Nicotine & Tobacco Research
Nicotine & Tobacco Research Advance Access published October 24, 2011
© The Author 2011. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.
All rights reserved. For permissions, please e-mail: firstname.lastname@example.org
endings (Ginzel, 1973), and the act of inhalation gives a strong
sensorimotor stimulation in the airways. Nicotine from ciga-
rette smoke first acts on receptors in the upper and lower respi-
ratory airways where it causes reflex actions followed by
stimulation of sensory nerves in the heart, aorta, and carotid
sinus region as the drug proceeds through the circulation
(Ginzel, 1975). Studies with the respiratory system have shown
that the “scratch” in the throat evoked by tobacco smoke seems
to be part of the rewarding pleasure derived from smoking
(Levin, Rose, & Behm, 1990; Rose, Zinser, Tashkin, Newcomb,
& Ertle, 1984). The results of experiments with rats suggest
that this activating effect is mediated by direct rapid nervous
stimulation through peripheral afferents to, for example, locus
coeruleus (Comroe 1960; Tung, Ugedo, Grenhoff, Engberg, &
The high level of dependence that develops to cigarettes
and tobacco is hard to reconcile with the notion that it is solely
an addiction to nicotine. Some of the evidence for this is
a) Animals do not self-administer nicotine as readily as they
do “hard drugs” like amphetamine, cocaine, and heroin
(Villegier, Blanc, Glowinski, & Tassin, 2003).
b) Nicotine is also a relatively weak reinforcer in human laboratory
studies (Hughes, Rose, & Callas, 2000; Perkins, Gerlach,
Broge, Fonte, & Wilson, 2001)
c) Abstinent smokers seem to prefer a much reduced nicotine
content cigarette over nicotine-containing products like gum
and the reduced nicotine cigarette reduces craving (Barrett,
2010; Buchhalter, Acosta, Evans, Breland, & Eissenberg,
2005; Donny, Houtsmuller, & Stitzer, 2007) and alters brain
nicotinic acetylcholine receptor occupancy (Brody et al., 2009).
The so-called “scratch” in the throat may be of importance
for these effects.
d) Although nicotine replacement treatment is an effective aid
for quitting smoking, its efficacy is moderate (Fiore et al.,
2008) even if doses that replace most or all nicotine from the
cigarettes are used (Dale et al., 1995).
e) There is no evidence for the abuse of pure nicotine.
When the first version (the Tolerance Questionnaire, Fagerström,
1978) of the Fagerström Test for Nicotine Dependence (FTND;
Heatherton, Kozlowski, Frecker, & Fagerström, 1991) was
developed, tobacco smoking was not regarded as an addiction.
Nevertheless, evidence that this might be the case was beginning
to appear, and some researchers became increasingly interested
in investigating the importance of nicotine in the smoking
habit and educating the public about it. The research led to a
profound change in the understanding of cigarette smoking,
and in 1988, the U.S. Surgeon General, in the remarkable book
Nicotine Addiction, established once and “forever” the impor-
tance of nicotine in tobacco smoking (U.S. Department of
Health and Human Services [U.S. DHHS], 1988). However, as
the role of nicotine was established, researchers lost sight of the
possibility that other determinants might also be important.
More recently, it has been found that, although nicotine is the
most important addictive component of tobacco smoke, it is
probably not the only substance involved in the development of
tobacco dependence. In light of what is now known about what
determines cigarette smoking, it seems timely to propose a
renaming of the FTND to the Fagerström Test for Cigarette De-
pendence (FTCD). The background for this is discussed in this
Nicotine as a Determinant for
Nicotine plays a central role in tobacco use. It is a necessary con-
dition for regular tobacco use but is it sufficient? Cigarette
smoking seems to create a dependence in users as fast if not
faster than other drugs (DiFranza & Ursprung, 2010) and develops
to a level or degree of dependence equal to the so-called hard
drugs (U.S. DHHS, 1988). Most of the effects from nicotine
come from it being absorbed in the lungs and then rapidly
transferred by the blood to the brain and other potential targets.
The effects on the brain of nicotine delivered in this way are the
primary focus of most contemporary research. However, nicotine
may also have important direct effects on the peripheral nervous
system. Nicotine has been found to stimulate sensory nerve
Determinants of Tobacco Use and
Renaming the FTND to the Fagerström
Test for Cigarette Dependence
Karl Fagerström, Ph.D.
