Effects of abstinence from tobacco: Etiology, animal
models, epidemiology, and significance: A subjective
John R. Hughes
Received 22 September 2005; accepted 2 April 2006
This article updates a 1990 review of the effects of tobacco abstinence by reviewing (a) the etiology, (b) animal
models, (c) the epidemiology, and (d) the clinical significance of tobacco abstinence effects. The author searched
several databases to locate more than 3,500 citations on tobacco abstinence effects between 1990 and 2004. For
brevity, the review does not evaluate these effects in regard to craving, hunger, or performance. Data collection and
study conclusions were based on the author’s subjective judgment. The most validated etiological model suggests
that withdrawal is related to decreased dopaminergic activity, but how this relates to nicotine receptor changes is
unclear. The two most validated animal models describe increases in intracranial self-stimulation thresholds or
observable physical signs. Significant withdrawal symptoms occur in at least half of smokers when they try to quit.
Withdrawal appears to produce clinically significant distress and impairment. Increases in depression after
abstinence, but not other symptoms, prospectively predict relapse. In conclusion, the proposed neurobiological
mechanisms by which withdrawal occurs leave several unanswered questions. Although animal models have been
developed, how well they mimic withdrawal in humans is unclear. Tobacco withdrawal is common and can be
distressing. Withdrawal-induced depression appears to undermine the smoker’s ability to remain abstinent.
In 1990, the author and some colleagues published a
comprehensive, critical review of scientific studies on
the effects of abstinence from tobacco (Hughes,
Higgins, & Hatsukami, 1990). The present article
updates this review by examining some of the more
important questions about a drug withdrawal syn-
drome; that is, (a) what is its cause, (b) are animal
models available, (c) how often does it occur, and (d)
does it cause distress or interfere with the individual’s
ability to stop drug use (Hughes, Higgins, & Bickel,
1994). One companion article to this review recom-
mended several methods to improve the internal and
external validity of withdrawal studies (Hughes, in
press). The other companion article concluded that
anger, anxiety, depression, difficulty concentrating,
impatience, insomnia, and restlessness are valid
withdrawal symptoms that peak in the first few days
after abstinence and last 2–4 weeks (Hughes, 2007).
Since the 1990 review, several review articles on
tobacco abstinence effects have discussed theoretical,
measurement, and clinical validity issues (American
Psychiatric Association, 2000; Baker, Piper, Fiore,
McCarthy, & Majeskie, 2004; Eissenberg, 2004;
Hughes, 1994; Hughes & Hatsukami, 1992; Hughes
et al., 1994; Patten & Martin, 1996a, 1996b; Piasecki,
Kenford, Smith, Fiore, & Baker, 1997; Shiffman,
West, & Gilbert, 2004; Sommese & Patterson, 1995).
In addition, two extended critiques of nicotine
dependence have questioned the existence or impor-
tance of nicotine withdrawal (Atrens, 2001; Frenk &
Dar, 2000). The present review adds to this literature
in that it provides a more detailed critique of the
topics listed above.
ISSN 1462-2203 print/ISSN 1469-994X online # 2007 Society for Research on Nicotine and Tobacco
John R. Hughes, M.D., Departments of Psychiatry, Psychology, and
Family Practice, University of Vermont, Burlington, VT.
Correspondence: John R. Hughes, M.D., University of Vermont,
Department of Psychiatry, 38 Fletcher Place, Burlington, VT 05401-
1419, USA. Tel: +1 (802) 656-9610; Fax: +1 (802) 656-9628; E-mail:
Nicotine & Tobacco Research Volume 9, Number 3 (March 2007) 329–339
MEDLINE, PsychAbstracts, EMBASE, SSCI, and
the U.S. Centers for Disease Control Tobacco
Information and Prevention Database using the
‘‘tobacco,’’ crossed with ‘‘substance withdrawal
syndrome.’’ The author also searched titles and
abstracts forthe terms
‘‘tobacco,’’ ‘‘smok-,’’ ‘‘nicotin-,’’ and ‘‘withdrawal.’’
In addition, the author asked for publications on this
topic from subscribers to the Society for Research on
Nicotine and Tobacco (SRNT) E-mail list as well as
from authors of relevant abstracts presented at recent
College on Problems of Drug Dependence, National/
World Conferences on Tobacco or Health, Society
for Behavioral Medicine, and SRNT meetings. The
author used reference lists from articles collected by
these methods and from his own collection of studies.
Finally,the author searched
PsychAbstracts using the terms ‘‘substance with-
drawal syndrome’’ and ‘‘drug withdrawal,’’ crossed
with ‘‘review article,’’ to locate articles on non-
nicotine drug abstinence effects to suggest insights
and topics. The review limited these searches to the
period January 1990 to December 2004.
These methods produced more than 3,500 cita-
tions. Based on titles, the author read 792 abstracts.
