Journal of Clinical Neuroscience 13 (2006) 457–465

www.elsevier.com/locate/jocn

Clinical study

Cognitive status of young and older cigarette smokers:

Data from the international brain database
Robert H. Paul a,*, Adam M. Brickman a, Ronald A. Cohen a, Leanne M. Williams b,c,d,
Raymond Niaura a, Sakire Pogun e, C. Richard Clark f, John Gunstad a, Evian Gordon b
a
Centers for Behavioral and Preventive Medicine, Department of Psychiatry, Brown Medical School, 1 Hoppin Street, Providence RI 02903, USA
b
The Brain Resource International Database, The Brain Dynamics Centre, Westmead Hospital, Sydney, Australia
c
Department of Psychological Medicine, University of Sydney, Sydney, Australia
d
School of Psychology, University of Sydney, Sydney, Australia
e
Center for Brain Research and School of Medicine, Department of Physiology, Ege University, Bornova, Izmir, Turkey
f
Flinders University, Adelaide, Australia

Received 30 September 2004; accepted 5 April 2005

Abstract

Previous studies that have examined the impact of cigarette smoking on cognition have revealed mixed results; some studies report no
impact and others report detrimental effects, especially in older individuals. Few studies, however, have examined the effects of cigarette
smoking on both young and old healthy individuals using highly robust and standardized methods of cognitive assessment. This study
draws on an international database to contrast cognitive differences between younger and older individuals who regularly smoke ciga-
rettes and non-smokers. Data were sampled from 1000 highly screened healthy individuals free of medical or psychiatric health compli-
cations. A cohort of 62 regular smokers (n = 45 < 45 years of age; n = 17 P 45 years) with a Fagerstrom nicotine dependency score of 1
or more were identified and matched to a cohort of 62 healthy nonsmokers (n = 43 < 45 years; n = 19 P 45 years) on demographic vari-
ables and estimated intelligence. Performances on cognitive measures of attention, reaction time, cognitive flexibility, psychomotor
speed, and memory were considered for analysis. As a group, smokers performed more poorly than nonsmokers on one measure of exec-
utive function. A significant age and smoking status interaction was identified with older smokers performing more poorly than older
nonsmokers and younger smokers on a measure of long-delayed recall of new information. Cigarette smoking is associated with isolated
and subtle cognitive difficulties among very healthy individuals.
 2006 Elsevier Ltd. All rights reserved.

Keywords: Smoking; Nicotine; Cognition; Assessment

1. Introduction people of the risks of smoking. Furthermore, smoking rates

Smoking and associated nicotine addiction remains a
major public health concern throughout the world.
Chronic smoking is recognized as a significant risk factor
for cancer, heart disease, and other health problems. While
smoking prevalence has declined over the past two decades
in the US, millions of Americans continue to smoke, de-
spite an intense public health initiative aimed at informing
*
Corresponding author. Tel.: +401 793 8786; fax: +401 793 8287.
E-mail address: Rpaul@lifespan.org (R.H. Paul).
continue to be extremely high in other parts of the world.
While the reasons for this are complex, one important con-
tributing factor may be that nicotine directly impacts brain
systems, including cognitive functions, motivation, and
emotional experience.1–3 The potential importance of these
neuropsychological effects provides compelling grounds for
research aimed at examining the effects of cigarette
smoking.
Acute cigarette smoking is associated with improved
cognitive performance in laboratory settings,4–6 but the
cognitive effects of chronic cigarette smoking are less well