Fagerström Consulting, Kagerod, Sweden
Corresponding Author: Karl Fagerström, Ph.D., Fagerström Consulting, Jordkull 3670, 26878 Kagerod, Sweden.
Received April 6, 2011; accepted May 26, 2011
by guest on October 24, 2011
Determinants of tobacco use and renaming the FTND
for Smoking Other Than
Tobacco seems to have additional effects beyond nicotine. In
the trivial sense, tobacco smoke is made up of thousands of
chemicals. The more interesting question is whether any of these
also contributes to reinforcing properties of tobacco smoke. It
has been known for some time that cigarette smoke inhibits
monoamine oxidase (MAO), the enzyme that catalyses the me-
tabolism of monoamine neurotransmitters, such as dopamine,
thus potentiating their effects in the brain of smokers and thereby
contributing significantly to reward and dependence (Fowler
et al., 1999, 2003). Nicotine is not directly responsible for this
effect (Fowler et al., 1999). Acetaldehyde, an established constit-
uent of tobacco smoke, is a potent inhibitor of MAO (both
the A and the B subtypes), and it has been suggested that this
compound causes the MAO inhibition. In experimental rats,
nicotine self-administration is enhanced when the animals are
also treated with acetaldehyde. Other studies suggest that the
condensation products of acetaldehyde, salsolinol, and the
harmans are more likely candidates as the inhibitors MAO.
Salsolinol (Rodd et al., 2003) and harmans (Baum, Hill, &
Rommelspacher, 1996) are also themselves directly rewarding in
rats. Other tobacco-containing alkaloids, like myosmine, anatabine,
anabasine and nornicotine, also seem to have rewarding effects
in the sense that they substitute for nicotine in drug discrimina-
tion tests, increase nicotine self-administration (Clemens, Cailille,
Stinus, & Cador, 2009), and reduce avoidance to noxious stimuli
(Holtman, Crooks, Johnson-Hardy, & Wala, 2010).
Until relatively recently, cigarette smoking was regarded as
simply a strong habit, and many smokers still hold that view. Is
it possible that in pursuing the search for the mechanisms
underpinning the dependence upon nicotine and tobacco,
researchers may have overlooked the other aspects of the smoking
habit that may also be important. These could include:
a) The habit and conditioning associated with smoking
b) The role of the object—that is, the cigarette itself
c) The psychosocial aspects of smoking.
Habit and Conditioning
The half-life of nicotine is short, about 2 hr, and it is even shorter
for many of the other pharmacologically active substances
found in tobacco smoke. That necessitates frequent administra-
tion in order to obtain both its negative or positive reinforcing
effects. Thus, in order to maintain the desired levels of nicotine
and the other components of tobacco smoke, the smoker
repeats smoking-associated behavior (e.g., taking the cigarette out
of the pack, maybe 15 times/day, lighting it, holding it for 5–
10 min, and inhaling the smoke 10 times/cigarette) many times
each day. Each inhalation gives a sensory impact, first in the
mouth followed by the throat and the lungs and finally the
exhalation through mouth and or nose. This entire procedure
can be relaxing by itself although the inhalation and exhalation
of tobacco smoke seems to be especially important (McClernon,
Westman, & Rose, 2004). It is not inconceivable that all these
behaviors are difficult to break in themselves. Behaviors without
chemical reinforcers such as nail biting, betting, and computer
gaming can be hard to break and can be associated with with-
drawal symptoms when trying to stop (Gilbert, Gilbert, &
Schultz, 1998). Also nonsubstance addictions like pathological
gambling seem to share the same brain functioning mechanisms
as drug addictions (van Holst, van den Brink, Veltman, &
Goudriaan, 2010). Maybe these activities share some common-
alities with obsessive compulsive behaviors that are anxiety
reducing and anxiety provoking when inhibited. Since smoking
is relatively ritualized, that is, takes place in mostly the same situ-
ations, conditioning occurs such that stimuli by themselves can
elicit craving responses. This is supported by the evidence that
nicotine self-administration in rats is greatly enhanced when
paired with nicotine-associated stimuli such as light (Caggiula
et al., 2009). Although nicotine may be necessary in or at least
facilitating the early conditioning of pleasure and craving for
certain stimuli, it is possible that, with frequent repetition, these
stimuli become very resistant to extinction. It is noteworthy that
nonnicotine cigarettes are preferred to nicotine-containing gum
and relieves withdrawal symptoms better for the periods
(weeks) that it has been studied (Barrett, 2010; Buchhalter et al.,
2005; Donny et al., 2007).
