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Does carbon monoxide play a role in cigarette smoke dependence?

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Purpose: Nicotine is the primary constituent of cigarette smoke responsible for dependence but other components may play a role. Carbon monoxide (CO) is one candidate since it is synthesized endogenously with multiple physiological effects. This investigation was conducted to determine whether CO alters cravings associated with cigarette smoke withdrawal. Methods: With ethics approval and consent, 131 smokers were assigned to receive: (1) inhaled CO + Nicotine nasal spray (2) Air + Nicotine nasal spray (3) CO + Placebo nasal spray or (4) Air + Placebo nasal spray. Two craving scales (adapted from Hughes and Hatsukami [Hughes, J.R., & Hatsukami, D. (1986). Signs and symptoms of tobacco withdrawal. Archives of General Psychiatry, 43, 289–294] and Shiffman-Jarvik [Shiffman, S.M., & Jarvik, M.E. (1976). Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology, 50, 35–39] referred to as HH and SJ, respectively) and a mood state questionnaire were used to assess withdrawal relief. Results: Craving scores were reduced pre- to post-treatment to some extent in all groups. On the last test day, HH revealed time by treatment differences between CO + Nicotine and either CO Only (p = 0.03) or Nicotine Only (p = 0.02). SJ revealed overall differences in pre- to post-treatment cravings (p = 0.03) with marginal time by treatment differences between craving scores in the Placebo group versus the Nicotine Only and the Nicotine + CO groups (p = 0.06 and 0.07, respectively). Treatment subjects were almost twice as likely to inhale the maximal gas (odds ratios = 1.6–2.0) compared to Placebo, suggesting that all treatments (including CO Only) were discriminated from Placebo. Conclusions: Our investigation suggests that CO exerts pharmacological effects, which may modulate craving processes associated with cigarette withdrawal, and exploration for the role of CO and other cigarette smoke constituents is warranted.
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Addiction Research and Theory, Early Online: 1–7
Copyright ß2011 Informa UK Ltd.
ISSN: 1606-6359 print/1476-7392 online
DOI: 10.3109/16066359.2011.583701
RESEARCH ARTICLE
Does carbon monoxide play a role in cigarette smoke dependence?
Brian Milne
1
, Elizabeth Vandenkerkhof
2
, Rachel Phelan
1
, James Brien
3
, Lutz Forkert
4
,
& Kanji Nakatsu
3
1
Department of Anesthesiology, Queen’s University, Kingston General Hospital, Victory 2, 76 Stuart Street,
Kingston, ON K7L 2V7, Canada,
2
Department of Anesthesiology and School of Nursing, Queen’s University,
Kingston General Hospital, Victory 2, 76 Stuart Street, Kingston, ON K7L 2V7, Canada,
3
Department of
Pharmacology and Toxicology, Queen’s University, Botterell Hall, 18 Stuart Street, Kingston, ON K7L 3N6,
Canada, and
4
Department of Medicine, Queen’s University, Etherington Hall, 94 Stuart Street, Kingston,
ON K7L 3N6, Canada
(Received 20 October 2010; revised 12 April 2011; accepted 13 April 2011)
Purpose: Nicotine is the primary constituent of
cigarette smoke responsible for dependence but
other components may play a role. Carbon monox-
ide (CO) is one candidate since it is synthesized
endogenously with multiple physiological effects.
This investigation was conducted to determine
whether CO alters cravings associated with cigarette
smoke withdrawal.
Methods: With ethics approval and consent, 131
smokers were assigned to receive: (1) inhaled
CO þNicotine nasal spray (2) Air þNicotine nasal
spray (3) CO þPlacebo nasal spray or (4)
Air þPlacebo nasal spray. Two craving scales
(adapted from Hughes and Hatsukami [Hughes,
J.R., & Hatsukami, D. (1986). Signs and symptoms
of tobacco withdrawal. Archives of General
Psychiatry,43, 289–294] and Shiffman-Jarvik
[Shiffman, S.M., & Jarvik, M.E. (1976). Smoking
withdrawal symptoms in two weeks of abstinence.