0967-5868/$ - see front matter  2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jocn.2005.04.012
458 R.H. Paul et al. / Journal of Clinical Neuroscience 13 (2006) 457–465
understood. Investigators that have examined the impact
of chronic cigarette smoking have reported mixed results.
Results from a number of large-scale studies have revealed
no observable effect of cigarette smoking on cognition in
community-drawn older individuals.7–11 In contrast, an
equal number of studies investigating large cohorts of older
individuals have revealed modest associations between cig-
arette smoking and poor cognitive function.12–15 Psycho-
motor speed, attention, and executive function (such as
abstraction and cognitive flexibility) are the cognitive do-
mains most consistently implicated in these studies.
These cognitive changes may reflect concomitant cere-
brovascular disease secondary to smoking-related hyper-
tension, and/or other comorbid health factors. However,
Brody et al.16 reported reduced volume of the prefontal
grey matter, anterior cingulate cortex, and cerebellum in
smokers compared to nonsmokers, suggesting that direct
smoking-related alterations in cortical volume rather than
secondary effects of cerebrovascular disease may underlie
the cognitive changes associated with smoking.
The inconsistent findings in the literature regarding the
impact, if any, of chronic cigarette smoking on cognitive
function may be associated with confounding factors inher-
ant in the methodology. Most studies that included older
individuals, included participants who reported comorbid
physical health conditions that are independently associ-
ated with cognitive impairment (such as diabetes and
hypertension). Further, most studies that have examined
cognition using sensitive and standardized cognitive tests
were limited by small sample sizes, while many studies that
examined large cohorts of individuals frequently relied on
very brief cognitive tests that lacked the requisite sensitivity
to detect significant interactions between cigarette smoking
and cognition.13 No study has examined the impact of
chronic smoking in a relatively large cohort of young and
older smokers using robust neuropsychological methods.
The purpose of the present study was to address these
methodological issues by examining a relatively large
cohort of otherwise healthy smokers and demographi-
cally-matched nonsmokers using highly sensitive and stan-
dardised neuropsychological measures. Importantly, both
young and older adult smokers were included to determine
whether cognitive changes associated with smoking were
age-dependent. We predicted that smoking would be nega-
tively associated with cognitive function among the older
subjects, while younger smokers would perform equally
well as nonsmokers on the cognitive tests.
2. Methods
The present study makes use of data acquired from the
Brain Resource International Database. Six laboratories
(New York, Rhode Island, Holland, London, Adelaide
and Sydney), participated in the data acquisition in a total
quality-controlled manner. At the time of the present
study, the database contained demographic, psychiatric,
health and cognitive data on 1000 healthy individuals.
Exclusion criteria for the parent database included any
mental or physical condition with the potential to influence
cognitive performance, including a personal history of
mental illness, physical brain injury, neurological disorder
or other medical condition (hypertension, diabetes, cardiac
disease, thyroid disease), and/or a personal history of drug
or alcohol addiction. Importantly, those individuals report-
ing a history of hypertension, diabetes, cardiac disease, and
thyroid disease were excluded from the study. The
SPHERE17 was administered to identify individuals with
significant mental illness. Subjects were excluded if they
had a family history of attention deficit hyperactivity disor-
der, schizophrenia, bipolar disorder, or a genetic disorder.
An ethics committee reviewed the protocol at each site of
data acquisition and all subjects voluntarily signed a writ-
ten informed consent form to participate in the database.
2.1. Study sample
As part of the parent study, all participants were asked
questions about smoking behavior, and responses were
compiled into a Fagerstrom dependency score,18 which
provides an index of nicotine dependency. Of the 1000
healthy individuals, 62 were at least 18 years of age and
were identified as smokers (defined as a Fagerstrom score
of 1 or higher). Only individuals over the age of 17 were in-
cluded to avoid developmental confounds on cognitive per-
formance. A comparison group of 62 healthy nonsmokers
was randomly selected from the database. These individu-
als were selected based on earning a Fagerstrom score of
0, and representing the range of age and education values
identified for the participants identified as smokers. A re-
search assistant visually reviewed the basic demographic
data for the nonsmokers (age and education), and ran-
domly selected subject identification codes until 62 individ-
uals were selected. This semi-matching process was
conducted blind to all dependent variables of interest (that
is cognitive performances).
Demographic characteristics for the study sample are
presented in Table 1; differences were compared with t-tests
and the Pearson’s chi-square test. Briefly, average age was
not significantly different (p > 0.05) between younger
smokers and younger nonsmokers or between older smok-
ers and older nonsmokers. There were no significant differ-
ences (p > 0.05) among any of the groups in terms of sex
distribution, number of years of education, or scores on
the Spot-the-Word Test, which provides a reasonable esti-
mation of overall intellectual functioning.19
2.2. Procedure
Prior to data acquisition at one of the laboratories in the
consortium, each subject was assigned an eight-digit identi-
fication number for anonymity, and subjects answered self-
report web-based questions, including questions about
smoking, personality and emotional experience. As de-
scribed above, participants completed the CIDI to identify
 R.H. Paul et al. / Journal of Clinical Neuroscience 13 (2006) 457–465 459