From these, the author read 375 articles that
appeared to be relevant to the above topics. Of these
articles, 111 were cited in the present review.
authorlocated studiesvia searchesof
Study selection, data extraction, and data synthesis
between 1990 and 2004, including in-press articles.
The review does not include abstracts because many
abstracts are never published, most provide insuffi-
cient methodological information, and the existing
published literature appeared sufficient. This method
may have led to publication bias (Cook et al., 1993)
but did promote a ‘‘best evidence synthesis’’ (Slavin,
For brevity, this article focuses on core symptoms
of tobacco withdrawal that are shared by the most
Association’s Diagnostic and Statistical Manual of
Mental Disorders (American Psychiatric Association,
Health Organization, 1993): anxiety, difficulty con-
centrating, depressed mood, increased appetite,
insomnia, irritability, and restlessness. The review
does not cover craving, hunger, performance, and
several other symptoms because (a) the etiology,
animal models, incidence, and significance for crav-
ing (Sayette, 2000; Tiffany, 1990; Tiffany, Carter, &
Singleton, 2000), hunger (Froom, Melamed, &
Benbassat, 1998; K. A. Perkins, 1993; Varner, 1999;
Ward, Klesges, & Vander Weg, 2001), and perfor-
mance (Heishman, 2002; Heishman, Taylor, &
Henningfield, 1994; Kassel, 1997; Levin, 1992;
Sherwood, 1993) differ from the symptoms included
(e.g., they have different time courses and controlling
variables), (b) factor analyses suggest the symptoms
discussed in this review are highly correlated with
each other but not with craving, hunger, and
performance (Hughes, 2007, in press), (c) craving,
hunger, and performance each have a literature of
over 1,000 citations, and (d) craving, hunger, and
performance have already been reviewed elsewhere
(Froom et al., 1998; Heishman, 2002; Heishman
et al., 1994; Kassel, 1997; Levin, 1992; K. A. Perkins,
1993; Sayette, 2000; Sherwood, 1993; Tiffany, 1990;
Tiffany et al., 2000; Varner, 1999; Ward et al., 2001).
No verification of data extraction was done. The
author used his subjective judgment of methodolo-
gical quality, representativeness of results, and
importance of the topic to choose the data and
articles to cite. Interpretation of the results was based
solely on the author’s judgments.
This review uses the term ‘‘deprivation’’ to refer to
experimenter-induced abstinence and other terms
(e.g., ‘‘cessation’’ and ‘‘quitting’’) to refer to partici-
pant-initiated abstinence. It distinguishes between
‘‘offset’’ abstinence effects (a unidirectional change
upon abstinence) vs. withdrawal effects (a bidirec-
tional change with a finite time course). ‘‘Nicotine’’
abstinence or withdrawal refers to studies that
otherwise, the term ‘‘tobacco’’ abstinence or with-
drawal is used.
This and the next section of this review cover
etiological theories and animal models. Although the
review presents these topics separately, some etiologi-
cal theories were developed from animal models, and
some animal models were developed from etiological
theories (Table1). The descriptions that follow are
brief, given that these topics have been reviewed
elsewhere (Balfour, 2004; Kenny & Markou, 2001;
Koob & LeMoal, 2001; Laviolette & van der Kooy,
2004; Watkins, Koob, & Markou, 2000).
The 1990 review concluded that neurobiological
causes of nicotine withdrawal had not been well
EFFECTS OF ABSTINENCE FROM TOBACCO: A SUBJECTIVE REVIEW
developed or tested (Hughes et al., 1990). Since then,
several etiological models have been tested (Table1).
The most commonly cited paradigm for withdrawal
states is the ‘‘opponent process’’ model (Koob &
LeMoal, 2001; A. Perkins, Gerlach, Broge, Fonte, &
Wilson, 2001; Siegel, Baptista, Kim, McDonald, &
Weise-Kelly, 2000; Solomon & Corbit, 1973). This
model postulates that drug intake recruits an
opposing homeostatic reaction that accounts for
tolerance and withdrawal. For example, assume that
a drug produces stimulation. This should recruit a
physiological process that produces sedation and
grows with repeated use. The overall effect of the
drug is the sum of the drug effect and the opposing
process; thus, the drug effect decreases over time and
is the basis for tolerance. Then when drug is
removed, only the opposing process occurs, which
explains why most withdrawal syndromes have
effects opposite that of the drug itself. Many of the
symptoms of tobacco withdrawal (anger, anxiety,
depression, difficulty concentrating, and hunger) are,
in fact, opposite the effects produced by nicotine use
itself. However, several withdrawal symptoms are
not the opposite of nicotine effects (e.g., impatience,
insomnia, restlessness). In addition, nicotine is
typically thought of as a stimulant, yet the typical
symptoms of stimulant withdrawal (fatigue, hyper-
somnia, and psychomotor retardation; American
Psychiatric Association, 2000) are not tobacco with-
Conditioning theorists have modified the oppo-
nent process model to propose that stimuli (internal
or external) that reliably precede drug intake or
withdrawal can become conditioned to drug intake
or withdrawal and, over time, come to elicit the
opposing process even before drug intake occurs
(Siegel et al., 2000; Solomon & Corbit, 1973).