Psychopharmacology,50, 35–39] referred to as HH
and SJ, respectively) and a mood state questionnaire
were used to assess withdrawal relief.
Results: Craving scores were reduced pre- to post-
treatment to some extent in all groups. On the last
test day, HH revealed time by treatment differences
between CO þNicotine and either CO Only
(p¼0.03) or Nicotine Only (p¼0.02). SJ revealed
overall differences in pre- to post-treatment cravings
(p¼0.03) with marginal time by treatment differ-
ences between craving scores in the Placebo group
versus the Nicotine Only and the Nicotine þCO
groups ( p¼0.06 and 0.07, respectively). Treatment
subjects were almost twice as likely to inhale the
maximal gas (odds ratios ¼1.6–2.0) compared to
Placebo, suggesting that all treatments (including
CO Only) were discriminated from Placebo.
Conclusions: Our investigation suggests that CO
exerts pharmacological effects, which may modulate
craving processes associated with cigarette with-
drawal, and exploration for the role of CO and other
cigarette smoke constituents is warranted.
Keywords: Carbon monoxide, cigarette smoke, dependence,
clinical investigation, craving scales
INTRODUCTION
Although nicotine is the primary constituent of ciga-
rette smoke responsible for dependence and intense
cravings, there is increasing evidence that other
components such as nitric oxide (NO) (Vleeming,
Rambali, & Opperhuizen, 2002), acetaldehyde and
unidentified monoamine oxidase inhibitors (MAOIs)
may be contributing factors (Leroy et al., 2009; Sharma
& Brody, 2009). There are well over 4000 known
components of cigarette smoke including polonium,
butane, chromium, toluene, cadmium, lead, arsenic,
hydrogen cyanide, vinyl chloride, formaldehyde,
benzo-[a]-pyrene, nitrosamines, ammonia, NO and
carbon monoxide (CO; National Council on
Alcoholism and Drug Abuse, 2009). While many of
these constituents are known for their cytotoxic or
carcinogenic effects, it is likely that many others exert
biological actions, which are not yet recognized or
understood. A major component of cigarette smoke is
Correspondence: Kanji Nakatsu, Department of Pharmacology and Toxicology, Queen’s University, Botterell Hall, 18 Stuart Street,
Kingston, ON, K7L 3N6 Canada. Tel: (613) 533-6107. Fax: (613) 533-6412. E-mail: nakatsu@queensu.ca
1
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CO, which has long been known for its toxicity and has
more recently become recognized as an important
signalling molecule. CO is synthesized endogenously
and is acknowledged to have numerous important
biological functions involving the vasculature and the
central nervous system (Li & Moore, 2007; Pae, Lee,
Jo, & Chung, 2009). Endogenous CO is produced from
the oxidation of heme by heme oxygenases, which are
found in abundance in the spleen, liver, testes and the
brain. The purpose of this investigation was to test the
hypothesis that CO plays a role in the maintenance of
cigarette smoke dependence, in addition to nicotine.
However, because our participants were long-estab-
lished smokers, we could not address a role for CO in
the development of dependence on cigarette smoke.