Table 1
Demographic characteristics of younger and older smokers and nonsmokers
Nonsmokers Smokers
Younger Older Total Younger Older Total
n 43 19 62 45 17 62
Age  26.56 (7.05) 55.79 (8.59) 35.52 (15.51) 29.53 (7.29) 54.65 (6.06) 36.42 (13.25)
Percent women 42% 63% 48% 56% 53% 55%
Years of Educationà 14.47 (2.14) 14.84 (2.81) 14.58 (2.35) 14.18 (1.98) 13.29 (2.28) 13.94 (2.09)
Spot-the-Wordà 48.37 (6.11) 49.16 (5.64) 48.61 (5.94) 48.43 (5.17) 46.86 (8.47) 48.04 (6.11)
Fagerstrom§ N/A N/A N/A 3.38 (2.05) 3.94 (2.22) 3.54 (2.09)
All data presented as mean (SD).
à
No significant differences (p > 0.05) among younger and older smokers and nonsmokers.
 
No significant differences (p > 0.05) between younger smokers and nonsmokers or between older smokers and nonsmokers.
§
No significant difference (p > 0.05) between younger and older smokers.

significant mental illness. Participants also completed an
abbreviated version of the Depression Anxiety Stress
Scales (DASS)20 to quantify symptoms of depression, anx-
iety and stress. The DASS uses a four-point scale with a
Likert-type response format to measure depression, anxiety
and stress on three distinct scales. Participants underwent
neurocognitive testing lasting approximately 45 minutes
and an electroencephalogram. Only the neurocognitive re-
sults are reported in this study. Per requirements of the
database, participants were asked to refrain from caffeine
and nicotine for at least 2 hours prior to testing, and to re-
frain from alcohol for at least 12 hours prior to testing.
Objective verification of abstinence from these substances
was not available.
2.3. Cognitive test battery
Subjects were seated in a sound attenuated room, in
front of a touch-screen computer (NEC MultiSync LCD
1530V NEC Australia, Mulgrave, VIC, Australia). The
cognitive tests were administered in a fixed order using
pre-recorded task instructions (via headphones), and the
touch-screen computer was used for answers. The test bat-
tery consisted of the following tests: motor tapping, choice
reaction time, continuous performance test, letter fluency,
Austin mazes, span of visual memory, digit span, verbal
list-learning and recall, verbal interference, and switching
of attention (See Tables 2, 3). This computerized battery
has been shown to have good validity and reliability.21
The measures are described in greater detail below.
2.3.1. Motor tapping task
Subjects were required to tap a circle on the touch-
screen with their index finger, as fast as possible for 60
seconds. The dependent variable was the average duration
between taps for the dominant hand.
2.3.2. Choice reaction time task
Subjects were required to attend to the computer screen
as one of four circles was illuminated. Immediately follow-
ing presentation, the subject then had to touch the illumi-
nated circle as quickly as possible. Twenty trials were
administered with a random delay between trials of 2–4
seconds. The dependent variable was the mean reaction
time across trials.
2.3.3. Letter fluency
Subjects were required to generate words that began
with the letters F, A, and S. Sixty seconds were allotted
for each letter and proper nouns were not allowed. The

Table 2
Descriptive statistics for performance on the neuropsychological test battery as a function of age and smoking status
Young nonsmoker Young smoker Older nonsmoker Older smoker
Motor tapping 193.59 (103.86) 188.22 (46.35) 184.18 (19.94) 200.57 (67.62)
Choice reaction time 731.10 (146.77) 702.09 (109.14) 769.32 (140.68) 841.92 (235.37)
FAS 16.05 (3.94) 15.30 (5.01) 14.72 (3.53) 12.60 (4.88)
CPT reaction time (msec) 495.97 (104.74) 529.93 (98.92) 490.50 (69.60) 512.75 (144.84)
CPT false positives (msec) 1.46 (2.09) 1.45 (2.06) 1.89 (2.00) 1.42 (1.63)
Maze errors 26.64 (10.52) 36.25 (20.23) 57.70 (40.08) 70.05 (52.30)
Maze trials 6.97 (2.62) 8.55 (3.06) 10.47 (3.76) 12.13 (4.03)
Digit span forward 6.39 (1.45) 6.36 (1.51) 6.53 (1.31) 5.29 (1.49)
Digit span reverse 5.02 (1.79) 5.02 (1.68) 4.37 (2.17) 3.44 (1.50)
Span of visual memory 5.74 (0.76) 5.49 (1.18) 4.89 (1.02) 4.90 (1.12)
Verbal learning total learning 28.39 (10.53) 27.19 (8.71) 31.14 (4.67) 30.40 (5.72)
Verbal learning delayed recall 8.57 (2.27) 8.73 (2.03) 8.00 (1.52) 5.70 (2.26)
Verbal interference 13.71 (3.08) 12.19 (3.33) 8.36 (3.14) 8.93 (3.63)
Switching of attention 1 (sec) 20.14 (49.98) 19.97 (49.45) 26.64 (77.13) 27.43 (80.26)
Switching of attention 2 (sec) 41.01 (10.79) 45.98 (10.95) 53.33 (91.39) 54.79 (83.29)
All data are presented as mean (SD), FAS = F, A, S letter fluency, CPT = continuous performance test.
460 R.H. Paul et al. / Journal of Clinical Neuroscience 13 (2006) 457–465