However, such elicited opponent processes are not
prominent in more recent conditioning accounts of
smoking (Bevins & Palmatier, 2004; Niaura et al.,
Biological conceptualizations of nicotine and
other drug dependencies usually focus on receptor
changes (Koob & LeMoal, 2001; Littleton, 2001).
Several lines of evidence suggest that nicotinic
acetylcholinergic receptors (nAChRs) mediate the
expression of nicotine withdrawal but exactly how
they do so is unclear (Dani & Heinemann, 1996;
Kenny & Markou, 2001). Central nAChRs appear
to mediate the affective and motivational aspects of
(Kenny & Markou, 2001; Koob & LeMoal, 2001).
Both the a7 and a4 subunits of the nAChRs
influence nicotine withdrawal (Kenny & Markou,
2001). The role of nAChRs in nicotine withdrawal
remains unclear partly because nicotine is somewhat
unusual in that chronic use causes an increase, not a
decrease, in receptor number (Kenny & Markou,
2001; Littleton, 2001). Exactly why this occurs is not
completely clear (Vallejo, Buisson, Bertrand, &
Green, 2005). One hypothesis is that the resensitiza-
tion of these receptors when nicotine is removed
causes withdrawal, but the biological and beha-
vioral mechanisms for how this would occur have
not been specified (Kenny & Markou, 2001;
Littleton, 2001). In addition, the one study of
nAChR binding did not find that abstinence
changed binding affinity or sites (Dagher et al.,
A recent model of nicotine withdrawal that has
empirical evidence posits that, whatever the receptor
changes are, the downstream effect of abstinence is a
decrease in dopamine release (Kenny & Markou,
2001; Koob & LeMoal, 2001; Watkins et al., 2000).
Nicotinic receptors occur on dopamine cells in
several brain structures, and abstinence from nicotine
decreases both dopaminergic activity and the sensi-
tivity of dopamine receptors in these areas (Smolka,
Budde, Karow, & Schmidt, 2004). Some evidence
suggests that decreases in dopamine in the mesolim-
bic system mediate somatic manifestations of with-
drawal and that decreases in dopamine in the nucleus
accumbens mediate affective and motivational com-
ponents (Koob & LeMoal, 2001; Watkins et al.,
2000). These decreases in dopamine are hypothesized
to lead to negative affect and decreased reward
sensitivity. Furthermore, the withdrawal symptoms
of anger, anxiety, and depression are thought to be
expressions of this increased negative affect. Whether
Table 1. Proposed etiologies and associated animal models.
Etiological modelAnimal model
Mediation via opioid systems
Increased threshold for intracranial self-stimulation
Conditioned place aversion
Frontal lobe asymmetry
NICOTINE & TOBACCO RESEARCH
this construct of negative affect would include the
remaining symptoms (difficulty concentrating, impa-
tience, insomnia, and restlessness) is unclear.
The several lines of evidence for this theory are
covered in the next section, on animal models. The
two studies testing this hypothesis in humans found
supporting results. In both studies, during tobacco
abstinence, monetary reinforcers were less able to
motivate cognitive performance (Al-Adawi & Powell,
1997; C. S. Pomerleau, Mehringer, Marks, Downey,
& Pomerleau, 2000). However, a third study in
humans failed to find any changes in dopamine
metabolites in peripheral blood after smoking cessa-
tion (Zeidenberg et al., 1977). In addition, cortisol is
thought to be a marker not only of stress responses
but also of dopamine function (Reuter & Hennig,
2003). Three studies failed to find cortisol changes
with abstinence (al’Absi, Amunrud, & Wittmers,
2002; Benowitz, Kuyt, & Jacob, 1984; Hughes,
Arana, Stewart, & Workman, 1988), whereas several
other human studies did find a decrease in cortisol
(al’Absi, Hatsukami, Davis, & Wittmers, 2004; Dols,
van den Hout, Kindt, & Willems, 2002; Gilbert et al.,
Martinko, 1995; O. F. Pomerleau, Pomerleau,
& Marks, 2000; Puddey, Vandongen, Berlen, &
English, 1984). Two studies found that greater
declines in cortisol were associated with greater
withdrawal symptoms and greater relapse (al’Absi
et al., 2004; Dols et al., 2002). However, animal
studies suggest that abstinence increases rather than
decreases cortisol (Benwell & Balfour, 1979). In
summary, most human studies appear to be con-
sistent with the theory that nicotine withdrawal is
related to a decrease in dopaminergic activity
although other neurotransmitter systems may be
involved (see below).
