Alcohol & Alcoholism Vol. 42, No. 3, pp. 174–185, 2007
doi:10.1093/alcalc/agm020
THE NEUROBIOLOGICAL AND NEUROCOGNITIVE CONSEQUENCES OF CHRONIC
CIGARETTE SMOKING IN ALCOHOL USE DISORDERS
TIMOTHY C. DURAZZO1,2∗ , STEFAN GAZDZINSKI1 and DIETER J. MEYERHOFF1,2
1 Center
for Neuroimaging of Neurodegenerative Diseases, Department of Veteran’s Affairs Medical Center San Francisco, San Francisco, CA
2 Department of Radiology, University of California San Francisco, San Francisco, CA, USA
Abstract — A vast body of research attests to the adverse effects of chronic smoking on cardiac, pulmonary, and vascular function
as well as the increased risk for various forms of cancer. However, comparatively little is known about the effects of chronic
smoking on human brain function. Although smoking rates have decreased in the developed world, they remain high in individuals
with alcohol use disorders. Despite the high prevalence of comorbid chronic smoking in alcohol use disorders, very few studies
have addressed the potential neurobiological or neurocognitive effects of chronic smoking in alcohol use disorders. Here, we briefly
review the existing literature on the neurobiological and neurocognitive consequences of chronic cigarette smoking and summarize our
neuroimaging and neurocognitive studies on the effects of comorbid chronic excessive alcohol consumption and cigarette smoking in
treatment-seeking and treatment-naı̈ve populations. Our research suggests comorbid chronic cigarette smoking modulates magnetic
resonance-detectable brain injury and neurocognition in alcohol use disorders and that neurobiological recovery in our abstinent
alcoholics is adversely affected by chronic smoking. Consideration of the potential separate effects and interactions of chronic
smoking and alcohol consumption may foster a better understanding of specific mechanisms and neurocognitive consequences of
brain injury in alcoholism and of brain recovery during sustained abstinence from alcohol. The material presented also contributes
to ongoing discussions about treatment strategies for comorbid alcoholism and cigarette smoking and will hopefully stimulate
further research into the neurobiological and neurocognitive consequences of chronic smoking in alcoholism and other substance use
disorders.
INTRODUCTION
An extensive body of research indicates that chronic alcohol use disorders (i.e. alcohol abuse and dependence) are
associated with abnormalities in brain morphology, cerebral glucose and amino acid metabolism, monoaminergic and
cholinergic transmitter systems, microcellular structure and
function, regional cerebral blood flow and neurocognition
(Oscar-Berman, 2000; Rourke and Loberg, 1996; Sullivan,
2000). In alcohol use disorders, the concurrent misuse of
other substances (e.g. psychostimulants, cannabinoids) is well
documented (Bjork et al., 2003; Degenhardt and Hall, 2003;
Kampman et al., 2004). Therefore, it is possible that the neurobiological and neurocognitive abnormalities in alcohol use
disorders may be, at least in part, due to, or compounded by,
the concurrent use of other substances. The most frequently
used substances among individuals with alcohol use disorders are tobacco products. Approximately 80% of alcoholdependent individuals in North America are regular smokers
(Hurt et al., 1994; Pomerleau et al., 1997; Romberger and
Grant, 2004) and an estimated 50–90% of individuals seeking
treatment for alcoholism are heavy smokers (Room, 2004).
Several theories attempt to explain the concurrent heavy use
of alcohol and tobacco products. It has been postulated that
nicotine and alcohol potentiate each other’s rewarding properties (Narahashi et al., 2001; Rose et al., 2003; Barrett et al.,
2006), which is supported by human and animal research
demonstrating that nicotine increases voluntary alcohol intake
(Le et al., 2003; Barrett et al., 2006). Others suggest that
nicotine may counteract the adverse effects of alcohol on
*Author to whom correspondence should be addressed at: San Francisco
Veterans Administration Medical Center, Center for Imaging of Neurodegenerative Disease (114M), 4150 Clement St., San Francisco, CA 94121,
USA. Tel: (415) 221-4810 X4157; Fax: (415) 668-2864;
E-mail: [email protected]
cognition and motor incoordination (Prendergast et al., 2002),
or that paired use of nicotine and alcohol produce a classical conditioned cue reactivity, leading to cravings for both
substances (Drobes, 2002). A genetic susceptibility for concurrent cigarette smoking and alcoholism has also been proposed (Madden and Heath, 2002; Wilhelmsen et al., 2005; Le
et al., 2006).
In the United States, the mortality rate associated with
cigarette smoking has been reported to be substantially greater
than in alcohol-induced diseases (Hurt et al., 1996). Epidemiological research has indicated that mortality associated with
chronic cigarette smoking is related to its adverse effects
on cardiac and pulmonary function, central and peripheral
vascular systems, as well as its carcinogenic properties (see
Feeman, 1999; Bartal, 2001). Furthermore, a growing body of
research suggests chronic smoking is associated with abnormalities in brain morphology, cerebral blood flow, neurochemistry, and neurocognition. Yet, the vast majority of previous research on alcohol use disorders did not consider the
potential contribution of chronic smoking to the neurobiological and neurocognitive abnormalities reported. Consequently,
it is presently unclear if chronic smoking influences the neurobiological and neurocognitive abnormalities typically reported
for individuals afflicted with alcohol use disorders.
In early analyses of our neuroimaging and neurocognitive
studies of alcohol-dependent individuals, primarily composed
of US Armed Services Veterans in treatment, we consistently
observed significant differences between smokers and nonsmokers on many of our neuroimaging and neurocognitive
measures. As chronic cigarette smoking is very common in
this population, we postulated that the neurobiological and
neurocognitive abnormalities observed in alcoholics might be,
at least partially, attributable to the concurrent chronic smoking. Here, after a brief literature overview of the biological
 The Author 2007. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved
CHRONIC SMOKING AND ALCOHOLISM
and neurocognitive consequences of chronic cigarette smoking, we review our neuroimaging and neurocognitive evidence of the adverse effects of chronic smoking on human
brain neurobiology and function in our treatment-seeking and
treatment-naı̈ve alcoholic samples.
