Psychopharmacological interactions between nicotine and ethanol

Psychopharmacological interactions betweennicotine and ethanol

Jed E. Rose, Lisa H. Brauer, Frederique M. Behm, Matthew Cramblett,Kevin Calkins, Dawn Lawhon

[Received 2 May 2002; accepted 29 October 2002]

Epidemiological, clinical, and laboratory evidence has shown a positive correlation between cigarette smoking andethanol use, and previous studies suggest some commonality in the neural pathways mediating effects of nicotine andethanol. In this study, the subjective and behavioral interactions among nicotine, ethanol, and the nicotinic antagonistmecamylamine were investigated. The main objectives were to determine how the rewarding effects of nicotine mightbe modified by ethanol, and to compare the effects of ethanol with those of a nicotinic antagonist (mecamylamine). Atotal of 48 smokers who regularly consumed alcoholic beverages participated in four laboratory sessions presenting a2 (nicotine vs. denicotinized cigarette smoke)62 (10mg oral mecamylamine hydrochloride vs. placebo)62 (ethanol.5 g/kg vs. placebo) design, with ethanol as a between-subjects factor. Dependent measures included blood alcoholconcentration (BAC), as assessed by breath alcohol detector; subjective drug effects; and rate of ad lib smokingduring a 2-hr period. Results showed that peak BAC averaged .03 g/dl in the ethanol condition. Ethanol potentiatedsome of the subjective rewarding effects of nicotine, including smoking satisfaction, stimulant as well as calmingeffects, and relief of craving for cigarettes. During the ad lib smoking period, mecamylamine decreased satisfactionassociated with the nicotine-containing cigarettes; mecamylamine also induced smoking but only in the placeboethanol condition. These results highlight the potent interaction between ethanol and nicotinic systems, and suggestthat ethanol can potentiate the rewarding effects of nicotine as well as offset some of the effects of a nicotinicantagonist.

Introduction

Alcohol abuse and cigarette smoking are the two

leading causes of preventable morbidity and mortality

in the United States (Bien & Burge, 1990; Centers for

Disease Control and Prevention, 1993). The combined

use of cigarettes and alcohol presents health risks

over and above the risks posed by smoking alone

(Bien & Burge; Sikkink & Fleming, 1992) and thus

constitutes a serious public health problem that

deserves additional research attention. In particular,

the pharmacological basis of the interaction between

alcohol and nicotine needs to be investigated so that

effective pharmacologically based strategies for treat-

ing alcohol and tobacco use can be developed.

Strong epidemiological, clinical, and laboratory evi-

dence indicates a behavioral link between cigarette

smoking and alcohol use. For instance, epidemiolo-

gical studies have consistently shown a high correla-

tion between alcohol consumption and cigarette

smoking (Bien & Burge, 1990; Istvan & Matarazzo,

1984; Zacny, 1990). The prevalence of smoking is

higher in heavy drinkers than in moderate or non-

drinkers, and alcohol consumption is higher in smokers

than in nonsmokers (Rimm, Chan, Stampfer, Colditz,

& Willett, 1995). Moreover, the prevalence of cigarette

smoking in alcoholic patients is approximately 3

times higher than in the general population (Dreher &

Frazer, 1967; Kalman, 1998), and the prevalence of

alcoholism in smokers is 10 times higher than among

nonsmokers (DiFranza & Guerrera, 1990). In a field

study of ad lib smoking, Shiffman et al. (1994)

Jed E. Rose, Ph.D., VA Medical Center and Department of

Psychiatry, Duke University Medical Center, Durham, NC; Lisa H.

Brauer, Ph.D., Department of Psychiatry, University of Minnesota,

Minneapolis, MN; Frederique M. Behm, B.S., Matthew Cramblett,

M.A., Kevin Calkins, M.P.T. and Dawn Lawhon, M.A.,

Department of Psychiatry, Duke University Medical Center,

Durham, NC.

Correspondence: Jed E. Rose, Ph.D., Nicotine Research Program,

Duke University and VA Medical Centers, 2200 W. Main Street, Suite

B-150, Durham, NC 27705, USA. Tel.: z1 (919)-416-1515; Fax: z1

(919)-286-1388; E-mail: [email protected]

Nicotine & Tobacco Research Volume 6, Number 1 (February 2004) 133–144

ISSN 1462-2203 print/ISSN 1469-994X online # 2004 Society for Research on Nicotine and Tobacco

DOI: 10.1080/14622200310001656957

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demonstrated that smoking was almost twice as likely

to occur when normal volunteers were drinking than

when they were not, even when other situational or

contextual variables were taken into account.

Finally, laboratory studies have shown that one of

the most potent pharmacological influences affecting

cigarette smoking is ethanol consumption. A number

of studies have shown that acute ethanol administra-

tion increases ad lib smoking behavior (e.g., Griffiths,

Bigelow, & Liebson, 1976; Henningfield, Chait, &

Griffiths, 1984; Mello, Mendelson, Sellers, & Kuehnle,

1980; Mintz, Boyd, Rose, Charuvastra, & Jarvik,

1985; Mitchell, deWit, & Zacny, 1995); however, the

reasons for this increase are unclear. One factor may

be that the sedative or performance-impairing side-

effects of ethanol are offset by nicotine intake. Several

investigators have reported that cigarette smoking

diminishes the performance decline caused by ethanol

on visual information processing tasks (Michel &

Battig, 1989; Tong, Booker, & Knott, 1978) and on

mental arithmetic and reaction-time performance

(Knott & Venables, 1979). Neurophysiological find-

ings provide potential mechanisms by which nicotine

could reverse sedative effects of ethanol. For example,

ethanol inhibits glutaminergic transmission at NMDA

and kainate receptors as well as activity of voltage-

gated calcium channels (Samson & Harris, 1992). In

contrast, nicotine has been shown to facilitate

glutamate release (McGehee, Heath, Gelber, Devay,

& Role, 1995).