Table 3
Effects of age group and smoking status on cognitive performance
Motor tapping
Choice reaction time
FAS
CPT reaction time
CPT false positives
Maze errors
Maze trials
Digit span forward
Digit span reverse
Span of visual memory
Verbal learning total learning
Verbal learning delayed recall
Verbal interference
Switching of attention 1
Switching of attention 2
Y = younger, O = older, NS = nonsmokers, S = smokers, YS = younger smokers, OS = older smokers, ONS = older nonsmokers.
Main effect of age group
F(1,120) = 0.010, p = 0.92
F(1,111) = 8.36, p = 0.005
F(1,115) = 4.87, p = 0.029
F(1,115) = 0.280, p = 0.598
F(1,115) = 0.239, p = 0.26
F(1,118) = 31.97, p < 0.001
F(1,118) = 30.06, p < 0.001
F(1,124) = 5.537, p = 0.109
F(1,123) = 9.82, p = 0.002
F(1,123) = 12.62, p = 0.001
F(1,66) = 1.42, p = 0.237
F(1,66) = 8.92, p = 0.004
F(1,109) = 33.34, p < 0.001
F(1,122) = 34.61, p < 0.001
F(1,123) = 26.45, p < 0.001
Main effect of smoking status
F(1,120) = 0.139, p = 0.71
F(1,111) = 0.501, p = 0.48
F(1,115) = 2.47, p = 0.119
F(1,115) = 1.723, p = 0.192
F(1,115) = 0.322, p = 0.572
F(1,118) = 3.67, p = 0.058
F(1,118) = 6.23, p = 0.014
F(1,124) = 4.869, p = 0.029
F(1,123) = 5.41, p = 0.195
F(1,123) = 0.361, p = 0.549
F(1,66) = 0.151, p = 0.699
F(1,66) = 3.14, p = 0.081
F(1,109) = 0.413, p = 0.522
F(1,122) = 0.067, p = 0.796
F(1,123) = 2.45, p = 0.120
Age group X smoking Post hoc test
status interaction
F(1,120) = 0.536, p = 0.47
F(1,111) = 2.72, p = 0.10 Y<O
F(1,115) = 0.57, p = 0.45 Y<O
F(1,115) = 0.075, p = 0.785
F(1,115) = 0.308, p = 0.580
F(1,118) = 0.057, p = 0.811 Y<O
F(1,118) = 0.004, p = 0.951 Y < O, NS < S
F(1,124) = 4.255, p = 0.041 NS < S, ONS < OS,
YS < OS
F(1,123) = 1.69, p = 0.196 Y<O
F(1,123) = 0.428, p = 0.514 Y<O
F(1,66) = 0.008, p = 0.928
F(1,66) = 4.19, p = 0.045 Y < O, ONS < OS,
YS < OS
F(1,109) = 1.961, p = 0.164 Y<O
F(1,122) = 0.163, p = 0.687 Y<O
F(1,123) = 0.729, p = 0.395 Y<O