NEUROBIOLOGICAL AND NEUROCOGNITIVE
CONSEQUENCES OF CHRONIC
SMOKING—LITERATURE REVIEW
Chronic smoking, independent of alcohol use disorders, has
been linked to abnormalities in brain morphology, neurochemistry, cerebral blood flow as well as neurocognition. Chronic smokers compared to non-smokers demonstrated lower cortical gray matter volumes and densities
in the prefrontal cortex, smaller left anterior cingulate volume, and lower gray matter densities in the right cerebellum
(Brody et al., 2004), as well as increased generalized brain
atrophy with advancing age (Hayee et al., 2003). Nicotine
and/or cigarette smoking modulates brain gamma aminobutyric acidGamma Aminobutyric Acid (GABA) concentrations
in animals and humans (Zhu and Chiappinelli, 1999; Epperson
et al., 2005). Proton magnetic resonance spectroscopy indicated cortical GABA concentrations were lower in female
chronic smokers (and modulated by menstrual cycle phase),
but GABA levels were not different in a small sample of
male smokers relative to non-smokers (Epperson et al., 2005).
Chronic smokers showed lower global cerebral blood flow and
limbic system blood flow than non-smokers (Zubieta et al.,
2001; Rose et al., 2003; Domino et al., 2004). Additionally, electrophysiological studies indicated that current and
former smokers demonstrated diminished P300 amplitudes
and hypoactivation of the anterior cingulate, orbitofrontal
and prefrontal cortices, compared to never smokers (Neuhaus
et al., 2006).
While acute nicotine administration has been found to transiently improve some areas of cognition, most prominently
on measures of sustained attention in healthy non-smokers
(Sacco et al., 2004), a growing body of evidence suggests
chronic cigarette smoking adversely affects both neurocognition and postural stability. Specific dysfunction among active
chronic smokers has been reported in auditory-verbal learning and memory (Hill et al., 2003; Schinka et al., 2003),
prospective memory (Heffernan et al., 2005), working memory (Spilich et al., 1992; Ernst et al., 2001), executive functions (Razani et al., 2004; Paul et al., 2006), visual search
speeds (Richards et al., 2003), processing speed and cognitive flexibility (Kalmijn et al., 2002), general intellectual
abilities (Deary et al., 2003), and postural stability (Iki et al.,
1994). In addition, adolescent daily smokers showed deficits
in accuracy of working memory, with individuals who began
smoking at a younger age demonstrating a greater level of
impairment (Jacobsen et al., 2005). Furthermore, prospective
longitudinal research with non-demented adults suggests that
chronic cigarette smoking is associated with abnormal rates
of decline of verbal memory in middle age (Richards et al.,
2003) and general cognitive functioning in the elderly (Ott
et al., 2004). Chronic smoking is also linked to increased
risk for various forms of dementia, most notably Alzheimer’s
175
disease (Ott et al., 1998; Launer et al., 1999; Merchant et al.,
1999). It is apparent that the patterns of brain structural
(Fein et al., 1990; Tivis et al., 1995; Oscar-Berman, 2000;
Sullivan et al., 2000a; Sullivan et al., 2000b; Sullivan et al.,
2003), brain perfusion (Nicolas et al., 1993; Mampunza et al.,
1995; Demir et al., 2002) and neurocognitive (Fein et al.,
1990; Tivis et al., 1995; Oscar-Berman, 2000) abnormalities
reported for alcohol use disorders are very similar to those
reported in chronic cigarette smokers (as described above).
Taken together, it appears that chronic cigarette smoking
has similar effects on human brain morphology and neurocognition as chronic alcohol use disorders. Nevertheless,
the neurobiological effects of chronic smoking were rarely
considered in past neuroimaging or neurocognitive studies
of individuals with alcohol use disorders. Thus, it is uncertain if the full extent of the neurobiological abnormalities
reported in neuroimaging studies of alcohol use disorders are
solely related to chronic, excessive alcohol consumption, or if
concurrent chronic cigarette smoking contributes to the aberrations observed.
NEUROBIOLOGICAL AND NEUROCOGNITIVE
CONSEQUENCES OF CHRONIC SMOKING IN
ALCOHOL USE DISORDERS—A REVIEW OF OUR
RESEARCH (see Table 1)
Characterization of alcohol use disorders cohorts
Treatment-seeking alcoholics. One-week abstinent alcoholics
in treatment were retrospectively divided into chronic smokers and non-smokers based on self-report of smoking history
at enrollment. In these cross-sectional studies, the smoking
alcoholics and non-smoking alcoholics groups were largely
composed of Caucasian male, Armed Services Veterans, who
were 50 ± 9 years of age, with 14 ± 2 years of education, and generally unemployed at the time of enrollment.
Non-smoking and smoking light drinking control participants
were recruited from the community. Inclusion criteria for
treatment-seeking alcoholics required consumption of more
than 150 alcoholic drinks per month (one standard alcohol
containing drink equivalent = 12 oz of beer, 5 oz of wine,
or 1.5 oz of liquor, all corresponding to 13.6 grams pure
alcohol) for at least 8 years prior to enrollment for men, and
consumption of greater than 80 drinks per month for at least
6 years prior to enrollment for women. All treatment-seeking
alcoholics met diagnostic and statistical manual for mental
disorders, fourth edition (DSM-IV) criteria for alcohol dependence with physiological dependence. Primary exclusion criteria are fully detailed in Durazzo et al. (2004). In summary,
all participants were free of general medical, neurological, and
neuropsychiatric conditions known or suspected to influence
neurocognition, except hepatitis C, hypertension and unipolar mood disorders. Current or past unipolar mood disorders
(e.g. dysthymia, major depression, substance-induced unipolar mood disorder) were not exclusionary, given the reported
high comorbidity with both alcoholism (Gilman and Abraham, 2001) and chronic cigarette smoking (Fergusson et al.,
2003). Overall, both the smoking and non-smoking alcoholics
groups manifested a similar frequency of concurrent unipolar mood disorders. No subject met criteria for substance
176
T. C. DURAZZO et al.
dependence in the 5 years prior to enrollment. With the exception of one participant who met DSM-IV criteria for current
cannabis abuse, no other alcoholics met criteria for substance
abuse in the 5 years prior to enrollment. Non-smoking alcoholics consumed approximately 200 drinks per month over
lifetime, while smoking alcoholics consumed approximately
45% more drinks per month over lifetime than non-smoking
alcoholics. Smoking alcoholics consumed approximately 20
cigarettes per day over about 20 years. All smoking alcoholics were actively smoking at all assessment points and
were allowed to smoke ad libitum prior to magnetic resonance
studies, and prior to and during neurocognitive assessment.
We quantified brain structure with high-resolution magnetic
resonance imaging (MRI) (Gazdzinski et al., 2005), brain
metabolite concentrations with proton magnetic resonance
spectroscopic imaging (Durazzo et al., 2004), and brain blood
flow with perfusion-weighted MRI using with pulsed arterial
spin labeling (Gazdzinski et al., 2006). A brief neurocognitive battery, emphasizing processing speed, learning and
memory and working memory was administered after approximately 1 week of abstinence. After approximately 1 month
of sustained sobriety, a comprehensive neurocognitive battery
Table 1. Published magnetic resonance and neurocognitive studies of comorbid chronic alcohol use disorders and cigarette smoking from D.J.