Conversely, another factor accounting for the

behavioral association of ethanol and smoking is

that ethanol might enhance the positive rewarding

effects of nicotine. Both drugs have been shown to

increase neuronal firing rates in ventral tegmental area

dopamine cells and to enhance dopamine release in

the nucleus accumbens, implicated in drug reinforce-

ment (Corrigall, 1995; Reavill, 1990). Thus, an addi-

tive or synergistic enhancement of rewarding effects

may result from concurrent intake of ethanol and

nicotine.

Other findings suggest direct interactions of ethanol

with nicotinic receptors. For example, El-Fakahany,

Miller, Abbassy, Eldefrawi, and Eldefrawi (1983)

reported that cation flux through nicotinic ion

channels was enhanced by ethanol. Other investigators

have reported similar results (Forman & Miller, 1989;

Nagata et al., 1996; Wood, Forman, & Miller, 1991).

However, the action of ethanol on certain subtypes of

nicotinic receptor (e.g., a7) may be to inhibit function

(Yu, Zhang, & Weight, 1995). An antagonistic effect

of ethanol at central nicotinic receptors could help

explain concurrent use of ethanol and tobacco, if

smokers attempt to compensate for the reduction in

nicotine receptor activation by smoking more inten-

sively. Alternatively, a facilitatory action of ethanol at

receptors mediating nicotine reward also could

account for the behavioral association between

ethanol intake and smoking.

The present study was conducted to gain a better

understanding of the acute interactions between

ethanol and nicotine. The first goal was to help

resolve whether ethanol potentiates or antagonizes the

rewarding effects of nicotine inhaled in cigarette

smoke. Subjective and behavioral responses to nico-

tine-containing and denicotinized tobacco cigarettes

were compared between subjects receiving alcoholic

vs. placebo beverages. A second aim was to compare

the acute effects of ethanol to a known nicotinic

receptor antagonist, mecamylamine. Several studies

have shown that mecamylamine attenuates the reward-

ing effects of nicotine and induces increases in ad

lib smoking behavior (Nemeth-Coslett, Henningfield,

O’Keeffe, & Griffiths, 1986; Pomerleau, Pomerleau, &

Majchrzak, 1987; Rose et al., 1994; Rose, Sampson,

Levin, & Henningfield, 1988; Stolerman, Goldfarb,

Fink, & Jarvik, 1973). To the extent that ethanol

antagonizes nicotine effects in a similar fashion to

mecamylamine, an attenuation in rewarding effects

coupled with an increase in smoking might be

expected. By contrast, to the extent that ethanol and

mecamylamine have opposite effects, alcohol should

enhance the rewarding effects of smoking and

decrease smoke intake.

A final aim of the study was to explore whether

mecamylamine might attenuate the rewarding effects

of ethanol. Nicotinic influences on ethanol reward

have been suggested by Blomqvist, Engel, Nissbrandt,

and Soderpalm (1993), who showed that ethanol-

induced dopamine release, presumed to underlie

reinforcement, was blocked by administration of

mecamylamine.Moreover, Blomqvist, Ericson, Johnson,

Engel, and Soderpalm (1996) and Le, Corrigall,

Harding, Juzytsch, and Li (2000) reported that

nicotine administration increased ethanol self-

administration and mecamylamine reduced ethanol

consumption in rats. We predicted that the subjective

rewarding effects of ethanol in human volunteers

might be decreased by mecamylamine administration.

Method

Participants

Participants were recruited by newspaper advertise-

ments (offering US$10/hr for their participation) and

word-of-mouth. To be included in the study, partici-

pants had to be aged 21–55 years, smoke at least 20

cigarettes per day, and have an afternoon expired-air

carbon monoxide (CO) concentration of at least 15

parts per million. Inclusion also depended on self-

reported consumption of at least four alcoholic

beverages per occasion at least once per week. At a

screening physical examination, informed consent was

134 PSYCHOPHARMACOLOGICAL INTERACTIONS

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obtained, a medical history was taken, and blood and

urine samples were collected for complete blood

chemistry and chemical analysis (including pregnancy

testing for women). An electrocardiogram also was

performed. Potential participants were excluded if

they reported a current axis I psychiatric disorder,

according to Diagnostic and Statistical Manual of

Mental Disorders (4th ed.) criteria (American Psychia-

tric Association, 1994), other than nicotine depen-

dence, or current use of antibiotics, sulfonamides,

antihypertensive agents, or psychotropic medications.

Other exclusion criteria were pregnancy, hypertension

(systolic blood pressurew140mmHg, diastolic blood

pressurew90mmHg), hypotension (systolic blood

pressurev90mmHg, diastolic blood pressurev

60mmHg), cardiac or cerebrovascular disease,

impaired renal function, history of seizure or syncope,

glaucoma, urinary retention, and prostatic hypertro-

phy. Participants became familiar with the controlled

smoke delivery apparatus (to be used in subsequent

laboratory sessions) during this screening session by

smoking one cigarette ad lib.

Experimental design

A total of 48 participants came to the laboratory for

four sessions presenting a 2 (nicotine-containing vs.

denicotinized smoke)62 (10mg oral mecamylamine

hydrochloride vs. placebo)62 (ethanol .5 g/kg vs.

placebo) mixed between- and within-subjects design.

The ethanol condition varied between subjects (to

reduce the number of sessions required for each

subject), and the mecamylamine and nicotine condi-

tions varied within subjects. The .5-g/kg dose of

ethanol was chosen because previous studies have

shown it to produce reliable effects on mood and

behavior (e.g., Pohorecky, 1977; Shippenberg &

Altshuler, 1985). Similarly, a dose of 10mg mecamy-

lamine hydrochloride has been shown to produce

robust effects on smoking behavior (Rose et al., 1988).

