L, Bartolini A (2001) Local
anaesthetic activity of (+)- and (-)-menthol. Planta medica 67(2):174-6
doi:10.1055/s-2001-11515
Geiss VL (1972) Bw Process I: Reductions of Tobacco Nicotine Using Selected
Bacteria. In: Williamson B (ed). British American Tobacco
Geiss VL (1975) Bw Process VI: Metabolism of Nicotine and Other Biochemistry of the
Bw Process. In: Williamson B (ed). British American Tobacco
Gervais A, O'Loughlin J, Meshefedjian G, Bancej C, Tremblay M (2006) Milestones in
the natural course of onset of cigarette use among adolescents. CMAJ :
Canadian Medical Association journal = journal de l'Association medicale
canadienne 175(3):255-61 doi:10.1503/cmaj.051235
Gibb RM (1974) [untitled memo]. In: Tobacco BA (ed).
Girdhar G, Xu S, Bluestein D, Jesty J (2008) Reduced-nicotine cigarettes increase
platelet activation in smokers in vivo: a dilemma in harm reduction. Nicotine &
tobacco research : official journal of the Society for Research on Nicotine and
Tobacco 10(12):1737-44 doi:10.1080/14622200802443528
Givel MS (2011) History of Bhutan's prohibition of cigarettes: implications for neo-
prohibitionists and their critics. The International journal on drug policy 22(4):306-
10 doi:10.1016/j.drugpo.2011.05.006
Nicotine reduction
72
Glautier S (2004) Measures and models of nicotine dependence: positive reinforcement.
Addiction 99 Suppl 1:30-50 doi:10.1111/j.1360-0443.2004.00736.x
Grady SR, Marks MJ, Collins AC (1994) Desensitization of nicotine-stimulated
[3H]dopamine release from mouse striatal synaptosomes. Journal of
neurochemistry 62(4):1390-8
Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA (2004) Nicotine dependence
and psychiatric disorders in the United States: results from the national
epidemiologic survey on alcohol and related conditions. Archives of general
psychiatry 61(11):1107-15 doi:10.1001/archpsyc.61.11.1107
Gravely LEN, R.P.; Geiss, V.L. (1973) Bw Process: IV Evaluation of Low Nicotine
Cigarettes Used for Consumer Product Testing. In: Williamson B (ed). British
American Tobacco
Gray N, et al. (2005) Toward a comprehensive long term nicotine policy. Tobacco
control 14(3):161-5 doi:10.1136/tc.2004.010272
Green CR (1979) Denicotinization of low nicotine, high sugar flue cured tobacco. In:
Reynolds R (ed).
Gregory CF (1980) Observation of free nicotine changes in tobacco smoke/#528. Brown
& Williamson
Gritz ER, Nielsen IR, Brooks LA (1996) Smoking cessation and gender: the influence of
physiological, psychological, and behavioral factors. Journal of the American
Medical Women's Association 51(1-2):35-42
Gross J, Lee J, Stitzer ML (1997) Nicotine-containing versus de-nicotinized cigarettes:
effects on craving and withdrawal. Pharmacology, biochemistry, and behavior
57(1-2):159-65
Guillem K, et al. (2005) Monoamine oxidase inhibition dramatically increases the
motivation to self-administer nicotine in rats. The Journal of neuroscience : the
official journal of the Society for Neuroscience 25(38):8593-600
doi:10.1523/JNEUROSCI.2139-05.2005
Guillem K, Vouillac C, Koob GF, Cador M, Stinus L (2008) Monoamine oxidase
inhibition dramatically prolongs the duration of nicotine withdrawal-induced place
aversion. Biological psychiatry 63(2):158-63 doi:10.1016/j.biopsych.2007.04.029
Gullotta FH, C.; Martin, B. (1991) The Effects of Nicotine and Menthol on
Electrophysiological and Subjective Responses. Philip MOrris
Gullotta FPH, C.S.; Martin, B.R. (1990) Electrophysiological and subjective effect of
cigarettes delivering varying amounts of nicotine. In: Morris P (ed).
Gullotta FPS, C. (1981) The effects of cigarette smoking on pattern reversal evoked
potentials (preps). In: Morris P (ed).
Nicotine reduction
73
Gullotta FPS, C. (1982) Electrophysiological studies – 820000 annual report. In: Morris
P (ed).
Hanson HM, Ivester CA, Morton BR (1979) Nicotine self-administration in rats. NIDA
research monograph(23):70-90
Harris AC, Pentel PR, Burroughs D, Staley MD, Lesage MG (2011) A lack of
association between severity of nicotine withdrawal and individual differences in
compensatory nicotine self-administration in rats. Psychopharmacology
217(2):153-66 doi:10.1007/s00213-011-2273-9
Harvey DM, Yasar S, Heishman SJ, Panlilio LV, Henningfield JE, Goldberg SR (2004)
Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in
human cigarette smokers. Psychopharmacology 175(2):134-42
doi:10.1007/s00213-004-1818-6
Hatsukami DK (2013) Ending tobacco-caused mortality and morbidity: the case for
performance standards for tobacco products. Tobacco control 22 Suppl 1:i36-7
doi:10.1136/tobaccocontrol-2012-050785
Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M (2013a) Nicotine
reduction: strategic research plan. Nicotine & tobacco research : official journal of
the Society for Research on Nicotine and Tobacco 15(6):1003-13
doi:10.1093/ntr/nts214
Hatsukami DK, Biener L, Leischow SJ, Zeller MR (2012) Tobacco and nicotine product
testing. Nicotine & tobacco research : official journal of the Society for Research
on Nicotine and Tobacco 14(1):7-17 doi:10.1093/ntr/ntr027
Hatsukami DK, et al. (2013b) Reduced nicotine content cigarettes and nicotine patch.
Cancer epidemiology, biomarkers & prevention : a publication of the American
Association for Cancer Research, cosponsored by the American Society of
Preventive Oncology 22(6):1015-24 doi:10.1158/1055-9965.EPI-12-1439
Hatsukami DK, et al. (2007) Developing the science base for reducing tobacco harm.
Nicotine & tobacco research : official journal of the Society for Research on
Nicotine and Tobacco 9 Suppl 4:S537-53 doi:10.1080/14622200701679040
Hatsukami DK, et al. (2010a) Reduced nicotine content cigarettes: effects on toxicant
exposure, dependence and cessation. Addiction 105(2):343-55
doi:10.1111/j.1360-0443.2009.02780.x
Hatsukami DK, Lemmonds C, Tomar SL (2004) Smokeless tobacco use: harm
reduction or induction approach? Preventive medicine 38(3):309-17
doi:10.1016/j.ypmed.2003.10.006
Hatsukami DK, et al. (2010b) Nicotine reduction revisited: science and future directions.
Tobacco control 19(5):e1-10 doi:10.1136/tc.2009.035584
Nicotine reduction
74
Heeschen C, Weis M, Cooke JP (2003) Nicotine promotes arteriogenesis. Journal of the
American College of Cardiology 41(3):489-96
Heinz AJ, Kassel JD, Berbaum M, Mermelstein R (2010) Adolescents' expectancies for
smoking to regulate affect predict smoking behavior and nicotine dependence
over time. Drug and alcohol dependence 111(1-2):128-35
doi:10.1016/j.drugalcdep.2010.04.001
Heishman SJ, Kleykamp BA, Singleton EG (2010) Meta-analysis of the acute effects of
nicotine and smoking on human performance. Psychopharmacology 210(4):453-
69 doi:10.1007/s00213-010-1848-1
Hendricks PS, Prochaska JJ, Humfleet GL, Hall SM (2008) Evaluating the validities of
different DSM-IV-based conceptual constructs of tobacco dependence. Addiction
103(7):1215-23 doi:10.1111/j.1360-0443.2008.02232.x
Henningfield J, Pankow J, Garrett B (2004a) Ammonia and other chemical base
tobacco additives and cigarette nicotine delivery: issues and research needs.
Nicotine & tobacco research : official journal of the Society for Research on
Nicotine and Tobacco 6(2):199-205 doi:10.1080/1462220042000202472
Henningfield JE, et al. (2004b) Reducing tobacco addiction through tobacco product
regulation. Tobacco control 13(2):132-5
Henningfield JE, Benowitz NL, Slade J, Houston TP, Davis RM, Deitchman SD (1998)
Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American
Medical Association. Tobacco control 7(3):281-93
Henningfield JE, Fant RV, Tomar SL (1997) Smokeless tobacco: an addicting drug.
Advances in dental research 11(3):330-5
Henningfield JE, Goldberg SR (1983) Control of behavior by intravenous nicotine
injections in human subjects. Pharmacology, biochemistry, and behavior
19(6):1021-6
Henningfield JE, Hatsukami DK, Zeller M, Peters E (2011) Conference on abuse liability
and appeal of tobacco products: conclusions and recommendations. Drug and
alcohol dependence 116(1-3):1-7 doi:10.1016/j.drugalcdep.2010.12.009
Henningfield JE, Miyasato K, Jasinski DR (1983) Cigarette smokers self-administer
intravenous nicotine. Pharmacology, biochemistry, and behavior 19(5):887-90
Henningfield JE, Shiffman S, Ferguson SG, Gritz ER (2009) Tobacco dependence and
withdrawal: science base, challenges and opportunities for pharmacotherapy.
Pharmacology & therapeutics 123(1):1-16 doi:10.1016/j.pharmthera.2009.03.011
Hoffmann D, Hoffmann I (1997) The changing cigarette, 1950-1995. Journal of
toxicology and environmental health 50(4):307-64
doi:10.1080/009841097160393
Nicotine reduction
75
Houghton KS (1990) Monthly Development Summary - May, 1990., Philip Morris
Hughes JR, Baker T, Breslau N, Covey L, Shiffman S (2011) Applicability of DSM
criteria to nicotine dependence. Addiction 106(5):894-5; discussion 895-7
doi:10.1111/j.1360-0443.2010.03281.x
Hughes JR, Gulliver SB, Amori G, Mireault GC, Fenwick JF (1989) Effect of instructions
and nicotine on smoking cessation, withdrawal symptoms and self-administration
of nicotine gum. Psychopharmacology 99(4):486-91
Hughes JR, et al. (2004) Concordance of different measures of nicotine dependence:
two pilot studies. Addictive behaviors 29(8):1527-39
doi:10.1016/j.addbeh.2004.02.031
Hukkanen J, Jacob P, 3rd, Benowitz NL (2005) Metabolism and disposition kinetics of
nicotine. Pharmacological reviews 57(1):79-115 doi:10.1124/pr.57.1.3
Hurt RD, Robertson CR (1998) Prying open the door to the tobacco industry's secrets
about nicotine: the Minnesota Tobacco Trial. JAMA : the journal of the American
Medical Association 280(13):1173-81
Hyland A, et al. (2005) Access to low-taxed cigarettes deters smoking cessation
attempts. American journal of public health 95(6):994-5
doi:10.2105/AJPH.2004.057687
Hyland A, et al. (2006) Cigarette purchase patterns in four countries and the relationship
with cessation: findings from the International Tobacco Control (ITC) Four
Country Survey. Tobacco control 15 Suppl 3:iii59-64 doi:10.1136/tc.2005.012203
IEC; Industrial Economics, Incorporated,. (2013) Modeling the Health Benefits of a
Nicotine Standard for Tobacco Products Sold in Canada.
Institute of Medicine (1994) The nature of nicotine addiction. In Growing Up Tobacco
Free—Preventing Nicotine Addiction in Children and Youths (eds. Lynch, B.S.,
Bonnie, R.J.). National Academy Press, Washington D.C., p 28-68
Jarvis MJ, Bates C (1999) Eliminating nicotine in cigarettes. Tobacco control 8(1):106-7;
author reply 107-9
Joel DL, Denlinger RL, Dermody SS, Hatsukami DK, Benowitz NL, Donny EC (2012)
Very low nicotine content cigarettes and potential consequences on
cardiovascular disease. Current cardiovascular risk reports 6(6):534-541
doi:10.1007/s12170-012-0266-9
Johnson DP (1977) Low Nicotine Tobacco In: Reynolds R (ed).
Johnson MW, Bickel WK, Kirshenbaum AP (2004) Substitutes for tobacco smoking: a
behavioral economic analysis of nicotine gum, denicotinized cigarettes, and
nicotine-containing cigarettes. Drug and alcohol dependence 74(3):253-64
doi:10.1016/j.drugalcdep.2003.12.012
Nicotine reduction
76
Joossens L, Raw M (2003) Turning off the tap: the real solution to cigarette smuggling.
The international journal of tuberculosis and lung disease : the official journal of
the International Union against Tuberculosis and Lung Disease 7(3):214-22
Joossens L, Raw M (2008) Progress in combating cigarette smuggling: controlling the
supply chain. Tobacco control 17(6):399-404 doi:10.1136/tc.2008.026567
Juliano LM, Brandon TH (2002) Effects of nicotine dose, instructional set, and outcome
expectancies on the subjective effects of smoking in the presence of a stressor.
Journal of abnormal psychology 111(1):88-97
Juliano LM, Fucito LM, Harrell PT (2011) The influence of nicotine dose and nicotine
dose expectancy on the cognitive and subjective effects of cigarette smoking.
Experimental and clinical psychopharmacology 19(2):105-15
doi:10.1037/a0022937
Kandel DB, Hu MC, Griesler PC, Schaffran C (2007) On the development of nicotine
dependence in adolescence. Drug and alcohol dependence 91(1):26-39
doi:10.1016/j.drugalcdep.2007.04.011
Kassel JD, Evatt DP, Greenstein JE, Wardle MC, Yates MC, Veilleux JC (2007a) The
acute effects of nicotine on positive and negative affect in adolescent smokers.
Journal of abnormal psychology 116(3):543-53 doi:10.1037/0021-
843X.116.3.543
Kassel JD, et al. (2007b) Smoking topography in response to denicotinized and high-
yield nicotine cigarettes in adolescent smokers. The Journal of adolescent health
: official publication of the Society for Adolescent Medicine 40(1):54-60
doi:10.1016/j.jadohealth.2006.08.006
Kassman AJK, D.B.; Lilly, A.C.; Sherwood, J.F. (1986) Alkaloid Reduced Tobaco (ART)
Program Current Status and Plans for 1987. . Philip Morris
Kentucky Tobacco Research Board (1977) Kentucky Tobacco Research Board - 1977
Annual Review. In: Collection NM (ed).
Kirsch I, Lynn SJ (1999) Automaticity in clinical psychology. The American psychologist
54(7):504-15
Kota D, Martin BR, Damaj MI (2008) Age-dependent differences in nicotine reward and
withdrawal in female mice. Psychopharmacology 198(2):201-10
doi:10.1007/s00213-008-1117-8
Kota D, Martin BR, Robinson SE, Damaj MI (2007) Nicotine dependence and reward
differ between adolescent and adult male mice. The Journal of pharmacology
and experimental therapeutics 322(1):399-407 doi:10.1124/jpet.107.121616
Lando HA, et al. (1999) Age of initiation, smoking patterns, and risk in a population of
working adults. Preventive medicine 29(6 Pt 1):590-8
doi:10.1006/pmed.1999.0590
Nicotine reduction
77
Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH (2000)
Smoking and mental illness: A population-based prevalence study. JAMA : the
journal of the American Medical Association 284(20):2606-10
Lawrence D, Considine J, Mitrou F, Zubrick SR (2010) Anxiety disorders and cigarette
smoking: Results from the Australian Survey of Mental Health and Wellbeing.
The Australian and New Zealand journal of psychiatry 44(6):520-7
doi:10.3109/00048670903571580
Lawrence D, Mitrou F (2009) One-third of adult smokers have a mental illness. The
Australian and New Zealand journal of psychiatry 43(2):177-8
Le Foll B, Goldberg SR (2005) Control of the reinforcing effects of nicotine by
associated environmental stimuli in animals and humans. Trends in
pharmacological sciences 26(6):287-93 doi:10.1016/j.tips.2005.04.005
Le Foll B, Wertheim C, Goldberg SR (2007) High reinforcing efficacy of nicotine in non-
human primates. PloS one 2(2):e230 doi:10.1371/journal.pone.0000230
Le Houezec J, Aubin HJ (2013) Pharmacotherapies and harm-reduction options for the
treatment of tobacco dependence. Expert opinion on pharmacotherapy
14(14):1959-67 doi:10.1517/14656566.2013.818978
Le Houezec J, McNeill A, Britton J (2011) Tobacco, nicotine and harm reduction. Drug
and alcohol review 30(2):119-23 doi:10.1111/j.1465-3362.2010.00264.x
Lee LY, Gerhardstein DC, Wang AL, Burki NK (1993) Nicotine is responsible for airway
irritation evoked by cigarette smoke inhalation in men. Journal of applied
physiology 75(5):1955-61
Lee S, Ling PM, Glantz SA (2012) The vector of the tobacco epidemic: tobacco industry
practices in low and middle-income countries. Cancer causes & control : CCC 23
Suppl 1:117-29 doi:10.1007/s10552-012-9914-0
Legresley E, Lee K, Muggli ME, Patel P, Collin J, Hurt RD (2008) British American
Tobacco and the "insidious impact of illicit trade" in cigarettes across Africa.
Tobacco control 17(5):339-46 doi:10.1136/tc.2008.025999
Leonard S, Adams CE (2006) Smoking cessation and schizophrenia. The American
journal of psychiatry 163(11):1877 doi:10.1176/appi.ajp.163.11.1877
Leonard S, et al. (2001) Smoking and mental illness. Pharmacology, biochemistry, and
behavior 70(4):561-70
Lessov-Schlaggar CN, Pergadia ML, Khroyan TV, Swan GE (2008) Genetics of nicotine
dependence and pharmacotherapy. Biochemical pharmacology 75(1):178-95
doi:10.1016/j.bcp.2007.08.018
Nicotine reduction
78
Levin ED, et al. (2007) Adolescent vs. adult-onset nicotine self-administration in male
rats: duration of effect and differential nicotinic receptor correlates.
Neurotoxicology and teratology 29(4):458-65 doi:10.1016/j.ntt.2007.02.002
Levin ED, Rezvani AH, Montoya D, Rose JE, Swartzwelder HS (2003) Adolescent-
onset nicotine self-administration modeled in female rats. Psychopharmacology
169(2):141-9 doi:10.1007/s00213-003-1486-y
Lewis A, Miller JH, Lea RA (2007) Monoamine oxidase and tobacco dependence.
Neurotoxicology 28(1):182-95 doi:10.1016/j.neuro.2006.05.019
Licht AS, et al. (2011) How do price minimizing behaviors impact smoking cessation?
Findings from the International Tobacco Control (ITC) Four Country Survey.
International journal of environmental research and public health 8(5):1671-91
doi:10.3390/ijerph8051671
Lindson-Hawley N, Aveyard P, Hughes JR (2012) Reduction versus abrupt cessation in
smokers who want to quit. The Cochrane database of systematic reviews
11:CD008033 doi:10.1002/14651858.CD008033.pub3
Lu Y, Marks MJ, Collins AC (1999) Desensitization of nicotinic agonist-induced
[3H]gamma-aminobutyric acid release from mouse brain synaptosomes is
produced by subactivating concentrations of agonists. The Journal of
pharmacology and experimental therapeutics 291(3):1127-34
Matta SG, et al. (2007) Guidelines on nicotine dose selection for in vivo research.
Psychopharmacology 190(3):269-319 doi:10.1007/s00213-006-0441-0
McClave AK, McKnight-Eily LR, Davis SP, Dube SR (2010) Smoking characteristics of
adults with selected lifetime mental illnesses: results from the 2007 National
Health Interview Survey. American journal of public health 100(12):2464-72
doi:10.2105/AJPH.2009.188136
McNeill A, Hammond D, Gartner C (2012) Whither tobacco product regulation? Tobacco
control 21(2):221-6 doi:10.1136/tobaccocontrol-2011-050258
McQuown SC, Belluzzi JD, Leslie FM (2007) Low dose nicotine treatment during early
adolescence increases subsequent cocaine reward. Neurotoxicology and
teratology 29(1):66-73 doi:10.1016/j.ntt.2006.10.012
Mecredy GC, Diemert LM, Callaghan RC, Cohen JE (2013) Association between use of
contraband tobacco and smoking cessation outcomes: a population-based cohort
study. CMAJ : Canadian Medical Association journal = journal de l'Association
medicale canadienne 185(7):E287-94 doi:10.1503/cmaj.111861
Megerdichian CL, Rees VW, Wayne GF, Connolly GN (2007) Internal tobacco industry
research on olfactory and trigeminal nerve response to nicotine and other smoke
components. Nicotine & tobacco research : official journal of the Society for
Nicotine reduction
79
Research on Nicotine and Tobacco 9(11):1119-29
doi:10.1080/14622200701648458
Mineur YS, Picciotto MR (2009) Biological basis for the co-morbidity between smoking
and mood disorders. Journal of dual diagnosis 5(2):122-130
doi:10.1080/15504260902869964
Mineur YS, Picciotto MR (2010) Nicotine receptors and depression: revisiting and
revising the cholinergic hypothesis. Trends in pharmacological sciences
31(12):580-6 doi:10.1016/j.tips.2010.09.004
Moolchan ET, et al. (2002) The Fagerstrom Test for Nicotine Dependence and the
Diagnostic Interview Schedule: do they diagnose the same smokers? Addictive
behaviors 27(1):101-13
Mooney ME, Johnson EO, Breslau N, Bierut LJ, Hatsukami DK (2011) Cigarette
smoking reduction and changes in nicotine dependence. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
13(6):426-30 doi:10.1093/ntr/ntr019
Murray JE, Bevins RA (2007) Behavioral and neuropharmacological characterization of
nicotine as a conditional stimulus. European journal of pharmacology 561(1-
3):91-104 doi:10.1016/j.ejphar.2007.01.046
National Cancer Institute (2001) Monograph 13: Risks Associated with Smoking
Cigarettes with Low Tar Machine-Measured Yields of Tar and Nicotine.
Bethesda, MD: National Cancer Institute
O'Connor RJ (2012) Non-cigarette tobacco products: what have we learnt and where
are we headed? Tobacco control 21(2):181-90 doi:10.1136/tobaccocontrol-2011-
050281
O'Loughlin J, et al. (2003) Nicotine-dependence symptoms are associated with smoking
frequency in adolescents. American journal of preventive medicine 25(3):219-25
Olausson P, Jentsch JD, Taylor JR (2003) Repeated nicotine exposure enhances
reward-related learning in the rat. Neuropsychopharmacology : official publication
of the American College of Neuropsychopharmacology 28(7):1264-71
doi:10.1038/sj.npp.1300173
Olausson P, Jentsch JD, Taylor JR (2004) Nicotine enhances responding with
conditioned reinforcement. Psychopharmacology 171(2):173-8
doi:10.1007/s00213-003-1575-y
Palmatier MI, Coddington SB, Liu X, Donny EC, Caggiula AR, Sved AF (2008) The
motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose.
Neuropharmacology 55(8):1425-30 doi:10.1016/j.neuropharm.2008.09.002
Palmatier MI, Liu X, Caggiula AR, Donny EC, Sved AF (2007a) The role of nicotinic
acetylcholine receptors in the primary reinforcing and reinforcement-enhancing
Nicotine reduction
80
effects of nicotine. Neuropsychopharmacology : official publication of the
American College of Neuropsychopharmacology 32(5):1098-108
doi:10.1038/sj.npp.1301228
Palmatier MI, Liu X, Matteson GL, Donny EC, Caggiula AR, Sved AF (2007b)
Conditioned reinforcement in rats established with self-administered nicotine and
enhanced by noncontingent nicotine. Psychopharmacology 195(2):235-43
doi:10.1007/s00213-007-0897-6
Palmatier MI, O'Brien LC, Hall MJ (2012) The role of conditioning history and reinforcer
strength in the reinforcement enhancing effects of nicotine in rats.