Meyerhoff lab
Neuroimaging studies
Study
Participants
Method
Primary findings
Durazzo et al., 2004
10 nsALC; 14 sALC;
19 nsLD; 7 sLD
1
Gazdzinski et al.,
2005
13 nsALC; 24 sALC;
23 nsLD; 7 sLD
High-resolution 3D MRI and brief
neurocognitive battery at 1 week
of abstinence from alcohol
Gazdzinski et al.,
2006
10 nsALC; 19 sALC;
19 nsLD
MR pulsed arterial spin labeling at 1
week of abstinence from alcohol
Durazzo et al., 2007
16 nsHD; 17 sHD;
20 nsLD
High-resolution 3D MRI; HD
actively drinking at time of study
Durazzo et al., 2006a
11 nsALC; 14 sALC
Repeat 1 H MRSI at 1 week and
after 1 month of abstinence from
alcohol; brief neurocognitive
battery at 1 week of abstinence
and comprehensive
neurocognitive battery at 1 month
of abstinence
—ALC associated with ↓ frontal NAA and Cho and ↓
parietal and thalamic Cho.
—Smoking associated with ↓ midbrain NAA and Cho and ↓
cerebellar vermis Cho.
—sALC vs. nsALC: 10% ↓ NAA in frontal WM; 15% ↓
NAA and 21% ↓ Cho in the midbrain.
—sALC: greater nicotine dependence and higher # of
cigarettes smoked per day negatively correlated with
thalamic and lenticular NAA
—ALC associated with ↓ parietal and temporal GM, and ↓
frontal and parietal WM
—Smoking associated with ↓ parietal, temporal and occipital
GM, and ↑ temporal and frontal WM
—nsALC: visuospatial learning and memory positively
correlated with temporal and occipital WM volumes
—sALC: no significant structure-function relationships
—sALC vs. nsLD: perfusion 19% ↓ in frontal GM and 12%
↓ in parietal GM
—sALC vs. nsALC: perfusion 18% ↓ in frontal GM and 11%
↓ in parietal GM
—nsALC vs. nsLD: no significant differences in GM
perfusion
—sALC: parietal GM perfusion inversely correlated with # of
cigarettes smoked per day
—sHD vs. nsLD: ↓ frontal, parietal, temporal and total GM
—sHD vs. nsHD: ↓ temporal and total GM
—nsHD vs. nsLD: no significant neocortical GM volume
differences
—nsALC over 1 month of abstinence: ↑ frontal WM NAA; ↑
Cho in frontal, parietal, temporal GM; ↑ Cho in frontal,
parietal, temporal, occipital WM.
—sALC: ↑ frontal GM NAA; ↓ parietal and occipital WM
NAA; ↑ frontal GM and WM Cho.
—nsALC: improving visuospatial learning positively related
to increasing frontal and occipital WM NAA; improving
visuomotor scanning speed related to increasing parietal
GM NAA; improving visuospatial learning, visuospatial
memory and working memory, related to increasing
thalamic NAA; improving visuospatial learning related to
increasing frontal GM Cho.
—nsALC: longer smoking duration related to decreasing
frontal WM NAA, frontal WM Cho, and thalamic Cho.
H MRSI and brief neurocognitive
battery at 1 week of abstinence
from alcohol
(continued overleaf )
CHRONIC SMOKING AND ALCOHOLISM
177
Table 1. (Continued )
Neurocognitive studies
Study
Participants
Method
Primary findings
Durazzo et al., 2005
20 nsHD; 13 sHD;
Comprehensive neurocognitive
battery; hazardous drinkers were
actively drinking at time of study
—sHD: greater perseverative errors, perseverative responses,
and total errors on WCST than both nsHD and nsLD.
nsHD and nsLD not significantly different.
—sHD vs. nsHD: differences on WCST measures not due to
disparities in age, education, estimated premorbid verbal
intelligence, lifetime alcohol consumption
—nsLD: greater postural stability than sHD and nsHD
—nsALC superior to sALC on measures of auditory-verbal
learning and memory, processing speed, cognitive
efficiency, and static postural stability
—Group differences not due to disparities in age, education,
estimated premorbid verbal intelligence, lifetime alcohol
consumption
—sALC: longer smoking duration negatively correlated with
executive skills, visuospatial learning, general cognitive
efficiency, and static postural stability.
22 nsLD
Durazzo et al., 2006b
20 nsALC; 22 sALC,
Comprehensive neurocognitive
battery at 1 month of abstinence
from alcohol
Note: ALC, alcohol dependence; Cho, choline-containing compounds; GM, gray matter; NAA, N-acetylaspartate; MR, magnetic resonance; MRI, magnetic
resonance imaging; nsALC, non-smoking treatment seeking alcoholic; nsHD, non-smoking treatment-naı̈ve hazardous drinker; nsLD, non-smoking light
drinking control; 1 H MRSI, proton magnetic resonance spectroscopic imaging; sALC, smoking treatment seeking alcoholic; sHD, smoking treatment-naı̈ve
hazardous drinker; sLD, smoking light drinking control; WM, white matter; WCST, Wisconsin Card Sorting Test
assessed functions known to be adversely affected by chronic
alcoholism (Durazzo et al., 2006b) and proton magnetic resonance spectroscopic imaging procedures were repeated for
longitudinal analyses (Durazzo et al., 2006a) at that time.
Treatment-naı̈ve hazardous drinkers. Individuals seeking
treatment for alcohol use disorders constitute only a small
fraction of persons afflicted with chronic alcoholism in the
developed world, yet most of what is known about the effects
of chronic alcoholism on the human brain has been derived
from volunteers recruited from inpatient or outpatient treatment programs. Information from treatment-naı̈ve, actively
drinking hazardous drinkers may be more relevant to the general Western population as the vast majority of individuals
with alcohol use disorders are not in treatment. Our group
observed abnormalities in regional brain metabolites (Meyerhoff et al., 2004), volumes (Cardenas et al., 2005) as well
as neurocognition (Rothlind et al., 2005) in treatment-naı̈ve
hazardous drinkers. In these studies, the potential effects of
chronic cigarette smoking were not considered. Therefore,
in retrospective analyses, we divided our hazardous drinking
participants into smokers and non-smokers, based on selfreport of smoking history at enrollment. Smoking hazardous
drinkers reported smoking daily or nearly every day. They
were actively smoking at the time of study and allowed to
smoke ad libitum prior to magnetic resonance scans and prior
to and during neurocognitive assessment. Information regarding number of cigarettes smoked per day was not obtained
in these earlier studies. The smoking and non-smoking hazardous drinker groups consisted primarily of Caucasian males,
averaging 44 ± 10 years of age, with 14 ± 2 years of formal
education. Classification as a hazardous drinker required an
average consumption of at least 100 (80 for women) standard
alcoholic drinks per month for a minimum of 3 years prior to
enrollment and active alcohol consumption at time of study.