METHODS
Following approval from our institutional ethics review
board, 131 healthy smokers (62 females and 69 males)
provided signed informed consent for participation in
the study. Participants were recruited through local
newspaper and poster advertisements. In order to be
eligible, participants were required to be heavy
smokers (i.e. greater than 20 cigarettes per day),
between the ages of 25 and 55, in good health and
willing to stop smoking for 4 consecutive days. Study
participants were paid a $100 honorarium at
completion of the study. Complete demographic char-
acteristics for this study population are summarized in
Table I. This double-blind study comprised four groups
of participants, matched by age and gender, assigned to
receive five daily treatments of either: (1) inhaled CO
(4% CO in air as in Hoffman & Hoffman, 1997) þ
nicotine via nasal spray (0.5 mg per dose)
(CO þNicotine), (2) inhaled air þnicotine nasal spray
(Nicotine Only), (3) inhaled CO þplacebo nasal spray
(CO Only) or (4) inhaled air þplacebo nasal spray
(Placebo) over a 3-h time period. Nicotine and placebo
nasal sprays were gifts from Pharmacia Upjohn,
Sweden. The CO and air treatments were delivered
through standardized devices designed to monitor puff
frequency and duration; the resistance properties and
‘feel’ of a cigarette were simulated by terminating the
delivery tubing with a cigarette filter; participants were
instructed to inhale ‘as usual’. The placebo nasal spray
contained small quantities of a pepper-like additive to
produce a faint burning sensation of the mucous
membranes similar to that provoked by nicotine. For
safety reasons, the maximal amount of gas permitted
per session was limited to 1000 mL.
Timeline for study procedures
Participants were in the laboratory for 3 h per day for 4
consecutive days. The first day was a training day
intended for participants to become acquainted with the
study environment and procedure. On this day, all
subjects were blinded to the fact that they received
placebo and these data were not included in the
analyses. At conclusion of the training day, subjects
were instructed to abstain from smoking for the next
3 days. At the beginning of each study day (days 1–3),
subjects were tested for expired CO to ensure absti-
nence. Subjects were then allowed to relax for 10–
20 min, and asked to complete a baseline craving
questionnaire before the testing procedure was initi-
ated. Cravings for cigarette smoke were evaluated by
means of questionnaires which were deposited as
Supplementary Materials; Part 1 (items 1–18) and
Part 2 (items 19–43) were adapted from Hughes and
Hatsukami (1986) and Shiffman and Jarvik (1976),
respectively, and are referred to as HH and
Table I. Demographic and smoking characteristics of total study sample stratified by intervention.
Total (n¼131) Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Placebo (n¼29) CO (n¼33) Nicotine (n¼36) CO/Nicotine (n¼34)
Age (n¼124) 37.9 (8.1) 38.0 (9.0) 40.3 (6.9) 36.6 (8.4) 36.5 (8.1)
Body mass index (n¼127) 25.5 (5.5) 24.3 (4.5) 25.0 (4.8) 26.9 (6.9) 25.5 (5.2)
No. (%) No. (%) No. (%) No. (%)
Male 69 (47.3) 15 (51.7) 18 (56.2) 18 (50.0) 18 (52.9)
Female 62 (52.7) 14 (48.3) 14 (43.8) 18 (50.0) 16 (47.1)
No. of cigarettes smoked per day
20–24 65 (49.6) 15 (52.7) 15 (45.5) 20 (57.1) 15 (44.1)
25–29 51 (38.9) 9 (31.0) 13 (39.4) 13 (37.1) 16 (47.1)
30 15 (11.5) 5 (16.3) 5 (15.1) 2 (5.7) 3 (8.8)
No. of years smoked
10 16 (12.2) 2 (6.9) 5 (15.2) 3 (8.6) 6 (17.6)
410 115 (87.8) 27 (93.1) 28 (84.8) 32 (91.4) 28 (82.3)
No. of years smoked 20 cigarettes per day
10 57 (43.5) 12 (41.4) 12 (36.4) 17 (48.6) 16 (47.1)
410 74 (56.5) 17 (58.6) 21 (63.6) 18 (51.4) 18 (52.9)
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SJ subsequently. Questionnaires were repeated,
between treatments 3 and 4 within each day and
again following all treatments on each of the 4 test
days.
Analysis
Those subjects with expired CO levels 420 ppm at the
beginning of any test day were excluded from the study
and their data removed from the analysis. Summary
statistics (frequency, per cent, mean and standard
deviation) were calculated for demographic variables
and smoking characteristics in each of the four study
groups. Craving for cigarettes was scored as the sum of
scores from 1 (not present) to 4 (severe intensity) on
the first five items of HH, and as total number of
positive responses on the first seven items of SJ.