Psychopharmacology 219(4):1119-31 doi:10.1007/s00213-011-2439-5
Pankow JF (2001) A consideration of the role of gas/particle partitioning in the
deposition of nicotine and other tobacco smoke compounds in the respiratory
tract. Chemical research in toxicology 14(11):1465-81
Pankow JF, Tavakoli AD, Luo W, Isabelle LM (2003) Percent free base nicotine in the
tobacco smoke particulate matter of selected commercial and reference
cigarettes. Chemical research in toxicology 16(8):1014-8 doi:10.1021/tx0340596
Panzano VC, Wayne GF, Pickworth WB, Connolly GN (2010) Human
electroencephalography and the tobacco industry: a review of internal
documents. Tobacco control 19(2):153-9 doi:10.1136/tc.2009.032805
Parascandola M (2011) Tobacco harm reduction and the evolution of nicotine
dependence. American journal of public health 101(4):632-41
doi:10.2105/AJPH.2009.189274
Parascandola M, Augustson E, O'Connell ME, Marcus S (2009) Consumer awareness
and attitudes related to new potential reduced-exposure tobacco product brands.
Nicotine & tobacco research : official journal of the Society for Research on
Nicotine and Tobacco 11(7):886-95 doi:10.1093/ntr/ntp082
Pavananunt P (2011) Illicit cigarette trade in Thailand. The Southeast Asian journal of
tropical medicine and public health 42(6):1531-9
Pearson JL, Abrams DB, Niaura RS, Richardson A, Vallone DM (2013) Public support
for mandated nicotine reduction in cigarettes. American journal of public health
103(3):562-7 doi:10.2105/AJPH.2012.300890
Perkins K, Sayette M, Conklin C, Caggiula A (2003) Placebo effects of tobacco smoking
and other nicotine intake. Nicotine & tobacco research : official journal of the
Society for Research on Nicotine and Tobacco 5(5):695-709
doi:10.1080/1462220031000158636
Perkins KA, Ciccocioppo M, Conklin CA, Milanak ME, Grottenthaler A, Sayette MA
(2008) Mood influences on acute smoking responses are independent of nicotine
Nicotine reduction
81
intake and dose expectancy. Journal of abnormal psychology 117(1):79-93
doi:10.1037/0021-843X.117.1.79
Perkins KA, et al. (2009a) Variability in initial nicotine sensitivity due to sex, history of
other drug use, and parental smoking. Drug and alcohol dependence 99(1-3):47-
57 doi:10.1016/j.drugalcdep.2008.06.017
Perkins KA, Donny E, Caggiula AR (1999) Sex differences in nicotine effects and self-
administration: review of human and animal evidence. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
1(4):301-15
Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula A (2006) Sex
differences in the influence of nicotine dose instructions on the reinforcing and
self-reported rewarding effects of smoking. Psychopharmacology 184(3-4):600-7
doi:10.1007/s00213-005-0103-7
Perkins KA, Gerlach D, Broge M, Fonte C, Wilson A (2001a) Reinforcing effects of
nicotine as a function of smoking status. Experimental and clinical
psychopharmacology 9(3):243-50
Perkins KA, et al. (2001b) Dissociation of nicotine tolerance from tobacco dependence
in humans. The Journal of pharmacology and experimental therapeutics
296(3):849-56
Perkins KA, Grottenthaler A, Ciccocioppo MM, Conklin CA, Sayette MA, Wilson AS
(2009b) Mood, nicotine, and dose expectancy effects on acute responses to
nicotine spray. Nicotine & tobacco research : official journal of the Society for
Research on Nicotine and Tobacco 11(5):540-6 doi:10.1093/ntr/ntp036
Perkins KA, Jacobs L, Ciccocioppo M, Conklin C, Sayette M, Caggiula A (2004) The
influence of instructions and nicotine dose on the subjective and reinforcing
effects of smoking. Experimental and clinical psychopharmacology 12(2):91-101
doi:10.1037/1064-1297.12.2.91
Perkins KA, Sanders M, D'Amico D, Wilson A (1997) Nicotine discrimination and self-
administration in humans as a function of smoking status. Psychopharmacology
131(4):361-70
Philip Morris (1995a) Alkaloid Reduced Tobacco (ART) Program. Philip Morris
Philip Morris (1995b) Study Concept: The Electrophysiological and Subjective Effects of
Smoking Cigarettes with Constant Nicotine But Varying Tar Levels. Philip Morris
Picciotto MR, Addy NA, Mineur YS, Brunzell DH (2008) It is not "either/or": activation
and desensitization of nicotinic acetylcholine receptors both contribute to
behaviors related to nicotine addiction and mood. Progress in neurobiology
84(4):329-42 doi:10.1016/j.pneurobio.2007.12.005
Nicotine reduction
82
Pickworth WB, Fant RV, Nelson RA, Rohrer MS, Henningfield JE (1999)
Pharmacodynamic effects of new de-nicotinized cigarettes. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
1(4):357-64
Plescia F, Brancato A, Marino RA, Cannizzaro C (2013) Acetaldehyde as a drug of
abuse: insight into AM281 administration on operant-conflict paradigm in rats.
Frontiers in behavioral neuroscience 7:64 doi:10.3389/fnbeh.2013.00064
Rees VW, Kreslake JM, Wayne GF, O'Connor RJ, Cummings KM, Connolly GN (2012)
Role of cigarette sensory cues in modifying puffing topography. Drug and alcohol
dependence 124(1-2):1-10 doi:10.1016/j.drugalcdep.2012.01.012
Rickett FLP, P.M. (1980) A Review Of Methods For Reduction Of Nicotine In Tobacco.
American Tobacco
Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ, Li TK (2002)
The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of
alcohol-preferring rats. Pharmacology, biochemistry, and behavior 72(1-2):55-64
Roiko SA, Harris AC, LeSage MG, Keyler DE, Pentel PR (2009) Passive immunization
with a nicotine-specific monoclonal antibody decreases brain nicotine levels but
does not precipitate withdrawal in nicotine-dependent rats. Pharmacology,
biochemistry, and behavior 93(2):105-11 doi:10.1016/j.pbb.2009.04.011
Rooke C, McNeill A, Arnott D (2013) Regulatory issues concerning the development
and circulation of nicotine-containing products: a qualitative study. Nicotine &
tobacco research : official journal of the Society for Research on Nicotine and
Tobacco 15(6):1052-9 doi:10.1093/ntr/nts235
Rose J, Behm F (2004a) Effects of low nicotine content cigarettes on smoke intake.
Nicotine & tobacco research : official journal of the Society for Research on
Nicotine and Tobacco 6(2):309-19 doi:10.1080/14622200410001676378
Rose JE (2006) Nicotine and nonnicotine factors in cigarette addiction.
Psychopharmacology 184(3-4):274-85 doi:10.1007/s00213-005-0250-x
Rose JE (2008) Disrupting nicotine reinforcement: from cigarette to brain. Annals of the
New York Academy of Sciences 1141:233-56 doi:10.1196/annals.1441.019
Rose JE, Behm FM (2004b) Extinguishing the rewarding value of smoke cues:
pharmacological and behavioral treatments. Nicotine & tobacco research : official
journal of the Society for Research on Nicotine and Tobacco 6(3):523-32
doi:10.1080/14622200410001696501
Rose JE, Behm FM, Ramsey C, Ritchie JC, Jr. (2001) Platelet monoamine oxidase,
smoking cessation, and tobacco withdrawal symptoms. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
3(4):383-90 doi:10.1080/14622200110087277
Nicotine reduction
83
Rose JE, Behm FM, Westman EC, Bates JE, Salley A (2003) Pharmacologic and
sensorimotor components of satiation in cigarette smoking. Pharmacology,
biochemistry, and behavior 76(2):243-50
Rose JE, Behm FM, Westman EC, Coleman RE (1999) Arterial nicotine kinetics during
cigarette smoking and intravenous nicotine administration: implications for
addiction. Drug and alcohol dependence 56(2):99-107
Rose JE, Behm FM, Westman EC, Johnson M (2000) Dissociating nicotine and
nonnicotine components of cigarette smoking. Pharmacology, biochemistry, and
behavior 67(1):71-81
Rose JS, Dierker LC (2010) DSM-IV nicotine dependence symptom characteristics for
recent-onset smokers. Nicotine & tobacco research : official journal of the Society
for Research on Nicotine and Tobacco 12(3):278-86 doi:10.1093/ntr/ntp210
Rubinstein ML, Luks TL, Moscicki AB, Dryden W, Rait MA, Simpson GV (2011)
Smoking-related cue-induced brain activation in adolescent light smokers. The
Journal of adolescent health : official publication of the Society for Adolescent
Medicine 48(1):7-12 doi:10.1016/j.jadohealth.2010.09.016
Schroeder SA, Morris CD (2010) Confronting a neglected epidemic: tobacco cessation
for persons with mental illnesses and substance abuse problems. Annual review
of public health 31:297-314 1p following 314
doi:10.1146/annurev.publhealth.012809.103701
Shadel WG, Lerman C, Cappella J, Strasser AA, Pinto A, Hornik R (2006) Evaluating
smokers' reactions to advertising for new lower nicotine quest cigarettes.
Psychology of addictive behaviors : journal of the Society of Psychologists in
Addictive Behaviors 20(1):80-4 doi:10.1037/0893-164X.20.1.80
Shahan TA, Bickel WK, Badger GJ, Giordano LA (2001) Sensitivity of nicotine-
containing and de-nicotinized cigarette consumption to alternative non-drug
reinforcement: a behavioral economic analysis. Behavioural pharmacology
12(4):277-84
Shahan TA, Bickel WK, Madden GJ, Badger GJ (1999) Comparing the reinforcing
efficacy of nicotine containing and de-nicotinized cigarettes: a behavioral
economic analysis. Psychopharmacology 147(2):210-6
Shahan TA, Odum AL, Bickel WK (2000) Nicotine gum as a substitute for cigarettes: a
behavioral economic analysis. Behavioural pharmacology 11(1):71-9
Shannon; Dube; Walker; Reynolds JSN, A.;Perfetti, T.;Ingebrethsen, B.;Saintsing,
B.;Simmons, S.;Shelar, G.;Shu, K.;Dufour, W.;Young, H.;Wallace, G.;Yena,
C.;Rix, C. (1992) [untitled]. RJ Reynolds
Shatenstein S (1999) Eliminating nicotine in cigarettes. Tobacco control 8(1):106;
author reply 107-9
Nicotine reduction
84
Shoaib M, Schindler CW, Goldberg SR (1997) Nicotine self-administration in rats: strain
and nicotine pre-exposure effects on acquisition. Psychopharmacology
129(1):35-43
Shojaei AH, Khan M, Lim G, Khosravan R (1999) Transbuccal permeation of a
nucleoside analog, dideoxycytidine: effects of menthol as a permeation
enhancer. International journal of pharmaceutics 192(2):139-46
Shram MJ, Funk D, Li Z, Le AD (2008a) Nicotine self-administration, extinction
responding and reinstatement in adolescent and adult male rats: evidence
against a biological vulnerability to nicotine addiction during adolescence.
Neuropsychopharmacology : official publication of the American College of
Neuropsychopharmacology 33(4):739-48 doi:10.1038/sj.npp.1301454
Shram MJ, Li Z, Le AD (2008b) Age differences in the spontaneous acquisition of
nicotine self-administration in male Wistar and Long-Evans rats.
Psychopharmacology 197(1):45-58 doi:10.1007/s00213-007-1003-9
Shram MJ, Siu EC, Li Z, Tyndale RF, Le AD (2008c) Interactions between age and the
aversive effects of nicotine withdrawal under mecamylamine-precipitated and
spontaneous conditions in male Wistar rats. Psychopharmacology 198(2):181-90
doi:10.1007/s00213-008-1115-x
Slade J, Bero LA, Hanauer P, Barnes DE, Glantz SA (1995) Nicotine and addiction. The
Brown and Williamson documents. JAMA : the journal of the American Medical
Association 274(3):225-33
Smith TE (1972) Tobacco and Smoke Characteristics of Low Nicotine Strains of Burley.
In: Tobacco BW (ed). British American Tobacco
Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny EC (2013)
Gradual and Immediate Nicotine Reduction Result in Similar Low-Dose Nicotine
Self-Administration. Nicotine & tobacco research : official journal of the Society
for Research on Nicotine and Tobacco 15(11):1918-1925 doi:10.1093/ntr/ntt082
Sofuoglu M, Mooney M (2009) Subjective responses to intravenous nicotine: greater
sensitivity in women than in men. Experimental and clinical psychopharmacology
17(2):63-9 doi:10.1037/a0015297
Sofuoglu M, Yoo S, Hill KP, Mooney M (2008) Self-administration of intravenous
nicotine in male and female cigarette smokers. Neuropsychopharmacology :
official publication of the American College of Neuropsychopharmacology
33(4):715-20 doi:10.1038/sj.npp.1301460
Sorge RE, Clarke PB (2009) Rats self-administer intravenous nicotine delivered in a
novel smoking-relevant procedure: effects of dopamine antagonists. The Journal
of pharmacology and experimental therapeutics 330(2):633-40
doi:10.1124/jpet.109.154641
Nicotine reduction
85
Strasser AA, Lerman C, Sanborn PM, Pickworth WB, Feldman EA (2007) New lower
nicotine cigarettes can produce compensatory smoking and increased carbon
monoxide exposure. Drug and alcohol dependence 86(2-3):294-300
doi:10.1016/j.drugalcdep.2006.06.017
Stratton K, Shetty P, Wallace R, Bondurant S (2001) Clearing the smoke: the science
base for tobacco harm reduction--executive summary. Tobacco control
10(2):189-95
Suzuki J, Bayna E, Dalle Molle E, Lew WY (2003) Nicotine inhibits cardiac apoptosis
induced by lipopolysaccharide in rats. Journal of the American College of
Cardiology 41(3):482-8
Taioli E, Wynder EL (1991) Effect of the age at which smoking begins on frequency of
smoking in adulthood. The New England journal of medicine 325(13):968-9
doi:10.1056/NEJM199109263251318
Talhout R, Opperhuizen A, van Amsterdam JG (2007) Role of acetaldehyde in tobacco
smoke addiction. European neuropsychopharmacology : the journal of the
European College of Neuropsychopharmacology 17(10):627-36
doi:10.1016/j.euroneuro.2007.02.013
Tengs TO, Ahmad S, Savage JM, Moore R, Gage E (2005) The AMA proposal to
mandate nicotine reduction in cigarettes: a simulation of the population health
impacts. Preventive medicine 40(2):170-80 doi:10.1016/j.ypmed.2004.05.017
Tidey JW, Rohsenow DJ, Kaplan GB, Swift RM, Ahnallen CG (2013) Separate and
combined effects of very low nicotine cigarettes and nicotine replacement in
smokers with schizophrenia and controls. Nicotine & tobacco research : official
journal of the Society for Research on Nicotine and Tobacco 15(1):121-9
doi:10.1093/ntr/nts098
Trauth JA, Seidler FJ, McCook EC, Slotkin TA (1999) Adolescent nicotine exposure
causes persistent upregulation of nicotinic cholinergic receptors in rat brain
regions. Brain research 851(1-2):9-19
Trauth JA, Seidler FJ, Slotkin TA (2000) Persistent and delayed behavioral changes
after nicotine treatment in adolescent rats. Brain research 880(1-2):167-72
USDHHS UDoHaHS, . (1988) The health consequences of smoking: nicotine addiction.
A report of the Surgeon General. Public Health Service, Centers for Disease
Control, Office on Smoking and Health, Rockville, Maryland
Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP (2002) Nicotine-induced conditioned
place preference in adolescent and adult rats. Physiology & behavior 77(1):107-
14
Nicotine reduction
86
Villegier AS, Lotfipour S, McQuown SC, Belluzzi JD, Leslie FM (2007) Tranylcypromine
enhancement of nicotine self-administration. Neuropharmacology 52(6):1415-25
doi:10.1016/j.neuropharm.2007.02.001
Wahl SK, Turner LR, Mermelstein RJ, Flay BR (2005) Adolescents' smoking
expectancies: psychometric properties and prediction of behavior change.
Nicotine & tobacco research : official journal of the Society for Research on
Nicotine and Tobacco 7(4):613-23 doi:10.1080/14622200500185579
Walker N, Bullen C, McRobbie H (2009) Reduced-nicotine content cigarettes: Is there
potential to aid smoking cessation? Nicotine & tobacco research : official journal
of the Society for Research on Nicotine and Tobacco 11(11):1274-9
doi:10.1093/ntr/ntp147
Walker N, et al. (2012) The combined effect of very low nicotine content cigarettes,
used as an adjunct to usual Quitline care (nicotine replacement therapy and
behavioural support), on smoking cessation: a randomized controlled trial.
Addiction 107(10):1857-67 doi:10.1111/j.1360-0443.2012.03906.x
Watkins SS, Epping-Jordan MP, Koob GF, Markou A (1999) Blockade of nicotine self-
administration with nicotinic antagonists in rats. Pharmacology, biochemistry, and
behavior 62(4):743-51
Watson CH, Trommel JS, Ashley DL (2004) Solid-phase microextraction-based
approach to determine free-base nicotine in trapped mainstream cigarette smoke
total particulate matter. Journal of agricultural and food chemistry 52(24):7240-5
doi:10.1021/jf049455o
Watson NL, Carpenter MJ, Saladin ME, Gray KM, Upadhyaya HP (2010) Evidence for
greater cue reactivity among low-dependent vs. high-dependent smokers.
Addictive behaviors 35(7):673-7 doi:10.1016/j.addbeh.2010.02.010
Wayne GF, Carpenter CM (2009) Tobacco industry manipulation of nicotine dosing.
Handbook of experimental pharmacology(192):457-85 doi:10.1007/978-3-540-
69248-5_16
Wayne GF, Connolly GN (2009) Regulatory assessment of brand changes in the
commercial tobacco product market. Tobacco control 18(4):302-9
doi:10.1136/tc.2009.030502
Wayne GF, Connolly GN, Henningfield JE (2004) Assessing internal tobacco industry
knowledge of the neurobiology of tobacco dependence. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
6(6):927-40
Wayne GF, Connolly GN, Henningfield JE, Farone WA (2008) Tobacco industry
research and efforts to manipulate smoke particle size: implications for product
regulation. Nicotine & tobacco research : official journal of the Society for
Nicotine reduction
87
Research on Nicotine and Tobacco 10(4):613-25
doi:10.1080/14622200801978698
Wellman RJ, DiFranza JR, Savageau JA, Dussault GF (2004) Short term patterns of
early smoking acquisition. Tobacco control 13(3):251-7
doi:10.1136/tc.2003.005595
West RJ, Jarvis MJ, Russell MA, Carruthers ME, Feyerabend C (1984) Effect of nicotine
replacement on the cigarette withdrawal syndrome. British journal of addiction
79(2):215-9
Westman EC, Behm FM, Rose JE (1996) Dissociating the nicotine and airway sensory
effects of smoking. Pharmacology, biochemistry, and behavior 53(2):309-15
Wetter DW, Kenford SL, Smith SS, Fiore MC, Jorenby DE, Baker TB (1999) Gender
differences in smoking cessation. Journal of consulting and clinical psychology
67(4):555-62
Wilkinson JL, et al. (2006) Interoceptive Pavlovian conditioning with nicotine as the
conditional stimulus varies as a function of the number of conditioning trials and
unpaired sucrose deliveries. Behavioural pharmacology 17(2):161-72
doi:10.1097/01.fbp.0000197456.63150.cd
Williams JM, Ziedonis D (2004) Addressing tobacco among individuals with a mental
illness or an addiction. Addictive behaviors 29(6):1067-83
doi:10.1016/j.addbeh.2004.03.009
Wood T, Wewers ME, Groner J, Ahijevych K (2004) Smoke constituent exposure and
smoking topography of adolescent daily cigarette smokers. Nicotine & tobacco
research : official journal of the Society for Research on Nicotine and Tobacco
6(5):853-62
World Health Organization (1992.) International statistical classification of diseases and
related health problems, 10th revision. World Health Organization., Geneva
World Health Organization (2003) Framework Convention on Tobacco Control. In.
http://www.who.int/fctc/en/
World Health Organization SGoTPR, . (2012) Report on the Scientific Basis of Tobacco
Product Regulation: fourth report of a WHO study group. WHO Technical Report
Series; No. 967. In.
http://www.who.int/tobacco/publications/prod regulation/trs 967/en/index.html
York JE (1977) Control Of Nicotine In tobacco And Cigarette Smoke. American Tobacco
Zacny JP, Stitzer ML (1988) Cigarette brand-switching: effects on smoke exposure and
smoking behavior. The Journal of pharmacology and experimental therapeutics
246(2):619-27
Nicotine reduction
88
Zeller M, Hatsukami D, Strategic Dialogue on Tobacco Harm Reduction G (2009) The
Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action
in the US. Tobacco control 18(4):324-32 doi:10.1136/tc.2008.027318
Ziedonis D, et al. (2008) Tobacco use and cessation in psychiatric disorders: National
Institute of Mental Health report. Nicotine & tobacco research : official journal of
the Society for Research on Nicotine and Tobacco 10(12):1691-715
doi:10.1080/14622200802443569
Figure 3. Examples of marketing claims to use e-cigarettes to “smoke anywhere” and
“circumvent smokefree laws” (www.smokingeverywhere,com; www.elitensmoke.com)
Figure 4. Katherine Heigl smoking an e-cigarette on the set of the David Letterman Show,
September 2009)
1
Figure 5. Celebrity Jenny McCarthy in Lorillard’s Blu e-cigarette television commercial (as of
October 2013)
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DRAFT e-cigarette background paper 10-14-13
Rachel Grana, Stan Glantz, Neal Benowitz
WHO Background Paper on ENDS
DRAFT– v. October 14, 2013
BACKGROUND
E-cigarettes (also known as electronic nicotine delivery systems or ENDS) are a class of
products intended to deliver nicotine-filled aerosol (commonly called “vapor”) to a user by
aerosolizing a heated solution typically comprised of propylene glycol, glycerol (glycerine),
nicotine and flavoring agents (Figure 1). E-cigarettes without nicotine are also available. The
first of these devices that started the trend in use we describe in this report was invented by a
Chinese pharmacist, Hon Lik, in 2003. The U.S. patent application for the device states that "An
electronic atomization cigarette that functions as substitutes for quitting smoking and cigarette
substitutes.
" (Patent #8,490,628 B2) E-cigarette sales have risen rapidly since they entered the
marketplace in 2007.(Cobb, Byron et al. 2010) Products are marketed as healthier alternatives to
tobacco smoking, as useful in quitting smoking and reducing cigarette consumption, and useful
for circumventing smokefree laws and the ability to "smoke anywhere."(Grana and Ling under
review) Part of the exponential rise in sales over the past 3 years (2010-2013) has been due to
widespread advertising via television commercials and print advertisements, which often feature
celebrities, for the most popular brands, including those owned by tobacco
companies.(Felberbaum 2013)
Figure 1. Electronic cigarette
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DRAFT e-cigarette background paper 10-14-13
In 2009, the WHO Study Group in Tobacco Product Regulation (TobReg) addressed the
emerging regulatory issues pertaining to e-cigarettes. The committee noted that there was very
little published scientific evidence on the health effects of e-cigarettes, or their efficacy for
smoking cessation (stated in TobReg Report 955)(World Health Organization 2009) and that
there was not sufficient evidence to support the cessation and health claims made by companies
and those in the public health community who were advocating e-cigarettes for harm reduction.