Sessions were conducted with two to four subjects

(not necessarily the same across sessions) and lasted

from 15.30 hr to 21.00 hr. To provide a recreational

environment, subjects had access to a television and

VCR with videotapes, magazines, a radio, and board

games. Participants were instructed to refrain from

smoking after noon on days when sessions occurred,

and from ingesting ethanol or other drugs (with the

exception of usual caffeine consumption) 24 hr before

the session. Moderate smoking deprivation was

imposed in an attempt to ensure that smoking

would be rewarding within the laboratory context,

and abstinence from alcohol and other drugs was

required to avoid confounding drug effects with the

alcohol manipulation as well as to avoid untoward

drug–drug interactions.

Drug preparation

The ethanol dose was administered (single blind) in

three drinks containing equal portions of ethanol to

total a .5-g/kg dose. The ethanol was mixed with 5 oz.

of orange or cranberry juice (according to each

subject’s preference) in each drink. Placebo beverages

contained 5ml ethanol floated on 5 oz. of juice to

mask taste and smell (Mintz et al., 1985). Mecamy-

lamine and placebo (dextrose) capsules were packaged

for double-blind administration by the Duke Uni-

versity Medical Center Pharmacy.

Methods of controlling nicotine dose administered in

cigarette smoke

Denicotinized cigarettes. Denicotinized tobacco

cigarettes were used to control for the sensory and

motor aspects of cigarette smoking as well as the

amount of tar and CO delivered. We obtained de-

nicotinized cigarettes from two sources. One type

(manufactured by Philip Morris, Inc., Richmond,

Virginia), which we have used in several previous

studies, contained tobacco from which the nicotine

was extracted by supercritical carbon dioxide. These

cigarettes have a taste similar to nicotine-containing

brands of cigarette, and the tar delivery, when

smoked according to U.S. Federal Trade Commis-

sion criteria, is 9mg. However, the nicotine delivery

is extremely low, less than .1mg. Hasenfratz,

Baldinger, & Battig (1993) measured smoking beha-

vior and nicotine intake after smoking in these deni-

cotinized vs. nicotine-containing cigarettes and

found that plasma nicotine levels increased less than

2 ng/ml after the denicotinized cigarette were

smoked. In studies using these cigarettes, we also

have confirmed that they produce virtually no boost

in arterial or venous plasma nicotine levels (Rose,

Behm, Westman, & Coleman, 1999). A second

source of denicotinized cigarettes used was Ultra-

Tech, Inc. (Lafayette Hills, Pennsylvania); the nico-

tine delivery of these cigarettes was .06mg when

smoked according to FTC criteria. The type of deni-

cotinized cigarette used was balanced across ethanol

conditions and was administered single blind, mask-

ing identifying labels on the cigarettes.

Controlled smoke delivery apparatus. Prior to the ad

lib smoking period, a controlled volume of smoke

was delivered using a simple apparatus that has

been validated in previous studies (Levin, Rose, &

Behm, 1989). The device used a glass syringe pre-

loaded with a measured amount of air that was sup-

plied to the burning cigarette with each puff. When

the subject took a puff, the syringe barrel slid

within the glass housing until the specified volume

of air (smoke) was drawn into the mouth, and no

further smoke could be obtained until the device

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was reset for the next puff. To minimize variability

in nicotine absorption arising from variations in

inhalation, subjects were instructed to inhale deeply

and hold their breath for 5 s after each puff.

Gilbert, Jensen, & Meliska (1989) found that this

manipulation was adequate to ensure consistent

boosts in plasma nicotine levels after smoking

nicotine-containing cigarettes. Mean puff volume,

interpuff interval, and number of puffs were indivi-

dualized to each subject based on their ad lib smok-

ing behavior assessed at the screening physical and

were held constant across sessions.

Procedure

Participants arrived at the laboratory at approxi-

mately 15.30 hr, and provided a breath sample that

was analyzed for blood alcohol concentration (BAC)

to ensure they were ethanol free. Baseline measures,

both physiological and subjective effects (see discus-

sion of dependent measures, below), were taken, and

participants then swallowed a capsule containing

either mecamylamine or placebo. A light meal was

served with decaffeinated beverages. Two hours after

administration of mecamylamine, ethanol administra-

tion began. Participants consumed three beverages

evenly spaced over approximately 40min. They were

required to finish each drink within 5min.

Approximately 30min after completion of the last

drink, participants then smoked one cigarette through

the controlled smoke delivery apparatus, inhaling the

same number of puffs and mean puff volume they

inhaled when smoking ad lib through the apparatus at

the screening physical visit. After controlled smoking,

an ad lib smoking period of 2 hr began. Participants

smoked as many cigarettes as they desired of the type

provided (preferred brand vs. denicotinized cigarettes).

Cigarettes smoked during the ad lib period were the

same type as the cigarette used to administer the

controlled smoke dose.

At the end of the ad lib smoking period, a blood

sample (20ml) was drawn from a vein in each

subject’s arm for analysis of nicotine, cotinine, and

mecamylamine. Participants were then transported

home when their BAC was less than .05 g/dl.

Dependent measures: Physiological measures

Cardiovascular measures. Heart rate and systolic

and diastolic blood pressures were measured using

an automatic sphygmomanometer (Model HEM-707;

Omron Healthcare, Vernon Hills, Illinois). Measures

were taken at baseline, before participants consumed

each ethanol beverage (120, 140, and 160min after

mecamylamine administration), and before and after

controlled smoking (200 and 215min). Measures

were taken both sitting (at least 3min) and after

standing 1min to assess orthostatic hypotension,

which is a potential side-effect of mecamylamine

(Armstrong et al., 1960).

Blood alcohol concentration. BAC was measured

using an Alco-Sensor IV machine (Intoximeter, Inc.,

St., Louis, Missouri). Participants were instructed to

inhale deeply and then exhale into the mouthpiece

until the required volume of air was expired. BAC

measures were taken at baseline; 15min after each

beverage was consumed (140, 160, and 180min);

and at the beginning, midpoint, and end of the ad

lib smoking period. At least 10min separated BAC

measures from cigarette smoking.