Non-smoking hazardous drinkers consumed approximately
130 ± 80 drinks per month over lifetime. Smoking hazardous
drinkers consumed approximately 45% more drinks per month
over lifetime than non-smoking hazardous drinkers, which
is consistent with the greater lifetime alcohol consumption
we observed in our treatment-seeking, smoking alcoholics.
Approximately 90% of hazardous drinkers participants met
DSM-IV criteria for alcohol dependence and the remaining
hazardous drinkers met criteria for alcohol abuse. Exclusion
criteria are fully detailed in Cardenas et al. (2005). In short,
all participants were free of general medical, neurological, and
psychiatric conditions known or suspected to influence brain
morphology. Participants were excluded if they met DSM-IV
criteria for dependence on any other substance than alcohol or
nicotine in the 6 months prior to enrollment and no hazardous
drinker participant met criteria for abuse of other substances
at the time of study.
Cross-sectional quantitative MR studies in alcohol use
disorders
Quantitative volumetric MRI in 1-week-abstinent, treatmentseeking alcoholics. High-resolution 3D MRIs were acquired
from 13 non-smoking alcoholics, 24 smoking alcoholics, 23
non-smoking light drinkers and light drinkers and 7 smoking
light drinkers (Gazdzinski et al., 2005). Quantitative volumetric measures of neocortical gray matter, white matter, subcortical structures and sulcal and ventricular cerebral spinal fluid
were derived from high-resolution T1 -weighted magnetic resonance images as previously detailed (Cardenas et al., 2005).
Regional brain volumes were converted to age-corrected zscores based on the non-smoking light drinkers control group.
Multivariate analysis of variance for all measured regions
178
T. C. DURAZZO et al.
yielded main effects for both alcohol dependence and smoking
status. Follow-up analyses demonstrated significant alcohol
effects for the parietal and temporal gray matter, with less gray
matter in treatment-seeking alcoholics than light drinkers. Significant smoking effects were found for parietal, temporal,
and occipital gray matter, where smokers demonstrated less
gray matter in these regions than non-smokers. These effects
remained significant after covarying for the greater lifetime
alcohol consumption in smokers. Alcohol effects were also
seen for the frontal white matter, and parietal white matter,
with smaller white matter in alcoholics compared to light
drinkers. Significant smoking effects were observed for the
temporal white matter and a trend for frontal white matter
were observed, with greater white matter volumes in smokers compared to non-smokers. Follow-up tests revealed that
smoking alcoholics had significantly smaller neocortical gray
matter volumes than non-smoking light drinkers in all four
lobes, but non-smoking alcoholics and non-smoking light
drinkers were not significantly different in gray matter volume
in any lobe. Consistent with our findings in a treatment-naı̈ve
hazardous drinker cohort (see below), we observed strong
trends for larger temporal and frontal white matter volume
in smoking alcoholics compared to non-smoking alcoholics.
These trends were apparent after controlling for the greater
lifetime alcohol consumption in smoking alcoholics. For nonsmoking alcoholics, visuospatial learning and memory were
positively correlated with temporal white matter and occipital white matter volumes, whereas no significant structurefunction relationships were observed for smoking alcoholics.
This suggests that chronic smoking in recovering alcoholics
may further disrupt alcohol-induced disturbances in functional
neurocircuitry (Sullivan and Pfefferbaum, 2005) that subserves such abilities as learning and memory, executive skills
and working memory. In this study, both chronic, excessive
alcohol consumption and chronic smoking were associated
with significant neocortical gray matter loss. The larger white
matter volumes in smokers may reflect mild cytotoxic and/or
vasogenic swelling secondary to smoking-induced alterations
in mitochondrial function (Alonso et al., 2004) and/or vascular endothelial damage (Hawkins et al., 2002).
Quantitative volumetric MRI in treatment-naı̈ve hazardous
drinkers. We previously reported in Cardenas et al. (2005)
that actively drinking hazardous drinkers demonstrated
smaller regional neocortical gray matter volumes compared
to light drinking controls; however, the potential effects of
chronic cigarette smoking on regional brain volumes were
not addressed in that report. From the 49 hazardous drinker
participants in Cardenas et al. (2005), we identified 17 smoking hazardous drinkers who reported consistently smoking
daily or nearly every day for at least 6 months prior to
study enrollment and compared them to 16 non-smoking
hazardous drinkers and 20 non-smoking light drinkers from
the Cardenas et al. (2005) sample (Durazzo et al., 2007).
All subjects were equivalent in age. Multivariate analyses
yielded significant group differences for regional neocortical
gray matter, and follow-up tests indicated smoking hazardous
drinkers demonstrated significantly smaller volumes than nonsmoking light drinkers in the frontal, parietal, temporal gray
matter and for total neocortical gray matter. Notably, smoking hazardous drinkers had significantly smaller temporal
and total gray matter volumes than non-smoking hazardous
drinkers, whereas gray matter volumes in non-smoking hazardous drinkers did not differ significantly from those in nonsmoking light drinkers. The smaller temporal and total gray
matter volumes observed in smoking hazardous drinkers relative to non-smoking hazardous drinkers were apparent after
covarying for greater lifetime alcohol consumption in smoking hazardous drinkers. The groups did not differ significantly
on lobar white matter, subcortical structure or cerebrospinal
fluid volumes; however, we found trends for larger white
matter volumes in smoking hazardous drinkers relative to
non-smoking hazardous drinkers, which is consistent with the
volumetric findings in our treatment-seeking alcoholics (see
Section in Quantitative volumetric MRI in 1-week-abstinent,
treatment-seeking alcoholics). The absence of cortical gray
matter volume differences between the non-smoking hazardous drinkers and non-smoking light drinkers groups in this
study is consistent with our volumetric findings in 1-week
abstinent non-smoking alcoholics (Gazdzinski et al., 2005).
The non-smoking treatment-seeking alcoholics in Gazdzinski
et al., 2005 consumed nearly three times as much ethanol
(in kilograms) over lifetime than our non-smoking hazardous
drinkers and nearly twice as much as smoking hazardous
drinkers, yet they still did not show significant neocortical
gray matter volume reductions in any lobar region relative to
non-smoking light drinkers.