Because the results for time points 2 and 3 within each
day were very similar, they are reported as a single
mean score at time 2. Mean summary statistics were
calculated for the HH and SJ craving scales as well as
the Profile of Mood State (POMS) questionnaire.
Means and standard deviations were calculated for
time by group for each study day. Repeated measures
general linear modelling (GLM) was used to examine
differences in change scores from baseline to post-
treatment across each study group. GLM was also used
to examine the primary outcome measures including
the overall craving and the POMS scores. An overall
F-test was performed for each one-way ANOVA and
comparison between groups was conducted only if the
overall test was statistically significant ( p< 0.05, two
tailed). Therefore, there were six possible comparisons
(four groups) for each of the six outcomes assessed.
However, given the preliminary nature of this inves-
tigation, we did not control for type I error. The volume
of gas consumed (mLs) was analysed using a gener-
alized estimating equation (GEE; Zeger & Liang,
1986), thus the results are expressed as odds ratios
(ORs) with 95% confidence intervals (CIs).
Multivariable modelling was not conducted due to
the small sample size.
RESULTS
Demographic and smoking characteristics for the study
population are shown in Table I. There were no
significant differences among treatment groups for any
of the characteristics examined. The age range was
25–55 years.
For all treatment groups, there was a statistically
significant decrease in many of the test scores from the
baseline to post-treatment assessments over the 3 test
days. In almost all of the tests, the mean craving scores
dropped between time 1 and time 2 on each test day, as
did the POMS tension and anxiety scores (Table II). In
contrast, there were relatively few significant differ-
ences observed between treatment groups. We did not
include all of the analyses in this manuscript but rather,
only those with direct relevance to our primary
outcome (Table II).
Craving scores
For the sake of brevity, only the HH and SJ craving
scores for the last day of data collection are shown in
graphical form (Figure 1a and b, respectively). These
data are thought to best represent the overall craving
profiles as measured by each scale and are thought to
be most stable and unaffected by factors such as
novelty and anxiety associated with introduction to the
experimental setting. Although all of the scales contain
subscales, we focused primarily on the craving
subscales of HH and SJ. With respect to the HH
withdrawal scale (Figure 1a), all treatments (including
placebo) resulted in reductions in craving scores from
pre- to post-treatment with a significant time by group
interaction (i.e. p¼0.01, Table II). Post hoc multiple
comparisons revealed that the changes from pre- to
post-treatment scores for the CO þNicotine group
differed significantly both from the CO Only group
(mean difference for [CO þNicotine]–CO Only ¼2.8
[95% CI 0.2, 5.5], p¼0.03) and the Nicotine Only
group (mean difference for [CO þNicotine]–Nicotine
Only ¼3.0 [95% CI 0.3, 5.6], p¼0.02). However, no
significant differences were observed between the pre-
and post-treatment scores of subjects in the Placebo
group and any of the other treatment groups. In
contrast, when assessments were done using the SJ
craving scale, subjects in the Placebo group did not
exhibit any relief from craving (Figure 1b) but there
was a significant overall time treatment interaction
(p¼0.03). The changes from pre- to post-treatment
scores for both the Nicotine Only and CO þNicotine
groups were reduced relative to the post-treatment
scores of those in the placebo group (mean difference
for Placebo – [CO þNicotine]¼1.3 [95% CI 2.8,
0.1], p¼0.07; and Placebo – Nicotine Only ¼1.4
[95% CI 2.9, 0.0], p¼0.06). The data from which
Figure 1(a) and (b) were generated are shown in bold in
Table II. Other differences among the treatment groups
(Table II) that are not shown as figures are described
below. The somatic subscale of the HH craving scale
was the only subscale to identify significant differences
between groups over time. On day 3, the
CO þNicotine group reported the highest score at
time 1 and the lowest post-treatment score at time 2.