total number of correct words generated across the three
trials was the dependent measure.
2.3.4. Continuous performance test
A series of letters (B, C, D or G) were presented to the
subject on the computer screen (for 200 milliseconds), sep-
arated by an interval of 2.5 seconds. If the same letter ap-
peared twice in a row, the subject was asked to press
buttons with the index finger of each hand. Speed and
accuracy of response were equally stressed in the task
instructions. There were 125 stimuli presented in total, 85
being non-target letters and 20 being target letters (that
is, repetitions of the previous letter). The dependent vari-
ables were the reaction time and number of false positives.
2.3.5. Austin mazes
The subject was presented with a grid (8 · 8 matrix) of
circles on the computer screen. The object of the task
was to identify the hidden path through the grid, from
the beginning point at the bottom of the grid to the end
point at the top. The subject was able to navigate around
the grid by pressing arrow keys. The subject was presented
with one tone (and a red cross at the bottom of the screen)
if they made an incorrect move, and a different tone (and a
green tick at the bottom of the screen) if they made a cor-
rect move. The purpose of the task was therefore to assess
how quickly the subject learned the route through the maze
and their ability to remember that route. The trial ended
when the subject completed the maze twice without error
or after 10 minutes had elapsed. The dependent variables
were the number of errors on the test and the number of
trials required to complete the maze without error on two
consecutive trials.
2.3.6. Digit span
Subjects were presented with a series of digits (for exam-
ple, 4,2,7. . .) presented individually for 500 ms and sepa-
rated by a one second interval. The subject was then
immediately asked to enter the digits on a numeric keypad
on the touch-screen, either in forward order or backwards
(reverse digit span task). The number of digits in each se-
quence was gradually increased from 3 to 9. The dependent
measure was the maximum number of digits the subject
recalled without error.
2.3.7. Span of visual memory
This test was a visual analogue of a digit span test. Sub-
jects were presented with squares arranged in a random
pattern on the computer screen. The squares were high-
lighted in a sequential order on each trial. Subjects were re-
quired to repeat the order in which the squares were
highlighted. The total number correct was the dependent
variable.
2.3.8. Verbal list-learning
The participants were read a list of 12 words, which they
were asked to memorize. The list contained 12 words from
the English language. Words were closely matched on con-
creteness, number of letters and frequency. The list was
presented four times in total and the subject was required
to recall as many words as possible after each presentation.
The subject was then presented with a list of distracter
words and asked to recall those. The subject was then
asked to recall the 12 words from the original list. The
dependent variable was the number of words correctly re-
called across the four learning trials, and the number of
words recalled on the long delay free recall trial.
2.3.9. Verbal interference
This test was a computerized modification of the Stroop
test.22 Participants were presented with color words printed
in incongruent ink and they were required to name the col-
or of the ink rather than read the word. Total number of
correct trials was the dependent variable.
 R.H. Paul et al. / Journal of Clinical Neuroscience 13 (2006) 457–465
2.3.10. Switching of attention task
This modified version of the Trail Making Test con-
sisted of two parts. The first required the connecting of
numbers in ascending sequence (that is, 1-2-3- etc). On
the first test (switching of attention 1), 25 numbers, in cir-
cles, were placed on the touchscreen and the subject was in-
structed to press them in the correct order. This tests the
basic ability to hold attention on a simple task. The second
test (switching of attention 2) required the connecting of
numbers and letters in an ascending but alternating se-
quence (that is, 1-A-2-B etc.). The numbers 1–13 and the
letters A–L were presented in circles on the touch-screen.
2.4. Data analysis