The Cigarette as an Object
The cigarette looks very much the same today as hundred years
ago from brand to brand and country to country. This suggests
that its shape, from color and size, has some appeal. It is soft,
warm, and comfortable to hold and put to the lips. Although
very little research has explored the rewarding effects of just
handling and manipulating a cigarette, it may not be unreason-
able to believe that it can contribute somewhat to the pleasant
smoking experience. If the cigarette has any similarities to the
function of a pacifier is not known but not completely implau-
sible. Whether the cigarette box, lighter, or matches too have
any rewarding function is even less clear. Anecdotally, patients
report that holding and caressing their cigarette pack can give
some relief of stress.
Cigarette Smoking and Psychosocial
Cultural drugs in general have psychosocial functions. We often
drink coffee and alcohol together, and it can function as a lubricant
for social behavior. That is true also for smoking. Offering a
cigarette can be a means by which one contacts an unknown
person. It can be a reason to take a break or pause from a boring
task sometimes together with other smokers. This has the
potential to increase bonding and togetherness. When caught
on the spot, lighting a cigarette gives a smoker some time to
formulate thoughts. Although smoking today in many cultures
is disproved of, there are still cultures or subcultures where
smoking makes the smoker identify and conform with others. It
can stimulate activities with its rewarding properties (have to
finish this before I can have a cigarette), be a “friend” when an
individual is lonely, and in certain circumstances, smoking gives
the hands something to do and, in doing so, diminish anxiety.
by guest on October 24, 2011
Nicotine & Tobacco Research
Smoking as a Broad Complex
It should come as no surprise that stopping use of nicotine
replacement, with its much less behavioral involvement, is easier
to do than stopping cigarettes. Also there are differences in the
ways in which different nicotine replacement products are used.
While there is almost no long-term use of patches, it is not
so uncommon with nicotine gum. Also, it seems that quitting
smokeless tobacco, which has fewer behavioural components
and is a more solitary thing than smoking, is easier than stop-
ping smoking (Fagerström, Gilljam, Metcalfe, Tonstad, & Messig,
2010). One of the reasons that it is as difficult to stop smoking as
it is to stop use of hard drugs that usually are stronger reinforc-
ers may be because of the contribution of the nonnicotine fac-
tors discussed above. An analogy with caffeine may be useful to
explain why smokers prefer a reduced nicotine cigarette over one
with normal nicotine concentration. Consider the case of a reg-
ular and frequent coca cola user who becomes tired and thirsty
and longs for a cold coke but is offered a hot cup of coffee. If the
primary motivation to drink coca cola is to get caffeine, the hot
cup of coffee should do as well. Most likely, the coke drinker will
entirely refuse the hot coffee as much as most smokers wanting
a cigarette reject a nicotine gum. This occurs partly because the
craving for the coke and cigarette is not just about the drug but
also includes all the other features that go with the respective
objects. The much more rapid nicotine delivery from cigarettes
may also contribute to the higher dependence potential with
cigarettes. The pH of modern cigarettes is so low that it almost
requires inhalation into the lungs for effective nicotine absorp-
tion. The design of the filter also enables very close titration of
Shifting Orientation From Nicotine to
Many clinical researchers, epidemiologists, and clinicians when
working with cigarette smoking and smokers often use the
term “nicotine dependence” to describe their work, although
what they are studying is tobacco smoking. Apart from using a
too narrow term, it also may send signals like it is nicotine that
is the problem. Nicotine is not the major problem from a
health point of view. Pure or medicinal nicotine is probably not
that much different from caffeine and certainly less dangerous
than alcohol. Nicotine is a strong determinant for dependence,
but dependence to cigarette smoking is a multifaceted and
broad dependence. Nicotine can also to some degree be part of
the solution to the smoking problem if the need for tobacco
smoking could be substituted by pure nicotine. What should be
highlighted as the problem is tobacco and particularly smoked
tobacco. Cigarettes smoke causes both the physical diseases
and the strong dependence. It is also worth noting that in
the International Classification of Diseases and Injuries by
World Health Organization (World Health Organization,
1993) contrary to the American Psychiatric Association’s
(1994) DSM system , the term “tobacco dependence” is used
rather than nicotine dependence. Emphasizing tobacco does
not mean that nicotine should be ignored. It remains an integral
component of tobacco.