In one model of nicotine withdrawal in nonhumans
(see next section), withdrawal signs are similar to
those of opiate withdrawal. Most studies have found
that opiate agonists relieve and opiate antagonists
precipitate the somatic signs of withdrawal in nonhu-
mans (Malin, 2001). Thus, one possible etiology of
tobacco withdrawal is that it is mediated via down-
stream opiate receptor activity. Most randomized
controlled trials of opioid antagonists in humans do
not report that opiate antagonists precipitate with-
drawal (David, Lancaster, & Stead, 2006); however,
the one study to specifically examine this topic
(Krishman-Sarin, Rosen, & O’Malley, 1999). Also,
although opioid and nicotine withdrawal syndromes
share several symptoms, many opioid signs and
symptoms (e.g., rhinorrhea and gooseflesh) do not
occur in tobacco withdrawal. Finally, abstinence was
found not to change levels of beta-endorphin in
humans (Wewers, Tejwani, & Anderson, 1994).
Some lines of evidence suggest that decreased
serotonergic function may cause nicotine withdrawal
(Balfour, 2003; Liem & Markou, 2001; Watkins et al.,
2000). Given that decreased serotonin is associated
with poor mood and motivation, this possibility
would be consistent with the observed signs and
symptoms of tobacco withdrawal. Nicotine also
increases release of glutamate (an excitatory trans-
mitter), which increases dopamine cell firing; thus,
withdrawal could be related to decreased glutamate
functioning (Kenny & Markou, 2004; Watkins et al.,
2000). Other mediators of withdrawal that have been
releasing factor (Kenny & Markou, 2001; Watkins
et al., 2000).
In summary, the biological theory with the most
supportive evidence, according to this author, is that
withdrawal is related to a decrease in dopamine, which
However, this theory would suggest that depression
should be one of the most common symptoms. In
reality, it is one of the least common (see below). In
addition, most of the prototypic symptoms of depres-
sion (decreased interest or pleasure in activities, weight
loss, agitation or retardation, loss of energy, guilt;
American Psychiatric Association, 2000) are not
tobacco withdrawal symptoms.
In contrast to these biologically based theories,
one behavioral theory is that withdrawal is an
epiphenomenon of extinction; that is, it is a
behavioral reaction to the loss of a reinforcer. In
fact, the symptoms of tobacco withdrawal are similar
to those associated with loss of nondrug reinforcers
in nonhumans (Hughes et al., 1990). In one retro-
spective survey, reinforcer losses in humans (e.g.,
death of a loved one, relationship break-up, food
deprivation) were found to produce withdrawal
symptoms similar to nicotine withdrawal (Gilbert,
Gilbert, & Schultz, 1998). One interpretation of these
results is that they suggest withdrawal is not
biologically based (Atrens, 2001; Frenk & Dar,
2000). However, loss of nondrug reinforcers (e.g.,
food) is associated with several neurotransmitter
changes (Massa, 1983; Myers & Davis, 2002).
One theory notes that withdrawal is associated with
frontal lobe asymmetries in electroencephalographic
depression; however, whether such asymmetries are a
cause or a result of withdrawal symptoms is unclear.
Because cessation of smoking significantly increases
the symptoms of tobacco withdrawal and caffeine
intoxication, several studies have examined whether
caffeine intoxication couldbe amajor causeof tobacco
withdrawal (Swanson, Lee, & Hopp, 1994); however,
(Oliveto et al., 1991).
EFFECTS OF ABSTINENCE FROM TOBACCO: A SUBJECTIVE REVIEW
Most animal models of nicotine abstinence effects
operationalize abstinence by an ‘‘extinction’’ proce-
dure in which the experimenter either stops delivering
nicotine or makes responses no longer deliver
nicotine (Hughes & Bickel, 1997). Each of these
procedures has problems. The large majority of
animal studies involve experimenter-administered
nicotine. In many models, experimenter-administered
drug produces dramatically different neurobiolo-
gical outcomes than does self-administered drug
(Dworkin, Mirkis, & Smith, 1995). Thus cessation
of experimenter-administered vs. self-administered
nicotine likely has different results. Whether this is
true for nicotine deprivation has not been tested. Of
course, stopping self-administered nicotine would
appear to be more generalizable than stopping
Even the studies using cessation of self-adminis-
tered nicotine in nonhumans may have problems.
These studies produce extinction by making pressing
the drug lever no longer deliver drug. This is not
analogous to smoking cessation (Hughes & Bickel,
1997). A more realistic model could be based on a
behavioral analysis of smoking cessation that would
suggest most smokers stop either because of (a)
recent delivery of a tobacco-related punisher, (b)
anticipation of such a punisher, (c) reinforcement for
stopping tobacco use, or (d) alternate reinforcers that
successfully compete with tobacco use. Thus more
generalizable models of smoking cessation in nonhu-
mans would involve suppression of self-administra-
tion because of a punishment contingency or a
competing reinforcer (Hughes & Bickel, 1997).
Unfortunately, this review could not locate animal
studies of nicotine withdrawal using these paradigms.