The report states (p.7), "In addition to nicotine dependence, the sensory effects of the product,
social and marketing forces and perceptions of harmfulness and potential benefits should be
considered in examining the initiation, patterns of use and development of addiction."(World
Health Organization 2009) Meanwhile, e-cigarette prevalence has increased dramatically with
rapid increase in prevalence in many countries between 2008 and 2012 (Table 1, bottom of
document)
Both the 2009 TobReg Report 955 and the 2012 World Health Organization Framework
Convention on Tobacco Control (FCTC) Conference of the Parties report on e-cigarettes
(November 2012)(FCTC/COP/5/13 2012) articulated concerns about how the products may
interfere with implementation of the FCTC, particularly Articles 8, 9, 10, 11, 13, because e-
cigarettes mimic tobacco cigarettes, thus interfering with denormalization and limits on the
indirect promotion of tobacco use/products. E-cigarettes may hinder protection from exposure to
tobacco smoke (Article 8) because, while e-cigarettes emit less air pollution into the environment
than conventional cigarettes, they still subject bystanders to “passive vaping.” E-cigarettes are
widely advertised and promoted (often inaccurately) as being exempt from clean indoor air laws.
In addition, the similar appearance of people using e-cigarettes and those using conventional
cigarettes can complicate enforcement of restrictions on smoking conventional cigarettes. In
addition, the e-cigarette vapor has not been proven safe for inhalation by bystanders. A main
concern with the products was lack of data on the safety of the ingredients in the e-cigarette
solution, especially the safety of repeated inhalation of a heated mixture of propylene glycol and
other chemicals. In 2009, TobReg recommended that if e-cigarettes were to be considered
medicines or tobacco products, they would be subject to the labeling and warnings requirements
in Articles 10 and 11. The TobReg report placed great emphasis on the products potential
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DRAFT e-cigarette background paper 10-14-13
interference with Article 13, which addresses advertising and sponsorship by industry. Both
Articles 8 and 13 address the denormalization of tobacco products and indirect promotion of
tobacco products could be undermined in that the appearance of a cigarette-like product that
produces a smoke-like vapor.
While the number of published studies on e-cigarettes has increased dramatically, there
has been constant innovation in the marketplace of these products and many questions about
their safety, efficacy for harm reduction and cessation, and total impact on public health remain
unanswered. Both the individual risks and benefits and the total impact of these products occur in
the context of the widespread and continuing availability of conventional cigarettes and other
tobacco products, with high levels of “dual use” of e-cigarettes and conventional cigarettes at the
same time, which raises questions about the suggested harm reduction benefits. It is important to
assess e-cigarette toxicant exposure and individual risk as well as health effects of e-cigarettes as
they are actually used in order to ensure safety and to develop evidence-based policies and a
regulatory scheme that protects the entire population, children and adults, smokers and non-
smokers, in the context of how the tobacco industry is marketing and promoting these products.
This report reviews of the literature on e-cigarettes available as of September 2013, as
well as an update of tobacco industry involvement in the e-cigarette market, global regulations
pertaining to e-cigarettes and potential options for regulation. [NOTE:literature table in progress]
PRODUCTS (TYPES, ENGINEERING)
Electronic nicotine delivery systems (ENDS) have many names, including electronic
cigarettes, e-cigarettes and e-hookah. For the purposes of this report all these products will be
referred to as e-cigarettes. Product engineering has been evolving since the first e-cigarettes were
documented as arriving on the global market in 2007(Pauly, Li et al. 2007). As of late 2013,
there was wide variability in product engineering, including varying concentrations of nicotine in
the solution that e-cigarettes use to generate the nicotine aerosol (also called e-liquid), varying
volumes of solution in the product, different carrier compounds (most commonly propylene
glycol with or without glycerol (glycerine), a wide range of additives and flavors, and battery
size (which affects how hot the vaporizer gets). Battery size differences results in great
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DRAFT e-cigarette background paper 10-14-13
variability in the products' ability to heat and convert the nicotine solution to an aerosol and,
consequently, a wide range of levels of actual nicotine delivery as well as the nature of the other
chemicals delivered to users and emitted into the surrounding environment. Products come with
a variety of nicotine strengths (including some without nicotine), usually expressed in mg/ml of
solution or percent concentration. Quality control of the products themselves is highly variable
and users can modify many of the projects. In addition, as the types and design of products and
their contents continue to evolve rapidly, it is increasingly difficult to determine what an e-
cigarette "is," what is may contain, and what it is delivering to the user and the surrounding
environment.
The first e-cigarettes were cigarette-shaped, plastic or metal devices comprising three
parts: a battery, an atomizer (which attaches to the battery and has a heating element to convert
the liquid into a vapor) and a cartridge (which attaches to the atomizer and contains additional
heating elements and a wick or fiber where the liquid is placed; Figure 1). In subsequent models
a cartridge was created called a cartomizer, which combined the atomizer and the wick/fiber
(Figure 2). The cartridge is either refillable or pre-filled with e-liquid. The cigarette-shaped and
sized devices are often called “mini” e-cigarettes or "cig-a-likes" by users (who often call
themselves “vapers”). There are disposable and rechargeable models (Figure 2). More recent
designs are pen-shaped and sized with larger-sized cartomizers (Figure 2) in order to hold more
nicotine solution to reduce the amount of times a user needs to refill throughout the day. Some
cartridges, called clearomizers, which hold about 1-2ml of e-liquid, are now transparent to allow
the user to monitor how much fluid is in the device. The devices with larger cartomizers or
clearomizers are sometimes referred to as "tank" systems and hold about 2-3 ml of solution.
There are also much larger capacity and technologically sophisticated "tank system" devices
(Figure 2) that have various mechanical and, even digital display, features. One such feature is a
larger metal casing to hold larger and higher voltage batteries than found in the mini or pen style
e-cigarettes. In tank devices the atomizers and batteries can be replaced with more powerful
batteries (often called variable voltage devices) or lower electrical resistance atomizers that allow
the user to control the heat level provided to the atomizer which aerosolizes the e-liquid.
Furthermore, since the first e-cigarette products hit the market, users have been modifying the
devices and creating their own; instructions to do so are widely available on the Internet on e-
cigarette forum sites and YouTube. A concerning trend that has been occurring at least in the
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DRAFT e-cigarette background paper 10-14-13
U.S. and is owed largely to the refillable nature of e-cigarettes, is the use of the devices to smoke
marijuana in the form of liquid and wax dabs, which is a concentrated form of marijuana, mainly
comprising THC.( http://www.nbcnewyork.com/investigations/ECigarettes-Drugs-Marijuana-Vapor-
Pens-Smoking-I-Team-227269001.html and http://www.myfoxla.com/story/22305076/its-the-latest-
cannabis-craze-a-concerntrated-marijuana-known-as-wax)
Figure 2. Examples of different products
E-liquids are offered in a variety of flavors. A content analysis of 59 e-cigarette websites
conducted 2012,(Grana and Ling under review) e-cigarettes and the nicotine solution were found
to come in tobacco (95%), menthol (97%), coffee (61%), fruit (73%), candy (71%) and alcohol
(10%) flavors, as well as unique flavors such as “cola” and “Belgian waffle.” (Grana and Ling,
under review). Flavor is an important product characteristic in determining who is attracted to a
product and the ability to get started on a product. The 2012 US Surgeon General’s Report
Preventing Tobacco Use among Adolescents and Young Adults found that flavored
(conventional) tobacco products are disproportionately used by youth and initiators (U.S.
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DRAFT e-cigarette background paper 10-14-13
Department of Health and Human Services 2012). In recognition of the key role that flavors play
in promoting youth tobacco use, cigarettes with these characterizing flavors (with the exception
of menthol) have been banned in the U.S. and a flavor ban on nicotine containing products
(which includes e-cigarettes) was included in the proposed EU Tobacco Products Directive
(TPD) before the vote by EU Parliament on October 2013 which deleted that proposal.(European
Parliament 2013) As of September 2013, there were no restrictions on the use of flavors in e-
cigarettes anywhere in the world.
PRODUCT SAFETY
There are safety issues with electronic cigarette devices and liquid. Trtchounian and
Talbot (2011) examined 6 brands of products for design, content, labeling, quality and product
information including warnings.(Trtchounian and Talbot 2011) Most of the e-cigarette starter
kits purchased came with some instructions. Most provided information about the battery and
how to connect the parts of the devices, but did not come with a list of product ingredients, or
health warning messages. Most of the products leaked when handled and cartridges came with
fluid leaked on them, creating the potential for dermal nicotine exposure and potential nicotine
poisoning.(Trtchounian and Talbot 2011)
Major injuries and illness have resulted from e-cigarette use, which may be related to
lack of basic safeguards in the product design and manufacturing process, as well as the contents
of the solution. Tobacco product adverse events can be reported to the Food and Drug
Administration (FDA), Center for Tobacco Products (CTP). Chen (2012) summarized the 47
adverse event reports filed with the FDA CTP between 2008 and early 2012 regarding e-
cigarettes; finding that 8 of these 47 adverse events were serious health issues with examples
including hospitalization due to congestive heart failure, hypotension, pneumonia, and chest
pain.(Chen 2013) Reporting of an adverse event does not indicate causation, but it does raise
questions of biological plausibility that need to be addressed. There was also a reported infant
death due to choking on an e-cigarette. Examples of less serious adverse events include nausea,
vomiting and sore throat. Moreover, one e-cigarette company also instructs users to draw on the
product differently from a cigarette because they might experience adverse reactions, stating: “If
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DRAFT e-cigarette background paper 10-14-13
you find yourself smoking your e-cigarette the way you smoke a traditional cigarette, you are
doing something wrong.
As a matter of fact, if you vape your e-cig as you smoke your
cigarette you will find yourself with a sore throat, sore lungs, an incessant cough and
irritation in your mouth and throat.” (bold font in original text -
http://www.metroecigs.com/content/how-do-you-inhale-an-electronic-cigarette.asp
)
An18-month old girl in the U.S. became seriously ill after drinking e-cigarette liquid in a
refill container that was left in the child's reach and did not come with a child-proof cap.(Shawn
and Nelson 2013) A child in Israel died of nicotine poisoning from drinking her grandfather’s e-
cigarette solution.(Winer May 29, 2013) E-cigarettes have exploded and caught fire, causing
serious injury. A man in Florida suffered severe burns and lost half his tongue due to an e-
cigarette battery exploding in his face.(CBS NEWS February 16, 2012) A woman in Atlanta
escaped serious injury from an e-cigarette that exploded in her home, starting a fire .(Strickland
2013) These problems are common enough that e-cigarette internet forums and some retail
websites advise that the lithium batteries may explode or overheat when left to charge for long
periods of time or in direct heat exposure or if charged with the wrong charger or a powerful
electrical source. The e-cigarette forum e-cigarette-forum.com has a section in which advice is
given about the risks of specific battery types: http://www.e-cigarette-
forum.com/forum/blogs/baditude/4848-9-battery-basics-mods-imr-protected.html. Because e-
cigarettes are not regulated there is no systematic collection of information on these issues. It is
also unknown to what extent these problems could be eliminated by stronger regulatory
standards on the product itself.
MARKETING
While most attention from the biomedical community has been on the e-cigarette device,
the aerosol that it delivers to users (and, to a lesser extent, bystanders), and the potential of e-
cigarettes for cessation of conventional cigarettes, much of the public discourse and popular
understanding about use of e-cigarettes has been determined by how they have been marketed.
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DRAFT e-cigarette background paper 10-14-13
Patterns of tobacco product adoption are driven and reinforced by marketing, so it is
important to understand the marketing claims and selling propositions consumers encounter with
regard to e-cigarettes. Product marketing designed to attract different segments of the population
(such as youth, current smokers, former smokers) will determine use patterns which is one of the
main factors contributing to total public health burden from tobacco use. Consumer perceptions
of tobacco products (whether cigarettes, smokeless tobacco products, or e-cigarettes) and their
risks and benefits are important factors in determining uptake and consequently the total public
health burden due to tobacco use. For example, claims that e-cigarettes are less harmful than
cigarettes may encourage adoption by non-smokers (potentially children) as well as smokers
seeking to quit conventional cigarettes. Promotion of e-cigarettes as a convenient alternative to
cigarettes when a smoker cannot light up would blunt the effect of smokefree laws on smoking
cessation. The explicit promotion of dual use (as has been done with snus) for places where
people cannot smoke cigarettes (Figure 3) has important implications for the ultimate use
patterns and health impact of introducing e-cigarettes into the marketplace.
Grana and Ling (under review at AJPM)(Grana and Ling under review) systematically
reviewed a sample of single-brand e-cigarette retail websites (n=59) that were online in 2012 to
determine the main marketing messages, type of products sold and unique marketing features on
the sites. They found that the most popular claims were that the products are healthier (95%),
cheaper (93%) and cleaner (95%) than cigarettes, can be smoked anywhere (88%), can
circumvent smokefree policies (71%), do not produce secondhand smoke, and are modern.
Health claims were also made through pictorial and video representations of doctors, which was
present on 22% of sites. Cessation-related claims (ranging from overt statements that one can use
the product to quit smoking to indirect claims such as you’ll never want to smoke tobacco
cigarettes again) were found on 64% of sites. Claims about effects on bystanders frequently
included statements that e-cigarettes emit "only water vapor" that is harmless to others (76%).
While originally promoted almost exclusively on the internet, marketing expenditures for
e-cigarettes have increased dramatically, with the increasing promotion of e-cigarettes on
television in some countries (e.g., U.S., U.K.). In the U.S. television advertising is largely by
Lorillard, Inc., a multinational tobacco company based in the U.S. and the first of the cigarette
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DRAFT e-cigarette background paper 10-14-13
companies to enter the e-cigarette business when it purchased Blu brand e-cigarettes in
2012(Esterl April 25, 2012) and Sky Cig brand e-cigarettes in 2013.(Esterl October 1, 2013) As
of late 2013, Lorillard had the biggest US national TV campaign which includes use of
celebrities to glamorize e-cigarettes and shows them inhaling and exhaling what looks like
smoke.
The use of celebrities in product marketing has been occurring since at least 2009.(Grana,
Glantz et al. 2011) In Poland, a popular ad as of March 2012 featured actor Olaf Lubaszenko
with the tagline ‘You can smoke wherever you want.’ In the U.S. Katherine Heigl, a famous U.S.
actress went on the David Letterman Show, a popular late night program in the U.S. and spent
much of her interview discussing her quit attempt with the e-cigarette and even smoked an e-
cigarette on stage with Mr. Letterman (Figure 4). At the time, she had a relationship with the
company where a portion of sales of an e-cigarette called the Pitbull were donated to a charity of
her choice, Compassion Revolution. The video of the interview with David Letterman was on the
site as well as posted on other websites and widely used in many online press releases and
advertorials. In the U.K. the commercials range from showing young people out enjoying
themselves (SkyCig) to older people who are tired of missing out on major life events due to
their smoking (E-Lites), a sentiment more associated with the harm reduction or NRT approach.
Jenny McCarthy, a TV host and model, appears in a 2013 Blu advertisement that glamorizes e-
cigarette use and emphasizes the romantic opportunity it creates (Figure 5). Moreover, this
advertisement is set in a bar which recalls the pairing of cigarettes and alcohol and makes that
connection for e-cigarettes, and is likely to appeal to older adolescents and young adults, the
population that spends disproportionately more time out in bars trying to develop romantic
relationships. Blu also has another actor in its commercials, Stephen Dorff, whose rugged good
looks recall the Marlboro Man but in a suit, and e-cigarette brand NJOY uses rebel rockstar
Courtney Love.
The fact that a large majority of e-cigarette retail websites encouraged the use of the
products anywhere and everywhere (88%), specifically noting places where cigarette smoking
would be banned (71%) and places for socializing, has direct implications for regulation of e-
cigarettes and implementation of the FCTC. These messages can be used to undermine the idea
of smoking restrictions and existing smokefree laws designed to apply to tobacco smoke. It is
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DRAFT e-cigarette background paper 10-14-13
important to note that both the e-cigarette companies and the tobacco companies are focusing on
creating positive social norms for these products, introducing them into smokefree environments
and promoting them as socially acceptable. The totality of the messaging creates familiarity
among smokers by emphasizing the similarity to a cigarette and the smoking experience while
simultaneously assuring the smokers and their family and friends (and perhaps kids) that it is
entirely different than a cigarette. A 2013 commercial for the e-cigarette, FIN, comes with the
tagline “Rewrite the Rules,” and a direct quote from the commercial states, “There was a time
when no one was offended by it – that time has come again.”
Television and radio have been unavailable to the cigarette and other tobacco companies
to market their products in the US (as well as much of the world) since the 1970s. E-cigarette
advertising on television and radio is mass marketing of an addictive nicotine product for use in a
recreational manner to new generations who have never experienced such marketing.
Advertising that emphasizes use anywhere and to get around clean indoor air laws promotes dual
use of e-cigarettes and cigarettes.
As of 2013, e-cigarette companies (including cigarette companies who have purchased e-
cigarette companies) are marketing e-cigarettes using the same claims, tactics and media
channels that were effective at marketing cigarettes to attract young people and deter smokers
from quitting before use of these channels to market cigarettes was banned.
PREVALENCE
Adults
U.S. Samples
Using data from U.S.-based ConsumerStyles survey (which is a mail-back survey of a
national sample of adults), Regan et al. (2013) found that awareness of e-cigarettes doubled from
2009 to 2010 (16.4% to 32.2%) and ever use of e-cigarettesmore than tripled from 0.6% in 2009
to 2.7% in 2010.(Regan, Promoff et al. 2013) Ever use was most common among men, younger
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DRAFT e-cigarette background paper 10-14-13
adults and those with lower socioeconomic status. Ever use was higher among smokers than
among the general population in 2010 (18.2% v 2.7%, respectively). Current smokers who had
tried e-cigarettes did not differ from non-users in intention to quit or past-year quit attempts.
King et al (2013), analyzed data from a companion dataset to the ConsumerStyles, called
HealthStyles, collected in 2010 (mail-based and web-based modalities) and 2011 (web-based
mode).(King, Alam et al. 2013) They found awareness of e-cigarettes had increased from about
40% to about 58% and ever use had doubled from 3.4% to 6.2% between 2010 and 2011. Ever
use was higher in current smokers at both waves (6.8% of the 2010 mail-based sample, 9.8% of
the 2010 web-based sample and 21% of the 2011 web-based sample). Ever use among former
smokers increased dramatically from 2010 to 2011, from 0.6% and 2.5% in the 2010 samples to
7.4% in the 2011 online sample. Authors note data were weighted to be nationally-representative
and the Styles surveys typically yield estimates of smoking prevalence that are almost identical
to the nationally-representative National Health Interview Survey.(King, Alam et al. 2013;
Regan, Promoff et al. 2013) Moreover, both of these studies reported a similar percentage of
U.S. adults who were aware of e-cigarettes in 2010 as the nationally-representative sample in
Pearson et al. in 2010(Pearson, Richardson et al. 2012) (32.2% Regan,(Regan, Promoff et al.
2013) 38.5% and 40.9% in King(King, Alam et al. 2013) vs. 40.3% in Pearson(Pearson,
Richardson et al. 2012).
Pearson et al (2012) estimated e-cigarette use prevalence in two studies, the Legacy
Longitudinal Study of Smokers (LLSS) and a nationally-representative general population online
survey, both conducted in 2010.(Pearson, Richardson et al. 2012) Smokers in the LLSS and the
nationally online sample were similar on all demographics except age (those in the LLSS were
on average younger) and smoking characteristics and desire to quit with the exception that a
greater proportion of smokers in the LLSS had made more than one quit attempt (69% v 31%,
respectively). Overall awareness in the online nationally-representative sample (n=2649) was
40.2% and ever use was 3.4%, awareness among smokers was 57% and ever use was 11.4%.
Among LLSS cohort (n=3648), awareness was 57.0% and ever use was 6.4%. Moreover in the
online sample, almost all current use (past 30-day) of e-cigarettes was among current smokers:
4.1%, compared to 0.5% of former smokers and 0.3% of never smokers. (Current use was not
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DRAFT e-cigarette background paper 10-14-13
measured in the LLSS.) In addition, although a low percentage of former smokers (2%) had used
e-cigarettes, that rate was over twice the rate among never smokers (0.77%)(Pearson et al.,
2012).In the online nationally-representative survey the odds of being an e-cigarette user was
associated with intention to quit in the next 6 months (adjusted OR = 1.74; 95% CI: 1.02, 2.98),
compared to never expecting to quit; but this was not evident in the LLSS cohort(Pearson et al.
2012).
In a 2010 nationally-representative, mixed-mode survey (telephone-based n=1504, online
n=1736; total n=3240), McMillen et al. (2013) assessed the ever use of emerging tobacco
products including e-cigarettes among adults in the U.S. Ever use of e-cigarettes among all
respondents was 1.8%, with highest rates of use among daily (6.2%), non-daily (8.2%)
smokers.(McMillen, Maduka et al. 2012) Past 30-day (current) e-cigarette use did not exceed 1%
for any of the “emerging tobacco products, which included e-cigarettes, but 19.7% of ever e-
cigarette users reported past 30-day use.
Popova and Ling (2013) found that among a nationally representative panel of current
and recent former smokers, 20.1% had ever used e-cigarettes.(Popova and Ling 2013) Ever e-
cigarette use was more common in women than men (OR=0.79, 95% CI: 0.63-0.99), persons of
Asian ethnicity than white (OR=2.76, 95% CI: 1.03, 7.39), and those aged 18-29 years compared
to 60 years or older (OR=2.32, 95% CI: 1.57, 3.42). Among smokers, those with some college
education compared to those with a bachelors degree (OR=2.09; 95% CI: 1.13, 3.86) and those
with incomes less than $15,000 compared to those with incomes of $60,000 or greater were more
likely to be current (past 30-day) e-cigarette users (OR=1.95, 95% CI: 1.17, 3.25). Respondents
who had ever tried e-cigarettes were significantly more likelyto have tried to quit in the past year
and failed than persons who had not tried to quit (OR=1.78, 95% CI: 1.25, 2.53).
U.S. Regional Samples
Choi and Forster (2013) found that among young adults aged 20-28 in the Midwestern
US surveyed in 2011, ever use of e-cigarettes was 7.0% and past 30-day use was 1.2%.(Choi and
Forster 2013) Among those aware of e-cigarettes, most believe e-cigarettes are less harmful than
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DRAFT e-cigarette background paper 10-14-13
conventional cigarettes (52.9%) and 44% believe they can help with quitting smoking. Ever use
was more common among 20-24 year olds (25-28 year olds), men, current smokers, and those
who believe e-cigarettes are less harmful than conventional cigarettes and can be used for in
smoking cessation.
Sutfin and colleagues (2013) found that among college students in North Carolina
surveyed in 2009, ever use of e-cigarettes was 4.5% while past 30-day use was 1.5%, with
highest use among current smokers.(Sutfin, McCoy et al. 2013) Importantly, they found that
12% of e-cigarette users were never smokers. E-cigarette use was not associated with intention to
quit smoking.