Stress, anxiety, and depression scores on the DASS were
analysed with analyses of variance. For these comparisons,
one-way ANOVAs were conducted with age group (2:
younger, older) and smoker status (2: non-smoker, smoker)
as independent factors, and each DASS subscore as a
dependent variable. The two age groups included individu-
als less than 45 years old (<45 years of age; smoking group
n = 45, nonsmoking group n = 43) and individuals 45 years
of age and older (P45 years of age, smoking group n = 17,
nonsmoking group n = 19). The 45 years of age criterion is
consistent with previous studies that have examined the ef-
fects of cigarette smoking on cognition among healthy indi-
viduals.10,13 Performance on the cognitive measures was
compared using univariate ANOVAs with age group (2:
younger, older) and smoker status (2: non-smoker, smoker)
entered as independent variables. Finally, correlational
analyses between the Fagerstrom dependency score and
performance on the cognitive measures were performed
for the two smoking groups together and separately.
3. Results
No differences were found between males and females,
so all analyses were conducted collapsed across sex. Smok-
ers endorsed significantly more anxiety symptomatology
on the DASS than nonsmokers (main effect of smoking sta-
tus; p = 0.026). Smokers reported significantly more
depression than nonsmokers (main effect of smoking sta-
tus, p = 0.045) and younger individuals reported more
depressive symptoms than older individuals (main effect
of age group, p = 0.017). There were no other significant
main effects or interactions involving smoking status or
age group on the DASS measures. Correlation coefficients
between DASS anxiety and depression scores and scores on
the neuropsychological tests were examined to determine
whether these two measures influenced neurocognitive per-
formance. The only significant association to emerge was
between the depression score and the digit span score
(r = 0.186, p = 0.039). The ANOVA involving the digit
span test was therefore run with and without the depression
measure of the DASS as a covariate.
461
Results of the univariate analyses revealed the signifi-
cant impact of age on most measures. Younger individuals
performed better than older individuals on letter fluency,
Austin maze errors, Austin maze completion, choice reac-
tion time, long-delay free recall, verbal interference, switch-
ing of attention 1, switching of attention 2, and span of
visual memory.
The impact of smoking status was observed on the Aus-
tin mazes test, with smokers performing more poorly than
nonsmokers (p = 0.014; see Fig. 1) and on the digit span
test (p = 0.029; see Fig. 2). When DASS depression scores
were held as a covariate, the significance level on the digit
span test was reduced to a trend level, although the effect
size was not markedly different (p = 0.053). No other main
effects of smoking status were noted.
As illustrated in Figs. 3 and 4, respectively, a smoking
status and age interaction was observed on the digit span
test (p = 0.041) and long-delay free recall of the verbal list
learning test (p = 0.045). Post hoc analyses revealed that
older smokers performed significantly worse than older
nonsmokers (p < 0.05) and younger smokers (p < 0.05) on
both these measures, but that younger smokers did not dif-
fer from their nonsmoker counterparts (p > 0.05). When
DASS depression scores were held as a covariate, the sig-
nificant smoking status and age interaction was reduced
to a trend for the digit span test (p = 0.058).
Correlation analyses between performances on the cog-
nitive measures and the Fagerstrom Nicotine Dependence
Scale revealed no significant correlations when the older
and younger smokers were considered together. However,
when separated by age group, there was only a significant
10.00
9.00
Mean number of trials
8.00
7.00
nonsmoker smoker
Smoking Status
Fig. 1. Significant main effect of smoking status on the maze completion
test (F = 6.23, df = 1, 114, p = 0.014). Plots represent mean number of
trials required to complete the maze without error on two consecutive
trials and bars represent standard errors of the mean. Note that greater
number of trials required is indicative of worse performance.
462 R.H. Paul et al. / Journal of Clinical Neuroscience 13 (2006) 457–465