The 1990 review concluded that the major valid
measures of tobacco withdrawal in nonhumans were
weight gain and disruption of operant performance
both in obtaining reinforcers and in avoiding punish-
ers (Hughes et al., 1990). Recent reviews indicate the
above measures are still valid (Malin, 2001; Mathieu-
Kia, Kellogg, Butelman, & Kreek, 2002; Stolerman,
1999; Watkins et al., 2000). Since the 1990 paper,
several new paradigms have been developed.
One widely validated paradigm describes several
observable signs similar to those of opiate abstinence
(teeth-chattering, chewing, grasping, writhing, tre-
mors, body shakes) that occur reliably upon nicotine
deprivation in rodents (Malin, 2001). This model has
been replicated in several different laboratories and
has survived many rigorous validity tests (e.g.,
nicotine antagonists precipitate this set of symp-
toms). In addition, opioid antagonists and agonists
have usually been found to precipitate or relieve the
syndrome. One liability of this model is that these
withdrawal signs in animals do not appear to be
similar to those in humans (Hughes, 2007). A second
liability is that most of the symptoms are somatic
symptoms, and somatic symptoms may be less
important in drug withdrawal syndromes than are
behavioral or subjective symptoms (Hughes et al.,
1994; Koob & LeMoal, 2001). A third liability is that
peripheral nicotine antagonists can precipitate these
somatic signs (Malin et al., 1992), suggesting they
may be related to non-central nervous system
Another widely validated animal model measures
electrical thresholds for intracranial self-stimulation
(ICSS) during nicotine deprivation. In this paradigm,
animals press a lever to deliver stimuli to certain
‘‘reward centers’’ in the brain. The amount of
electricity needed to engender this self-administration
is called the ICSS. Conditions that increase the ICSS
are said to decrease ‘‘reward sensitivity.’’ Several
increases the ICSS (Watkins et al., 2000). The
increased ICSS is also posited to represent dysphoria
and has been associated with decreased dopaminergic
functioning during abstinence (Koob & LeMoal,
2001). In fact, these changes in motivation and affect
have been hypothesized to be more important aspects
of withdrawal than somatic signs because they
presumably are more linked to relapse (Koob &
LeMoal, 2001). One important gap in the studies is
the time course of ICSS changes to determine
whether they represent offset or withdrawal effects.
A third animal model (Emmett-Oglesby, Mathis,
Moon, & Lal, 1990; Koob & LeMoal, 2001; Watkins
et al., 2000) examines conditioned place aversion
(CPA) to nicotine withdrawal. In this model, a drug
or a condition (i.e., nicotine withdrawal) is paired
repeatedly with place A but not with place B. Then if
during testing the animal repeatedly selects place B
over place A, the drug or condition is said to have
produced a CPA. Nicotine withdrawal does reliably
produce a CPA. This result is important because it
verifies the assumption in negative reinforcement or
opponent process models that withdrawal is a
punisher. A related model has shown anxiety-like
responses such as increased avoidance responding
(i.e., nicotine makes it more likely that an animal
works to avoid a punisher) and decreased social
Oglesby et al., 1990).
A final model uses the drug discrimination
procedure (Emmett-Oglesby et al., 1990). In this
model, when the animal receives a drug, it is
reinforced for pressing lever A but not lever B.
When this model is used to examine nicotine with-
drawal, animals are first reinforced to press lever A
when they receive an anxiogenic drug. Then, during
testing, instead of receiving the drug, the animal is
put into nicotine deprivation. When this occurs, the
NICOTINE & TOBACCO RESEARCH
animal reliably presses lever A, suggesting that
nicotine withdrawal is similar to receipt of an
anxiogenic substance (Emmett-Oglesby et al., 1990).
This model appears to be a somewhat less reliable
marker of nicotine abstinence (Irvine et al., 2001).
In summary, nicotine deprivation can cause several
phenomena in animals: Disrupted operant perfor-
mance, avoidance behavior, weight gain, anxiety-like
behaviors, decreased reward sensitivity, and opioid-
like withdrawal behaviors. Some of these phenomena
have been associated with specific biological changes.
Although some of the models have outcomes that are
not topographically similar to those seen in humans
or appear to model only one facet of withdrawal,
they could still be useful models. The major out-
standing issue for these models is their validity and
utility. For example, do the same variables that
influence tobacco withdrawal in humans (see below)
also influence these models? Further, can these
models be used to screen medications for their ability
to relieve withdrawal in humans? Most important, do
these withdrawal outcomes predict probability of
reinstatement of drug use in animals (i.e., cause
Several review articles have focused on prospective
studies of tobacco withdrawal (Hughes, 2007).
Prospective experimental studies have high internal
validity; however, their external validity is limited
because of their small, self-selected samples. Thus,
to determine prevalence rates, this review focuses on
the results of large, population-based surveys of
withdrawal. However, some of these surveys’
methodological limitations need to be discussed
first. First, almost all of these studies are retro-
spective and thus are subject to memory, selection,
and rationalization biases. Second, these retro-
spective studies cannot control for the natural
occurrence of these symptoms, independent of
cessation. These two biases likely produce over-
estimates of incidence. Third, the denominator used
in prevalence calculations varied across studies.