When renaming the FTND, should it be Fagerström Test for
Tobacco Dependence or FTCD? Tobacco comes in many forms
like cigarettes, water pipe, cigars, smokeless tobacco, and pipe
smoking among many others. These products are obviously
very different not only in their physical characteristics but also
in the cultural norms and prescriptions that are surrounding
them. The total dependence panorama will most likely vary
from a cigarette smoker to someone who uses tobacco in a
different form, for example, a smokeless tobacco (Fagerström
et al., 2010). A general questionnaire for tobacco dependence would
need to be validated against all forms of tobacco use from cigarettes
to smokeless tobacco. That has not been done with the FTND, and
moreover, most of the questions in the questionnaire relate specifi-
cally to smoking behavior. Therefore, it seems appropriate to
rename the FTND the Fagerström Test for Cigarette Dependence.
Declaration of Interests
American Psychiatric Association. (1994). Diagnostic and statis-
tical manual of mental disorders: DSM-IV-TR, Fourth edition.
Washington, DC: Author.
Barrett, S. P. (2010). The effects of nicotine, denicotinized
tobacco, and nicotine-containing tobacco on cigarette craving,
withdrawal, and self-administration in male and female smokers.
Behaviour Pharmacology, 21, 144–152. doi:10.1097/FBP.0b013
Baum, S. S., Hill, R., & Rommelspacher, H. (1996). Harman-
induced changes of extracellular concentrations of neurotrans-
mitters in the nucleus accumbens of rats. European Journal of
Pharmacology, 314, 75–82. doi:10.1016/S0014-2999(96)00543-2
Brody, A. L., Mandelkern, M. A., Costello, M. R., Abrams, A. L.,
Scheibal, D., Farahi, J., et al. (2009). Brain nicotinic acetylcho-
line receptor occupancy effect of smoking a denicotinized ciga-
rette. International Journal of Neuropsychopharmacology, 12,
Buchhalter, A. R., Acosta, M. C., Evans, S. E., Breland, B., &
Eissenberg, T. (2005). Tobacco abstinence symptom suppres-
sion: The role played by the smoking-related stimuli that are
delivered by denicotinized cigarettes. Addiction, 100, 550–559.
Caggiula, A. R., Donny, E. C., Palmatier, M. I., Liu, X.,
Chaudhri, N., & Sved, A. F. (2009). The role of nicotine in
smoking: A dual-reinforcement model. Nebraska Symposium on
Motivation, 55, 91–109.
Clemens, K. J., Cailille, S., Stinus, L., & Cador, M. (2009). The
addition of five minor tobacco alkaloids increases nicotine-
induced hyperactivity, sensitization and intravenous self-
administration in rats. International Journal of Psychopharmacology,
12, 1355–1366. doi:10.1017/S1461145709000273
by guest on October 24, 2011
Determinants of tobacco use and renaming the FTND
Comroe, J. H. (1960). The pharmacological action of nicotine.
Annals of New York Academy of Sciences, 90, 48–51.
Dale, L. C., Hurt, R. D., Offord, K. P., Lawson, G. M.,
Croghan, I. T., & Schroeder, D. R. (1995). High-dose nicotine
patch therapy. Percentage of replacement and smoking cessation.
Journal of the American Medical Association, 274, 1353–1358.
DiFranza, J., & Ursprung, W. W. (2010). A systematic review of
the International Classification of Diseases criteria for the diag-
nosis of tobacco dependence. Addictive Behaviors, 35, 805–810.
Donny, E. C., Houtsmuller, E., & Stitzer, M. L. (2007). Smoking
in the absence of nicotine: Behavioral, subjective and physiological
effects over 11 days. Addiction, 102, 324–334. doi:10.1111/
Fagerström, K. (1978). Measuring degree of physical depen-
dence to tobacco smoking with special reference to individual-
ization of treatment. Addictive Behaviors, 3, 235–241.
Fagerström, K., Gilljam, H., Metcalfe, M., Tonstad, S., &
Messig, M. (2010). Stopping smokeless tobacco varenicline:
Randomized double blind placebo controlled trial. British
Medical Journal, 341doi:10.1136 /bmj.c6549
Fiore, M. C., Jaen, C. R., Baker, T. B., Bailey, W. C., Benowitz,
N., Curry, S. J., et al. (2008). Treating tobacco use and depen-
dence: 2008 update. Rockville, MD: U.S. Department of Health
and Human Services. Retrieved from http://www.ahrq.gov/path/
Fowler, J. S., Logan, J., Wang, G. J., Volkow, N. D., Telang, F.,
Zhu, W., et al. (2003). Low monoamine oxidase B in peripheral
organs in smokers. Proceedings of the National Academy of
Sciences of the United States of America, 30, 11600–11605.