Quantitative metabolite imaging in1-week-abstinent,
treatment-seeking alcoholics. Ten non-smoking alcoholics,
14 smoking alcoholics, 19 non-smoking light drinkers and 7
smoking light drinkers were compared on levels of common
brain metabolites in gray matter and white matter of the
four neocortical lobes, basal ganglia, midbrain and cerebellar
vermis, obtained via short-echo time, multislice proton
magnetic resonance spectroscopic imaging (Durazzo et al.,
2004). Concentrations of N -acetylaspartate (a surrogate
marker of neuronal viability), choline-containing compounds
(choline; a marker of cell membrane synthesis/turnover), and
other metabolites were derived from spectra measured in
three parallel planes through the centrum semiovale, basal
ganglia, and cerebellar vermis. Regional atrophy-corrected
metabolite concentrations were calculated by combining
proton magnetic resonance spectroscopic imaging and
segmented MRI data (Meyerhoff et al., 2004). Analysis of
covariance, with age as a covariate, indicated that chronic
alcohol dependence, independent of smoking, was associated
with lower frontal N -acetylaspartate and choline levels,
as well as lower parietal and thalamic choline. Chronic
cigarette smoking was associated with lower midbrain
N -acetylaspartate and choline and with lower cerebellar
vermis choline. The smoking alcoholics group compared
to the non-smoking alcoholics group demonstrated 10%
lower N -acetylaspartate concentrations in the frontal white
matter and 15% lower N -acetylaspartate and 21% lower
choline in the midbrain. In addition, smoking alcoholics
showed trends to lower N -acetylaspartate in the parietal
gray matter and lenticular nuclei relative to non-smoking
alcoholics. The regional metabolite concentration differences
between smoking alcoholics and non-smoking alcoholics
remained significant after controlling for the greater lifetime
alcohol consumption in smoking alcoholics. Numerically,
smoking alcoholics evidenced the lowest N -acetylaspartate
and choline levels of all four groups in virtually all regions
measured. In non-smoking alcoholics, cerebellar vermis N acetylaspartate was positively related to visuospatial learning
and visuospatial memory, whereas in smoking alcoholics,
cerebellar vermis N -acetylaspartate was positively related
to visuomotor scanning speed and incidental learning. In
smoking alcoholics, higher nicotine dependence and number
of cigarettes smoked per day were negatively correlated
with thalamic and lenticular N -acetylaspartate levels. Thus,
chronic smoking in 1-week-abstinent treatment-seeking
alcoholics was associated with greater metabolite abnormalities in a ‘dose’-dependent manner. Overall, our results
suggest that cigarette smoking had independent and additive
adverse effects on regional brain metabolites, in particular
on markers of neuronal viability and cellular membrane
turnover/synthesis.
Quantitative brain blood flow in 1-week-abstinent,
treatment-seeking alcoholics. Ten non-smoking alcoholics,
19 smoking alcoholics and 19 non-smoking light drinkers,
matched on age, were compared on regional neocortical
gray matter blood flow (Gazdzinski et al., 2006) using a
non-invasive pulsed arterial spin labeling method that imaged
primarily the frontal and parietal lobes (Jahng et al., 2003;
Gazdzinski et al., 2006). Multivariate analyses indicated
significant group differences for perfusion in both frontal
and parietal gray matter. Follow up univariate tests indicated
frontal gray matter perfusion in smoking alcoholics was 18%
lower than non-smoking alcoholics and 19% lower than
non-smoking light drinkers. Parietal gray matter perfusion
in smoking alcoholics was 11% lower than in non-smoking
alcoholics and 12% lower than non-smoking light drinkers.
The regional perfusion differences between smoking alcoholics and non-smoking alcoholics remained significant after
controlling for the greater lifetime alcohol consumption in
smoking alcoholics. Gray matter perfusion was similar in
non-smoking alcoholics and non-smoking light drinkers.
Parietal gray matter perfusion in smoking alcoholics was
inversely correlated with the number of cigarettes smoked per
day. There was no relationship between the interval of last
cigarette smoked and frontal or parietal gray matter perfusion
in smoking alcoholics. This suggests that the chronic effects
of cigarette smoking, rather than the acute effects of nicotine
exposure or withdrawal, modulated brain perfusion in our
treatment-seeking alcoholics, which is consistent with results
in non-alcoholic chronic smokers (e.g. Yamashita et al.,
1988; Rourke et al., 1997).
Cross-sectional neurocognitive studies in alcohol use
disorders
One-month abstinent, treatment-seeking alcoholics. We
examined neurocognition in 20 non-smoking alcoholics and
22 smoking alcoholics, matched on age and education, with
a comprehensive test battery after 34 ± 9 days of abstinence
(Durazzo et al., 2006b). Functions evaluated included executive skills, fine motor skills, general intelligence, learning
and memory, postural stability, processing speed, visuospatial skills, and working memory. Multivariate analyses of
variance and subsequent univariate tests revealed that nonsmoking alcoholics were superior to smoking alcoholics on
measures of auditory-verbal learning and memory, processing
Executive Skills (age adjusted z-score)
CHRONIC SMOKING AND ALCOHOLISM
179
1.5
r = -0.63, p = .001
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0
5
10
15
20
25
30
35
Smoking Duration (years)
40
45
Fig. 1. Relationship between smoking duration and executive skills in
smoking treatment seeking alcoholics.
speed, cognitive efficiency, and static postural stability. These
group differences were not a function of group disparities
in age, education, estimated premorbid verbal intelligence,
lifetime alcohol consumption, or other measured comorbid
psychiatric or medical factors. In smoking alcoholics, longer
smoking duration was negatively correlated with executive
skills (see Fig. 1), visuospatial learning, general cognitive efficiency, and static postural stability. Our findings are consistent
with other recent research indicating chronic cigarette smoking modulates neurocognition in alcohol use disorders (e.g.
Friend et al., 2005; Glass et al., 2006).