Some studies used all lifetime smokers, and some
used only current smokers who had tried to quit and
failed. Prevalence rates based on these groups likely
produced under- and overestimates, respectively.
Fourth, the large majority of studies either failed to
include all valid withdrawal symptoms or added
unvalidated symptoms. Finally, few studies reported
when the quit attempts occurred (i.e., 1 year ago or
30 years ago).
In a large, population-based survey, 37% of all
smokers endorsed ‘‘feeling sick’’ with stopping
smoking at some point in their life (Henningfield,
1995). In a very small, population-based U.S. study,
76% of current smokers reported at least one
withdrawal symptom in their lifetime (Hale et al.,
1993). In other countries, the rates of ever having a
symptom were much smaller, for example, 41%
among ‘‘representative primary care’’ ever-smokers
in Germany (Hoch, Muehlig, Hofler, Lieb, &
Wittchen, 2004) and 42% of female and 46% of
male current smokers in Japan (Yoshimura, 2000).
Two large retrospective studies have reported on
individual symptoms (Table2). In a study of current
U.S. smokers in an HMO, lifetime prevalence of
individual symptoms among smokers who had ever
tried to quit ranged from 22% to 62% (Breslau,
Kilbey, & Andreski, 1992). A similar ranking
among symptoms but with smaller rates (1%–30%)
was seen in a population-based sample of current
German smokers (John, Meyer, Ulfert, Rumpf, &
The surveys described above report on lifetime
prevalence and thus cannot describe the probability
(or incidence) of withdrawal symptoms on a given
attempt. The ideal such study would be large,
prospective, population-based sample of smokers
about to stop smoking. Although such a study is
not available,two close
(Table2). A U.S. study recruited 554 New Year’s
Unfortunately, this study did not collect precessation
scores; thus, the incidence rates from this study do
not account for the natural occurrence of these
symptoms independent of smoking cessation and the
rates should be somewhat falsely inflated. In this
study, at 2 days postcessation (when symptoms
peaked), the incidence of the valid symptoms ranged
from 18% to 55%, with the exception of insomnia
(8%). The rank order of prevalence of symptoms was
consistent with the previously described retrospective
studies. A second U.S. prospective study recruited
630 smokers about to quit and included a precessa-
tion score (Hughes, 1992). This study calculated the
incidence of a symptom as the number of partici-
pants whose score was higher during abstinence than
precessation. At 2 days postcessation (when scores
were at their highest), incidence rates ranged from
31% to 53% across the valid symptoms listed above.
In the U.S. HMO retrospective study (Breslau et al.,
1992) and in the two U.S. prospective studies (Gritz
et al., 1991; Hughes, 1992), a mean of four symptoms
was endorsed. Consistent with these findings, half
(49%) of the self-quitters in the second U.S.
prospective study met DSM-III-R criteria of having
at least four symptoms (Hughes, 1992).
In summary, epidemiological data suggest that (a)
most symptoms are endorsed by one-third to
one-half of smokers when they quit and (b) about
half of smokers have significant withdrawal (i.e.,
more than four symptoms) when they try to quit.
EFFECTS OF ABSTINENCE FROM TOBACCO: A SUBJECTIVE REVIEW
One method to examine clinical significance is to
determine whether abstinence produces clinically
Association, 2000). One test of this method deter-
mines whether observers noted symptoms; all four
studies found that several withdrawal symptoms are
readily observable (Hughes, 1992; Hughes, Gust,
Skoog, Keenan, & Fenwick, 1991; Hughes &
Hatsukami, 1986; Tate, Stanton, Green, & Schmitz,
1996). Another test examines whether the magnitude
of distress from withdrawal is as great as that
experienced by those seeking treatment for mental
disorders. Several withdrawal studies have recorded
scores on the Profiles of Mood States (POMS) scale
(McNair, Lorr, & Droppelman, 1992) during absti-
nence. In fact, POMS scores during cigarette
abstinence are similar to those seen among psychia-
tric outpatients (Hughes, 2006).
Another method is to determine whether absti-
nence symptoms interfere with daily functioning.
One study found increased work accidents on a
national ‘‘No-Smoking Day’’ (Waters, Jarvis, &
Sutton, 1998), but this finding was not replicated in
a secondtest examining
(Knowles, 1999). A third analysis found an increase
in work absences in the first 3 months postcessation;
however, whether this was related to withdrawal
symptoms orto smoking-related
prompted cessation and continued into the first 3
months of abstinence is unclear (Sindelar, Duchovny,
Falba, & Busch, 2005).
Probably the most important test of clinical
significance is whether withdrawal symptoms under-
mine the individual’s ability to stop smoking. Several
studies have reported that greater postabstinence
withdrawal scores predict relapse (Patten & Martin,
1996a); however, high postabstinence ratings could be
related, not to withdrawal, but rather to psychiatric
comorbidity or other factors that existed prior to
smoking cessation. To more specifically examine
withdrawal per se, this review examined only studies
that tested whether the increase in a symptom
postcessation prospectively predicted later relapse.