The Nicotine Only group reported a slight increase in
somatic scores following treatment. In addition, the
change from pre- to post-treatment scores for
the Nicotine Only and the post-treatment scores for
the CO þNicotine group were significantly different
(mean difference Nicotine Only – [CO þNicotine]¼
1.2 [95% CI 2.3, 0.2], p¼0.01). On the somatic
subscale of the HH craving scale, the overall scores for
the Nicotine Only group was the only score which
was significantly different from Placebo (p¼0.03,
Table II). With respect to the POMS tension and
anxiety scale, the Nicotine Only group had the highest
DOES CARBON MONOXIDE PLAY A ROLE IN CIGARETTE SMOKE DEPENDENCE? 3
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score on day 1 at time 1 and showed the greatest
reduction following treatment but the post-treatment
scores for Nicotine Only remained higher than those
reported by the CO Only group post-treatment
(p¼0.03). On the Tension and Anxiety subscale of
the POMS, the overall scores for the Nicotine Only
group were the only ones that differed from those in the
Placebo group ( p¼0.05, Table II). Although the
Table II. Effect of nicotine and CO on HH and SJ craving scores.
Group assignment n
Time 1 Time 2 Change Overall p-value p-value p-value
Mean (SD) Mean (SD)
Mean
difference
Time group
interaction
Placebo vs.
all groups
Placebo vs.
each group
HH craving score – total day 2
Placebo 25 28.4 (7.0) 24.0 (4.4) 4.3 0.02 0.29
CO only 29 26.2 (5.9) 23.6 (5.0) 2.6 0.11
Nicotine only 31 26.2 (6.9) 23.8 (4.8) 2.4 0.08
CO/Nicotine 30 29.8 (10.2) 24.8 (7.1) 5.1 0.53
HH craving score – total day 3
Placebo 24 26.2 (8.0)24.0 (6.2)2.2 0.01 0.96
CO only 29 25.0 (5.8)23.7 (5.1)1.3 0.26
Nicotine only 29 24.0 (6.1)23.7 (5.5)1.2 0.24
CO/Nicotine 31 27.2 (8.8)23.0 (4.8)4.2 0.13
SJ craving scores – total day 3
Placebo 25 5.0 (2.1)5.1 (1.2)þ0.1 0.03 0.01
CO only 29 4.5 (2.5)3.9 (2.3)0.6 0.18
Nicotine only 31 4.9 (2.5)3.6 (2.4)1.3 0.02
CO/Nicotine 31 4.8 (2.4)3.7 (2.2)1.2 <0.01
HH craving scores – somatic day 3
Placebo 24 10.8 (2.8) 10.5 (2.2) 0.3 0.02 0.95
CO only 30 11.0 (2.3) 10.7 (1.9) 0.3 0.97
Nicotine only 29 10.5 (2.3) 10.8 (2.4) þ0.4 0.03
CO/Nicotine 31 11.3 (3.5) 10.4 (2.0) 0.9 0.22
POMS-tension/anxiety – day 1
Placebo 25 16.4 (4.3) 13.4 (3.4) 3.0 0.03 0.37
CO only 30 15.5 (5.1) 13.1 (3.0) 2.3 0.49
Nicotine only 32 19.3 (7.0) 13.9 (3.6) 5.4 0.05
CO/Nicotine 29 17.8 (6.1) 14.0 (3.7) 3.8 0.49
POMS-confusion – day 2
Placebo 23 11.7 (5.0) 10.7 (4.8) 0.9 0.02 0.72
CO only 28 10.4 (2.8) 10.5 (2.8) þ0.1 0.09
Nicotine only 26 11.3 (4.3) 10.8 (3.4) 0.5 0.47
CO/Nicotine 31 12.8 (5.0) 11.2 (3.5) 1.7 0.25
Note: Numbers shown in bold were used to generate Figure 1(a) and (b).
Figure 1. Mean craving scores on the HH (a) and SJ (b) craving scales for each of the treatment groups pre- and post-treatment on the
last treatment day. BL, Baseline (pre-treatment) and PT, post-treatment.