Treatment-naı̈ve hazardous drinkers. We described recently
that hazardous drinkers, without consideration of smoking
status, demonstrated poorer performance on measures of
working memory, balance, and executive function than nonsmoking light drinkers (Rothlind et al., 2005), which is generally consistent with results of previous research of heavy
social drinkers (see Parsons 1998; Parsons and Nixon, 1998
for review). However, these previous studies did not assess
the potential effects of chronic smoking on neurocognition
in this population. Therefore, we compared 20 non-smoking
hazardous drinkers, 13 smoking hazardous drinkers, and 22
non-smoking light drinkers from Rothlind et al. (2005) on
measures of executive function, processing speed, learning
and memory, and working memory (Durazzo et al., 2005). All
participants were matched on age and education. Multivariate
analyses indicated groups were different on the Wisconsin
Card Sorting Test, where both non-smoking light drinkers
and non-smoking hazardous drinkers made fewer perseverative errors, perseverative responses, and total errors than
smoking hazardous drinkers. Groups also differed on the
Fregly Sharpened Romberg (a measure of static postural
stability), where non-smoking light drinkers performed better than both smoking hazardous drinkers and non-smoking
hazardous drinkers, and non-smoking hazardous drinkers performed better than smoking hazardous drinkers. Group differences between smoking hazardous drinkers and non-smoking
hazardous drinkers remained significant after covarying for
greater lifetime alcohol consumption in smoking hazardous
drinkers. These findings suggest that in hazardous drinkers,
T. C. DURAZZO et al.
chronic cigarette smoking may account for a significant proportion of the executive dysfunction and balance previously
attributed solely to heavy alcohol consumption (e.g. Rothlind
et al., 2005). As in our treatment-seeking alcoholics, consideration of the effects of smoking on neurocognition and postural
stability appears to be warranted in treatment-naı̈ve hazardous
drinkers.
EFFECTS OF CHRONIC SMOKING ON
NEUROBIOLOGICAL AND NEUROCOGNITIVE
RECOVERY DURING ABSTINENCE FROM ALCOHOL
Quantitative morphometric MRI in treatment-seeking
alcoholics
Deformation based morphometry is a brain shape analysis
method that, in our application, employs robust fluid registration of serial structural MRIs to illuminate and quantitate brain
tissue and cerebrospinal fluid changes over time. We applied
this method to serial MRIs obtained in 17 treatment-seeking
alcoholics, who had sustained approximately 7 months of
abstinence from alcohol, compared to eight treatment-seeking
alcoholics, who had relapsed before repeat MRI. We observed
that tissue volume recovery in alcoholics occurs primarily
in the frontal white matter, subcortical nuclei, pons, cerebellum, hippocampi and sections of the corpus callosum
(Cardenas et al., 2007). Furthermore, our deformation based
morphometry analyses clearly indicated that chronic cigarette
smoking influenced the volume recovery during sustained
abstinence from alcohol. Specifically, these preliminary analyses indicated that abstinent smoking alcoholics had significantly lower tissue volume recovery rate than abstinent nonsmoking alcoholics in the left anterior hippocampus/amygdala
region, with trends for lower volume recovery rate in smoking
alcoholics in frontal and temporal gray matter. Results also
showed that greater nicotine dependence and longer smoking
duration in smoking alcoholics were related to slower tissue
recovery over 7 months of sobriety in regions of the corpus
callosum, basal ganglia and frontal lobe.
Longitudinal metabolite imaging in treatment-seeking
alcoholics
Eleven non-smoking alcoholics and 14 smoking alcoholics
were studied 6 ± 3 days after consumption of their last drink
(as described above) and again at 34 ± 10 days of abstinence from alcohol (Durazzo et al., 2006a). Repeated measures analysis of variance indicated that the non-smoking
alcoholics group showed significant increases in frontal white
matter N -acetylaspartate (+8%) and choline in the frontal
(+14%), parietal (+12%) and temporal (+8%) gray matter over 1 month of abstinence from alcohol. Significant
choline increases were also observed for non-smoking alcoholics in the white matter of the frontal (+16%), parietal
(+17%), temporal (+7%), and occipital (+13%) lobes. In
smoking alcoholics, over 1 month of abstinence from alcohol, N -acetylaspartate concentrations increased only in the
frontal gray matter (+5%), while N -acetylaspartate significantly decreased in the parietal white matter and occipital
white matter (both—6%). For smoking alcoholics, choline
increased in the frontal gray matter (+8%) and frontal
white matter (+11%). Overall, smoking alcoholics demonstrated numerically smaller and fewer regional increases
of N -acetylaspartate and choline concentrations over 1
month of abstinence than non-smoking alcoholics. The nonsmoking alcoholic group showed many significant relationships between changes of metabolite levels and neurocognition, attesting to the functional relevance of brain metabolite
changes. Specifically, in non-smoking alcoholics, improvements in visuospatial learning were related to increases of
frontal white matter N -acetylaspartate and occipital white
matter N -acetylaspartate; increases of parietal gray matter
N -acetylaspartate correlated with improvements of visuomotor scanning speed and incidental learning; increases of
thalamic N -acetylaspartate were related to improving visuospatial learning, visuospatial memory and working memory;
improving visuospatial learning also correlated with increasing frontal gray matter choline, frontal white matter choline
and thalamic choline. For smoking alcoholics, the only
significant relationships were between increasing midbrain
N -acetylaspartate and improving visuospatial learning, and
between increasing caudate N -acetylaspartate and improving
visuospatial memory. In smoking alcoholics, longer smoking
duration was related to lower longitudinal increases in frontal
white matter N -acetylaspartate (see Fig. 2), frontal white matter choline, and thalamic choline.
We also investigated volumetric changes in the hippocampus and changes in medial temporal lobe metabolite concentrations over 1 month of abstinence in 13 smoking alcoholics
and 11 non-smoking alcoholics. Over 1 month of sobriety,
medial temporal lobe N -acetylaspartate and choline levels in
non-smoking alcoholics significantly increased and normalized to non-smoking light drinkers levels. However, in smoking alcoholics, N -acetylaspartate and choline concentrations
did not change significantly and remained depressed relative
to non-smoking light drinkers. Increased N -acetylaspartate
and choline levels in both non-smoking and smoking alcoholics were associated with improvements in visuospatial
memory. Hippocampal volumes significantly increased in
both groups over 1 month of abstinence from alcohol, but
Percent Change in Frontal WM NAA
180
25
20
15
r = - 0.59, p = .02
10
5
0
-5
-10
-15
-20
0
5
10
15
20
25
30
Smoking Duration (years)
35
40
45
Fig. 2. Relationship between smoking duration and longitudinal change
in frontal white matter N-acetylaspartate in smoking treatment-seeking
alcoholics.
CHRONIC SMOKING AND ALCOHOLISM
increasing volumes correlated with improved visuospatial
learning only in non-smoking alcoholics.