Among the eight studies that examined whether
the increase in a total withdrawal discomfort score
predicted relapse, three studies found that it did
predict relapse (al’Absi et al., 2004; Piasecki, Fiore, &
Baker, 1998; Piasecki, Jorenby, Smith, Fiore, &
Baker, 2003b; Piasecki et al., 2000) and five found
that it did not (Hatsukami et al., 2000; Hughes et al.,
1991; Hughes & Hatsukami, 1986; K. A. Perkins et
al., 1996; Strasser et al., 2005). In terms of individual
symptoms, among the eight studies that examined
depression or negative affect, seven found that it
predicted relapse (Etter & Hughes, 2006; Hall et al.,
1998; Hughes, 1992; Killen, Fortmann, Schatzberg,
Hayward, & Varady, 2003; K. A. Perkins et al., 1996;
Strasser et al., 2005; Swan, Ward, & Jack, 1996) and
one found that it did not (C. Lerman et al., 2004).
Either all or almost all of the studies examining other
individual symptoms (anxiety, difficulty concentrat-
ing, restlessness, impatience, anger, and physical
symptoms) found these symptoms did not predict
relapse (Covey, Glassman, & Stetner, 1990; Etter &
Hughes, 2006; Hajek & Belcher, 1991; Hughes, 1992;
Hughes et al., 1991; McRobbie, Hajek, & Gillison,
2004; K. A. Perkins et al., 1996; Swan et al., 1996;
Ussher, West, Steptoe, & McEwen, 2003). Some
studies have suggested craving and weight loss
predict relapse (Hughes & Hatsukami, 1992); how-
ever, these symptoms are not covered in the present
The studies that found a relationship between
withdrawal and relapse did not appear to differ—on
sample size, validity of withdrawal assessments, when
withdrawal and relapse were measured postcessation,
sample characteristics, and the like—from the studies
that did not find such a relationship. However, a
recent set of articles (Piasecki et al., 1998; Piasecki
et al., 2003b; Piasecki et al., 2000) suggests that
improvements in data analysis can substantially
increase the power to detect withdrawal-relapse
relationships that may have been missed in prior
studies. For example, most prior studies have
examined whether severity of withdrawal at time 1
predicts relapse at time 2. The more recent articles
indicate that the temporal profile of withdrawal
symptoms (i.e., whether they decreased rapidly over
Table 2. Prevalence or incidence of tobacco withdrawal symptoms in generalizable studies.
Breslau et al. (1992)c
John et al. (2004)d
Gritz et al. (1991)e
Note.aLifetime prevalence (percent).bIncidence at peak (percent).cYoung adults in U.S. HMOs.dGerman population-based sample.
eNew Year’s self-quitters in United States.fSelf-quitters in United States.
NICOTINE & TOBACCO RESEARCH
time or stayed elevated) and duration are as
important as their severity in predicting relapse.
Also, prior studies have suffered from selection bias;
that is, dropouts from studies are likely to be those
with more severe withdrawal. However, recent data
analysis techniques can mitigate this problem. In
fact, analyses using these techniques do find a more
robust ability of withdrawal symptoms to predict
relapse (Piasecki et al., 1998; Piasecki, Jorenby,
Smith, Fiore, & Baker, 2003a; Piasecki et al., 2003b;
Piasecki et al., 2000). Finally, it may be that smokers’
reactions to withdrawal symptoms (e.g., distress vs.
stoicism) may be crucial in causing relapse (Brown,
although this possibility has not been well studied.
Studies of behavioral and neurobiological changes in
animals deprived of nicotine have provided the
beginnings of an etiological model of tobacco with-
drawal. The recent studies showing that nicotine
deprivation increases ICSS thresholds are especially
intriguing because they would be predicted from
biological findings that nicotine deprivation decreases
dopamine levels (Kenny & Markou, 2001; Koob &
LeMoal, 2001; Watkins et al., 2000) and from theories
that negative affect symptoms are central to tobacco
withdrawal (Baker et al., 2004; Hughes et al., 1990).
Given the recent increase in methods to assess
motivation and negative affect in humans (Baker
et al., 2004; Eissenberg, 2004), studies testing these
theories in humans are warranted. However, a true
biologically based etiological theory of withdrawal
likely must await empirical validation of why nicotine
increases receptors over time and what role, if any,
receptor occupancy has in causing tobacco with-
drawal (Balfour, 2003, 2004; Dani & DeBiasi, 2001;
Kenny & Markou, 2001; Watkins et al., 2000).
Nonbiological etiological theories of withdrawal have
not been well developed. Experimental studies that
show epiphenomena from extinction of nondrug
reinforcers in nonhumans (D. C. Lerman & Iwata,
1996) could be used to develop a behavioral account
of withdrawal. Unexplainably, almost no research has
been conducted in this area for decades.