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largest reduction from pre- to post-treatment was
observed on the second day of the POMS confusion
scale in the group inhaling CO þNicotine, the post--
treatment scores were lower for the CO Only group
than for the CO þNicotine group ( p¼0.02).
Volume of gas consumed
The amount of gas subjects were allowed to consume
was limited to 1000 mL for safety reasons. Over 50%
of participants consumed the maximum amount of gas
at each data collection interval rendering normal
regression analyses inappropriate. Thus, we modelled
the odds of consuming 41000 mL using the GEE to
compare the amounts of gas consumed by each group
in comparison to the Placebo group. While the results
were not statistically significant, the odds of
consuming the maximal volume of gas were higher
in all three treatment groups compared to the placebo.
For Placebo versus Nicotine þCO, the OR was 2.0
(95% CI ¼0.8–5.2; Figure 2). Likewise, compared to
Placebo, the Nicotine Only group (OR ¼1.9, 95%
CI ¼0.8–5.1) and the CO Only group (OR ¼1.6, 95%
CI ¼0.6–4.4) were more likely to consume 1000 mL
of gas.
DISCUSSION
The main observations made in this study were: (1) that
alterations in the craving profile for cigarette smoke
were highly variable and complex; (2) while we did
observe a substantial placebo effect, Nicotine þCO
decreased craving modestly but more than either CO or
Nicotine Only and (3) subjects in the placebo group
inhaled less gas (i.e. air) than in any of the treatment
groups. We interpret these observations as providing
some support for the validity of our hypothesis that CO,
in addition to nicotine plays a role in maintenance of
cigarette smoke dependence. Thus, it appears further
investigation of CO in this context may be warranted.
Figure 1(a) and (b) and Table II demonstrate a number
of instances in which CO appeared to modify the
cravings for cigarette smoke. CO þNicotine satisfied
cravings better on the HH scale than Nicotine Only
(Figure 1a). In comparison, the SJ scale revealed that
Nicotine þCO was just as efficacious as Nicotine Only,
and CO Only was effective at satisfying cravings to
some extent (Figure 1b).
The magnitude of the placebo effect and high
variability limited our ability to quantify clearly an
effect of CO on craving. The placebo effect is
pronounced in Figure 1(a). Given the extensive liter-
ature on the power of conditioning, associations and
expectations in addiction and relapse (Bevins, 2009;
Caggiula et al., 2009; Franklin et al., 2007; Markou &
Paterson, 2009), placebo effects were anticipated, but
their magnitude was underestimated. Although in some
instances, the large placebo effect made it difficult to
draw conclusions in terms of absolute differences
compared to placebo (Figure 1a), it was still possible to
detect relative differences between groups as an
indication of perceived efficacy. The magnitude of
the placebo effect supports the idea that acting out an
ingrained habit plays a large role in dependence on
cigarettes. The subjects of this study reported decreases
in craving after experiencing holding a cigarette filter
in their hands and inhaling through it, regardless of
whether they received nicotine and/or CO or not. The
fact that many subjects even tried to tap the non-
existent ashes off the experimental device suggests that
their experience was an effective simulation of inhaling
cigarette smoke. Given that placebo effects were
observed inconsistently may suggest that certain
aspects of the craving process are more easily affected
than others. Whatever the underlying mechanism, the
extensive literature on drug self-administration and
extinction would suggest that extending the study for a
longer time period and extending the period of
exposure to placebo (i.e. the absence of reinforcer)
might result in an extinction of the placebo effect
(Shram, Funk, Li, & Le, 2008). Another factor that
complicates data interpretation is the documented
ability of CO to induce physiological changes such as
blood vessel relaxation; it may be that smokers learn
to associate CO-induced cerebral vasodilation with
nicotine-induced neural stimulation.
The observations made with respect to the volume
of gas consumed are less conducive to interpretation in
terms of a placebo effect. Accordingly, it is difficult
to explain the findings in terms of the placebo, for
example, why subjects inhaling CO Only were 1.6
times more likely to inhale the maximal amount of gas
than those in the Placebo group (Figure 2). However,
one possible explanation for the increase in CO
consumption may be CO-induced tachypnea (Ernst &
Figure 2. Increased gas inhalation in the nicotine only, CO Only
and Nicotine þCO treatment groups with the corresponding OR.