POSSIBLE MECHANISMS PROMOTING GREATER
NEUROBIOLOGICAL AND NEUROCOGNITIVE
ABNORMALITIES IN CHRONIC SMOKERS WITH
ALCOHOL USE DISORDERS
Chronic effects of cigarette smoking
Chronic cigarette smoking is associated with significantly
increased risk for atherosclerosis (Bolego et al., 2002), as well
as abnormalities in vascular endothelial function (Hawkins
et al., 2002). These processes may impact the functional
integrity of the cerebrovasculature and contribute to the
decreased regional cerebral blood flow (Zubieta et al., 2001;
Rose et al., 2003; Domino et al., 2004) and/or white matter
disease (Fukuda and Kitani, 1996; Ding et al., 2003) observed
in chronic smokers. The neocortex is also reported to be
vulnerable to the effects of diffuse ischemia (see Chalela
et al., 2001 and references therein). Furthermore, it has been
suggested that late-myelinating areas such as the frontal and
temporal lobes may be particularly susceptible to increased
oxidative stress and cerebral hypoperfusion (see Bartzokis
2004a, 2004b), both of which have been described in chronic
smokers.
A multitude of toxic compounds are found in the particulate and gas phases of cigarette smoke (e.g., carbon monoxide
(CO), free radicals, nitrosamines, polynuclear aromatic compounds (Fowles et al., 2000)), which may directly or indirectly compromise brain tissue. For example, CO levels are
significantly higher in smokers (Deveci et al., 2004), which
is associated with decreased effective hemoglobin concentrations, diminished oxygen carrying capacity of erythrocytes
(Macdonald et al., 2004), as well as a diminished efficiency
of the mitochondrial respiratory chain (Alonso et al., 2004).
Chronic smoking has also been equated to a type of repeated
acute (mild) CO poisoning (Alonso et al., 2004), and is associated with nocturnal hypoxia (Casasola et al., 2002) as well
as chronic obstructive pulmonary disease and other conditions that may impair lung function (Bartal, 2001). Decreased
lung function has been associated with poorer neurocognition and increased subcortical atrophy among community
dwelling individuals 60–64 years of age (Sachdev et al.,
2006). Furthermore, cigarette smoke contains high concentrations of free radical species (e.g. reactive oxygen species)
known to promote oxidative damage or stress to cellular
structures as well as macromolecules including membrane
lipids, proteins, carbohydrates, and DNA (Moriarty et al.,
2003). Similarly, chronic and heavy alcohol consumption
and ethanol catabolism are associated with generation of
reactive oxygen species and other metabolic products that
may lead to oxidative damage to various cellular molecules
and structures, including phospholipids and DNA (Brooks,
2000). We propose that in smoking alcoholics, chronic exposure to the additional exogenous free radical species and
carbon monoxide found in cigarette smoke, in combination
with potentially diminished cardiopulmonary function or cerebrovascular integrity, may adversely affect the morphology
or metabolism of neural and glial tissue, particularly that
181
comprising the frontal-striatal-thalamic circuitry. Potentially
greater modulation of brain tissue comprising frontal-striatalthalamic circuitry in smokers is suggested by the pattern
of neuroimaging and neurocognitive findings in both alcoholic (Durazzo et al., 2004, 2005, 2006a, 2006b, 2007; Friend
et al., 2005; Glass et al., 2006; Gazdzinski et al., 2006) and
non-alcoholic (Spilich et al., 1992; Ernst et al., 2001; Kalmijn
et al., 2002; Brody et al., 2004; Razani et al., 2004; Brody,
2006; Paul et al., 2006) chronic smokers.
Therefore, a combination of chronically increased CO
levels, chronic exposure to reactive oxygen species from
both ethanol metabolism and cigarette smoke, and potentially compromised vascular and pulmonary function may all
contribute to the greater neurobiological abnormalities and
lower cognitive performance we observe in our smoking alcoholics and smoking hazardous drinkers cohorts. Furthermore,
chronic smoking may influence some aspects of neurocognition through modulation of regional monoaminergic, cholinergic, glutamatergic and GABAergic activity (see Bonvento
et al., 2003; Das, 2003; Pitsikas et al., 2003; Brody, 2006).
Thus, it is possible that the functional integrity of frontalstriatal-thalamic neural networks (see Mega and Cummings,
1994) is further altered in smoking alcoholics relative to
their non-smoking counterparts. Finally, it is feasible that
the brain regions adversely affected in alcohol use disorders
(e.g. neocortical gray matter) are rendered more vulnerable
to the effects of the potentially noxious compounds found in
cigarette smoke (or vice-versa).
Acute effects of nicotine
When investigating chronic cigarette smoking-induced neurobiological and neurocognitive dysfunction, independently or
in conjunction with alcohol use disorders and other conditions, it is important to distinguish between the effects of
acute nicotine ingestion/intoxication and withdrawal and the
consequences of chronic exposure to the multitude of noxious compounds contained in cigarette smoke. Acute nicotine
administration has been found to transiently improve some
areas of neurocognition, most appreciably on measures of
sustained attention, primarily in healthy non-smokers and
individuals with attention deficit hyperactivity disorder and
schizophrenia-spectrum disorders (see Rezvani and Levin,
2001; Sacco et al., 2004; Brody, 2006 for review). The halflife of nicotine in humans is approximately 2–3 h (Nakajima
and Yokoi, 2005), and the adverse effects of nicotine withdrawal on aspects of neurocognition may not be apparent for
12 h or longer (for review see Sacco et al., 2004). With respect
to our neurocognitive studies, all of our smoking participants
were allowed to smoke ad libitum prior to and during the
2–2.5 h neurocognitive assessment; therefore, our findings
were not likely a function of nicotine withdrawal. However,
the effects of acute nicotine administration on neurocognition
in smoking alcoholics and other substance abusers are not
clear (see Ceballos et al., 2006).
A few functional MRI studies have investigated the acute
effects of nicotine administration on brain activity during
task performance in healthy non-smokers (e.g. Kumari et al.,
182
T. C. DURAZZO et al.
2003; Thiel et al., 2005). Results suggested that, depending on the nature of the task, acute nicotine administration was associated with increased blood oxygenation leveldependentBlood Oxygenation Level-Dependent (BOLD) brain
activity and improved performance (Thiel et al., 2005) or
decreased BOLD activity and improved performance (Kumari
et al., 2003). The effects of acute cigarette smoking on functional imaging measures (in resting conditions or during task
activation) in healthy non-smokers have yet to be reported
(Brody, 2006). In chronic smokers deprived of tobacco for
more than 2 h, acute cigarette smoking elicits different patterns of relative perfusion responses, with increases of the
order of 6–8% in a number of brain regions including prefrontal and cingulate cortices as well as decreases in cerebellum and occipital lobes that were associated with plasma
nicotine levels (Rose et al., 2003; Domino et al., 2004; Brody,
2006). With respect to cerebral blood flow and glucose
metabolism some studies report a 7–10% decrease in global
glucose utilization following acute nicotine administration in
chronic smokers deprived from nicotine for 8 h or more
(Domino et al., 2000; Stapleton et al., 2003). Thus, the effects
of acute nicotine administration and acute cigarette smoking
on functional imaging measures and neurocognition appear
to depend on the extent of nicotine deprivation, the brain
region studied, resting versus activation conditions, and the
neurocognitive domain investigated (Brody, 2006).