Hawaiian sample of smokers and cessation for e-cigarette use motivation
A cross-sectional study of Hawaiian daily smokers (n=1567) conducted from 2010-2012,
examined e-cigarette use prevalence and associations with quitting attitudes and
behaviors.(Pokhrel, Fagan et al. 2013) Thirteen percent of participants reported having ever used
e-cigarettes to quit smoking (they did not assess any other reason for using the products).
Smokers who had used e-cigarettes to quit were younger, more highly motivated to quit, had
greater self-efficacy for quitting, and reported a longer recent quit duration than smokers who
had not used e-cigarettes to quit. In the multivariate logistic regression analyses, greater quit
motivation (OR = 1.14; 95% CI: 1.08, 1.21), quitting self-efficacy (OR = 1.18; 95% CI: 1.06,
1.36) and having ever used FDA-approved therapies (OR = 3.72; 95% CI: 2.67, 5.19) were
significantly associated with greater likelihood of having used e-cigarettes to quit smoking,
whereas age (OR=0.98; 95% CI: 0.97, 0.99) and Native Hawaiian ethnicity (OR = 0.68; 95% CI:
0.45, 0.99) were inversely associated with greater likelihood of using e-cigarettes for quitting.
International Samples
Adkison and colleagues (2013) estimated rates of e-cigarette use and perceptions of the
products in 2010 among current and former smokers in the International Tobacco Control Study
conducted in U.K, U.S., Australia and Canada.(Adkison, O'Connor et al. 2013) Likely reflecting
the fact that e-cigarettes are freely available in the UK and US and not legal for sale with
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DRAFT e-cigarette background paper 10-14-13
nicotine in Australia and Canada, the highest rates of awareness were in the U.K.(54%) and U.S.
(73%), while rates were much lower in Australia (40%) and Canada (20%). Prevalence of e-
cigarette trial (among those aware) was 20.4% in U.S., 17.7% in the U.K., 10% in Canada and
11% in Australia. Across countries use was higher among those of younger age, higher income,
reporting nondaily smoking and who perceive e-cigarettes as less harmful than cigarettes.
Despite larges differences in awareness among the countries, current use did not differ among
the countries (p=0.114).In current smokers, a marker of dependence (cigarettes per day) was not
associated with ever e-cigarette use or past 30-day use (p value not provided).
Dockrell et al (2013) analyzed data from a nationally representative survey of UK adults
(2010: n=12597 adults, 2297 smokers; 2010 n=12432, 2093 smokers) finding the prevalence of
e-cigarette trial and current use doubled from 2010 to 2012.(Dockrell, Morison et al. 2013) Ever
use in 2010 was not measured among former smokers or never smokers, only current non-daily
or daily smokers. In 2010, 5.5% of smokers had tried e-cigarettes but no longer used them, which
increased to 15.0% in 2012. Current use of e-cigarettes among smokers rose from 2.7% in 2010
to 6.7% in 2012.Ever e-cigarette use among former smokers in 2012 was 2.7% and current use
1.1%; ever use among never smokers in 2012 (only measured in that year) was 0.4% and current
use was 0.1%. About 33% of ever e-cigarette users continued to use in 2010 and in 2012.In a
multivariate model which included only ex- and current smokers, being an occasional (OR=4.32
95% CI: 2.89, 6.48)or daily smoker (OR=7.33 95% CI: 5.66, 9.48) increased odds of ever e-
cigarette use compared to ex-smokers, while older age (age ≥35) decreased odds of ever e-
cigarette use compared to 18-34 year olds (OR=0.58 95% CI: 0.43, 0.78). In the model for
current e-cigarette use, only being an occasional (OR=6.04 95% CI: 2.92, 12.49) or daily smoker
(OR=6.68 95% CI: 4.15, 10.77) increased odds of current e-cigarette use. Authors also analyzed
data from a 2010 survey of smokers (n=1308) that included a special battery of e-cigarette
questions. A majority of respondents reported that e-cigarettes: “might satisfy the desire to
smoke” (60%), “might help cut down on cigarettes” (55%), and “they might help me give up
smoking entirely (51%).”Perceived disadvantages included “might be too expensive” (53%),
“might not satisfy the desire to smoke enough” (39%), and might be mistaken for cigarettes
therefore frowned upon in public”(35%). Among e-cigarette triers (n=494, 37.7% of sample), the
most common reason for trying e-cigarettes was “as a substitute for smoking where smoking is
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DRAFT e-cigarette background paper 10-14-13
not allowed” (reported by 49% of daily pack a day smokers, 43% of those smoking 10-19
cigarettes per day, and 31% among those smoking 9 or fewer cigarettes per day, p=0.008).
Secondary reasons were to cut down (35%) and to quit smoking (31%). The finding that using e-
cigarettes to get around smokefree laws is likely reflected in the dominant pattern of dual use in
both 2010 and 2012 prevalence data reported in this study.
Single Gender Study
Douptcheva et al (2013) reported data analyses of the Cohort Study on Substance Use
Risk Factors (C-SURF), a longitudinal study of Swiss men who are interviewed during
enrollment in the army, to examine prevalence and predictors of e-cigarette use.(Douptcheva,
Gmel et al. 2013) Among the entire cohort of young men, aged 19-25, 4.9% of participants
reported ever trying e-cigarettes. Use differed by smoking status with 9.3% of current smokers
reporting trying e-cigarettes, 1.6% of former smokers and 0.4% of never smokers. Excluding 144
occasional e-cigarette users, the conducted an analyses of e-cigarette use among daily smokers
(n=1233) that compared daily dual users (25) to daily smokers who never use e-cigarettes
(1064); they found no statistically significant differences in cigarettes per day, nicotine
dependence or past year quit attempts.
Convenience Samples of Users: Prevalence, User perceptions
There have also been five studies with convenience samples that may provide
information about motivations for using e-cigarettes, attitudes and behavior. These studies likely
suffer from a bias toward recruitment of persons motivated to quit and enthusiastic about e-
cigarettes, limiting the generalizability of the findings.
In an online survey of 81 users of cessation websites and e-cigarette forums conducted in
2009, authors found that most respondents perceived the products as less harmful than cigarettes
and used the products to quit smoking or to cut down on conventional cigarette smoking.(Etter
2010) In a subsequent study conducted in 2010, Etter and Bullen (2011) surveyed 3587 adults
that were recruited from e-cigarette forums and smoking cessation websites, and employed a
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DRAFT e-cigarette background paper 10-14-13
similar questionnaire as Etter 2010.(Etter 2010; Etter and Bullen 2011) They found that top
reasons for using the e-cigarette was that users perceive them as less toxic, to ameliorate cravings
for and withdrawal from cigarettes, and to help them quit or avoid relapse.(Etter and Bullen
2011)
Siegel et al. (2011) obtained a list purchasers of Blu brand electronic cigarettes from the
company and invited them to complete a survey 6 months after making their first purchase (5000
purchasers, 4.5% response rate, sample n=222) in 2010.(Siegel, Tanwar et al. 2011) They found
that 31% reported they were not smoking tobacco cigarettes at the 6 month survey timepoint.
This study is limited by selection bias (purchasers of one particular product) andvery low
response rate (4.5%), making these data not generalizeable to e-cigarette users.
In 2011, Dawkins et al., (2012) conducted an online survey of 1347 adults recruited from
an electronic cigarette retail website.(Dawkins, Turner et al. 2013) Participants were 70% men,
mean aged 43 years, 96% white (72% European), and most (72%) used a "tank" type of e-
cigarette with nicotine-filled solution (1% reported using no-nicotine). Seventy-four percent of
respondents who had used an e-cigarette reported not smoking for at least a few weeks. Results
show that users perceive e-cigarettes as healthier than smoking and pleasant to use. In an analysis
of self-reported ex-smokers, "'time to first vape' was significantly longer than 'time to first
cigarette' (p<0.001)."
Goniewicz and colleagues (2012) surveyed Polish e-cigarette users recruited from online
forums and retail sites in 2010 (n=179) and found that a majority of e-cigarette users were
cigarette smokers when they initiated e-cigarette use (86%).(Goniewicz, Lingas et al. 2012)
Participants reported using the products as a less harmful alternative to smoking (41%) or to quit
smoking (41%) and 66% reported no conventional tobacco cigarette smoking at the time of the
survey. Twenty percent of never smokers who tried e-cigarettes stated they initiated tobacco
smoking after trying e-cigarettes, suggesting e-cigarette use can be a gateway to smoking and
dual use.
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In the Czech Republic, Kralikova et al (2012), surveyed 1738 (86% response rate) people
they identified as currently smoking or buying conventional cigarettes in 2012.(Cho, Shin et al.
2011; Kralikova, Novak et al. 2013) Forty-six point seven percent had heard of e-cigarettes but
never tried them, 23.9% had tried them once, 16.6% had tried them repeatedly, 9.7% reported
using them regularly. Of the fifty percent of respondents who had ever tried an e-cigarette,18.3%
reported regular use and 14% reported using them daily.A positive initial experience with e-
cigarette use was much higher among those who use e-cigarette regularly compared to those who
only tried them once (68.5% v 15.2%, respectively). Of those who tried only once or repeatedly,
“not satisfying” was the top reason given by both groups followed by “poor taste.”In depth
analyses were conducted for the sample of regular users (n=158). Among regular users, reasons
for trying e-cigarettes were to cut down (39%), use where smoking is not allowed (28%) and to
quit smoking (27%) (5.3% gave another reason). Regular users who reported that e-cigarettes
helped them cut down (n=93) smoked on average 9.7 (SD=6.5) cigarettes per day, while those
who did not report that e-cigarettes helped them cut down (N=61) smoked 13.1 (SD=7.0)
cigarettes per day (p<.005). Most non-reducers said they used the e-cigarette to circumvent
smokefree laws.
Youth
In a survey of Korean adolescent respondents to the 2008 Health Promotion Fund Project
survey (n=4,341), 10.2% of students were aware of e-cigarettes.(Cho, Shin et al. 2011) Overall,
only 0.5% of students reported having tried an e-cigarette, but there were significant differences
in use by gender (0.91% among males, 0.18% among females, p<0.001) and having ever used
conventional cigarettes (2.0% among ever cigarette users, 0.15% among never cigarette users,
p<0.001)
A subsequent study of adolescent (aged 13-18) respondents to the 2011 Korean Youth
Risk Behaviour Survey (n=75,643) found that prevalence of e-cigarette use had greatly increased
in just 3 years to 9.4% ever use and4.7% past 30 day use.(Lee, Grana et al. 2013) Use was also
much higher among respondents who used conventional cigarettes: 8.0% ever e-cigarette use
among current smokers, 1.4% ever e-cigarette use among non-smokers or former smokers and
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DRAFT e-cigarette background paper 10-14-13
3.6% current (past 30-day) use among smokers, 1.1% current use among non-smokers or former
smokers).
In the U.S., Pepper et al, 2013 found high levels of awareness of e-cigarettes (67%) but
little use among a sample of 228 adolescent males who participated in an online survey in 2011
(less than 1 percent had tried an e-cigarette).(Pepper, Reiter et al. 2013) However, in the
multivariate logistic regression only current smoking was strongly associated with increased
willingness to try an e-cigarette (OR=10.25, CI: 2.88, 36.46). In the bivariate logistic regression,
holding a negative opinion of “the typical smoker” was associated with less willingness to try an
e-cigarette (OR=0.58, 95% CI: 0.43, 0.79). These findings demonstrate that adolescent boys who
use cigarettes are also susceptible to using e-cigarettes and that negative perceptions of being a
smoker may be protective against e-cigarette smoking.
The first national estimates of e-cigarette use among U.S. youth from the National Youth
Tobacco Survey document rapid growth of e-cigarette use of e-cigarette use among middle
school and high school students in the U.S. from 2011-2012.(Centers for Disease Control and
Prevention 2013) Among middle school youth (grades 6-8), prevalence of ever trying an e-
cigarette doubled from 1.4% in 2011 to 2.7% in 2012. Similarly, current use (past 30-day use)
rose from 0.6% to 1.1%. Among high school youth, ever use doubled from 4.7% in 2011 to
10.0% in 2012, with current use rising from 1.5% in 2011 to 2.8% in 2012. Notably, dual use
with cigarette smoking accounts for most of the past 30-day e-cigarette use among middle school
youth (61.1%) and high school youth (80.5%). Initiation of nicotine exposure with e-cigarettes is
evidenced by the fact that 20% of middle school youth who had tried an e-cigarette and 7.2% of
high school youth who had tried an e-cigarette had not tried a conventional tobacco cigarette yet.
Goniewicz studied e-cigarette use among 20,240 students enrolled at 176 high schools
and universities in Poland.(Goniewicz and Zielinska-Danch 2012) Surveys were administered
September 2010 to June 2011. 23.5% of Polish teens aged 15-19 had ever used e-cigarettes and
8.2% reported past 30-day use. Among 20-24 year olds attending universities, 19.0% had ever
used an e-cigarette and 5.9% reported past 30-day use. In the whole sample, 3.2% of never
smokers had tried an e-cigarette.
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Conclusion
Awareness of and e-cigarette trial has at least doubled in the countries where data are
available from 2008 to 2012. In the U.S., awareness is more prevalent among men, but trial is
more prevalent among women. All studies of adult use show the highest rate of e-cigarette use
among current smokers, followed by former smokers, with little use among nonsmokers,
although e-cigarette trial and use rose in all of these categories over the past few years (Table 1).
E-cigarettes are most commonly being used concurrently with conventional tobacco cigarettes,
so-called dual use. The major epidemiologic studies have shown this phenomenon is occurring
across countries. In the European studies (UK, Swiss, Czech) the most common reasons given to
try e-cigarettes was to use them in places where smoking is restricted and to cut down on
smoking, followed by to help with quitting.
The data on e-cigarette use among adolescents is more limited but, like adults, shows
rapid increases in awareness and use in 3 countries (U.S., Poland and Korea). As with adults,
data suggests that e-cigarette use is most appealing and prevalent among youth who are also
experimenting with or current users of tobacco cigarettes. Dual use with conventional cigarettes
is the predominant pattern of e-cigarette use - 61% in middle school students and 80% among
high school students. Among middle school youth, 20% of those who had tried e-cigarettes had
never tried a tobacco cigarette, which suggests that some youth are initiating nicotine addiction
with e-cigarettes. Although it is unclear if e-cigarette use among youth leads to cigarette
smoking, this possibility should be strongly considered given the widespread availability of
cigarettes, and in the U.S., little cigars, cigarillos and smokeless tobacco products. These results
indicate rapid market penetration of e-cigarettes among youth, with trial among high school
students (10.0%) in 2012 even higher than the 2011 rate for adults, 6.8%.(King, Alam et al.
2013)
These findings are troubling for what they suggest about the trajectory of developing
tobacco use. In a longitudinal cohort study of Swedish adolescents that examined trajectories of
tobacco use, adolescents who initiated tobacco use with both cigarettes and snus had a
significantly elevated risk of progression to current smoking at 18 years old compared to snus
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DRAFT e-cigarette background paper 10-14-13
initiators (OR= 2.54 (95% CI: 1.68-3.91).(Galanti, Rosendahl et al. 2008) (Galanti et al.. 2008)
A study of U.S. Air Force recruits sheds light on the trajectory of use with different product
initiation. Those who were never smokers when they entered basic training, 5.1% were current
users and 2.5% past users of smokeless tobacco. At one-year follow-up the recruits who were
current or ever smokeless tobacco users were over 2 times more likely to have started smoking
than nonusers.(Haddock, Weg et al. 2001) Post et al. (2010) examined tobacco use and nicotine
dependence in Swedish adolescents and found that dual users reported the greatest odds of
endorsing the dependence symptoms.(Post, Gilljam et al. 2010) These adolescent dual users also
had the highest level of endorsing withdrawal symptoms when trying to quit.
CHEMICALANALYSES OF E-CIGARETTES
In 2009, the U.S. Food and Drug Administration (FDA) released a statement that
analyses of e-cigarette products revealed the presence of tobacco-specific impurities and one
cartridge contained a toxic contaminant used in antifreeze (diethylene glycol).(Food and Drug
Administration 2009) In 2011, Trehy et al (2011) published an FDA analysis of 4 e-cigarette
products for nicotine and minor tobacco alkaloids in liquids and in aerosol generated from the e-
cigarette.(Trehy, Ye et al. 2011) Minor alkaloids refer to alkaloids found in tobacco other than
nicotine which are present in much smaller quantities than nicotine. The products that were
purchased included NJOY, Smoking Everywhere, CIXI and Johnson Creek e-liquid. (It is not
clear in which year the products were purchased.) The puffing procedure was 100 ml puffs taken
every 60 seconds for 30 puffs. They found that amount of nicotine measured in the vapor was
impacted by the temperature of the solution, with repeated heating of the liquid in short intervals
(triggered by short puff intervals) enhancing nicotine release. Thus the amount of nicotine
delivered to the user is likely to be dependent on temperature achieved by the heat source and
inter-puff interval performed by the user. The analysis of nicotine content of cartridge e-liquid
from three of the brands revealed poor concordance of labeled and actual nicotine content,
including some labeled as having 0mg nicotine that had nicotine in them. Analysis of the refill
solution from the U.S. e-liquid company Johnson Creek showed good agreement (100-110% of
advertised content) between labeled and actual content. Liquids tested from one manufacturer
contained minor tobacco alkaloids, including myosmine, anatabine, anabasine and in some cases
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DRAFT e-cigarette background paper 10-14-13
cotinine and beta nicotyrine. It is likely that these alkaloids were extracted along with nicotine
from tobacco as part of the manufacturing process. The analysis of simulated e-cigarette use
found that individual puffs contained from 0 µg to 35µg nicotine per puff. Assuming a high
nicotine delivery of 30 µg/puff, it would take about 30 puffs to deliver the 1 mg of nicotine
typically delivered by smoking a conventional cigarette. A Marlboro cigarette was tested and
found to deliver 152-193µg/puff, so 6 or 7 puffs would deliver 1 mg. The levels of minor
alkaloids in vapor were below the limit of detection for both e-cigarettes, although levels could
be measured from the smoke of a Marlboro. Two products from CIXI labeled as Cialis and
Rimonabant flavor contained amino-tadalafil and rimonabant, medicines to treat erectile
dysfunction and a cannabinoid (THC) receptor antagonist, respectively. This study demonstrate
inconsistency in nicotine amount compared to labeled content of many but not all e-cigarette
products. It also shows that the highest nicotine product e-cigarette puff delivers 20% or less
nicotine than a puff of a conventional cigarette.
Goniewicz et al. (2012) analyzed 16 brands of e-cigarette products, and 20 samples
across brands.(Goniewicz, Kuma et al. 2013) They measured nicotine content in e-liquid and
used an adapted smoking machine to measure the nicotine content in 300 puffs of aerosol
generated from each product. The amount of nicotine measured in the e-liquid extracted from the
cartridges varied from labeled nicotine content by more than 20% in 9 of 20 samples. Similarly,
a 20% difference in marked content vs. actual content was found in 3 of 15 e-cigarette refill
liquid samples. Across products, nicotine content ranged from 0.5 mg (SD=0.1) to 15.4
mg(SD=2.1).
Cameron et al. (2013) analyzed 7 e-cigarette solutions (e-liquids) to determine
concordance between advertised or labeled and actual nicotine content.(Cameron, Howell et al.
2013) Among the 7 samples of e-liquid, 2 were labeled as containing 24mg/ml of nicotine and 5
were not marked with a specific nicotine content, but as "low," "medium," "high" and "super
high." For samples with only strength descriptors, expected concentrations were obtained from
information on the brands' websites (low=6-14mg/ml, medium=10-18mg/ml, high and super
high=25-36mg/ml). They found that, while all the samples contained nicotine, only 2 were in the
expected range and 4 were lower than specified.
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DRAFT e-cigarette background paper 10-14-13
Goniewicz et al (2013) analyzed the vapor from 12 brands of e-cigarettes for toxic and
carcinogenic compounds, including carbonyls, volatile organic compounds, tobacco-specific
nitrosamines.(Goniewicz, Knysak et al. 2013 (online first)) They also compared results from the
e-cigarette vapor to the puffs from a medicinal nicotine inhaler. They found varying levels of
carbonyls (e.g., formaldehyde, acetealdehyde and acrolein), volatile organic compounds (e.g.,
toluene) and tobacco-specific nitrosamines present in the e-cigarette vapor. E-cigarette products
varied widely in toxicant content per 150 puffs averaged across sampling timepoints (e.g.,
formaldehyde range: 3.2-56.1 µg; acrolein: 0-41.9 µg, TABLE 2). On one hand, levels of
toxicants in the vapor were 9-450 times lower than the same volume cigarette smoke (Table 2).
On the other, depending on brand, some toxicants were found at levels higher than the reference
product, the nicotine inhaler (e.g.,o-methylbenzaldehyde and formaldehyde). Five of the 11
toxicants measured were not detected in the nicotine inhaler at all, including acrolein, toluene,
p,m,-xylene, NNN, and NNK. They also report the presence trace amounts of three metals
(cadmium, nickel, and lead) in the e-cigarette vapor as well as in the nicotine inhaler.
TABLE 2. Levels of toxicants in e-cigarette vapor compared to nicotine inhaler and cigarette
smoke (data from Goniewicz et al., 2013)
Toxicant
Content in Nicotine Range in
Range in content in
inhaler mist
content in
conventional cigarette
vapor from
micrograms in
12 e-cigarette mainstream smoke from
samples (per
1 cigarette
15 puffs)
Formaldehyde
2.0
0.2-5.61
1.6-52
Acetaldehyde
1.1
0.11-1.36
52-140
Acrolein
ND
0.07-4.19
2.4-62
o-
0.7
.13-.71
--
methylbenzaldehyde
Toluene
ND
0-0.63
8.3-70
p,m-xylene
ND
0 - 0.2
--
NNN
ND
0 - 0.00043
0.0005-0.19
NNK
ND
0-0.00283
0.012-0.11
Cadmium
0.03
0 - 0.022
--
Nickel
0.19
0.011-0.029
--
Lead
0.04
0.003-0.057
--
ND=Not Detected; NOTE: Data were taken from Tables 3 and 4 in Goniewicz et al.
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2013. Lowest and highest values reported in each table were used for each toxicant
Kim et al. (2012) developed a liquid chromatography-tandem mass spectrometry method
for analyzing TSNAs in electronic cigarette replacement fluids.(Kim and Shin 2013) They
applied their method to 105 refill fluids from 11 different companies in the Korean market. They
specifically quantified NNN, NNK, NAT, and NAB, and they present data on total TSNAs in
each product. They found nearly a three order of magnitude variation in TSNA concentrations
among e-cigarette refill fluids, with total TSNA concentration ranging from 330 µg/ml to 8600
µg/ml. Their data demonstrate significant variability in TSNA composition and quantity among
different EC brands and illustrate the importance of screening numerous products to obtain an
overview of product variability.
Schripp et al. (2012) analyzed the vapor exhaled by users to determine the presence of
toxicants and address the question of secondhand vapor exposure.(Schripp, Markewitz et al.