The two most widely cited animal models of
withdrawal (opioid-withdrawal-like behaviors and
increased ICSS thresholds) are clearly significant
advances. However, the procedures to produce these
outcomes do not truly mimic abstinence in humans.
In addition, these models have not used reinstate-
ment paradigms to show that these withdrawal
outcomes are related to nicotine relapse. The
relationship of withdrawal and relapse cannot be
assumed. For example, although withdrawal symp-
toms from alcohol and other drugs are often thought
to cause relapse, this effect is either small or
nonexistent in animal models (Lyvers, 1998).
Large population-based epidemiological surveys
appear to validate the description of withdrawal from
small prospective studies. However, conclusions from
these surveys abouttheprevalenceofwithdrawalmust
be tentative given the probability of memory pro-
blems, rationalization bias, andselection bias; the lack
of consideration of baserates for these symptoms; and
the use of idiosyncratic lists of symptoms. The two
prospective studies of self-quitters clearly suggest that
most smokers have withdrawal symptoms when they
try to quit (Gritz et al., 1991; Hughes et al., 1991);
however, only one study reported valid incidence rates
(i.e., corrected for the natural occurrence of symp-
toms; Hughes et al., 1991). Thus, determining the
incidence of withdrawal in real-life cessation attempts
Although the prior review called for studies of the
clinical significance of tobacco withdrawal, few direct
tests have appeared in the intervening 15 years;
however, most of these tests do suggest that tobacco
withdrawal produces clinical distress and can impair
daily functioning. Although not reviewed in the
present article, another line of evidence of clinical
significance is the indirect evidence that stopping
smoking can precipitate a relapse to depression or
alcohol or drug use (Glassman, Covey, Stetner, &
Rivelli, 2001; Joseph, Willenbring,
The other important possible clinical significance
of withdrawal is its ability to undermine smoking
cessation. Although it makes logical sense that
withdrawal would play a major role in relapse to
tobacco (e.g., most relapse occurs in the first week
when withdrawal is at its greatest), showing this to be
the case has been difficult. Although often not
recognized, the same is true for human studies of
dependencies on other drugs such as alcohol and
opiates, in which negative reinforcement has long
been a major explanatory factor (Lyvers, 1998). In
the nicotine studies reviewed here, only depression
reliably predicted abstinence. This finding gives
credence to the notion that negative affect is the
most important part of tobacco withdrawal (Baker
et al., 2004). Conceptualizing negative affect as
central to tobacco withdrawal not only lends
parsimony but also suggests that the many empirical
facts we know about negative affect should be
applicable to tobacco withdrawal (Baker et al.,
2004). Another very real possibility is that other
tobacco withdrawal symptoms (e.g., insomnia and
difficulty concentrating) predict relapse but that
more sensitive data analysis techniques are needed
to detect this relationship (Piasecki et al., 2003b).
Clarification of the role of withdrawal in relapse is
important for two reasons. First, the paucity of
EFFECTS OF ABSTINENCE FROM TOBACCO: A SUBJECTIVE REVIEW
evidence on this topic has been cited in prior reviews
(Atrens, 2001; Frenk & Dar, 2000) as an important
flaw in the nicotine dependence conceptualization.
Second, withdrawal relief is often a developmental
target for medication development (Hughes, 1993).
The major limitation of the present review is that
the choice of material and the data extraction and
data synthesis methods are based solely on the
author’s subjective opinion. This limitation is miti-
gated somewhat by the author’s solicitation of
comments from experts (see Acknowledgments)
before submission. A second limitation is the
exclusion of three important withdrawal effects:
Craving, hunger, and performance outcomes.
Prior reviews of the etiology of tobacco with-
drawal have focused either on behavioral processes
(Baker et al., 2004; Eissenberg, 2004; Piasecki et al.,
1997) or biological process (Kenny & Markou, 2001;
Koob & LeMoal, 2001; Laviolette & van der Kooy,
2004; Watkins et al., 2000). The present article
reviews both topics and adds several theories not
covered in prior reviews. Similarly, the present
review’s conclusions about animal models are con-
sistent with prior reviews but also suggest models not
covered in prior reviews (Kenny & Markou, 2001;
Kyerematen, Morgan, Chattopadhyay, deBethizy, &
Vessell, 1994; Malin et al., 1992; Watkins et al.,
2000). Although a prior review examined the
epidemiology of nicotine dependence (Giovino,
Henningfield, Tomar, Escobedo, & Slade, 1995), it
did not review withdrawal per se, nor have other
reviews done so. One earlier review concluded the
evidence was insufficient to conclude that withdrawal
symptoms undermined cessation (Patten & Martin,
1996a). A second review concluded that depression
and craving predicted
Preparation of this manuscript was funded by National Institute on
Drug Abuse Senior Scientist Award DA00490. The author thanks
David Balfour, David Gilbert, David Malin, Athina Markou, Christi
Patten, Tom Piasecki, and Robert West for comments on this paper.
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