The OR indicates the likelihood that subjects in each group will
inhale the maximal amount of gas relative to the placebo group.
The ordinate represents the number of subjects (expressed as per
cent) in each group who consumed the maximal amount of gas
averaged over the different test sessions. Subjects in the CO
Only group were 1.6 times more likely to inhale the maximal
amount of gas compared to those in the Placebo group. Those in
the Nicotine Only or the Nicotine þCO groups were twice as
likely to inhale the maximum amount of gas compared to those
in the placebo group.
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Zibrak, 1998; Gautier & Bonora, 1983). Likewise, an
alternative explanation for the increased gas consump-
tion in conjunction with the nicotine nasal spray
(in addition to the rewarding properties), may be
nicotine-induced psychomotor stimulation (Wise,
1988). Since the amount of gas consumed was limited
to 1000 mL per session, we were unable to determine
the maximal amounts of gas that individuals would
have consumed if it were unlimited. However, subjects
in all of the treatment groups had almost twice the odds
of consuming the maximal amount of gas compared to
those in the placebo group; an effect which is reflected
in Figure 2. One could interpret this observation to
mean that test groups perceived an alleviation of
craving (either through direct or conditioned effects),
and subjects responded to this by trying to maximize
the amount of gas/air consumed. This might parallel
their ‘normal’ lives in which increased inhalation
would deliver increased amounts of nicotine, CO as
well as all other constituents present in cigarette
smoke. While these findings were not statistically
significant, the consistent trend suggests that at the
very least, the three treatment groups were discrimi-
nated from the placebo, at least at some level.
The other major complicating factor observed with
the questionnaires was the variability of responses.
Cravings associated with cigarette withdrawal are
complex processes during which individuals experi-
ence feelings of irritability, depression, anxiety,
cognitive and attention deficits, sleep disturbances
and increases in appetite (US Department of Health and
Human Services, National Institutes of Health, and
National Institutes on Drug Abuse, 2009). Cravings
encompass a myriad of different experiences based on
both psychological and physiological processes, so it is
not surprising that craving processes are highly vari-
able among individuals. Since the subjects in this
investigation were matched on demographic character-
istics and tested under controlled, double-blinded
conditions, we attribute the high variability observed
in this investigation to inter-individual variability in
craving processes rather than the experimental design.
There are a number of possible explanations for the
variability observed herein. The first may be that the
different scales were designed to measure different
aspects of the craving processes. Another explanation
could be that CO plays a role in the modulation of only
some aspects of the craving process. It may also be the
case that craving processes differ among individual
subjects with some people being more affected
physiologically/psychologically than others by the
contribution of the CO. This would be consistent
with Barrett’s suggestion of individual differences in
the roles of nicotine and other non-nicotine constituents
for the maintenance of smoking behaviour (Barrett,
2010). There is also considerable variability among
smokers in their exposure to nicotine and CO because
of differences in the way they smoke. Thus, a one ‘pack
a day’ smoker may receive substantial doses of
cigarette smoke components because he/she inhales
most of the smoke produced by a cigarette. Meanwhile
another ‘pack a day’ smoker may inhale much less
smoke because he/she inhales through the cigarette
infrequently. In summary, it seems possible that the
modulatory contribution of CO is relevant but is
masked significantly by variability in the data.
Our primary goal was to determine whether CO
either alone or in combination with nicotine altered the
cravings associated with cigarette smoke withdrawal
and it appears from this investigation that CO does
have an effect, albeit a variable one. In this respect, our
results are consistent with those reported by others.