2012) Three studies are described. In the first, a smoker in an 8m3 stainless steel chamber with
an air exchange rate of 0.3/hr who puffed 6 puffs from an e-cigarette separated by 60 seconds
each time. This puffing regimen in the chamber was repeated with 3 e-liquids (0mg nicotine,
apple flavor, 18mg nicotine, apple flavor, 18mg nicotine, tobacco flavor) and one tobacco
cigarette. In the second protocol, vapor from three different types of e-cigarettes puffed for 3
seconds each was pumped into a 10 L glass chamber with an air exchange rate of 3/hr. In the
third protocol an e-cigarette consumer exhaled one e-cigarette puff into a glass chamber. Three
e-cigarette devices were used for these experiments – two that used a “tank” system which is
directly filled with e-liquid and one that used a cartridge with a cotton fiber on which to drip the
e-liquid. Authors found that vapor from the 8m3 chamber analysis contained low levels of
formaldehyde, acetaldehyde, isoprene, acetone, acetic acid,2-butanodione (MEK),acetone and
proponal (Table 4 reproduced form article below).Analyses of the vapor in the second protocol
(10-l glass chamber) revealed high levels of 1,2-propanediol (propylene glycol), 1,2,3-
propanetriol, diacetin (from flavoring), traces of apple oil (3- methylbutyl-3-methylbutanoate),
and nicotine. When e-cigarette vapor was directly pumped into a glass chamber, propylene
glycol was the predominant element, with lower levels of others. Nicotine release was 0.1 to 0.2
µg/puff.
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McAuley et al (2012) conducted a risk assessment of e-cigarettes funded by the
Consumer Advocates for Smoke-free Alternatives Association, CASAA, a pro-e-cigarette
advocacy group.(McAuley, Hopke et al. 2012) Key details about the protocol for conducting
their "risk assessment" are not described and there are obvious problems with the study that do
not warrant its review in this report. In fact, a technical report (below) reviewing the existing
data on e-cigarette constituents that was also funded by CASAA excluded this study due to its
poor quality, stating:
“Although the quality of reports is highly variable, if one assumes that each report contains some
information, this asserts that quite a bit is known about composition of e-cigarette liquids and
aerosols. The only report that was excluded from consideration was work of McAuley et al.[23]
because of clear evidence of cross-contamination – admitted to by the authors – with cigarette
smoke and, possibly, reagents. The results pertaining to non-detection of tobacco-specific
nitrosamines (TSNAs) are potentially trustworthy, but those related to PAH are not since it is
incredible that cigarette smoke would contain fewer polycyclic aromatic hydrocarbons (PAH;
arising in incomplete combustion of organic matter) than aerosol of e-cigarettes that do not burn
organic matter [23]. In fairness to the authors of that study, similar problems may have occurred
in other studies but were simply not reported, but it is impossible to include a paper in a review
once it is known for certain that its quantitative results are not trustworthy.”
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Other problems with the analysis and findings include the fact that they did not detect any
benzo(a)pyrene in the conventional cigarette smoke despite the fact that it has been established
for over 50 years that benzo(a)pyrene is an important carcinogen in cigarette smoke. The most
unreliable conclusion in the paper (on page 855, second column, 11 lines from the top) is that
“neither vapor from e-liquids or cigarette smoke analytes posed a condition of ‘Significant Risk’
of harm to human health via the inhalation route of exposure." Given the authors' analysis found
that conventional cigarettes did not pose significant risk, there is likely a fatal error in the data,
analysis, or both. This paper's conclusions about e-cigarette toxicity does not appear credible as
it concludes that cigarettes are not dangerous to inhale.
In a technical report funded by The Consumer Advocates for Smoke-free Alternatives
Association (CASAA) Research Fund of the constituents in e-cigarette cartridges and liquid,
Burstyn (2013) employs occupational threshold limit values (TLVs) to evaluate the potential risk
posed by various toxins at various levels in e-cigarettes.(Burstyn 2013) In reviewing the
evidence of risk due to propylene glycol or glycerine exposure the report states that assuming a
high level of consumption around 5-25ml of solution a day could produce levels of exposure to
propylene glycol and glycerin to justify concern. The author noted that the assessment is limited
by "the quality of much of the data that was available for [the] assessment was poor." Based on
calculated levels of inhalation, the author concludes that
“…there is no evidence that vaping produces inhalable exposures to contaminants of the aerosol
that would warrant health concerns by the standards that are used to ensure safety of workplaces.
However, the aerosol generated during vaping as a whole (contaminants plus declared
ingredients), if it were an emission from industrial process, creates personal exposures that would
justify surveillance of health among exposed persons in conjunction with investigation of means
to keep health effects as low as reasonably achievable.Exposures of bystanders are likely to be
orders of magnitude less, and thus pose no apparent concern.”
TLVs are an outmoded approach to assessing health effects for occupational chemical exposures
that lead to much higher permissible levels of exposure than contemporary agencies use for
setting occupational health standards. In addition, occupational exposures are generally much
higher (often orders of magnitude higher) than levels considered acceptable for ambient or
population-level exposures. (Employing an occupational standard to evaluate risk to the general
population is the same approach to risk assessment as those conducted for secondhand smoke by
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those affiliated with the tobacco industry, which concluded that secondhand tobacco smoke
could not produce any adverse health effects.) Occupational exposures also do not consider
exposure to sensitive subgroups, such as people with medical conditions, children and infants,
who might be exposed to secondhand e-cigarette emissions.
Particulate Matter
Inhaled particle size is an important determinant of where particles will be deposited in
the respiratory system and the resulting adverse health effects (U.S. EPA
http://www.epa.gov/pm/). All particles less than 10 microns in size reach the respiratory system
and potentially cause health problems in the circulatory and respiratory systems.
(http://www.epa.gov/pm/health.html). Those whose diameter falls between 2.5 and 10 microns
are considered “inhalable coarse particles” and impact the upper airway. Fine particles are
defined as particles less than equal to 2.5 micron. Ultrafine particles or nanoparticles, are
particles less than or equal to 0.1 micron (0.1 micron = 100 nM). (For reference, conventional
cigarette smoke particles have a median size of 200-400 nM.) Both terms ultrafine and
nanoparticle are used interchangeably in the scientific community. Fine particles (2.5 micron and
smaller) reach the lower lung. The ultrafine particles are mostly inhaled and exhaled, but some
do deposit in the lower lung. Ultrafine liquid particles would coalesce with lung fluid to form a
film, and constituents would be absorbed after impaction as for larger particles. Solid ultrafine
or nano-particles (carbonaceous or metal) can be absorbed directed into cells, and could be toxic.
Frequent or high levels ofexposure to fine and ultrafine particles can trigger inflammatory
processes and heart attacks(Pope, Burnett et al. 2009) and respiratory problems.(Mehta, Shin et
al. 2013) Because of these health concerns, the U.S. EPA has standards for particulate exposure
by particle size: http://www.epa.gov/air/criteria.html. However, the EPA standards are related to
outdoor air pollution particles, which are carbonaceous. It is not clear is the ultrafine particles in
e-cigarette vapor will have the same health effects and toxicity as carbonaceous particles to the
extent that they are pure liquid particles.
Schripp et al. (2012) observed two peaks in the particle diameter distribution in e-
cigarette exhaled aerosol, one at 100 nm and one at 30 nm(Figure reproduced below).(Schripp,
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Markewitz et al. 2012) Particle size was observed to decrease as a function of time with specified
time intervals, 1, 5, 10 minutes in both the 8m3 chamber and the glass 10 liter chamber,
presumably due to evaporation. Exhaled e-cigarette aerosol contained mostly propylene glycol
and smaller amounts of related VOCs, apple oil (flavorant) and nicotine. The authors conclude
that
"’passive vaping’ must be expected from the consumption of e-cigarettes." Like secondhand
cigarette smoke, levels of these chemicals in real environments where e-cigarettes are being used
will depend on the density of users and properties of the ventilation system.
Metals in e-cigarette liquid and aerosol were studied by Williams et al (2013) who
performed various laboratory analyses on 22 dissected cartomizers (the atomizer and cartridge
combined into a single component).(Williams, Villarreal et al. 2013) They examined metal
content and quantity in both cartomizer e-liquid and the corresponding vapor using electron
microscopy and energy dispersive x-ray spectroscopy. Both the e-liquid and the Poly-fil fibers
used to absorb the e-liquid so it can be heated and converted to an aerosol, which comes into
contact with heating elements in the cartomizers, contained heavy metals (tin, nickel, copper,
lead, chromium). Tin, which appeared to originate from solder joints, was found in the form of
both particles and tin whiskers in cartomizer fluid and Poly-fil. E-cigarette fluid containing tin
was cytotoxic to human pulmonary fibroblasts. E-cigarette aerosol also contained metals. Levels
of nickel were measured that were 2-100 times
higher than found in Marlboro cigarette smoke.
The nickel and chromium possibly originated from the heating element, which conventional
cigarettes would not have. Some nickel, tin and chromium in the aerosol was in the form of
nanoparticles (<100 nM). These metal nanoparticles can deposit into alveolar sacs in the lung,
potentially causing respiratory problems. This study analyzed e-cigarette models that employ
Poly-fil fiber to contain the e-liquid, which is not used in some “tank” systems, where liquid
surrounds a heating element or wick. Therefore, it is unknown how the type of e-cigarette device
might influence which particles are produced, how many and at what size. There is evidence that
some metal nanoparticles may harm human health (from studies of titanum) but the overall
health significance is unclear.
Zhang et al. (2103) examined the size of particles and likely deposition in the human
body. They examined e-cigarette aerosol produced by a single brand of e-cigarette
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(BloogMaxXFusion) using both propylene glycol and vegetable glycerin-based liquids.(Zhang,
Sumner et al. 2013) They generated the aerosol by using a smoking machine that was altered to
take 25ml aerosol samples for analysis. In order to assess the likely deposition of particles in the
human respiratory system, they used two factors: particle size and lung ventilation rates (one for
a"reference worker" one for a "heavy worker," 1.2 m3/hr and 1.688 m3/hr, respectively). They
found that e-cigarette and tobacco cigarettes produce aerosols with similar particle size, with
some particles are in the nanoparticle range (Figure reproduced below). Excerpt:
“The e-cig with
PG solution generated an immediate peak at 117 nm of 170,000 d N/d log Da (Figure 3), with a
VMAD of 250 nm and GSD of 1.6. The VG solution produced an immediate peak at 180 nm of
21,600 d N/d log Da (Figure 4), with a VMAD of 440 nm and GSD of 1.3. The total volume of
PG particles was about 30% greater than that of the VG aerosol. The conventional filtered
cigarette produced a comparable pattern, with a peak at 215 nm, VMAD of 250 nm, and GSD
of 1.4.” The calculated human deposition model predicted that 73-80% of particles are
distributed into the exhaled vapor, while 7%–18% of particles would be deposited in alveoli
resulting in arterial delivery and 9%–19% would be deposited in the head and airways, resulting
in venous delivery. In total, about 20-27% of particles are predicted to be deposited in the
circulatory system and into organs from e-cigarette vapor, which is comparable to the 25-35%
for conventional cigarette smoke. As expected, the heavy worker model showed more alveolar
delivery across puffs compared to the reference worker who would have more head and airway
delivery. It is important to note that 25ml would be less aerosol than a user would be expected to
inhale (personal communication with Dr. Prue Talbot, UC Riverside).
Ingebrethsen et al. (2012) (all from RJ Reynolds tobacco company) conducted a study of
particle size in e-cigarette vapor using three methods (spectral transmission, electric mobility,
and gravimetric).(Ingebrethsen, Cole et al. 2012) The spectral method enabled particles in e-
cigarette aerosol to be measured without dilution. They found the aerosol particles to average
250–450 nm in size, which is comparable to what has been found with conventional cigarettes.
Testing two brand of e-cigarette (one disposable, one rechargeable) and one tobacco cigarette,
authors found that the geometric mean particle size ranged from 238 to 387 nm, and was similar
for e-cigarette and tobacco cigarettes. (The authors did not describe the composition of the e-
liquids, which can potentially affect particle size and concentration.)
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Based on the data from all these studies one would expect that e-cigarette vapor could be
inhaled into the deep lung, similarly to a tobacco cigarette. The particle concentrations (109/cm3)
were also similar for e-cigarette and conventional tobacco cigarettes. However, the particles in
the Schripp study may be smaller than those that are inhaled because of evaporation prior to
measurement, as discussed by Ingebrethsen. (Figure reproduced below)
FIGURE: Example of particle sizes: clockwise from left to right: Schripp et al. 2012; Zhang et
al. ;Ingbrethesen et al. 2012;
Figure 4a) Aerosol size distribution during consumption of an e-cigarette in an 8-m3 chamber
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Figure 3. Single puff with propylene glycol-based e-liquid
Cytotoxicity
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Bahl et al (2012) screened 41 e-cigarette refill fluids obtained from 4 companies (year of
purchase not reported) for cytoxicity (measured as the ability to kill half of the cells in a culture
using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay procedure)
to three cell types: human pulmonary fibroblasts, human embryonic stem cells, and mouse neural
stem cells.(Bahl, Lin et al. 2012) The latter two cells types were chosen as early prenatal and
early postnatal models. A hierarchy of cytotoxicity was determined based on e-cigarette liquid
that killed 50% of the cells (IC50) for the human embryonic stem cells, which were the most
sensitive of the three cell types tested. Results showed that: (1) cytoxicity varied among products
with some being highly toxic and some having low or no cytoxicity, (2) nicotine did not cause
cytotoxicity, (3) all companies has some products that were non-cytotoxic and some that were
highly cytotoxic, (4) one company had products that were non-cytotoxic to pulmonary
fibroblasts but cytotoxic to both types of stem cells, (5) cytotoxicity was related to the
concentration and number of flavorings used. The finding that the stem cells were more sensitive
than the differentiated adult pulmonary fibroblasts cells suggests that adult lungs are probably
not the most sensitive system to the effects of exposure to e-cigarette aerosol. These findings
also raise concerns about pregnant women who use e-cigarettes or are exposed secondhand e-
cigarette vapor.
In a study funded by FlavorArt e-cigarette liquid manufacturers, Romagna and
colleagues (2013) compared the cytotoxicity of aerosol produced from 21 flavored (12 tobacco
flavored and 9 fruit or candied flavored; all contained nicotine) brands of e-cigarette liquid to
smoke from a reference conventional tobacco cigarette.(Romagna, Allifranchini et al. 2013)
Samples were analyzed for cytotoxicity using an embryonic mouse fibroblast cell line (3T3) via
the MTT assay according to UNI ISO 10993-5 standards, which defines cytoxicity as a 30%
decrease in viability of treated cells vs. untreated controls. Only aerosol from coffee-flavored e-
liquid produced a cytotoxic effect average of 51% viabilityat 100% concentration of solution).
They concluded that e-cigarette aerosol is much less toxic than cigarette smoke and could be
useful products in tobacco harm reduction.
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Conclusion
The studies of what is in e-cigarettes are limited by the selection of a handful of products
tested (from the hundreds on the market) and by puffing protocol which may or may not reflect
actual users puffing behavior. Considering these limitations, the published research demonstrates
a lack of standards and quality control for e-cigarettes.(Hadwiger, Trehy et al. 2010; Trehy, Ye et
al. 2011; Cameron, Howell et al. 2013; Goniewicz, Kuma et al. 2013) The e-liquid that is
aerosolized in e-cigarette devices is not uniform in ingredient content and proportion; some do
not even include nicotine. Studies have detected varying levels of nicotine content from labeled
amounts, and the presence of volatile organic compounds, tobacco-related carcinogens, metals
and chemicals. For the carbonyl compounds (formaldehyde) and the VOCs, the data show lower
levels than a cigarette but higher levels than the nicotine inhaler.(Goniewicz, Knysak et al. 2013
(online first)) In addition, the data in Table 2 demonstrate that, depending on brand and sample,
an e-cigarette possibly delivers 14 times as much formaldehyde, 7 times as much actaldehyde, 6
times as much o-methylbenzaldehyde as a nicotine inhaler, as well as additional toxicants and
carcinogens (acrolein, toulene, p,m-xylene, NNN and NNK), which were not detected at all in
the nicotine inhaler (the reference for this study). Some of the chemicals in e-cigarette aerosol
are cytotoxic to human cells, particularly embryonic cells. Several chemical that have been found
in e-cigarette vapor and e-liquid are on human carcinogens or reproductive toxicants maintained
by the California Proposition 65 list, including nicotine, acetaldehyde, formaldehyde, nickel,
lead, toluene (http://oehha.ca.gov/prop65/prop65 list/Newlist.html).
Studies that have measured the diameter of the particles comprising e-cigarette vapor
have detected small (<10microns in diameter), fine (<2.5microns in diameter) and
ultrafine/nanoparticles (<1 micron in diameter).(Schripp, Markewitz et al. 2012; Williams,
Villarreal et al. 2013; Zhang, Sumner et al. 2013) The size of particles is important for how they
can deposit in the body’s bloodstream, cells and organs. The smaller the particle size, the easier
it is for chemicals to enter the bloodstream and cells, potentially effecting damage or changes.
Very small particles mostly get inhaled and exhaled. However some fraction of these particles,
at least of certain types, may be absorbed directly. Medium sized particles (cig smoke size) are
optimal to impact and release their constituents into the airways, and then be absorbed.
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At minimum, these studies show that e-cigarette vapor is not merely "water vapor" as is
often claimed in the marketing for these products. The thresholds for human toxicity of potential
toxicants in e-cigarette vapor are not known, and the possibility of health risks to primary users
of the products and those exposed passively to the product emissions must be considered. Based
on these studies, the e-cigarettes tested have lower levels of toxicants than conventional
cigarettes. However, these studies suggest that switching smokers to a pharmaceutical nicotine
inhaler as a harm reduction strategy (long term use among those unable/unwilling to quit) would
be a safer approach than using these brands of e-cigarettes, as it delivers fewer toxicants and
does not emit fine and ultrafine particulate matter into the environment.
BIOLOGICAL EFFECTS
Nicotine Absorption
Vansickel et al. (2010) conducted a study with 32 healthy smokers to examine nicotine
absorption from e-cigarettes, cardiovascular effects on craving and withdrawal after using an e-
cigarette.(Vansickel, Cobb et al. 2010) Participants with no experience of prior e-cigarette use
were asked to participate in each of 4product use protocols(own brand of cigarette, 18mg NJOY
“NPRO” e-cigarette, 16mg Crown Seven “Hydro” e-cigarette, and sham-unlit cigarette)
separated by 48 hours and after 12 hours of abstinence from tobacco smoking. Flavor of e-
cigarette cartridge was matched to the type usually used by the participant. Biological measures
were blood plasma nicotine, carbon monoxide (CO), heart rate and subjective effects on craving
and withdrawal. They found that 5 minutes after puffing in each condition both e-cigarettes and
sham resulted in little or no change from baseline in blood plasma nicotine levels but the
expected increased occurred with own brand of tobacco cigarettes (18.8 ng/ml) (Figure
reproduced from article below). After 5 minutes of puffing, heart rate increased only for own
cigarette brand from 65.7(SD=10.4) to 80.3(SD=10.9) beats per minute. Neither e-cigarette
product raised CO, but own cigarette brand smoking raised CO as expected. E-cigarettes
decreased some nicotine/tobacco abstinence withdrawal symptomsat lower levels than own
conventional cigarette brand at some timepoints in the protocol. This study shows smokers could
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experience some modest relief of some withdrawal symptoms and positive subjective effects
with e-cigarette use with minimal systemic delivery of nicotine.
In a cross-over trial, (Bullen et al 2011) 40 adult smokers were randomized to the
following groups at different times: e-cigarette (Ruyan V8) 16 mg nicotine, 0mg e-cigarette,
Nicorette inhalator, or their usual cigarette for four days (with three days in between test
rounds).(Bullen, McRobbie et al. 2010) The 16mg e-cigarette resulted in similar serum level of
nicotine as the Nicorette inhalator in a similar amount of time (1.3ng/ml at 19.6 min and
2.1ng/ml at 32.0 min, respectively), with the inhaler taking longer. However, both the e-cigarette
and the nicotine inhaler achieved much lower peak blood plasma nicotine levels with a longer
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DRAFT e-cigarette background paper 10-14-13
time to peak concentration than a tobacco cigarette, which increased blood plasma nicotine to
13.4ng/ml at 14.3 min. The 16 mg e-cigarette and nicotine inhalator reduced desire to smoke
over the 60 minute puffing period more than the 0 mg e-cigarette (See Reproduced Figure 2
below). Both 16mg e-cigarette and the nicotine inhalator reduced the desire to smoke and
withdrawal symptoms, with no statistically significant differences. Respondents reported a
similarly low level of "satisfaction" with both the 16mg e-cigarette and the nicotine inhalator
(approximately 3 on a 10 point scale, exact number not reported), but rated the 16mg e-cigarette
as more "pleasant to use" than the inhalator by 1.49 units on a 10 point visual analog scale
(VAS) scale (p=0.016). The cross-over design is a strength of the study as it tests the methods
within the same person at different times. However, authors noted that the 16mg e-cigarettes
failed to deliver nicotine to one-third of participants and participants reported failure of the
device to function and produce vapor. This study may also be limited by lack of a “practice
period” for participants to become familiar with how to use the e-cigarette or nicotine inhalator,
as participants had never used them and only 2 participants had ever used the nicotine inhalator.
This study was funded by the e-cigarette manufacturer, Ruyan Group Holdings Limited through
Health New Zealand Ltd., a company owned by one of the authors, M. Laugesen.
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Vansickel and Eissenberg (2013) conducted a second study of nicotine delivery and
craving suppression, this time in former smokers who were experienced e-cigarette users (at least
3 months of regular use) and brought their own e-cigarette device to use in the protocol (n=8) for
use during a 5-hr. session.(Vansickel and Eissenberg 2013) For the first part of the protocol,
plasma nicotine, heart rate and subjective effects were assessed at baseline and 5 and 15 minutes
after users took 10 puffs (at 30 second intervals) followed by a one-hour ad lib puffing session,
where blood was sampled every 15 minutes and during a 2-hour rest (no puffing) session where
blood was sampled every 30 minutes. Seven of the eight participants used “tank system” devices
with larger batteries than the cigarette-sized products which differed from their previous work
with the cigarette-shaped devices.(Vansickel, Cobb et al. 2010) Most of the participants used 18
mg/ml nicotine solution (n=6), 1 used 24mg/ml and one used 9mg/ml. Mean blood plasma
nicotine level reached 10.3 ng/ml (SEM = 2ng/ml)during the 10-puff protocol, which was much
higher than previous studies and comparable to that delivered by conventional cigarette smoking.
Blood plasma levels reached an even higher mean after one-hour of ad lib puffing (Figure
reproduced form the original article below). During ad lib puffing, heart rate increased from an
average of 73.2(SD=2.0beats per minute to 78(SD=1.9) within the first 5 minutes and remained
elevated throughout the hour, consistent with the expected effects of nicotine. Nicotine
withdrawal symptoms (e.g., restlessness) were relieved over the 75-minute puffing period
(Figure reproduced below). Overall, these results show effective nicotine delivery by the users’
own e-cigarettes compared to conventional cigarettes, and subjective effects on withdrawal
symptoms suggest the e-cigarette relieves symptoms of nicotine dependence.
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DRAFT e-cigarette background paper 10-14-13
Abuse Liability
Vansickelet al 2012 conducted a study of the abuse liability of an 18mg e-cigarette
(Vapor King brand) with 20 current, daily smokers.(Vansickel, Weaver et al. 2012) They tested
several aspects of abuse liability during a series of four within-subject sessions, 1 of which
allowed for product sampling to familiarize users with the device and 3 of which involved the
“multiple choice procedure,” (MCP) where participants sample the drug and then make two or
more discrete choices between it and another drug/preparation or a series of monetary values.
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DRAFT e-cigarette background paper 10-14-13
The first session involved 6, 10-puff bouts of 30 seconds inter-puff interval, each bout separated
by 30 minutes. During the MCP sessions, participants chose between 10 e-cigarette puffs and
varying amounts of money, 10 e-cigarette puffs and a varying number of own brand
conventional cigarette puffs, or 10 conventional cigarette puffs and varying amounts of money.