Expired-air carbon monoxide. Expired-air CO con-

centrations were measured by Breath CO Analyzer

(Vitalograph, Lenexa, Kansas). Participants were

instructed to inhale deeply and hold the breath for

15 s, timed by the technician. The participant then

exhaled all available air through the mouthpiece in

a steady stream. CO measures were taken at base-

line, before participants consumed each ethanol

beverage, before and after controlled smoking, and

at the end of the experimental session. The last mea-

surement served as an assessment of ad lib smoke

intake.

Dependent measures: Subjective effects

Smoking withdrawal symptoms. An abbreviated

version of a withdrawal questionnaire based on

Shiffman and Jarvik (1976) was used. The items com-

prised four subscales: Craving (craved a cigarette,

missed a cigarette, had urges to smoke), negative

affect (tense; irritable; and, scored oppositely, calm),

arousal (wide awake, able to concentrate), and appe-

tite (feel hungry). Participants completed this form

at baseline, midmeal (60min), before and after con-

trolled smoking, and before and after each cigarette

smoked during the ad lib smoking period.

Cigarette evaluation questionnaire. This question-

naire was administered immediately after the con-

trolled smoke presentation, to measure the subjective

rewarding and aversive effects of smoking. Items

assessed satisfaction (How satisfying were the puffs

you just took?), liking (How much did you like the

puffs you just took?), stimulating effects (Did it

make you feel more awake?, Did it reduce your

hunger for food?), calming effects (Did it calm you

down?, Did it help you concentrate?, Did it make

you feel less irritable?), nausea/dizziness (Did it

make you feel nauseated?, Did it make you dizzy?),

craving relief (Did it immediately reduce your crav-

ing for cigarettes?), enjoyment of airway sensations


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(Did you enjoy the sensations of the smoke in your

throat and chest?), estimated nicotine delivery (How

high in nicotine do you think the puffs were?), simi-

larity to usual brand (How similar to your own

brand were the puffs?), and strength (on the tongue,

in the nose, back of mouth and throat, windpipe

and chest).

After each ad lib cigarette, an abbreviated form of

this questionnaire was administered, which contained

all of the above items with the exception of estimated

nicotine delivery and similarity and strength in the

different respiratory regions.

Subjective mood. An abbreviated version of the

Profile of Mood States (POMS; McNair, Lorr, &

Droppleman, 1971) was used. This version of the

POMS included selected items with the highest

factor loadings on the anger (furious, angry), anxi-

ety (tense, nervous), confusion (forgetful, unable to

concentrate), depression (gloomy, sad), elation

(serene, elated), fatigue (exhausted, fatigued), friend-

liness (good natured, friendly), and vigor (energetic,

lively) scales. The questionnaire was administered at

baseline, midmeal, before ethanol consumption, after

the second and third beverages, before controlled

smoking, and before ad lib smoking.

Ethanol effect rating. Two scales were used to mea-

sure the effects of ethanol. The Sensation Scale

(Maisto, Connors, Tucker, McCollam, & Adesso,

1980) assessed alcohol-related sensations using 10-

point rating scales. The following scales have been

empirically derived: Central stimulant, impaired

function, dynamic peripheral, warmth/glow, gastroin-

testinal, and anesthetic. An additional questionnaire

was used to assess subjective effects of ethanol,

including feel effects, like effects, drunk, high, stimu-

lated, and sedated. Items were rated on seven-point

scales. These questionnaires were administered after

each ethanol beverage was consumed, before con-

trolled smoking, and before ad lib smoking.

Cognitive and psychomotor performance. Cognitive

and psychomotor performance were measured using

four tests of the Automated Neuropsychological

Assessment Metrics (ANAM) test battery (Reeves,

Bleiberg, & Spector, 1993): (a) Simple reaction time

(pressing a key as soon as possible after the appear-

ance of a snowflake design on the computer moni-

tor), (b) complex reaction time (spatial rotation),

determining as quickly as possible whether a four-

bar histogram pattern is the same as another pattern

rotated by 90 or 270 degrees, (c) delayed matching

to sample (subjects were shown a 464 matrix of

light and dark squares, then shown two patterns

and asked to identify the one they had just seen),

and (d) finger tapping (depressing the space bar of a

keyboard repeatedly as fast as possible, using the

index finger of the dominant hand, for three 10-s

trials, separated by 15-s rests). The ANAM battery

was administered before ethanol consumption, before

controlled smoking (also after ethanol consumption),

and after controlled smoking.

Smoking behavior. In addition to measuring expired-

air CO concentrations, study technicians counted the

number of cigarettes consumed during the ad lib

smoking period.

Nicotine and mecamylamine assays. To assess poten-

tial pharmacokinetic interactions between ethanol and

mecamylamine, samples of venous blood (10 cm3)

were collected at the end of each session. These

plasma samples were assayed for mecamylamine

by the Clinical Pharmacology Laboratory at the

University of California, San Francisco. Although a

single sampling point does not fully address poten-

tial pharmacokinetic interactions, we were able to

verify that the final drug concentrations achieved in

alcohol and placebo beverage conditions were com-

parable. Nicotine and cotinine also were analyzed in

these samples to provide an index of nicotine intake

from ad lib smoking.

Data analysis

To examine potential interactions among nicotine,

mecamylamine, and ethanol, we analyzed all depen-

dent variables measures using a multivariate approach

to repeated-measures analysis of variance (ANOVA;

Abacus Concepts, 1989). Denicotinized vs. nicotine-

containing cigarettes, mecamylamine vs. placebo, and

ethanol vs. placebo were independent variables. The

alpha criterion was .05. For the sake of brevity, if a

main effect or an interaction did not reach significance

or show a strong trend, it is not mentioned.

Statistically significant interactions were followed up

by an analysis of simple effects of one factor at each

level of the other factors. Because of an unbalanced

distribution of men and women in the two ethanol

conditions, analyses that showed significant effects

of ethanol were repeated with sex included as a

covariate. This approach did not affect the outcomes

derived from the initial analyses.