Barrett (2010) used a self-administration paradigm to
compare the reinforcing effect of nicotine or placebo
inhalers with de-nicotinized or nicotine-containing
tobacco. Although the latter treatment was the stron-
gest reinforcer, the de-nicotinized group reported
increased satisfaction, decreased intentions to smoke,
delayed onset to self-administer nicotine tobacco and
women reported a reduction in craving. These obser-
vations (like ours) support a role for non-nicotine
components in cigarette smoke dependence although
Barrett makes no reference to which components these
might be. Our observations lead us to suggest that CO
should be considered as a candidate. In addition, there
is evidence that CO plays a role in synaptic plasticity
and the process of learning and memory (Cutajar &
Edwards, 2007) which has also been reported for
nicotine (Mansvelder, Mertz, & Role, 2009).
Endogenous CO in the CNS is generated in situ by
heme oxygenase-2. For inhaled CO to have an effect it
has to be carried to the brain by the blood, either
dissolved in blood water or bound to haemoglobin.
This requirement for the distribution of CO is sup-
ported by Piantadosi, Zhang, Levin, Folz, and
Schmechel (1997) who observed both behavioural
and biological effects in rats with acute
inhalation of CO.
It is now well-recognized that not only CO, but also
NO and hydrogen sulphide (H
2
S) are all gases with
biological activity. All are produced endogenously,
have their own molecular targets and have been dubbed
the ‘gasotransmitters’. Although each has diverse
biological functions, all are known to interact with
one another and have effects on vascular homeostasis
(Li & Moore, 2007). More recently, ammonia, acetal-
dehyde, sulphur dioxide and nitrous oxide have been
suggested as other potential gaseous cell signalling
molecules (Li & Moore, 2007) and some of these are
known constituents of cigarette smoke. Given the
interactive effects of these ‘gasotransmitters’, and the
fact that cigarette smoke contains many other
constituents with known or suspected biological
actions, the target of this study may have been too
narrowly focussed, and even the combination of
nicotine and CO might not account for the full
spectrum of pharmacological activity of cigarette
smoke. It may be necessary to develop a new approach
6B. MILNE ET AL.
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that could include more of the entire chemical cocktail
contained in cigarette smoke and then function by
exclusion of CO, nicotine or other substances of
interest. The study of cigarette smoke dependence is
particularly challenging, not only for reasons men-
tioned above but also because of the manner in which it
is self-administered. Nicotine is self-administered
through oral inhalation, a factor not simulated in this
study. Future studies might overcome this obstacle by
using ‘electronic cigarettes’ or inhalers (like those used
by Barrett, 2010) which have been designed to deliver
nicotine in a manner which more closely simulates the
cigarette experience. The legal and market status of
electronic cigarettes, as well as their utility, continues
to evolve as this is being written.
The purpose of this investigation was to determine
whether CO is an important constituent of cigarette
smoke in its contribution to the dependency process as
revealed by alterations in specific aspects of the
craving repertoire and mood. We interpret this obser-
vation to mean that CO may play an important role at
least in some aspects of cigarette smoke dependence.
Therefore, we suggest that further investigations into
the contributions of the non-nicotine constituents in
cigarette smoke dependence are warranted.
ACKNOWLEDGEMENTS
The authors thank Andrew Day for advice and assistance
with some of the statistical analyses presented in this
article and Dr Fred Boland for advice on psychological
testing. The authors gratefully acknowledge The Heart
and Stroke Foundation of Ontario (HSFO) for funding this
research (Grant NA-3149).
Declaration of interest: None of the authors have any
conflicts of interest with publication of this manuscript.
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DOES CARBON MONOXIDE PLAY A ROLE IN CIGARETTE SMOKE DEPENDENCE? 7
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... Oral fluid has been used for the detection and quantification of cotinine, the main metabolite of nicotine, which is an alkaloid present in significant amounts in tobacco leaves. Other biomarkers identified to be present as a result of smoking are: thiocyanate ions [6], carbon monoxide [7], benzene [8] and polyaromatic hydrocarbons [9]. Analysis is commonly performed using immunoassays [10], high-performance liquid chromatography [11] and gas chromatography [12]. ...
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