Age group
< 45 years old
6.50
= > 45 years old
Mean number of digits recalled

9.00

Mean number of words recalled

6.00

8.00

5.50

7.00

5.00 6.00
nonsmoker smoker
Smoking Status

Fig. 2. Significant main effect of smoking status on the digit span test
(F = 4.87, df = 1, 120, p = 0.029). Plots represent mean number of correct
digits recalled and bars represent standard errors of the mean. nonsmoker smoker
Smoking Status

Fig. 4. Age by smoking status interaction on long delay free recall of the
Age group verbal list learning task, F(1,62) = 4.1, p < 0.05. Older smokers performed
< 45 years old
significantly worse (p < 0.05) than older nonsmokers and younger smok-
= > 45 years old ers. Plots represent mean number of correct words recalled on the long
delay free recall trial and bars represent standard errors of the mean.
6.50
Mean number of digits recalled

between these two groups on the Fagerstrom score. Results

of this analysis revealed no significant difference between
the two groups (young 3.9 ± 2.2; older 3.3 ± 2.0). These re-
6.00
sults are consistent with the correlation analysis demon-
strating a limited relationship between cognitive function
and the Fagerstrom score.

5.50 4. Discussion

Results of the current study reveal several important

5.00
nonsmoker smoker
Smoking Status
Fig. 3. Age by smoking status interaction on digit span test,
F(1,114) = 6.3, p < 0.05. Older smokers performed significantly worse
(p < 0.05) than older nonsmokers and younger smokers. Plots represent
mean number of correct digits recalled and bars represent standard errors
of the mean.
positive association between the scores on the Fagerstrom
Nicotine Dependence Scale and performance on the choice
reaction time test (r = 0.398, p = 0.008) in the younger
smokers. There were no significant associations in the older
smokers. Given the observation that older smokers exhib-
ited more cognitive changes than younger smokers, we con-
ducted a post hoc analysis to examine potential differences
findings. First, compared to nonsmokers, cigarette smokers
reported more symptoms of anxiety and depression and
exhibited poorer performance on measures of basic audi-
tory attention and executive functioning. The findings
suggest that even in medically, psychiatrically, and neuro-
logically healthy individuals, smoking is associated with in-
creased psychiatric symptomatology and poorer cognitive
functioning, albeit the latter was evident on only one cog-
nitive measure. Importantly, smokers did not perform bet-
ter than nonsmokers on any of the cognitive measures
employed in this study.
Second, cognitive abilities among older smokers were
weaker compared to age-matched controls and younger
smokers, suggesting that advanced age confers additional
risk for smoking-related cognitive changes. Age-related
cognitive decline was greater in smokers than in nonsmok-
ers on tests of long-term memory and basic auditory atten-
 R.H. Paul et al. / Journal of Clinical Neuroscience 13 (2006) 457–465
tion. Although cognitive functioning was less impacted in
younger smokers, there was a significant relationship be-
tween increased nicotine dependence and poorer perfor-
mance on a test of reaction time in this group. Third,
evidence of compromised cognitive performances among
this highly screened sample of healthy individuals suggests
that it is unlikely the observed findings can be attributed to
comorbid health problems.
The majority of previous studies have either focused on
acute administration of nicotine in young individuals3,5,6 or
on the chronic effects of cigarette smoking in older individ-
uals.7–15 Studies of acute administration have generally fo-
cused on the effects of nicotine among nicotine-naı̈ve
individuals, or the effects of acute nicotine administration
following a prescribed period of deprivation among
chronic smokers. Results from these studies reveal im-
proved cognitive performance on measures of information
processing, attention, and memory3,5,6 in both groups of
subjects, presumably reflecting the nootropic effects of nic-
otine in drug-naı̈ve individuals, and the reconstitution of
homeostasis following deprivation. The former is consis-
tent with animal studies demonstrating improved cognitive
function following the administration of nicotinic receptor
agonists23,24 and impaired performance following the
administration of receptor antagonists.25 Collectively,
these studies demonstrate significant cognitive benefits
associated with acute nicotine intake and cigarette smok-
ing, but it is important to note that these beneficial effects
do not extend to chronic smokers.
Studies that have examined the cognitive impact of
chronic cigarette smoking have produced mixed results.
Cervilla et al.7 examined 889 individuals over the age of
65 using a structured assessment protocol and reported
that smoking was significantly associated with cognitive
impairment independent of sex, age, alcohol use, occupa-
tional class, education, handicap, and depression. Simi-
larly, Zhou et al.11 examined 3012 individuals over the
age of 60 using the Mini Mental State Exam. Results of this
study revealed that current smoking was associated with a
significantly increased risk of cognitive impairment (rele-
vant risk = 2.3). However, related contributors (such as
hypertension, diabetes) were not considered. Similar results
have been demonstrated in smaller samples using more sen-
sitive measures of cognitive function.9 Interestingly, Kal-
mijn et al.10 reported reduced cognitive flexibility and
psychomotor speed among chronic smokers 45 and older,
which translated into cognitive performances associated
with four additional years of age.
Not all studies have reported deleterious effects of
chronic smoking on cognition in the elderly. Shinka
et al.15 and Elwood et al.13 did not identify a significant
interaction between cognition and chronic smoking. How-
ever, these studies were limited by inclusion of a small co-
hort of smokers and a limited cognitive battery,
respectively. Similarly, Ford et al.14 reported no significant