The monetary value at which users chose money over the 10 product puffs was considered the
"crossover value," or for e-cigarette and conventional cigarette choice condition crossover value
was when participants chose conventional cigarette puffs over the e-cigarette puffs. The
crossover values were higher for conventional cigarettes compared to e-cigarettes (average of
$1.06(SD=$0.16) for 10 e-cigarette puffs and average of $1.50(SD=$0.26) for 10 conventional
cigarette puffs (p<0.003). E-cigarettes delivered a similar level of nicotine as a cigarette, but
more slowly and require a greater number of puffs than cigarettes to achieve the same nicotine
level, and reduced withdrawal symptoms. The authors concluded that e-cigarettes deliver
nicotine, can reduce withdrawal symptoms and appear have lower abuse potential compared to
conventional cigarettes.
Conclusion
The early studies of nicotine absorption found that e-cigarettes delivered a lower level of
plasma nicotine than conventional cigarettes (Eissenberg 2010, Vansickel 2011, Bullen 2011),
with newerstudies demonstrates that when users are experienced and using their own product
(mostly tank systems) and engaged in more puff intervals nicotine absorption is similar to that of
conventional cigarettes (Vansickel 2013; Vansickel 2012).This difference in nicotine delivery is
likely due to the larger voltage batteries in the newer devices which produce more heat and/or
atomizers with lower resistance to the heat transfer, resulting in more efficient aerosolizing of the
liquid contained in the device. However, despite the greater efficiency at nicotine delivery in the
more recent study (Vansicket at al 2013), all of these studies show that e-cigarettes regardless of
nicotine delivery can modestly alleviate some symptoms of withdrawal and produce positive
subjective appraisal of the e-cigarette as pleasant to use. Moreover, the one study examining
abuse liability found that at least one model of cigarette-shaped 18mg e-cigarettes appear to have
a lower abuse liability than cigarettes. In the trial comparing nicotine inhalator to e-cigarettes, the
nicotine inhalator delivered a similar amount of nicotine as the 16mg e-cigarette, however
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DRAFT e-cigarette background paper 10-14-13
authors noted that the e-cigarette malfunctioned and did not deliver any nicotine in a third of
participants, which did not occur with the nicotine inhalator. This result highlights the need for
product regulation in terms of the device quality and labeling. Only a few brands and models of
e-cigarettes were tested in these studies, limiting the generalizeablity of the findings to other
products.
HEALTH EFFECTS
Vardavas et al. (2012) conducted a study examining pulmonary function after acute
ad
libpuffing of an e-cigarette (Nobacco, medium, 11mg)in a group of healthy cigarette
smokers(n=30).(Vardavas, Anagnostopoulos et al. 2012) All subjects were asked to use the same
e-cigarette device (>60% propylene glycol, 11 mg/ml nicotine) as desired for 5 minutes.Subjects
refrained from smoking tobacco cigarettes for 4 hr prior to study. On another day, 10 participants
selected randomly from the 30 participants were asked to sham-smoke an e-cigarette device with
the cartridge removed. Three lung function measures were assessed: spirometry, dynamic lung
volumes and resistance and expired nitric oxide (NO). E-cigarette use had no effect on
spirometric flows (such as FEV1/FVC) but did significantly increase airway resistance (18%)
and decrease expired NO (16%). Sham e-cigarette use had no significant effect, as expected.
Acute short term effects suggest that more prolonged e-cigarette use could have greater effects.
This study is limited by small sample size, the short period of abstinence before the protocol was
executed and the lack of comparison to smoking conventional tobacco cigarettes. Also, because
of the short length of exposure, this study cannot lead to any conclusions about the clinical
significance of the findings. In addition, smokers in general have high airway resistance with
dynamic testing and lower expired NO, likely due to oxidant stress. Despite these limitations,
this study suggests that e-cigarette constricts lung peripheral airways, possibly due to the irritant
effects of propylene glycol, which could be of concern particularly in people with chronic lung
disease such as asthma, emphysema or chronic bronchitis.
Flouris et al assessed the short term effects of active and secondhand e-cigarette and
conventional tobacco cigarette use on serum cotinine and pulmonary function in 15 cigarette
smokers and 15 never smokers.(Flouris, Chorti et al. 2013) A single brand of e-cigarette made in
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DRAFT e-cigarette background paper 10-14-13
Greece and a single e-liquid (> 60% propylene glycol; 11 mg/ml nicotine) was used. The authors
attempted to compute how many e-cigarette puffs would deliver the same amount of nicotine as
a conventional cigarette using a number of assumptions, some of which are not valid. For
example, authors assume that the smoking machine yield of each person’s cigarette indicates
amount of nicotine delivered to the smoker, yet there is little to no correlation between yield and
actual systemic delivery. The passive exposure study was conducted in a 60m3 chamber. The
ventilation (air exchange rate) was not specified. The secondhand cigarette smoke was generated
with a target air CO of 23 ppm which is extremely high but which simulates exposure in a very
smoky bar. E-cigarette vapor was generated using a pump that operated for the same duration as
the cigarette smoking and aerosol was released into the room. The study limitations include
using only type of e-cigarette product, studying people who were not regular e-cigarette users,
studying a specified puffing (vs
ad lib) regimen, using extremely high passive exposure
conditions, and studying short term pulmonary effects in healthy people (as opposed to
asthmatics, who would be expected to be more sensitive to a lung irritant).The authors found a
similar rise in serum cotinine with active tobacco cigarette or e-cigarette use immediately after
active use (mean increase about 20 ng/ml). The passive exposure the serum cotinine increase was
similar for e-cigarette and tobacco cigarette exposure (averaging 0.8 ng/ml for tobacco cigarette
and 0.5 ng/ml for e-cigarette). These results suggest that in cigarette smokers, some e-cigarette
devices deliver similar amounts of nicotine as tobacco cigarette smoking. With very heavy
passive exposure there is also similar systemic exposure to nicotine from tobacco and e-
cigarettes among bystanders. Active cigarette smoking resulted in a significant decrease in
expired lung volume (FEV1 / FVC) but not with active e-cigarette or with passive tobacco
cigarette or e-cigarette exposure.
Flouris et al. (2013) studied the effects of passive e-cigarette vapor on white blood cell
count. The study is exactly the same as that described by Flouris et al 2013,with a different
biomarker outcome.(Flouris, Poulianiti et al. 2012) This study presents the effects of tobacco
cigarettes and e-cigarettes, both with active use and passive exposure, on white blood cell count.
White cell count is known to be increased acutely and chronically by cigarette smoking,
reflecting a chronic inflammatory state, and is associated with future risk of acute cardiovascular
events. As expected, active conventional cigarette smoking and exposure to secondhand
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conventional cigarette smoke increased the total white blood cell count as well as granulocyte
and lymphocyte counts. Active e-cigarette use and passive exposure to e-cigarette vapor did not
result in a statistically significant increase in immunological biomarkers over one hour of
exposure. This study suggests that the increase in white cell count is mediated more by tobacco
combustion products than by nicotine. Although the data are not reported, the figure provided in
the paper suggests that the change, if any, is very small, and possibly not of clinical significance.
Since the protocol is the same as Flouris et al 2013 (respiratory effects), the same limitations
apply.
Hua and colleagues (2013) sought to determine the health impact of electronic
cigarettes, using an infodemiological approach.(Hua, Alfi et al. 2013) They collected
information posted on three electronic cigarette forums: Electronic Cigarette Forum, Vapers
Forum and Vapor Talk. Posts were reviewed for reports of both positive and negative health
impact. Data were then analyzed with Cytoscape. There were 405 symptoms reported, with
the majority negative (326 negative, 78 positive and 1 neutral). These effects encompassed
twelve anatomical regions/organ symptoms. The majority of the symptoms affected the mouth
and throat, and the respiratory system. Overall, examples of potentially serious negative health
effects included: increased blood pressure and asthma attack. Some of the symptoms reported
appeared opposite, such as increased and decreased blood pressure, indicating that users of the
product may be differently affected.
Conclusion
Only a few studies have directly investigated the health effects of exposure to the vapor,
and those investigated primary exposure by self-administration (Vardavas et al., 2012; Flouris et
al., 2013). One study describes the self-reported health-related events and symptoms reported on
e-cigarette fora (Hua 2013). Taken together these studies provide a very limited perspective on
the health effects from e-cigarettes. Studies are limited to products have been tested, but some do
demonstrate the ability for e-cigarette vapor exposure to result in biological effects. Long-term
biological effects are unknown at this time because e-cigarettes have not been in widespread use
long enough to assess these effects.
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EFFECTS ON CONVENTIONAL CIGARETTE CESSATION
As noted above e-cigarettes are promoted as devices to assist in smoking cessation and
most adults who use e-cigarettes are doing so because they believe that they will help them quit
smoking conventional cigarettes. The assumption that e-cigarettes will be as effective, or more
effective, than pharmaceutical nicotine replacement therapy has also motivated support for e-
cigarette use among some public health researchers and policy makers and (as discussed later)
formed the basis for public policies on the regulation of e-cigarettes.
Population-based studies
In Adkison et al. (2013) (ITC 4-Country Study noted above) authors presented a
longitudinal analysis of data from current and former smokers over 2 timepoints separated by a
year.(Adkison, O'Connor et al. 2013) E-cigarette users had a statistically significant greater
reduction in cigarettes per day from the first timepoint to the second, one year later (e-cigarette
users: 20.1cig.day to 16.3 cig/day; non-users: 16.9 cig/day to 15.0 cig/day). Although 85% of e-
cigarette users reported they were using the product to quit smoking at the initial wave, e-
cigarette users were no more likely to have quit one year later than non-users ( OR=0.81, 95%
CI: 0.43-1.53; p=0.52).
Vickerman et al. (2013) collected data about e-cigarette use among quitline callers from 6
U.S. states assessed at 7-months post enrollment.(Vickerman, Carpenter et al. 2013) 30.9%
reported they had ever tried e-cigarettes in their lifetime and the majority of those who have ever
tried them used them for less than one month (67.1%) and 9.2% were using them at 7-month
survey. Respondents' main reason for using e-cigarettes was tobacco cessation (51.3%), but it is
not known whether the ever use occurred as part of a quit attempt in the past 7 months.
Nevertheless, those who reported using e-cigarettes were statistically significantly less likely to
quit than those who had not used e-cigarettes (21.7% among callers who used for one month or
longer, 16.6% among those who used less than one month and 31.4% among never-users;
p<0.001).(Vickerman et al., 2013) The unadjusted odds of quitting were statistically significantly
lower for e-cigarette users compared to non-users (OR=0.50, 95% CI: 0.40-0.63).
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Grana, Popova and Ling (submitted to NEJM) explored predictors of quitting or relapse
among a population of smokers and recent former smokers (n=951) recruited from a nationally
representative online panel, who participated in a study in (2011) and one-year later
(2012).(Grana, Popova et al. 2013) In a logistic regression model, current e-cigarette use (past 30
days) at baseline did not predict greater likelihood of being quit at one-year follow-up (OR=0.82,
95% CI=0.39, 1.70), controlling only for demographics (age, gender, ethnicity and education). In
a second logistic regression model that included baseline cigarettes per day, time to first cigarette
and intention to quit in addition to baseline current e-cigarette use, only intention to quit
(OR=5.95, 95% CI=2.52, 14.06) and cigarettes per day (OR=0.97, 95% CI=0.94, 0.99) predicted
greater likelihood of being quit at one year follow-up and e-cigarettes remained non-significant
(OR=0.84, 95% CI=0.39, 1.81). Among recent former smokers at baseline (n=288), neither past
30-day e-cigarette use, nor measure of past history of cigarette dependence, predicted likelihood
of relapse at one year follow-up.
Conclusion
There are three population-based longitudinal studies of the effects of e-cigarette use on
cessation of conventional cigarettes. Several strengths and limitations should be noted. A
strength of the Adkison and Vickerman studies is the assessment of why participants were using
e-cigarettes, which is a limitation of the Grana study. In Adkison, 85% of e-cigarette users and in
Vickerman 66.5% of e-cigarette users indicated they were using the product to quit or switch “to
replace other tobacco,” which limits the possibility that lack of effect on quitting is observed due
to a lack of intention to quit by using the device. Although quitline callers represent a small
population of smokers motivated to quit, these data present a real-world estimate of the potential
effectiveness of using e-cigarettes to quit in a population of motivated to quit. However, this
study may be subject to recall bias as e-cigarette use and perceptions was only assessed at 7-
month follow-up.
As participants are not randomly assigned to use e-cigarettes in the real world, a strength
of the Vickerman and Grana studies are that they provide information on smoking
characteristics, including measures of tobacco dependence, which could potentially be a source
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of self-selection bias. In the Vickerman study those who tried e-cigarettes did not statistically
significantly differ from non-users in cigarettes per day or time to first cigarette, although they
were more likely to have tried to quit 2 or more times (Vickerman). In the Grana et al study, e-
cigarette users differed in cigarettes per day and time to first cigarette; however, in the
multivariate regression predicting quit status that included these dependence factors, e-cigarette
use remained non-significant. Therefore, it is unclear to what extent self-selection is occurring
and contributes to quit success or failure. More observational, population-based research that
assesses e-cigarette use, motivations for use and patterns of use as well as cessation motivation
and behavior is needed. In sum, taken together these studies suggest that e-cigarettes are not
associated with higher quit rates in the general population of smokers.
Clinical trials
Four clinical trials have attempted to examine the efficacy of e-cigarettes for smoking
cessation (2 with very small samples).(Polosa, Caponnetto et al. 2011; Bullen, Howe et al. 2013;
Caponnetto, Auditore et al. 2013; Caponnetto, Campagna et al. 2013) Three of the four studies
did not have a control group who were not using e-cigarettes.(Polosa, Caponnetto et al. 2011;
Caponnetto, Auditore et al. 2013) The other study compared e-cigarette efficacy to a standard of
care regimen with 21mg nicotine patch (Bullen 2013). None of the trials were conducted with
the level of behavioral support that accompanies most pharmaceutical trials for smoking
cessation.
Polosa et al. conducted a proof-of-concept study conducted in Italy in 2010 with
smokers18-60 year old not intending to quit in the next 30 days were offered ‘Categoria’ e-
cigarettes and instructed to use up to 4 cartridges (7.4mg nicotine content) per day as desired to
reduce smoking and to keep a log of cigarettes smoked per day, cartridges used per day and
adverse events.(Polosa, Caponnetto et al. 2011) Six-month follow-up was completed with 68%
(27/40) of participants. At 6-month follow-up, 13 were using both e-cigarettes and tobacco
cigarettes, 5 maintained exclusive tobacco cigarette smoking and 9 stopped using tobacco
cigarettes entirely and continued using e-cigarettes (Polosa et al., 2011). Cigarette consumption
was reduced by at least 50% in the 13 dual users (25 cigarettes per day (cpd) at baseline to 6 cpd
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at 6-months, p<0.001). Most common adverse events reported during the trial were throat
irritation, dry cough and mouth irritation, followed closely by headache, nausea and dizziness.
Participants reported they would recommend the e-cigarette to a friend yet noted the need for
better manufacturing practices as they were frustrated by problems they had operating their
devices. This study is limited by use of a non-standard cut-off for considering a smoker abstinent
by expired breath carbon monoxide (CO). Also, limitations include use of a product that was
noted for poor quality during the trial and lack of a comparison or control group, which could
make it difficult to determine if quit rates achieved were not due to chance.
A similar study was conducted by Caponnetto et al (2013) with 14 smokers with
schizophrenia not intending to quit in the next 30 days.(Caponnetto, Auditore et al. 2013)
Participants were provided the same “Categoria” e-Cigarette and CO, product use, number of
cigarettes smoked, and positive and negative symptoms of schizophrenia were assessed at
baseline, week-4, week-8, week-12 week-24 and week 52. Sustained 50% reduction in the
number of cigarettes per day smoked at week-52 in 7/14 (50%) participants and median of 30
cig/day decreased to 15 cig/day (p = 0.018). Sustained abstinence from smoking occurred with 2
participants (14.3%) by week 52. Most common side effect was dry cough followed by nausea,
throat irritation, and headache. Positive and negative aspects of schizophrenia were not increased
after smoking cessation in those who quit. The most common outcome was dual use of e-
cigarettes with conventional cigarettes. Study findings are not generalizeable to smokers with
mental illness due to very small sample size and lack of a control group.
Caponnetto et al. (2013) also conducted a randomized, quasi-controlled trial to examine
efficacy of different strength e-cigarettes for smoking cessation and reduction in three study
arms: 12 weeks of treatment with the 7.2mg nicotine e-cigarette, a 12-week nicotine tapering
regimen (6 weeks of treatment with a 7.2mg e-cigarette and 6 weeks with 5.4mg e-cigarette), and
12 weeks of treatment with a non-nicotine e-cigarette.(Caponnetto, Campagna et al. 2013)
Reduction occurred in the median value of cigarettes per day at all study visits among all three
treatment arms. At one-year follow-up the reduction in median level of cigarettes per day among
participants in the 7.2 mg nicotine e-cigarette group was 19 to 12 cpd; the tapered e-cigarette
group was 21 to 14 cpd and the non-nicotine e-cigarette group was 22 to 12 cpd. Differences in
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reductions between groups were not significant after week 8 assessment. There was no
statistically significant difference in 6-month or one year quit rate among the three conditions
(one year rates: 4% for placebo e-cigarette users, 9% for low nicotine e-cigarette users and 13%
for high nicotine e-cigarette users) (Capponetto 2013). The authors noted that those who initiated
quitting in the first few weeks of the study stayed quit, while those who did not remained dual
users throughout the study. In addition, 26% of quitters continued to use e-cigarettes at 1 year.
Problems with the study include lack of a control group not using e-cigarettes and noted lack of
product quality (the authors noted the devices malfunctioned often and new ones had to be sent
out frequently over the course of the treatment period). An author on all of these studies, R.
Polosa notes that beginning in February 2011, he served as a consultant for the Arbi Group Srl.,
the manufacturer of the ‘Categoria’ e-cigarette used in the study.
Bullen et al (2013) conducted the first randomized controlled clinical trial of e-cigarettes
compared to medicinal nicotine replacement therapy in Auckland, New Zealand. Adult smokers,
18+ who wanted to quit (n=657) were randomised using a 4:4:1 ratio to the 3 study arms (16mg
e-cigarettes n=289, 21mg NRT patch n=295, no-nicotine e-cigarette n=73).(Bullen, Howe et al.
2013) Voluntary telephone counseling was offered to all subjects. Subjects were observed at
baseline, week 1 (quit day), 12 weeks to 6 months. Fifty-seven percent of participants in the
nicotine e-cigarettes group reduced their cigarettes per day by ≥50% by 6 months compared to
41% in the patch group (p=0.002) and 45% in the non-nicotine e-cigarette group (p=0.08). Those
randomized to the nicotine patch group were less adherent to the treatment (46%) than the 16mg
e-cigarette group (78%) and the no-nicotine e-cigarette group (82%). This may be due to aspects
of the study methodology which may have biased the study against success in the nicotine patch
group. E-cigarettes were provided by mail for free to participants randomized to either the
nicotine or no-nicotine e-cigarette group. Participants in the patch group were provided with
usual care for quitline callers in New Zealand, where they are mailed cards redeemable for
nicotine patches at a pharmacy at a very reduced rate of about $4 USD for 12 weeks of nicotine
patches. In this study they were provided with monetary vouchers to compensate for the $4 that
had to be paid for the patches at time of card redemption. There were no statistically significant
differences in biochemically-confirmed (breath CO) self-reported continuous abstinence from
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quit day to 6 month follow-up between nicotine e-cigarette (7.3%), nicotine patch (5.8%), and
non-nicotine e-cigarette (4.1%).
While there are not any longitudinal studies of the effects of e-cigarette use on smoking
cessation in youth, there are two cross-sectional studies which suggest that in youth e-cigarettes
could be inhibiting cessation of conventional cigarettes.
As discussed above, Lee et al (submitted JAH) assessed the relationship between e-
cigarette use and current (past 30 day) smoking, quit attempts, and no longer using cigarettes
using the 2011 Korean Youth Risk Behaviour Web-based Survey of 75,643 students aged 13-18
years was analyzed with logistic regression.(Lee, Grana et al. 2013) They found that after
adjusting for demographics, current cigarette smokers were much more likely to use e-cigarettes
than non-smokers. Among current cigarette smokers, those who smoked more frequently were
more likely to be current e-cigarette users. Odds of being an e-cigarette user was 1.58 times
(95% CI: 1.39-1.79) higher among students who had made a quit attempt than those who had
not. Students no longer using cigarettes were rare among current e-cigarette users (OR 0.10, 95%
CI: 0.09-0.12)..
Dutra and Glantz (nearly submitted) examined e-cigarette use and conventional cigarette
smoking using the 2011 US National Youth Tobacco Survey (NYTS), which was administered
to a representative sample of U.S. middle and high school students (n=18,644). Among
experimenters with conventional cigarettes (>1 puff, <100 cigarettes), ever e-cigarette use was
associated with higher odds of ever smoking (>100 cigarettes; (OR=7.68, 95% CI [5.45-10.83])
and current smoking (OR=7.44, [5.39-10.27]). Current e-cigarette use was associated with an
odds of ever smoking of 7.27 [3.99-13.25] and an odds of current smoking of 6.68 [3.82-11.68].
Among experimenters, ever use of e-cigarettes was also associated with lower 30-day (2011:
OR=0.22 [0.16-0.30]), 6-month (2011: OR=0.22 [0.16-0.29]), and 1-year (2011: OR=0.22 [0.15-
0.32];) abstinence from cigarette smoking. Current e-cigarette use was also associated with lower
30-day (2011: OR=0.15 [0.08-0.28]), 6-month (2011: OR=0.17 [0.07-0.40]), and 1-year (2011:
OR=0.15 [0.07-0.34]) abstinence. Among ever smokers of cigarettes (>100 cigarettes), ever e-
cigarette use approached significance for the odds of abstaining from smoking in the past 30
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days in 2011 (OR=0.55 [0.31-1.01]). Current e-cigarette use was not a significant predictor of
smoking abstinence among ever smokers. Thus, e-cigarette use was associated with higher odds
of ever or current cigarette smoking and lower odds of abstinence from conventional cigarettes.
E-cigarettes appear to be promoting cigarette use among adolescents and discouraging quitting.
Conclusion
The quit rates produced in Capponnetto et al 2013 for non-nicotine e-cigarette 4%,
tapered nicotine e-cigarette 9% and 7.4mg e-cigarette 13%; 30-day abstinence at one year) were
not statistically significantly different. Similarly, in Bullen et al 2013, the quit rates for 16mg e-
cigarette, 21mg nicotine patch and 0mg e-cigarette showed no statistically significant differences
in continuous abstinence quit rates at 6 months (7.4%, 5.8%, 4.1% respectively). Both of these
studies did not show effects of e-cigarette use on quitting, beyond what is seen in unassisted
cessation studies with NRT (cite). Both the Capponnetto (2013) and the Bullen et al (2013)
randomized trials did not demonstrate a statistically significant difference in quit rates between
nicotine e-cigarette and non-nicotine e-cigarettes. In determining the effectiveness of a smoking
cessation therapy, active drug is considered efficacious when it outperforms its placebo form,
therefore the evidence to date demonstrates that e-cigarettes would not be considered efficacious
as nicotine replacement to produce cessation. It is possible that e-cigarettes act as substitutes for
the sensory and behavioral effects of conventional cigarettes. Important limitations of the current
research include the use of e-cigarettes that deliver relatively low levels of nicotine and provision
of minimal behavioral counseling. Studies with more modern products and with more intensive
behavioral counseling are ongoing.