We analyzed cigarette evaluations after the con-

trolled smoke delivery separately from those during

the ad lib smoking period. For the latter, we analyzed

the mean of the ratings of each dependent measure,

averaged across all ad lib cigarettes in a given session,

because no significant differences were observed

across successive cigarettes. Similarly, we averaged

withdrawal symptom ratings after each ad lib cigar-

ette, because they did not show trends over time.


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Moreover, because of the potential influence of the

amount smoked in the various conditions, we included

as a covariate the change in CO during the ad lib

smoking period. However, this approach did not

affect the results of the analyses presented below.

Results

Subjects

A total of 48 participants (20 males and 28 females)

with a mean age of 32.9 years (SD~9.2) completed

this study. Table 1 displays the characteristics of the

subject sample, including age, sex, and information

about cigarette smoking and habitual alcohol intake.

No significant differences were observed between

subjects in the ethanol and placebo conditions in

any of these variables (all p valuesw.1), with the

exception of sex. Despite the randomized assignment

to conditions, the no-ethanol condition contained a

higher proportion of males.

Effects of ethanol on the rewarding properties of

nicotine

Two sets of dependent measures—cigarette evaluation

and withdrawal symptoms—were critical in evaluating

the hypothesis that ethanol might enhance the

rewarding effects of nicotine in cigarette smoke.

Indeed, the results showed that ethanol potentiated

some of the actions of nicotine. Table 2 gives the

means for all subjective measures.

Cigarette evaluation. Nicotine delivery had a pro-

found influence on ratings of the rewarding

Table 1. Characteristics of study participants.

Characteristic

Alcohol (n~24) No alcohol (n~24)

Mean SD Mean SD

Age (years) 32.2 8.86 33.5 9.70Gender 6 male, 18 female – 14 male, 10 female –Cigarettes/day 20.6 9.49 24.3 9.27FTC nicotine (mg) .88 .303 .96 .382Years smoked 14.7 9.55 17.0 9.17Screening carbon monoxide level (ppm) 26.5 10.18 26.4 11.45FTND score 5.3 1.97 6.0 2.11Drinks/week 11.21 9.05 12.04 7.56

FTC, Federal Trade Commission; FTND, Fagerstom Test for Nicotine Dependence.

Table 2. Mean subjective ratings across conditions.

Rated item

Alcohol No alcohol

Mecamylamine Placebo Mecamylamine Placebo

Nic Denic Nic Denic Nic Denic Nic Denic

Controlled smokeSatisfaction 4.5 3.1 4.9 3.1 4.3 3.6 4.3 3.7Calming effect 3.3 2.8 4.0 2.4 2.9 2.3 3.0 2.5Stimulating effect 3.4 2.7 3.5 2.7 2.8 2.6 2.9 2.4Nausea/dizziness 1.6 1.6 2.4 1.3 1.5 1.6 1.7 1.4Enjoyment of airway sensations 3.0 3.7 3.2 3.2 4.1 4.1 3.8 4.3Craving relief 3.8 4.3 4.5 4.9 4.1 4.3 4.2 4.6Liking 4.7 3.3 5.0 3.1 4.5 3.4 4.6 3.8Estimated nicotine delivery 4.0 3.2 4.7 3.2 4.3 3.0 4.3 3.3Similarity 4.4 2.8 5.3 2.8 4.3 2.6 4.6 2.5Mean strength rating 3.9 3.1 3.8 2.9 3.9 3.2 4.0 3.5

Ad lib cigarettesSatisfaction 4.4 3.1 5.0 3.2 4.6 3.3 5.0 3.7Calming effect 3.1 2.4 3.0 2.2 2.4 1.9 2.3 2.1Stimulating effect 3.1 2.5 3.0 2.5 2.3 1.9 2.4 2.0Nausea/dizziness 1.3 1.3 1.4 1.3 1.3 1.3 1.2 1.3Enjoyment of airway sensations 3.3 2.7 3.7 2.5 3.8 3.0 4.2 3.3Craving relief 4.3 3.1 4.6 3.4 3.9 3.1 4.2 3.5

Withdrawal symptomsCraving 4.0 5.1 3.0 4.8 3.8 4.8 3.8 4.9Negative affect 2.6 2.8 2.1 2.6 2.1 2.5 2.2 2.5Arousal 4.0 3.6 4.4 3.8 4.5 3.9 4.4 4.3Appetite 1.4 1.6 1.5 1.6 1.4 1.4 1.5 1.5

Denic, denicotinized condition; Nic, nicotine condition.


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properties of the cigarettes smoked during controlled

presentations and during the ad lib smoking period.

The nicotine-containing cigarettes were rated signifi-

cantly higher than the denicotinized cigarettes in

terms of satisfaction, liking, enjoyment of respira-

tory tract sensations, reduction in craving, estimated

nicotine delivery, similarity to usual brand, and

strength in all regions of the respiratory tract (all F

valuesw10.00, p valuesv.003). A significant differ-

ence was observed between nicotine and denicoti-

nized cigarettes on stimulating and calming effects

during the ad lib smoking period, F(1, 46)~37.67,

F(1, 46)~33.68, p valuesv.0001.

Ethanol also influenced ratings of the rewarding

properties of cigarettes smoked. Ratings of satisfac-

tion after the presentation of the controlled dose of

smoke showed a significant nicotine by ethanol inter-

action, F(1, 46)~4.33, p~.04. As shown in Figure 1,

ethanol increased the difference in satisfaction

between nicotine and denicotinized cigarettes (irre-

spective of mecamylamine condition). This effect

appeared to be related both to an enhancement in

the satisfaction associated with the nicotine cigarettes

and to a decrease in satisfaction of the denicotinized

cigarettes, although the simple effects of ethanol in the

two cigarette conditions did not reach significance.

Liking ratings for the controlled smoke dose showed a

similar trend for alcohol to increase the discrimin-

ability of nicotine-containing and denicotinized cigar-

ettes: Ethanol by nicotine interaction, F(1, 46)~3.54,

p~.07. Because of concern that interactions between

cigarette type and alcohol might have been related in

part to the novelty of the denicotinized cigarettes, the

analyses of liking and satisfaction also were conducted

using rated similarity to the usual brand as a

covariate. The interaction of ethanol and nicotine

remained significant (p~.009 for both liking and

satisfaction).