impact of chronic smoking on cognitive function among
647 older individuals, though cognitive function was as-
463
sessed with a brief screening battery. Similar findings have
been reported by other investigators.12
The preceding discussion identifies an interesting para-
dox. While acute nicotine administration via cigarette
smoking is associated with improved cognitive performance
among smokers and nonsmokers, long-term smoking ap-
pears to correlate with decreased cognitive function or at
best no improvement in cognitive function. Our study is
one of the first to examine the effects of cigarette smoking
on cognitive function across the adult lifespan using a
highly sensitive and robust cognitive evaluation, possible
only via the International Brain Database. This represents
a significant advantage over previous studies, which exam-
ined the chronic effects of cigarette smoking in older indi-
viduals who were drawn from the community and many
of whom had comorbid health concerns. Further, many
studies relied on very brief cognitive evaluations or struc-
tured clinical interviews to determine cognitive function.11
Results from our study revealed that both young and
older smokers performed more poorly than demographi-
cally matched healthy control subjects (that is, significant
main effect of smoking status) and that these effects were
evident despite the rigorous screening of individuals for
physical and mental health parameters prior to inclusion
in the database. However, it is important to recognize that
the smokers, including older smokers, did not exhibit se-
vere cognitive deficits or poorer performance across all
tests.
The etiology of the cognitive changes evident among the
chronic smokers remains unclear. Chronic smoking is asso-
ciated with the release of potentially toxic substances in
both the peripheral, including cytokines, and interleukins26
(and central compartments), including nitric oxide27,28, as
well as alterations in nicotinic receptor density in the brain
parenchyma.29,30 Additional central neurotransmitter sys-
tems are also functionally altered in the context of chronic
cigarette smoking, including dopamine, norepinephrine
and GABA, among others.31–33 It is certainly possible that
cigarette smoking results in long-term modulation of neu-
rotransmitter concentrations and/or receptor densities that
ultimately interferes with effective cognitive performance.
Smoking or nicotine administration alters the number of
nicotinic receptors in the brain29,34 but it is unclear how
this modulates the effects of presynaptic neurotransmitter
release and the overall balance of the systems. Perhaps
these changes interact with normal age-related changes in
cerebral function to render older individuals more vulnera-
ble to the effects of smoking. This is an interesting possibil-
ity given the findings that smokers have reduced brain
volume compared to non-smokers.
It is important to note that participants in our study
were asked to refrain from nicotine for 2 hours prior to
the test session; a criterion for inclusion in the parent data-
base. This requirement raises the possibility that our young
and older smokers were in a state of withdrawal during the
test session. Previous studies have revealed deficits in infor-
mation processing, executive function and attention among
464 R.H. Paul et al. / Journal of Clinical Neuroscience 13 (2006) 457–465
chronic smokers after nicotine deprivation35,36 results con-
sistent with those observed in the current study. While the
possibility of withdrawal cannot be entirely ruled out, we
do not believe that nicotine withdrawal can account for
the findings of the current study, as previous studies have
demonstrated no deleterious effects on cognitive function
until after at least 4 hours of deprivation, and maximum
cognitive impact at 24 hours.37–39 Thus, it is unlikely that
the 2-hour abstinence period resulted in a functional im-
pact for our participants. It would be of interest, however,
if such a short period of abstinence was capable of produc-
ing demonstrable cognitive changes, since most smokers
that are in the workforce would be unable to smoke ciga-
rettes with sufficient regularity to avoid the cognitive de-
cline evident on a near hourly basis.
Other considerations regarding the methods employed
in the current study include the multinational cohort. It
would be of interest to determine whether country of origin
was an important factor associated with health outcomes
of chronic smoking. In addition, we did not obtain cotine
or other biologic markers of recent cigarette consumption
immediately prior to completing the cognitive evaluation.
It is possible that individuals in the smoking group engaged
in smoking prior to the assessment, though it is unclear in
what direction this would have influenced the pattern of re-
sults. This will be an important area of future research.
In summary, our data are among the first to describe
subtle cognitive difficulties in both young and older chronic
smokers. In addition, unlike much previous research,
which has concentrated on the immediate effects of nicotine
intake, the focus of the present study was to investigate the
effects of smoking that last beyond the immediate effects of
nicotine intake. Recognition that smoking is associated
with cognitive changes even among healthy individuals ar-
gues against its use as a long-term cognitive enhancer. Even
if smokers are able to avoid the common negative health
consequences associated with smoking (such as lung can-
cer), their central nervous system remains vulnerable to
the effects of smoking, and this may be particularly true
for older individuals. Results from our study strongly sup-
port the importance of smoking cessation for both younger
and older individuals.
Acknowledgement
The authors would like to thank the Brain Resource
International Database (www.BrainResource.com) scien-
tists. We also thank the individuals who gave their time
to take part in the study.
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