SUMMARY AND CONCLUSIONS
Although smoking rates in the general population of United
States has decreased over the last three decades, smoking
prevalence remains high especially among the economically
disadvantaged (Jha et al., 2006) and individuals with alcohol, substance use and other neuropsychiatric disorders (e.g.
schizophrenia-spectrum disorders, mood disorders) (Fergusson et al., 2003; Dani and Harris, 2005; Esterberg and Compton, 2005; Patkar et al., 2006). Our cross-sectional MR findings suggest that chronic cigarette smoking in alcohol use
disorders is associated with regional neocortical gray matter
volume loss, and smoking is linked to a significant (and possibly pathological) increase in temporal white matter volume.
Chronic smoking in alcohol use disorders is also associated
with perfusion abnormalities in the frontal and parietal gray
matter and appears to compound alcohol-induced neuronal
injury and cell membrane dysfunction in the frontal lobes and
midbrain. Taken together, our cross-sectional quantitative volumetric and blood flow studies suggest that chronic excessive
alcohol consumption per se was not associated with significant abnormalities in neocortical gray matter morphology
and perfusion in our alcohol use disorder cohorts; rather the
combination of chronic alcohol misuse and cigarette smoking
resulted in significant volume loss and diminished blood flow
in the neocortical gray matter relative to non-smoking controls. Similarly, our quantitative proton magnetic resonance
spectroscopic imaging results suggest the combination of
chronic excessive alcohol consumption and cigarette smoking
was associated with the greatest abnormalities in markers of
neuronal viability and cell membrane synthesis/turnover. Our
longitudinal findings suggest that chronic smoking in alcohol
use disorders adversely affected recuperation of regional biochemical markers of neuronal viability and cell membrane
synthesis/turnover during short-term abstinence as well as
recovery of brain volume with sustained abstinence from alcohol.
The significant relationships between magnetic resonance
measures and neurocognitive tests from both cross-sectional
and longitudinal MR studies indicate that our magnetic
resonance-derived neurobiological measures are robust predictors of brain function. Consistent with the greater morphologic, metabolic and blood flow abnormalities in the neocortex
and frontal-subcortical circuits we observed in alcohol use disordered smokers versus non-smokers, the smoking treatmentseeking alcoholics cohort demonstrated inferior performance
on measures of auditory-verbal learning and memory, processing speed, cognitive efficiency and static postural stability, and treatment-naı̈ve smoking hazardous drinker exhibited
poorer performance on measures of executive function relative to their non-smoking counterparts. Our neurocognitive
findings are consistent with these of Glass and colleagues
(Glass et al., 2006) who observed that higher smoking and
drinking severity was inversely related to measures of general
intelligence and cognitive efficiency, but only smoking severity individually predicted both general intelligence and cognitive efficiency. Our results are also consistent with Friend
et al. (2005) who reported that the combination of chronic
alcoholism and smoking predicted poorer performance on
measures of set-shifting and processing speed and observed
that non-smoking alcoholics performed superior to smoking alcoholics on tasks measuring set-shifting and processing
speed. Our morphological, metabolite and perfusion studies
along with the neurocognitive finding reported by us and others (i.e. Friend et al., 2005; Glass et al., 2006) suggest that
chronic smoking in alcohol use disorders may further compromise alcohol-induced disturbances in frontal-subcortical neurocircuitry (Sullivan and Pfefferbaum, 2005), thereby modulating relationships between magnetic resonance-derived neurobiological measures and neurocognition.
The brain morphological, metabolite, blood flow and neurocognitive abnormalities observed in our smoking alcoholic
cohorts may be related to chronic exposure to the numerous sources of oxidative stress and other noxious compounds
found in cigarette smoke. Additionally, smoking-induced
deficiencies in cardiovascular, pulmonary or cerebrovascular integrity may contribute to our findings, particularly in
individuals with a longer history of smoking. Although we
attempted to control for factors (e.g. age, drinking severity) that may have influenced our dependent measures, it
is possible that the greater neurobiological and neurocognitive abnormalities demonstrated by our alcoholic smokers
are at least partially related to potential unrecorded differences in nutrition, exercise, overall physical health, exposure
to environmental cigarette smoke or to genetic predispositions/vulnerabilities.
Overall, our studies with treatment-seeking and treatmentnaive cohorts demonstrate converging lines of evidence
that suggest chronic cigarette smoking adversely affects
both brain neurobiology and neurocognition in alcohol use
disorders, thus contributing to the growing body of literature
linking chronic smoking to brain injury and dysfunction.
Examining alcoholics as a homogeneous group, without
CHRONIC SMOKING AND ALCOHOLISM
consideration of smoking status, may obscure the ability
of magnetic resonance-derived neurobiological measures to
serve as useful surrogate markers of brain function as well as
neurocognitive studies to accurately delineate the functional
consequences of alcohol use disorders. As most of our
results were obtained retrospectively, additional prospective
research, with larger groups that include greater numbers of
females, is required to confirm our findings and evaluate
for sex effects, particularly since it is unclear if males and
females manifest the same degree or pattern of alcoholinduced neurobiological and neurocognitive abnormalities
(Mann et al., 1992; Parsons, 1998; Rosenbloom et al., 2004).
If chronic cigarette smoking does indeed modulate brain
neurobiology and neurocognition, it is possible that smoking
and non-smoking alcoholics may differ in the nature or
extent of their response to pharmacological and/or behavioral
interventions designed to promote abstinence from alcohol.
Our findings, in conjunction with the known mortality and
morbidity associated with chronic smoking, lend support
to the growing clinical initiative that encourages chronic
smokers entering treatment for substance use disorders to
participate in a smoking cessation program (see Romberger
and Grant, 2004 for review). At the very least, our preliminary
results suggest that the effects of concurrent chronic cigarette
smoking should be considered in future studies investigating
the consequences of alcohol use disorders on neurobiology
and neurocognition and their recoveries during abstinence, as
well as in research of other neuropsychiatric conditions in
which chronic cigarette smoking is prevalent (e.g. mood and
schizophrenia-spectrum disorders).
Acknowledgements — This research was supported by NIH R01 AA10788
(D.J. Meyerhoff), P01 AA11493 (M.W. Weiner).
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