After the controlled smoking, ratings of the calming

effect of smoking showed a trend for an interaction

of ethanol by nicotine by mecamylamine, F(1, 46)~

4.69, p~.07. Analyzing mecamylamine and no-

mecamylamine conditions separately, we found a

significant interaction of ethanol by nicotine in the

no-mecamylamine conditions, F(1, 46)~5.39, p~.02.

When broken into simple effects, a significant

enhancement was observed in the calming effect of

nicotine-containing cigarettes in the ethanol condition,

F(1, 46)~4.44, p~.04. During the ad lib smoking

period, mean ratings of the calming effects (including

both mecamylamine and no-mecamylamine condi-

tions) also showed an interaction of ethanol and

nicotine, F(1, 46)~4.36, p~.04; again, an analysis of

simple effects showed a specific potentiation by

ethanol of the calming effects of the nicotine-contain-

ing cigarettes, F(1, 46)~4.56, p~.04. Mean ratings of

the stimulating effects of smoking during the ad lib

smoking period also were enhanced by ethanol, but

this result was related to a main effect of ethanol, F(1,

46)~5.71, p~.02, for both types of cigarette.

Withdrawal symptoms. Alcohol potentiated the

effects of nicotine on certain withdrawal symptom

ratings (based on the mean of all postcigarette

assessments during the ad lib smoking period).

Craving for cigarettes showed a significant reduction

in the nicotine conditions relative to the denicoti-

nized cigarette conditions, F(1, 44)~46.03, p~.0001,

for the main effect of nicotine; and a mecamylamine

by ethanol interaction was observed, F(1, 44)~9.88,

p~.003. An analysis of simple effects showed that

in the no-mecamylamine conditions, ethanol enhanced

the reduction in craving associated with nicotine-

containing cigarettes, F(1, 45)~4.32, p~.04, for the

effect of ethanol in the nicotine cigarette condition;

F(1, 45)~.01, p~.9 in the denicotinized cigarette

condition, as shown in Figure 2. Mecamylamine

increased craving significantly only in the nicotine/

ethanol condition, F(1, 23)~17.23, p~.0004,

although a similar trend was observed in the denico-

tinized cigarette/ethanol condition, F(1, 23)~3.06,

p~.09.

Figure 1. Mean (¡SEM) ratings of smoking satisfac-tion following controlled presentations of cigarettesmoke, averaged across mecamylamine and no-mecamylamine conditions.

Figure 2. Mean (¡SEM) ratings of cigarette cravingand arousal during the ad lib smoking period.


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The stimulant effect of nicotine, as assessed by

ratings on the arousal scale of the withdrawal

questionnaire, also showed some evidence of potentia-

tion by ethanol. The overall analysis showed a trend

for a three-way interaction, F(1, 44)~2.85, p~.10;

when examined separately in mecamylamine and no-

mecamylamine conditions, an ethanol by nicotine

interaction was observed in the no-mecamylamine

conditions, F(1, 44)~3.74, p~.06. Further analysis of

simple effects in the no-mecamylamine conditions

showed that nicotine specifically increased arousal

(offset sedation) in the ethanol condition, F(1, 23)~

10.79, p~.003. Consistent with this finding, a trend

was observed in which ethanol reduced arousal only in

the denicotinized cigarette condition, F(1, 45)~2.94,

p~.09, for the effect of ethanol.

Nicotine’s influence on negative affect ratings was

not potentiated by ethanol. However, negative affect

did show a significant nicotine by mecamylamine by

ethanol interaction, F(1, 44)~4.29, p~.04. This

finding reflected the fact that ethanol increased

negative affect in the one condition in which nicotine

and mecamylamine were coadministered, F(1, 45)~

7.66, p~.008, as shown in Figure 3. Nicotine reduced

negative affect only in the ethanol/no-mecamylamine

condition, F(1, 23)~11.12, p~.003, and in the two

no-ethanol conditions, F(1, 22)~9.24, p~.006, and

F(1, 22)~2.78, p~.11, for the simple effect of nicotine

in these conditions.

Effects of mecamylamine

To address the second main aim of the study, we

analyzed the effects of mecamylamine on smoking

behavior and subjective ratings and found them to be

quite different from the pattern just described for

ethanol. Mecamylamine significantly decreased ratings

of smoking satisfaction (mean of ad lib cigarettes) for

the nicotine-containing cigarettes relative to the

denicotinized cigarettes, F(1, 46)~4.38, p~.04, for

the mecamylamine by nicotine interaction, and also

decreased enjoyment of respiratory tract sensations,

F(1, 46)~5.41, p~.02, for the mecamylamine by

nicotine interaction. An analysis of the simple effects

of mecamylamine showed that for satisfaction the

attenuation was more pronounced for the nicotine-

containing cigarettes. In the nicotine cigarette condi-

tion the mean rating was 4.5 (SD~1.14) with

mecamylamine vs. 5.0 (SD~1.02) without mecamyla-

mine, F(1, 47)~20.11, p~.0001; in the denicotinized

cigarette condition, the mean rating was 3.2 (SD~

1.37) vs. 3.5 (SD~1.29), F(1, 47)~4.35, p~.04.

Mecamylamine also specifically attenuated the enjoy-

ment of respiratory sensations of the nicotine-

containing cigarette: Mean rating of 3.5 (SD~1.72)

vs. 4.0 (SD~1.65), F(1, 47)~9.74, p~.003, for the

effect of mecamylamine. In the denicotinized cigarette

condition, the mean rating was 2.8 (SD~1.55) with

mecamylamine vs. 2.9 (SD~1.64), F(1, 47)~.18,

p~.7. A significant main effect was observed for

mecamylamine in attenuating the craving reduction

obtained from smoking, which held for both types

of cigarette: Mean rating of 3.6 (SD~1.41) vs. 3.9

(SD~1.44), F(1, 47)~9.28, p~.004.