Fowler, J. S., Wang, G. J., Volkow, N. D., Franceschi, D., Logan, J.,
Pappas, N., et al. (1999). Smoking a single cigarette does not
produce a measurable reduction in brain MAO B in non-smokers.
Nicotine & Tobacco Research, 1, 325–329. doi:10.1080/146222
Gilbert, G., Gilbert, B., & Schultz, V. L. (1998). Withdrawal
symptoms: Individual differences and similarities across
addictive behaviors. Personality and Individual Differences, 24,
Ginzel, K. (1973). Muscle relaxation by drugs which stimu-
late sensory nerve endings. The effect of nicotinic agents.
Neuropharmacology, 12, 149–164.
Ginzel, K. (1975). The importance of sensory nerve endings
as sites of drug action. Naunyn Schmiedebergs Archives of
Pharmacology, 288, 29–56. doi:10.1016/0028-3908(73)90084-1
Heatherton, F., Kozlowski, L. T., Frecker, R. C., & Fagerström, K. O.
(1991). The Fagerström test for nicotine dependence: A revision
of the Fagerström Tolerance Questionnaire. British Journal
of Addictions, 86, 1119–1127. doi:10.1111/j.1360-0443.1991.
Holtman, J. R., Crooks, P. A., Johnson-Hardy, J. K., & Wala, E. P.
(2010). The analgesic and toxic effects of nornicotine enantio-
mers alone and in interaction with morphine in rodents models
of acute and persistent pain. Pharmacology Biochemistry and
Behavior, 94, 352–362. doi: 10.1016/j.pbb.2009.09.017
Hughes, J. R., Rose, G. L., & Callas, P. W. (2000). Nicotine is
more reinforcing in smokers with a past history of alcoholism
than in smokers without this history. Alcoholism Clinical and
Experimental Research, 24, 1633–1638. doi:10.1111/j.1530-0277.
Levin, E. D., Rose, J. E., & Behm, F. (1990). Development of a
citric acid aerosol as a smoking cessation aid. Drug Alcohol
Dependence, 25, 273–279. doi:10.1016/0376-8716(90)90152-5
McClernon, F. J., Westman, E. C., & Rose, J. E. (2004). The
effects of controlled deep breathing on smoking withdrawal
symptoms in dependent smokers. Addictive Behaviours, 29,
Perkins, K. A., Gerlach, D., Broge, M., Fonte, C., & Wilson, A.
(2001). Reinforcing effects of nicotine as a function of smoking
status. Experimental and Clinical Pharmacology, 9, 243–250.
Rodd, Z. A., Bell, R. L., Zhang, Y., Goldstein, A., Zaffaroni, A.,
McBride, W. J., et al. (2003). Salsolinol produces reinforcing
effects in the nucleus accumbens shell of alcohol-preferring (P)
rats. Alcoholism Clinical and Experimental Research, 27, 440–
Rose, J. E., Zinser, M. C., Tashkin, D. P., Newcomb, R., &
Ertle, A. (1984). Subjective response to cigarette smoking fol-
lowing airway anesthetization. Addictive Behaviors, 9, 211–215.
Tung, C. S., Ugedo, L., Grenhoff, J., Engberg, G., & Svensson, T. H.
(1989). Peripheral induction of burst firing in locus coeruleus
neurons by nicotine mediated via excitatory amino acids.
Synapse, 4, 313–318. doi:10.1002/syn.890040407
U.S. Department of Health and Human Services. (1988). The
health consequences of smoking. Nicotine addiction: A Report of
the Surgeon-General. Rockville, MD: Author.
van Holst, R. J., van den Brink, W., Veltman, D. J., &
Goudriaan, A. E. (2010). Brain imaging studies in pathological
gambling. Current Psychiatry Reports, 12, 418–425. doi:10.1007/
Villegier, A. S., Blanc, G., Glowinski, J., & Tassin, J. P. (2003).
Transient behavioural sensitization to nicotine becomes long last-
ing with monoamine oxidase inhibitors. Pharmacology Biochemistry
& Behaviour, 76, 267–274. doi:10.1016/S0091-3057(03)00223-5
World Health Organization. (1993). The ICD-10 classification of
mental and behavioural disorders: Diagnostic criteria for research.
Geneva: World Health Organization. xiii+248p.
by guest on October 24, 2011