Reductions in cigarettes per day were observed in these studies (Polosa, Capponetto,
Caponnetto, Bullen) and in the population-based study (Adkison) among those who did not quit.
In the cigarette reduction analyses presented in some of the studies, many participants were still
smoking about half a pack cigarettes per day at the end of the study. Light smoking, even 1-4
cigarettes per day, is associated with markedly elevated cardiovascular disease risk.(Bjartveit and
Tverdal 2005)
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TOBACCO INDUSTRY INVOLVEMENT
In 2012 and 2013 major tobacco companies – Lorillard, Reynolds American Inc, (which
is 42% owned by British American Tobacco), Altria (Philip Morris), and British American
Tobacco -- purchased or developed e-cigarette products. Lorillard, Reynolds and Altria's
products are put forth by subsidiary companies: Lorillard Vapor Corporation, R.J.Reynolds
Vapor Company, and Nu Mark, LLC. (owned by Altria). Lorillard acquired e-cigarette
companies that produced Blu and SkyCig brands marketed under Lorillard Vapor Corporation.
As of 2013, Altria’s Mark Ten e-cigarette is in test market in Indiana, Reynolds’ product, the
Vuse, is in test market in Colorado and has planned to roll out national distribution and has
created a TV commercial for the launch. BAT markets the Vype in the U.K. In addition, a
smaller tobacco company, Swisher, that makes little cigars and cigarillos, also markets an e-
cigarette called the e-Swisher.
There is no evidence that the cigarette companies are acquiring or producing e-cigarettes
as part of a strategy to phase out regular cigarettes, but some claim to want to participate in
"harm reduction." Lorillard CEO Murray Kessler stated in a Sept. 23, 2013 interview with the
Wall Street Journal in which he claimed that e-cigarettes will provide smokers an unprecedented
chance to reduce their risk from cigarettes. Also, in
USA Today he published an op-ed on
September 23, 2013 where he stated: “E-cigarettes might be the most significant harm-reduction
option ever made available to smokers.”Shortly before this op-ed was published, however,
Lorillard gained approval from the US Food and Drug Administration to market a new non-
mentholated Newport conventional cigarette, demonstrating the inherent inconsistency in
messaging and deeds by expanding their cigarette line while touting their ability to offer a
product they claim reduces harm from cigarettes. In this way the cigarette companies get to have
it both ways, they offer an alternative to their products while continuing to market their products.
In fact as noted in the 2010 Surgeon General’s Report, "How Tobacco Smoke Causes Disease,"
the tobacco industry has used every iteration of cigarette design to undermine cessation and
prevention.
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The tobacco companies have e-cigarette issues on their radar as part of their policy
agenda. They are still engaging in “smokers rights” activities - where they use seemingly
independent groups to interact with consumers directly on political involvement in support of
their agenda. Altria has a website called “Citizens for Tobacco Rights” and Reynolds has
“Transforming Tobacco.” E-cigarette news and action alerts are featured on the homepages of
these websites and include instructions for taking action against bills designed to include e-
cigarette use in smokefree laws.
An e-cigarette market analysis report by Goldman-Sachs in 2013 noted that despite
currently comprising <1% total industry sales, there is the potential for e-cigarettes to account for
15% of US tobacco market profit by 2020. However, the report noted that “full conversion” from
cigarettes to e-cigarettes has not been achieved and most users are dual users with conventional
cigarettes. The report noted that products would have a longer lifespan because its users would
have a longer lifespan, reflecting the obvious goal of lifelong use of the products and uptake by
new users. Importantly, the market analysts remained positive on the long term growth of the
tobacco industry with e-cigarettes playing a role, not as a replacement for the tobacco products.
Likewise, after evaluating the cigarette companies’ internal documents and public
positions on snus as “harm reduction” in Europe, Gilmore et al. (2013)(Peeters S and Gilmore
AB 2013) found that they were entering the market to protect their cigarette business as long as
possible. They saw clear lessons for assessing the companies’ involvements in e-cigarettes:
While such evidence must be considered alongside the broader body of evidence around
snus and the fact it is significantly less harmful than smoked tobacco, collectively these
issues suggest that legalising snus sales in Europe may have considerably less benefit
than envisaged and could have a number of harmful consequences. Perhaps of greater
concern, however, given that harm reduction using nicotine products is already an
established element of tobacco control and recent research suggests scope for benefit via
newer nicotine products, are the recent industry investments in pure nicotine products.
These raise two concerns. First, one of competition: should such investments continue,
competition between cigarettes and clean nicotine products would decrease, limiting the
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potential for harm reduction to benefit public health and maintaining the status quo of
cigarettes. While a nicotine regulatory authority could ensure that regulation was
proportional to harm, it would be powerless to address the issue of competition, so this
situation needs close observation. Second, they may enable TTCs [transnational tobacco
companies], by presenting themselves as purveyors of nicotine rather than tobacco
products, to undermine Article 5.3 of the Framework Convention on Tobacco Control
which aims to protect public health policy from commercial and other vested interests of
the tobacco industry. Finally, if TTCs are genuinely interested in seeing their cigarette
consumers switch to snus (or pure nicotine products), rather than creating new
snus/nicotine users and/or dual use opportunities, we would expect to see detailed
strategic plans and cigarette sales reduction targets at least for the markets where they
intend to introduce these products. However, to this date we have yet to see this.
[citations eliminated] (Peeters S and Gilmore AB 2013)
CURRENT STATE OF GLOBAL REGULATION
Like e-cigarettes themselves, the policy environment related to e-cigarettes is rapidly
developing despite the lack of a large base of scientific evidence to support policy development.
Most policies are based on the assumptions that e-cigarettes will contribute to reducing the harms
of smoking by either promoting smoking cessation or, at least, replacing combusted cigarettes
with e-cigarettes. Of increasing concern is the mounting evidence of dual use and youth initiation
of e-cigarette use.
European Union Draft Tobacco Product Directive
The draft European Tobacco Product Directive (TPD) as amended on October 8, 2013
creates a new category of “nicotine-containing products” (NCP) for e-cigarettes.(European
Parliament 2013) The draft TPD accepts the assumption, contradicted by the scientific evidence
presented in this report, that e-cigarettes are effective cessation devices that should be made
widely available when it states, “Given the potential of nicotine-containing products to aid
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smoking cessation, Member States should ensure that they can be made available as widely as
tobacco products.”
The TPD allows marketing of all NCPs with a nicotine level of 30 mg/ml or less without
any screening for their quality, safety, or efficacy if they are not presented with medicinal or
therapeutic claims. (NCPs that exceed 30mg/ml are prohibited.) The 30 mg/ml threshold protects
almost all e-cigarette products currently on the market, as 36 mg/ml is typically the strongest
concentration offered in cartridges and e-liquid bottles. There are e-liquid preparations for sale in
very large quantities that exceed this concentration (100 mg/ml)
(http://wizardlabs.us/index.php?route=product/product&product_id=77), but in a content
analysis of e-cigarette retail websites in 2012, no product over 36 mg/ml was found (Grana, Ling
under review). The 30mg/ml level is higher than the nicotine content in any of the e-cigarette
devices tested in the studies published to date as reviewed in this report.
The draft TPD subjects e-cigarettes to pre-market authorization only if they are
“presented as having properties for treating or preventing disease” (i.e., “medicinal products”).
This is counter to the assumption made in the TPD that
all e-cigarette products should be
available because of their potential “… to aid smoking cessation.” This inconsistency within the
draft directive is evident when it notes that "Nicotine-containing products - including e-cigarettes
- are sold on the Union market. However Member States have taken different regulatory
approaches to address health and safety concerns associated with these products. There is a need
for harmonized rules, therefore all nicotine-containing products should be regulated under this
Directive as a related tobacco product.” To implement this policy, Article 3.7 provides that:
The proposal removes current legislative divergence between Member States and the
differential treatment between Nicotine Replacement Therapies and Nicotine Containing
Products, increases legal certainty and consolidates the on-going development in Member
States. It also encourages research and innovation in smoking cessation with the aim of
maximising health gains.
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Thus, the draft directive accepts as a premise that NCPs, including e-cigarettes, are "medicinal
products" within the meaning of Directive 2001/83/EC because they have properties that are
useful "for treating or preventing disease" by aiding smoking cessation. TPD Article 18 seems
inconsistent with these provisions, however, since it differentiates between NCPs that are
"presented as having properties for treating or preventing disease," which are required to get
premarket authorization under Directive 2001/83/EC under paragraph 2 of Article 18, and all
other NCPs, which need only follow the notification procedure set out in Article 17.
The TPD prohibits nicotine-containing products with the following types of additives:
additives such as vitamins that create the impression of health benefit or reduced risk; caffeine,
taurine and other stimulants associated with energy and vitality; and additives having coloring
properties for emissions. However, the additives which may impart a characterizing flavor that
increase product appeal to children (e.g., chocolate, cherry, strawberry, licorice, menthol) that
are explicitly prohibited from tobacco products (conventional cigarettes) are explicitly allowed in
e-cigarettes.
E-cigarette manufacturers and importers are nominally required to submit lists of all
ingredients contained in and emissions resulting from the use of their products by brand name
and type, and including quantities, but the TPD explicitly ensures protection for companies’
trade secrets, creating a loophole while will permit companies to avoid this disclosure
requirement by claiming that their ingredient lists are trade secrets, as they have done in response
to required submissions to the FDA in the United States.
The TPD requires that “each unit packet and any outside packaging of nicotine-
containing products carry the following health warning: ‘This product is intended for use by
existing smokers. It contains nicotine which is a highly addictive substance.’” The size and
placement of the warning is the same as for tobacco products for smoking other than cigarettes
and roll-your-own tobacco: 30%-35% of the external area of the unit pack and any outside
packaging, depending of the number of a Member State’s official languages.
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The TPD explicitly permits sales of e-cigarettes outside of pharmacies (including any that
might be registered as “medicinal products”). E-cigarette sales to buyers under age 18 are
prohibited.
The TPD imposes the same “limitations on advertising, sponsorship, audiovisual
commercial communication and product placement for tobacco products as set out in Directive
2003/33/EC and Directive 2010/13/EC” to e-cigarettes. It also prohibits co-branding of e-
cigarettes and tobacco products: “tobacco trademarks, brand names and symbols are not used on
nicotine-containing products.” The ability to co-brand products with a celebrity’s “brand” is
unclear.
The TPD is silent on the marketing of e-cigarette devices that do not contain nicotine, so
does not create any restrictions on the marketing or sale of these products, particularly to youth.
This is an important omission. In contrast to cigarettes or conventional nicotine replacement
therapies such as patch, gum, lozenge, there are many different e-cigarette-like products in the
current marketplace and many are not sold pre-filled and pre-assembled. (This situation also
contrasts with the most similar medicinal product, the nicotine inhaler, which is standardized for
use: It has only one cartridge of one nicotine concentration that only fits in one device.) With e-
cigarette products, different components of products are sold separately and can be used with
several different liquids with varying nicotine content. Indeed, one way that a company could
possibly legally evade regulation under the TPD would be to sell nicotine-free e-cigarettes as
consumer products then sell the nicotine fluid separately. It is not clear how the nicotine content
standards would apply in this context (e.g., bottles of e-liquid, different sized cartridges that can
be used on different devices). Moreover, it is not clear how every piece of these devices would
be regulated to ensure that they meet safety standards (whether regulated a medicines or
consumer products), or even if they would be allowed to be sold separately.
The definition of passive smoking, "'Passive smoking' means the involuntary inhalation
of smoke from the combustion of cigarettes or cigars or from the exhalation of one or more
smokers," excludes the so-called "vapor" from e-cigarettes, as it only includes the "combustion
of cigarettes or cigars." This omission would thus permit the use of e-cigarettes in places that are
currently regulated by laws that prohibit "passive smoking."
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Perhaps most significantly, the amendments to the TPD adopted on October 8, 2013
eliminated the authority of the European Commission to update the regulations related to e-
cigarettes as new information about marketing and use patterns and their direct health effects and
effects on cigarette consumption develops in the currently rapidly changing market. Specifically,
the requirement that:
The Commission shall be empowered to adopt delegated acts in accordance with Article
22 to adapt the requirements in paragraphs 3 and 4 taking into account scientific and
market developments and to adopt and adapt the position, format, layout, design and
rotation of the health warnings.
was deleted and replaced with a weak requirement for monitoring and preparation of a report
after 5 years that could recommend changes to the TPD (but not make any actual changes).
This change effectively insulates the e-cigarette companies from any science-based
regulations for at least 5 years and likely much longer, since it moves the issue back into the
political sphere where the tobacco companies are strongest.
(http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08275-2/abstract and
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000202)
NATIONAL POLICIES
FCTC Conference of the Parties Survey Results (2012)
FCTC Conference of the Parties’ report on e-cigarettes, (11/2012, n=33
Parties).(FCTC/COP/5/13 2012) Brazil, Singapore, the Seychelles and Uruguay ban e-cigarettes
from being sold or distributed in their countries. Several countries have proposed or enacted
regulations. Australia, New Zealand and Switzerland allow e-cigarettes without nicotine to be
sold, but residents may purchase e-cigarettes and e-liquid with nicotine over the Internet for
personal use (may not sell them in the country). Many with regulations focus on drug delivery
55
DRAFT e-cigarette background paper 10-14-13
device classification for e-cigarettes with nicotine and that make health claims. For example,
Germany's regulation separates e-cigarette products into consumer and medicinal by it nicotine
and health claims. If a product contains no nicotine and no health claim it is currently
unregulated. However if a product has nicotine in it and is marketed with a health claim, it must
go through their drug delivery regulatory scheme to be approved for retail, distribution and
advertisement as a medication. Similar regulations exist in Germany, Belgium, Turkey and the
U.K. where e-cigarette products require pre-market authorization if they contain nicotine and are
marketed with a health claim or if they are intended to be used for smoking cessation. By
contrast, in Korea, products
without nicotine are regulated as quit aid by the Korean Food and
Drug Administration (KFDA) and products with nicotine are treated as tobacco products and
regulated by Ministry of Finance.
United Kingdom
Policymaking on e-cigarettes in the U.K. is based on two assumptions: (1) harm
reduction implemented by shifting cigarette smokers to “cleaner” forms of nicotine delivery is an
effective public health policy (cite NICE standards); (2) e-cigarettes are a safe effective form of
nicotine replacement; and (3) the widespread introduction of e-cigarettes will increase cigarette
cessation and not increase initiation. Specifically, the U.K. Medicines and Healthcare Products
Regulatory Agency (MHRA) has announced they plan to regulate e-cigarettes as medicines
because MHRA believes that e-cigarettes function as nicotine replacement for smokers cutting
down or quitting:
The consistent evidence from a variety of sources is that most electronic cigarettes use is
to support stop smoking attempts or for partial replacement to reduce harm associated
with smoking. This is comparable to other nicotine replacement products (e.g., gums,
patches, inhalator), which are licensed as medicines. The current evidence is that
electronic cigarettes have shown promise in helping smokers quit tobacco but the quality
of existing NCPs [nicotine containing products, how MHRA labels e-cigarettes] is such
that they cannot be recommended for use.
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DRAFT e-cigarette background paper 10-14-13
The MHRA’s regulatory plans focus on ensuring consistency of nicotine delivery and
quality control of the e-cigarette devices. Since March 2011 MHRA reviewed evidence to
regarding safety of the devices and e-liquid and their own analysis of four e-cigarette products,
finding that existing products on the market are low quality and not assured for safety
(http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con286839.pdf).
Their evidence review, like this report, found that products have incongruous nicotine content
from labeled values and levels varied for identical products within the same brand and that is just
among a selection of brands among the hundreds on the market. The MHRA found diethylene
glycol in one product in accordance with the FDA analysis (2009) likely to be from improper
processing of propylene glycol. In addition, they found the presence of a toxic contaminant (1,3-
bis(3-phenoxyphenooxy) benzene), which they stated has no plausible reason for being in the
products. They concluded that the devices cannot be considered safe or effective nicotine
delivery devices as the content and delivery of nicotine differs from brand to brand and even
within brand. Moreover, their evidence review acknowledges that low levels of known tobacco-
specific carcinogens were found in products, likely from low-quality nicotine extraction
processes.
Research published after the EU draft directive and MHRA evidence review
(http://www.mhra.gov.uk/home/groups/commsic/documents/websiteresources/con286839.pdf)
were published provides additional information that should be considered in designing these
regulatory approaches. In contrast to the assumption that e-cigarettes would function as a better
form of NRT, population-based longitudinal studies which reflect real-world e-cigarette use
found that e-cigarette use is not associated with or predict successful quitting (Vickerman,
Adkison, Grana Popova and Ling, submitted) and the 1 clinical trial examining the effectiveness
of e-cigarettes (both with and without nicotine) compared to the medicinal nicotine patch found
that e-cigarettes are no better than nicotine patch and all treatments produced very modest quit
rates without counseling. Although more participants liked using the e-cigarette compared to
patch and would recommend it to a friend trying to quit.
MHRA noted that their regulation of e-cigarettes as medicines is in accordance with the
proposed EU Tobacco Products Directive before it was amended on October 8, 2013,
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DRAFT e-cigarette background paper 10-14-13
(http://ec.europa.eu/health/tobacco/docs/com_2012_788_en.pdf) which MHRA assumed will be
adopted in 2014 and come into effect by 2016. The MHRA specifies that their program seeks to
determine four dimensions to establish medicines licensing for e-cigarettes: “the nature, quality
and safety of unlicensed NCPs; the actual use of unlicensed NCPs in the marketplace; the
effectiveness of unlicensed NCPs in smoking cessation; and modelling of the potential impact of
bringing these products into medicines regulation on public health outcomes.” It is unclear the
specific steps to achieve these aims.
As part of what appears to be a broad consensus in the UK that the introduction of e-
cigarettes will reduce the harm of smoking, the anti-smoking advocacy group ASH UK has
announce that it "does not consider it appropriate to include e-cigarettes under smokefree
regulations," (http://www.ash.org.uk/files/documents/ASH_715.pdf), supporting one the e-
cigarette companies’ key marketing messages, namely that e-cigarettes can be used everywhere
without the restrictions and social stigma of smoking (Grana and Ling, under review; McKee,
2013). It is unclear how the UK plans to address the potential interference with enforcement of
existing smokefree laws and potential promotion of smoking as these are mimicking products.
The MHRA does not include any restrictions on e-cigarette marketing. An undated
document, “The Regulation of Nicotine Containing Products: Questions and Answers,” attempts
to address this issue:
24. What will be done by the Government to stop manufacturers making their
products attractive to young people/children – such as making fruit tasting
electronic cigarettes or doing special offers such as two for the price of one?
Medicines regulation prohibits advertising to children (under 16 years of age).Any
licensed medicines would have an age limit – likely to be 18 years of age. One of the
reasons for favouring medicines regulation is that it has controls on advertising and
promotion and sale and supply. We will look at applications from manufacturers on a
case-by-case basis.
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DRAFT e-cigarette background paper 10-14-13
If need be, we are able to set particular conditions on the way that products are presented
and promoted, especially if they become popular with young people.
At present, we are not aware of any widespread use of e-cigarettes by young people.
These assurances provide little or no protection against aggressive marketing of e-cigarettes to
youth; the tobacco companies are long-practiced at developing and implementing effective
marketing campaigns directed at youth with similar restrictions for decades all over the world.
Evidence published after this agency issued their intended policies has shown rapid e-cigarette
uptake among adolescents in the US, (with use doubling from 3.4% to 6.8% among all middle
school and high school youth from 2011 to 2012, with rates even higher among older youth in
high school 4.7% to 10.0%), mostly among current smokers.
France
In contrast to the position ASH UK took in England, the French Health Minister, Marisol
Touraine, announced on May 31, 2013 (World No Tobacco Day) that the French government
plans to extend existing smoking restrictions to e-cigarettes. These restrictions were undertaken
to prevent confusion in enforcement of the national smokefree law and prevent modeling of
smoking by a product that mimics cigarette smoking. (http://www.france24.com/en/20130531-
french-health-minister-electronic-cigarette-ban-public-places) It will also protect bystanders
from being exposed to secondhand e-cigarette vapor.
Spain
Although no national action has been taken, regional action has been pursued to treat e-
cigarettes the same as tobacco products under their existing state-wide smokefree law. The
Catalan Network of Smoke-free Hospitals and the Network of Primary Care issued a statement
that there is a lack of evidence of safety and efficacy for e-cigarettes and they act as mimicking
products which can create confusion and may interfere with “denormalization.” They stated:
“…the Catalan Network of Smoke-free Hospitals and Primary Care recommend that hospitals,
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DRAFT e-cigarette background paper 10-14-13
health centers and other healthcare facilities: - Prohibit by internal regulation the use of
electronic cigarettes on their premises, both in enclosed places (buildings) and outdoors, similar
to that established in the current legislation (Law 42/2010) of sanitary measures to control
tobacco snuff products. - Prohibit by regulation for internal system sale, promotion or advertising
of these devices in their units, similar to that established in the current Spanish smoke-free
legislation (Law 42/2010).”
India
In India e-cigarettes were declared as illegal under Drugs and Cosmetics Act by State
Drug Controller in Punjab and the government of India is preparing to ban them. (Per personal
communication from Dr.Rakesh Gupta, State Programme Officer, Tobacco Control Cell Punjab)
U.S.
As of October 2013, e-cigarette products remained unregulated by any federal authority,
particularly the US Food and Drug Administration (FDA). The Sottera Inc. case ruling that was
upheld on appeal in U.S. court, found that e-cigarettes could be regulated as tobacco products
unless they are marketed with health and therapeutic claims.(D.C. Circuit U.S. Court of Appeals
2010) The FDA accepted that ruling and issued a letter to stakeholders on April 25, 2011 stating
their intent to issue guidance about exercising their deeming authority over e-cigarettes in the
future, but, no such deeming authority or guidance had been issued.(FDA 2011)
In the absence of Federal regulations, 23 states have passed bills restricting sales to
minors and 3 bills have been passed prohibiting the use of e-cigarettes where smoking is also
restricted. There are several bills at the local level restricting many aspects of e-cigarette
distribution, sales and use, including minor access restrictions, use indoors and point of sale. The
Federal Aviation Administration issued a regulation prohibiting the use of e-cigarettes on
domestic flights.
Phillipines
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DRAFT e-cigarette background paper 10-14-13
The Philippine Food and Drug Administration recently recommended that e-cigarettes
should not be used indoors anywhere that smoking is prohibited.
http://www.fda.gov.ph/attachments/article/80233/FA2013-015.pdf
OVERALL SUMMARY
While most discussion of e-cigarettes among health authorities has concentrated on the
product itself, its potential toxicity and use of e-cigarettes to help people quit smoking, the e-
cigarette companies have been rapidly expanding using aggressive marketing, including
television and radio in many countries using messages that have been long-banned for cigarettes.
There appears to be no evidence to the contrary that if existing smokers switched completely
from conventional e-cigarettes (with no other changes in use patterns) there would be a lower
disease burden caused by nicotine addiction. Evidence available at this time, while limited,
however, points to high levels of dual use of e-cigarettes with conventional cigarettes, little
benefit for cessation (either on a population basis or compared to available and currently
regulated nicotine replacement therapy) and rapidly increasing youth initiation with e-cigarettes.