Another comparison of the behavioral effects of

ethanol and mecamylamine was afforded by the

measures of ad lib smoking, which showed mecamy-

lamine and ethanol to have quite distinct influences.

The boost in expired-air CO during the ad lib smoking

period showed a significant nicotine by mecamylamine

by ethanol interaction, F(1, 36)~4.92, p~.03, as

shown in Figure 4. In the no-ethanol condition,

mecamylamine induced a substantial increase in

smoke intake for the nicotine-containing cigarettes,

F(1, 19)~9.88, p~.006, for the simple effect of

mecamylamine. In contrast, no effect of mecamyla-

mine was observed in the ethanol condition; ethanol

tended to reduce the ad lib CO boost in the nicotine

cigarette/mecamylamine condition, F(1, 36)~3.28,

p~.08, for the simple effect of ethanol. The number

of cigarettes smoked followed the same pattern, with a

trend for the three-way interaction, F(1, 46)~2.57,

p~.1. In the no-ethanol condition, mecamylamine

increased the number of nicotine cigarettes smoked,

F(1, 23)~7.87, p~.01; as with CO a trend was

observed in which ethanol offset the increase in

smoking in the nicotine cigarette/mecamylamine

condition, F(1, 46)~3.17, p~.08, for the effect of

ethanol. Plasma nicotine and cotinine levels did not

show significant effects of ethanol or mecamylamine.

However, with plasma cotinine, as with expired-air

CO, ethanol appeared to attenuate the increase in

nicotine intake in response to mecamylamine. Among

subjects who showed mecamylamine-induced smoking

of the nicotine cigarettes, as reflected by cotinine levels

being higher in the mecamylamine than no-mecamy-

lamine condition, ethanol significantly decreased this

response, F(1, 41)~4.04, p~.05, for the simple effect

of ethanol.Figure 3. Mean (¡SEM) ratings of negative affectduring the ad lib smoking period.


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Mecamylamine effects on alcohol reward

To address the third major aim of the study, we

examined possible effects of mecamylamine on the

rewarding properties of ethanol, based on an analysis

of the ethanol sensation scale. The warmth/glow scale

showed a strong effect of ethanol: F(4, 180)~4.61,

p~.001, for the ethanol by time interaction; F(1,

45)~8.70, p~.005, at the end of the drinking period.

The mean ratings were 5.1 (SD~4.75) for ethanol vs.

2.0 (SD~3.30) for the no-ethanol condition. Anes-

thetic effect also showed an ethanol by time interac-

tion, F(4, 180)~2.53, p~.04, with a trend for an effect

at the end of the drinking period, F(1, 45)~2,61,

p~.11. Mean ratings were 14.0 (SD~11.54) for

ethanol and 9.2 (SD~10.0) for the no-ethanol

condition. None of these effects was significantly

altered by mecamylamine. The changes in mood from

baseline to the end of the drinking period were

analyzed as additional potential measures of response

to ethanol, but none showed significant effects.

Three dependent measures—blood ethanol levels,

mecamylamine concentrations, and results from the

cognitive performance battery—were taken primarily

to objectively quantify the potency of the pharmaco-

logical manipulations at the doses administered.

Blood alcohol concentrations. Figure 5 depicts the

BAC results for the different conditions. BAC was

similar across conditions, although slight differences

were observed in the time course, which were

reflected in a nicotine by time interaction, F(4,

64)~3.20, p~.02. However, including BAC as a

covariate did not change the outcome of the ana-

lyses reported above.

Plasma mecamylamine levels. End-of-session plasma

mecamylamine levels in the active mecamylamine

conditions did not differ significantly across ethanol

and no-ethanol groups, or between nicotine and

denicotinized cigarette conditions. For the active

mecamylamine conditions, the mean plasma meca-

mylamine levels were as follows: 21.2 ng/ml (SD~

8.44) for the ethanol/nicotine session, 21.6 ng/ml

(SD~6.67) for the no-ethanol/nicotine session,

19.0 ng/ml (SD~5.76) for the ethanol/denicotinized

cigarette session, 20.5 ng/ml (SD~4.06) for the no-

ethanol/denicotinized cigarette session, and below detec-

table limits in the placebo mecamylamine conditions.

Cognitive/psychomotor performance measures. Com-

plex reaction time on the spatial rotation task

showed a facilitation by nicotine after the controlled

dose of cigarette smoke. Nicotine significantly

increased spatial processing speed: Mean reaction

time of 1.64 s (SD~.489) for the nicotine condition

and 1.72 s (SD~.636) for the no-nicotine condition,

F(1, 45)~5.30, p~.03. Neither ethanol nor mecamy-

lamine had significant effects on performance, and

accuracy was not significantly affected by any of the

drugs.

Discussion

One main finding of the present study was that

ethanol potentiated many of the subjective rewarding

Figure 5. Mean (¡SEM) blood alcohol concentrationsas a function of time in the different experimental con-ditions. Points after drinks 1, 2, and 3 are labeledDR1, DR2, and DR3.

Figure 4. Mean (¡SEM) number of cigarettessmoked (A) and expired-air carbon monoxide (B) boostfor the ad lib smoking period.


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effects of nicotine, including satisfaction, liking, and

calming effects (cigarette evaluation scale measures).

These results are consistent with Glautier, Clements,

White, Taylor, and Stolerman (1996), who reported

that ethanol increased smoking satisfaction. However,

the latter study did not include denicotinized cigar-

ettes; thus, the specific interaction of ethanol and

nicotine could not be assessed. In our study,

significantly greater differences in ratings between

the nicotine-containing and denicotinized cigarettes

were observed after ethanol consumption relative to

the placebo beverage condition. In addition, nicotine

tended to reverse the subjective sedative effects of

ethanol (shown by the effect of nicotine to increase

ratings of subjective arousal in the ethanol/no-

mecamylamine condition, as shown in Figure 2). The

fact that the dose of ethanol used in the study was

relatively low and did not impair cognitive/psycho-

motor functioning, with BAC well within the range to

which social drinkers are exposed, highlights the

relevance of these findings to naturalistic environ-

ments. Thus, the potentiation of nicotine reward is

suggested as a possible explanation for the widely

observed behavioral association between consumption

of alcoholic beverages and cigarette smoking.