It is unclear what will be the trajectory of the dual use pattern among adults or children, but any
uptake in children is very concerning. Nicotine is a highly addictive substance with negative
effects on human brain development, which is still ongoing in adolescence.(Dwyer, Brodie and
Leslie, 2008; Liao, Chen, Lee, et al. 2012; Lichtensteiger et al, 1988; Navarro et al 1989; Dwyer,
McQuown, Leslie, 2009) Evidence from published studies examining dual use of smokeless
tobacco, snus and conventional cigarettes among youth and adults points toward a progression to
increased cigarette smoking and difficulty with quitting. Also, common reasons respondents give
for using the products are to circumvent smokefree laws and to cut down, which reinforce dual
use patterns. High rates of dual use which may result in greater total public health burden and
possibly increased individual risk if a smoker maintains an even low-level tobacco cigarette
addiction for many years instead of quitting.
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DRAFT e-cigarette background paper 10-14-13
E-cigarette devices and their components should be evaluated for safety by consumer
product safety regulatory authorities and consumers appropriately warned about risks and proper
handling. Although the data are limited, the studies to date indicate that e-cigarette vapor would
be a source of air pollution and is not "harmless water vapor" as is frequently claimed. Article 13
of the FCTC focuses on smoke-free policies to afford protections for the public and all workers
to breathe clean air. When evaluating the risks of exposure to e-cigarette vapor, the standard of
comparison should not be whether the vapor is better than the toxic chemical mixture in tobacco
cigarette smoke (which is already prohibited), it should be whether the product's emissions
introduce toxins into clean air, and their effect on existing public health protections. In contrast
to the paucity of research on e-cigarettes, there is an extensive scientific literature showing that
smoke-free policies protect nonsmokers from exposure to toxins and encourage smoking
cessation (USDHHS, 2006). 100% smoke-free policies have about twice the effect on
consumption and smoking prevalence than policies with exceptions (Fichtenberg and Glantz,
2002). Exceptions for e-cigarettes may similarly decrease the effects of smoke-free policies on
smoking cessation, and as noted in the CoP report, use of the products in smoke-free
environments may also decrease enforcement of Article 13. Introducing e-cigarettes into clean
air environments may result in population harm if use of the product reinforces acts of smoking
as socially acceptable, and/or if use undermines the effects of smoke-free policies on smoking
cessation. Strong smoke-free policies are an integral part of the recognized and proven
comprehensive global tobacco control policies (FCTC).
This assessment is based on the assumption that the current policy environment around
cigarettes will continue and that there will be little or no effective regulations of e-cigarette
marketing and promotion or of how and where e-cigarettes are consumed. This situation could
change if the following policies were all implemented:
Ban conventional cigarettes or regulate nicotine to non-addictive levels.
Subject and e-cigarette marketing to the same level of restrictions that apply to conventional
cigarettes (on the grounds that, while less dangerous than conventional cigarettes, e-
cigarettes still deliver the addictive drug nicotine together with other toxic chemicals)
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DRAFT e-cigarette background paper 10-14-13
Tax e-cigarettes at a level comparable to current taxation of conventional cigarettes (and
perhaps further increase the tax on conventional cigarettes)
Prohibit the use of e-cigarettes anywhere that use of conventional cigarettes is prohibited
E-cigarettes should not be sold to anyone who cannot legally buy cigarettes or sold in any
venues where sale of conventional cigarettes is prohibited.
E-cigarettes should not be co-branded with cigarettes or marketed in a way that promotes
dual use.
Should these policies be put in place, it is possible that current conventional smokers who
will not quit nicotine would shift to e-cigarettes without major dual use or youth initiation to
nicotine addiction with e-cigarettes. Absent this change in the policy environment it is reasonable
to assume that the behavior patterns that have been observed for e-cigarettes will persist, which
makes it unlikely that they will on balance contribute to reducing the harm of tobacco use and
could increase harm by perpetuating the life of conventional cigarettes.
At minimum, these policies should be implemented immediately:
Regulate e-cigarettes to ensure product quality and safety.
Prohibit the use of e-cigarettes anywhere where the use of conventional cigarettes is
prohibited
Prohibit claims that e-cigarettes are effective smoking cessation aids until such time as there
is convincing scientific evidence that such claims are true for e-cigarettes as they are actually
used in the general population.
Apply the same restrictions on e-cigarette advertising and promotion as apply to conventional
cigarettes
Ban the use of characterizing flavors in e-cigarettes
Because the product, the market, and the associated scientific evidence surrounding the e-
cigarette experiment are all evolving rapidly:
All legislation and regulations related to e-cigarettes should allow for flexibility to adapt
regulations expeditiously in response to new science, including evaluation of different
models for regulating e-cigarettes, as it accumulates.
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DRAFT e-cigarette background paper 10-14-13
No country or subnational jurisdiction should be compelled to permit the sale of e-
cigarettes.
Legislation and regulations regarding e-cigarettes need to take into account the fact that,
unlike conventional cigarettes and other tobacco products and medicinal nicotine
replacement therapies, e-cigarettes can be altered by users to change the nicotine
delivery and be used to deliver other drugs.
There should be transparency in the role of the e-cigarette and tobacco companies in
advocating for and against legislation and regulation, both directly and through third
parties.
FCTC Article 5.3 should be respected when developing and implementing legislation and
regulations related to e-cigarettes.
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DRAFT e-cigarette background paper 10-14-13
Table 1. Prevalence of e-cigarette use in various countries as measured by population-based surveys
Authors
Country, sample description, n
Ever use among general population
Ever use among smokers (%)
(%)
2009
2010
2011
2012
2009
2010
2011
2012
Regan et U.S., Adults 18+, n=10587 (2009); n= 10328
0.6
2.7
--
--
Not
18.2
--
--
al 2013
(2010), ConsumerStyles nationally-
report
representative survey
ed
King et
U.S., Adults, 18+, HealthStyles survey
--
2.1
6.2
--
--
6.8
21.2
--
al 2012
nationally-representative, mail-back
mail,
online
mail,
online
(n=4,184) andonline (n=2505) modes
3.3
9.8
n=6689 in 2010, online only n=4050 in 2011
online
online
Pearson
U.S., Adults 18+ , 2 samples
et al
2012
Nationally-representative online sample
--
3.4
--
--
--
11.4
--
--
(Knowledge Networks), 2010, n=2649
Legacy Longitudinal Study of Smokers
--
--
--
--
--
6.4
--
--
(smokers and former smokers), 2010,
n=3648
McMille
U.S., Adults 18+, nationally-representative
--
1.8
--
--
--
14.4
--
--
n at al
samples recruited via 2 survey modes:
2013
telephone-based (n=1504) and online
(n=1736), Social Climate on Tobacco
Control survey, 2010
Dockrell
U.K., Adults 18+, nationally-representative
--
--
--
--
--
2.7
--
6.7
et al
online panel (YouGov), 2010: n=12597
2013
adults; 2010 n=12432
Adkison
ITC 4-country survey, Adults 18+,* July
et al
2010-June 2011*
2013
U.S. (n=1520)
--
--
--
--
20.4
Canada (n=1581)
--
--
--
--
10.0
U.K. (n=1325)
--
--
--
--
17.7
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DRAFT e-cigarette background paper 10-14-13
Australia (n=1513)
--
--
--
--
11.0
Popova
U.S., Adults 18+, nationally-representative
--
--
--
--
--
--
20.1
--
and Ling online sample (Knowledge Networks),
2013
current and former smokers, n=1836
Cho
Korea, Adolescents, middle school and high 0.5*
--
--
--
--
--
--
--
2011
school, n=4,341, national survey of in
2008*
Lee et al Korea, Adolescents, 12-19,
2013
(under
review)
CDC
U.S., Adolescents, middle and high school,
--
--
MS: 1.4
MS: 2.7
--
--
--
--
NYTS
2011, 2012 (n’s not reported)
HS: 4.7
HS:
2013
10.0
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DRAFT e-cigarette background paper 10-14-13
References:
Adkison, S. E., R. J. O'Connor, et al. (2013). "Electronic Nicotine Delivery Systems: International Tobacco
Control Four-Country Survey." American Journal of Preventive Medicine
44(3): 207-215.
Bahl, V., S. Lin, et al. (2012). "Comparison of Electronic Cigarette Refill Fluid Cytotoxicity Using
Embryonic and Adult Models." Reproductive Toxicology.
Bjartveit, K. and A. Tverdal (2005). "Health consequences of smoking 1–4 cigarettes per day." Tobacco
Control
14(5): 315-320.
Bullen, C., C. Howe, et al. (2013). "Electronic cigarettes for smoking cessation: a randomised controlled
trial." The Lancet.
Bullen, C., H. McRobbie, et al. (2010). "Effect of an electronic nicotine delivery device (e cigarette) on
desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over
trial." Tobacco Control
19(2): 98.
Burstyn, I. (2013). Peering through the mist: What does the chemistry of contaminants in electronic
cigarettes tell us about health risks?
Cameron, J. M., D. N. Howell, et al. (2013). "Variable and potentially fatal amounts of nicotine in e-
cigarette nicotine solutions." Tobacco Control.
Caponnetto, P., R. Auditore, et al. (2013). "Impact of an Electronic Cigarette on Smoking Reduction and
Cessation in Schizophrenic Smokers: A Prospective 12-Month Pilot Study." International journal
of environmental research and public health
10(2): 446-461.
Caponnetto, P., D. Campagna, et al. (2013). "EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as
tobacco cigarettes substitute: a prospective 12-month randomized control design study." PloS
one
8(6): e66317.
CBS NEWS (February 16, 2012) "Electronic cigarette explodes in man's mouth, causes serious injuries."
Centers for Disease Control and Prevention (2013). "Notes from the Field: Electronic Cigarette Use
Among Middle and High School Students — United States, 2011–2012." Morbidity and Mortality
Weekly Report
62(35): 729-730.
Chen, I.-L. (2013). "FDA Summary of Adverse Events on Electronic Cigarettes." Nicotine & Tobacco
Research
15(2): 615-616.
Cho, J. H., E. Shin, et al. (2011). "Electronic-cigarette smoking experience among adolescents." Journal of
Adolescent Health
49(5): 542-546.
Choi, K. and J. Forster (2013). "Characteristics associated with awareness, perceptions, and use of
electronic nicotine delivery systems among young US Midwestern adults." American journal of
public health
103(3): 556-561.
Cobb, N. K., M. J. Byron, et al. (2010). "Novel Nicotine Delivery Systems and Public Health: The Rise of
the" E-Cigarette"." American journal of public health
100(12): 2340.
D.C. Circuit U.S. Court of Appeals (2010). Sottera, Inc. v. Food & Drug Administration. 627 F.3d 891.
Dawkins, L., J. Turner, et al. (2013). "‘Vaping’profiles and preferences: an online survey of electronic
cigarette users." Addiction.
Dockrell, M., R. Morison, et al. (2013). "E-cigarettes: Prevalence and attitudes in Great Britain." Nicotine
& Tobacco Research.
Douptcheva, N., G. Gmel, et al. (2013). "Use of electronic cigarettes among young Swiss men." Journal of
Epidemiology and Community Health: jech-2013-203152.
Esterl, M. (April 25, 2012) "Got a Light--er Charger? Big Tobacco's Latest Buzz." The Wall Street Journal.
Esterl, M. (October 1, 2013) "Lorillard to Buy U.K. Cigarette Maker."
69
DRAFT e-cigarette background paper 10-14-13
Etter, J. F. (2010). "Electronic cigarettes: a survey of users." BMC Public Health
10(1): 231.
Etter, J. F. and C. Bullen (2011). "Electronic cigarette: users profile, utilization, satisfaction and perceived
efficacy." Addiction
11: 2017-2028.
European Parliament (2013). Amendments to the proposal for a Directive of the European Parliament
and of the Council on the approximation of laws, regulations, and administrative provisions of
the Member States concerning the manufacture presentation and sale of tobacco and related
products (COM(2012)0788).
FCTC/COP/5/13 (2012). Report: Electronic Nicotine Delivery Systems, including electronic cigarettes.
WHO Framework Convention on Tobacco Control. Seoul, Republic of Korea.
FDA. (2011). "Letter to Stakeholders: Regulation of E-cigarettes and Other Tobacco Products."
Retrieved March 20, 2013, from
http://www.fda.gov/newsevents/publichealthfocus/ucm252360.htm.
Felberbaum, M. (2013). "Old Tobacco Playbook Gets New Use by E-cigarettes." Retrieved August 16,
2013, from http://bigstory.ap.org/article/old-tobacco-playbook-gets-new-use-e-cigarettes.
Flouris, A. D., M. S. Chorti, et al. (2013). "Acute impact of active and passive electronic cigarette smoking
on serum cotinine and lung function." Inhalation toxicology
25(2): 91-101.
Flouris, A. D., K. P. Poulianiti, et al. (2012). "Acute effects of electronic and tobacco cigarette smoking on
complete blood count." Food and Chemical Toxicology
50(10): 3600–3603.
Food and Drug Administration (2009) "FDA and public health experts warn about electronic cigarettes.".
Galanti, M. R., I. Rosendahl, et al. (2008). "The development of tobacco use in adolescence among “snus
starters” and “cigarette starters”: An analysis of the Swedish “BROMS” cohort." Nicotine &
Tobacco Research
10(2): 315-323.
Goniewicz, M. L., J. Knysak, et al. (2013 (online first)). "Levels of selected carcinogens and toxicants in
vapour from electronic cigarettes." Tobacco Control.
Goniewicz, M. L., T. Kuma, et al. (2013). "Nicotine levels in electronic cigarettes." Nicotine & Tobacco
Research
15(1): 158-166.
Goniewicz, M. L., E. O. Lingas, et al. (2012). "Patterns of electronic cigarette use and user beliefs about
their safety and benefits: An Internet survey." Drug and alcohol review.
Goniewicz, M. L. and W. Zielinska-Danch (2012). "Electronic cigarette use among teenagers and young
adults in Poland." Pediatrics
130(4): e879-e885.
Grana, R., L. Popova, et al. (2013). "E-cigarette use, smoking cessation and relapse: a national
longitudinal study." NEJM
under review.
Grana, R. A., S. A. Glantz, et al. (2011). "Electronic nicotine delivery systems in the hands of Hollywood."
Tobacco Control
20(6): 425-426.
Grana, R. A. and P. M. Ling (under review). "Smoking Revolution? A content analysis of electronic
cigarette retail websites." American Journal of Preventive Medicine.
Haddock, C. K., M. V. Weg, et al. (2001). "Evidence that smokeless tobacco use is a gateway for smoking
initiation in young adult males." Preventive medicine
32(3): 262-267.
Hadwiger, M. E., M. L. Trehy, et al. (2010). "Identification of amino-tadalafil and rimonabant in
electronic cigarette products using high pressure liquid chromatography with diode array and
tandem mass spectrometric detection." Journal of Chromatography A.
Hua, M., M. Alfi, et al. (2013). "Health-Related Effects Reported by Electronic Cigarette Users in Online
Forums." Journal of medical Internet research
15(4).
Ingebrethsen, B. J., S. K. Cole, et al. (2012). "Electronic cigarette aerosol particle size distribution
measurements." Inhalation toxicology
24(14): 976-984.
70
DRAFT e-cigarette background paper 10-14-13
Kim, H.-J. and H.-S. Shin (2013). "Determination of tobacco-specific nitrosamines in replacement liquids
of electronic cigarettes by liquid chromatography-tandem mass spectrometry." Journal of
Chromatography A.
King, B. A., S. Alam, et al. (2013). "Awareness and Ever Use of Electronic Cigarettes Among US Adults,
2010–2011." Nicotine & Tobacco Research: (online first).
Kralikova, E., J. Novak, et al. (2013). "Do e-cigarettes have the potential to compete with conventional
cigarettes? A survey of conventional cigarette smokers’ experiences with e-cigarettes." CHEST
Journal.
Lee, S., R. Grana, et al. (2013). "Electronic-cigarette use among Korean adolescents: A cross-sectional
study of market penetration, dual use, and relationship to quit attempts and former smoking."
Journal of Adolescent Health
under review.
McAuley, T., P. Hopke, et al. (2012). "Comparison of the effects of e-cigarette vapor and cigarette smoke
on indoor air quality." Inhalation toxicology
24(12): 850-857.
McMillen, R., J. Maduka, et al. (2012). "Use of emerging tobacco products in the United States." Journal
of Environmental and Public Health
2012.
Mehta, S., H. Shin, et al. (2013). "Ambient particulate air pollution and acute lower respiratory
infections: a systematic review and implications for estimating the global burden of disease." Air
Quality, Atmosphere & Health: 1-15.
Pauly, J., Q. Li, et al. (2007). "Letter: Tobacco-free electronic cigarettes and cigars deliver nicotine and
generate concern." Tobacco Control
16: 357-360.
Pearson, J. L., A. Richardson, et al. (2012). "E-cigarette awareness, use, and harm perceptions in US
adults." American journal of public health
102(9): 1758-1766.
Peeters S and Gilmore AB (2013). "Transnational Tobacco Company Interests in Smokeless Tobacco in
Europe: Analysis of Internal Industry Documents and Contemporary Industry Materials." PLoS
Med
10(9): e1001506.
Pepper, J. K., P. L. Reiter, et al. (2013). "Adolescent males' awareness of and willingness to try electronic
cigarettes." Journal of Adolescent Health
52(2): 144-150.
Pokhrel, P., P. Fagan, et al. (2013). "Smokers Who Try E-Cigarettes to Quit Smoking: Findings From a
Multiethnic Study in Hawaii." American journal of public health
103(9): e57-e62.
Polosa, R., P. Caponnetto, et al. (2011). "Effect of an electronic nicotine delivery device (e-Cigarette) on
smoking reduction and cessation: a prospective 6-month pilot study." BMC public health
11(1):
786.
Pope, C. A., R. T. Burnett, et al. (2009). "Cardiovascular mortality and exposure to airborne fine
particulate matter and cigarette smoke shape of the exposure-response relationship."
Circulation
120(11): 941-948.
Popova, L. and P. M. Ling (2013). "Alternative Tobacco Product Use and Smoking Cessation: A National
Study." American Journal of Public Health
103(5): 923-930.
Post, A., H. Gilljam, et al. (2010). "Symptoms of nicotine dependence in a cohort of Swedish youths: a
comparison between smokers, smokeless tobacco users and dual tobacco users." Addiction
105(4): 740-746.
Regan, A. K., G. Promoff, et al. (2013). "Electronic nicotine delivery systems: adult use and awareness of
the ‘e-cigarette’in the USA." Tobacco Control
22(1): 19-23.
Romagna, G., E. Allifranchini, et al. (2013). "Cytotoxicity evaluation of electronic cigarette vapor extract
on cultured mammalian fibroblasts (ClearStream-LIFE): comparison with tobacco cigarette
smoke extract." Inhalation toxicology
25(6): 354-361.
Schripp, T., D. Markewitz, et al. (2012). "Does e‐cigarette consumption cause passive vaping?" Indoor Air
23(1): 25-31.
71
DRAFT e-cigarette background paper 10-14-13
Shawn, L. and L. S. Nelson (2013). Smoking Cessation Can Be Toxic to Your Health. Emergency Medicine.
January: 7-19.
Siegel, M. B., K. L. Tanwar, et al. (2011). "Electronic cigarettes as a smoking-cessation tool: results from
an online survey." American Journal of Preventive Medicine
40(4): 472-475.
Strickland, J. (2013) "Woman says e-cigarette exploded, shot flames 4 feet across living room." WSB-TV
Sutfin, E. L., T. P. McCoy, et al. (2013). "Electronic cigarette use by college students." Drug and alcohol
dependence.
Trehy, M. L., W. Ye, et al. (2011). "Analysis of electronic cigarette cartridges, refill solutions,
and smoke for nicotine and nicotine related impurities." Journal of Liquid
Chromatography & Related Technologies
34(14): 1442-1458.
Trtchounian, A. and P. Talbot (2011). "Electronic nicotine delivery systems: is there a need for
regulation?" Tobacco Control
20(1): 47-52.
U.S. Department of Health and Human Services (2012). Preventing Tobacco Use Among Youth and
Young Adults: A Report of the Surgeon General. Atlanta, GA, U.S. Department of Health and
Human Services, Centers for Disease Prevention and Control, National Center for Chronic
Disease Prevention and Health Promotion, Office on Smoking and Health.
Vansickel, A. R., C. O. Cobb, et al. (2010). "A clinical laboratory model for evaluating the acute effects of
electronic “cigarettes”: nicotine delivery profile and cardiovascular and subjective effects."
Cancer Epidemiology Biomarkers & Prevention
19(8): 1945.
Vansickel, A. R. and T. Eissenberg (2013). "Electronic cigarettes: Effective nicotine delivery after acute
administration." Nicotine & Tobacco Research
15(1): 267-270.
Vansickel, A. R., M. F. Weaver, et al. (2012). "Clinical laboratory assessment of the abuse liability of an
electronic cigarette." Addiction
107(8): 1493-1500.
Vardavas, C. I., N. Anagnostopoulos, et al. (2012). "Short-term Pulmonary Effects of Using an Electronic
Cigarette Impact on Respiratory Flow Resistance, Impedance, and Exhaled Nitric Oxide." Chest
141(6): 1400-1406.
Vickerman, K. A., K. M. Carpenter, et al. (2013). "Use of Electronic Cigarettes Among State Tobacco
Cessation Quitline Callers." Nicotine & Tobacco Research.
Williams, M., A. Villarreal, et al. (2013). "Metal and silicate particles including nanoparticles are present
in electronic cigarette cartomizer fluid and aerosol." PloS one
8(3): e57987.
Winer, S. (May 29, 2013) "Police investigating a toddler's death from nicotine overdose." The Times of
Israel.
World Health Organization (2009). "WHO Study Group on Tobacco Product Regulation: Report on the
Scientific Basis of Tobacco Product Regulation." WHO Technical Report Series (955): i-21.
Zhang, Y., W. Sumner, et al. (2013). "In Vitro Particle Size Distributions in Electronic and Conventional
Cigarette Aerosols Suggest Comparable Deposition Patterns." Nicotine & Tobacco Research
15(2): 501-508.
Developmental nicotine effects citations:
Dwyer JB, Broide RS, Leslie FM. Nicotine and brain development.
Birth Defects Res C Embryo Today. Mar
2008;84(1):30-44.
Liao C-Y, Chen Y-J, Lee J-F, Lu C-L, Chen C-H. Cigarettes and the developing brain: Picturing nicotine as a
neuroteratogen using clinical and preclinical studies.
Tzu Chi Medical Journal. 2012;24(4):157-161.
72
DRAFT e-cigarette background paper 10-14-13
Lichtensteiger W, Ribary U, Schlumpf M, Odermatt B, Widmer HR. Prenatal adverse effects of nicotine on the
developing brain. In: Boer GJ, Feenstra MG, Mirmiran PM, Swaab DF, Van Haaren F, eds.
Progress in
Brain Research.Vol Volume 73: Elsevier; 1988:137-157.
Navarro HA, Seidler FJ, Eylers JP, et al. Effects of prenatal nicotine exposure on development of central and
peripheral cholinergic neurotransmitter systems. Evidence for cholinergic trophic influences in
developing brain.
Journal of Pharmacology and Experimental Therapeutics. December 1, 1989
1989;251(3):894-900.
Dwyer JB, McQuown SC, Leslie FM. The dynamic effects of nicotine on the developing brain.
Pharmacology &
Therapeutics. 2009;122(2):125-139.
73