Because of the rapidity of ethanol presentation used

in this study and the fact that BAC was decreasing

over most of the ad lib smoking period (Figure 5), the

interactions we note may be limited to situations in

which BAC is steady or declining. Additional research

will be necessary to clarify the role of ascending or

descending BAC in terms of interactions with nicotine.

A second result of the present study related to the

comparison of alcohol and mecamylamine. Overall,

the effects of mecamylamine tended to be opposite to

those of alcohol; whereas alcohol increased smoking

satisfaction, mecamylamine attenuated it, although

mecamylamine did not consistently affect other with-

drawal symptom ratings (Eissenberg, Griffiths, &

Stitzer, 1996; Nemeth-Coslett et al., 1986). Moreover,

mecamylamine induced additional smoking, which

was offset by alcohol. These results argue against an

interpretation of alcohol’s effects on smoking beha-

vior being related to nicotinic antagonism. This

argument must be tempered, however, by the fact

that alcohol on its own did not increase smoking

behavior in the present study; thus, we cannot rule out

the possibility that in other situations (and possibly

with other doses of alcohol) in which alcohol does

facilitate smoking, nicotinic antagonist effects might

be involved. Potentiation by alcohol of the rewarding

effects of nicotine could be predicted either to decrease

or increase ad lib smoking, depending on whether

smokers are seeking to maintain a constant level of

nicotine effect or whether attaining nicotine reward

stimulates seeking additional reward (i.e., priming).

Deprivation level and tolerance to nicotine also might

affect the direction or magnitude of the influence of

alcohol on ad lib smoke intake.

Ad lib smoking behavior showed an interesting

interaction among ethanol, nicotine, and mecamyla-

mine, in that ethanol reduced the degree to which

mecamylamine induced smoking of the nicotine-

containing cigarettes. Increased smoking after meca-

mylamine administration is a robust effect that has

been reported in several studies and was replicated in

the placebo beverage condition of the present study.

Possibly the attenuation of mecamylamine-induced

smoking in the ethanol condition resulted from

potentiation of some of the rewarding effects of

nicotine by ethanol. That is, if mecamylamine reduces

reward and alcohol increases it, the two influences

might be expected to cancel. The nicotine component

of smoking satisfaction (based on the comparison of

nicotine and denicotinized cigarettes) was indeed

increased by ethanol. Therefore, although subjects in

the mecamylamine/no-ethanol condition increased

their smoke intake, possibly in an attempt to maintain

a certain degree of nicotine effect, subjects in the

ethanol condition may not have needed to increase

smoking to obtain that same effect. Similarly, the

action of nicotine to reduce craving for cigarettes was

potentiated by ethanol (Figure 2), so that craving was

significantly lower in the ethanol condition when

subjects smoked nicotine-containing cigarettes. Thus,

even though mecamylamine increased craving in the

ethanol condition (when subjects smoked nicotine-

containing cigarettes), craving was not high. In fact,

craving was similar to that in the no-ethanol/

no-mecamylamine condition. Therefore, in the etha-

nol/mecamylamine condition, participants would have

had little motivation to engage in compensatory

smoking. In contrast, the additional smoking observed

in the mecamylamine/no-ethanol condition may have

been necessary to restore craving to a low level.

The interpretation just outlined is in accord with

recent neurophysiological data showing that ethanol

potentiates the action of nicotine and acetylcholine at

some subtypes of nicotinic receptors (Nagata et al.,

1996). However, other possible explanations for

ethanol offsetting smoking induced by mecamylamine

should be acknowledged. One alternative interpreta-

tion is that ethanol might have acted through

nonnicotinic mechanisms to substitute for some of

the psychological effects sought from smoking (e.g.,

relaxation), thus decreasing the motivation to com-

pensate for a reduced nicotine effect.

A third potential explanation for the interactive

effects on ad lib smoking is that ethanol, through its

sedative actions, may have reduced the importance of

reinforcing activities or interfered nonspecifically with

the willingness of subjects to expend effort to com-

pensate. However, the absence of cognitive perfor-

mance decrements after ethanol, and the selective


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increase in the rewarding effects of nicotine-containing

cigarettes, suggests a specificity of action as opposed

to a general influence of ethanol on motivation.

The final question addressed was whether mecamy-

lamine would block the rewarding mood effects of

ethanol, as had been predicted based on animal

studies showing that mecamylamine blocks dopamine

release elicited by ethanol and reduces ethanol self-

administration (Blomqvist et al., 1993, 1996; Le et al.,

2000). We did not find support for this prediction;

however, the relatively low dose of ethanol used in our

study did not reliably elicit euphoria, and thus the

ability of mecamylamine to block that effect of

ethanol could not be assessed. Future studies, perhaps

administering higher doses of ethanol (Holdstock,

King, & de Wit, 2000), will be needed to more fully

evaluate the potential usefulness of nicotinic antago-

nists in blocking ethanol reward.

The subjective and behavioral interactions between

ethanol and smoking observed in this laboratory study

also may have clinical implications for smoking

cessation treatment. For example, recognition of the

effects of ethanol on nicotine reward may lead to a

better understanding of the mechanisms linking

ethanol consumption with relapse to smoking (Shiff-

man, 1982). In addition, if the mechanisms by which

ethanol potentiates nicotine’s effects were understood,

perhaps treatments could be designed to potentiate the

efficacy of nicotine replacement techniques used in

smoking cessation treatment.

Acknowledgments

This study was supported by grant 5 RO1 AA 11128-03 from the

National Institute on Alcohol Abuse and Alcoholism. The study was

reviewed and approved by the Duke University Medical Center

Institutional Review Board.

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Psychopharmacological interactions between nicotine and ethanol

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