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ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH

Vol. 28, No. 7


July 2004

Alcohol Effects During Acamprosate Treatment:


A Dose-Response Study in Humans
Susan M. Brasser, Mary E. McCaul, and Elisabeth J. Houtsmuller

Background: Acamprosate (calcium acetyl homotaurinate) reduces alcohol intake in animals and increases abstinence rates in alcohol-dependent persons. Acamprosates mechanism of action, however,
remains poorly understood. In order to examine whether acamprosate/alcohol interactions contribute to
acamprosates efficacy, the present double-blind, placebo-controlled human laboratory study examined
effects of acamprosate on the pharmacokinetics and subjective, psychomotor, and physiological effects of
alcohol in heavy drinkers.
Methods: In a six-week within-subject design, participants were maintained on acamprosate (0, 2, and
4 g, p.o., double-blind, in counterbalanced order) for 11 days at each dose. Physiological, subjective, and
psychomotor measures were collected daily during each dosing cycle. During each acamprosate dose
condition, subjects were challenged with 0, 0.5, and 1.0 g/kg ethanol (p.o., counterbalanced order) during
three separate laboratory sessions. Subjective, physiological, and psychomotor effects of alcohol, and
breath alcohol levels were collected at baseline and at 30-min intervals for a 3-hr post-administration
period.
Results: Acamprosate alone did not substantially affect subjective, physiological, or psychomotor performance measures. Acamprosate did not alter alcohol pharmacokinetics, or alcohol-induced behavioral
impairment or tachycardia, and most subjective alcohol effects were also unaltered by acamprosate as well.
Although a trend appeared for acamprosate to increase subjective ratings of intoxication following the
lower (0.5 g/kg) alcohol dose, adjustment for individual differences in blood alcohol level eliminated this
effect, suggesting the trend was not due to a central effect of acamprosate.
Conclusions: Acamprosate does not alter alcohol pharmacokinetics, acute physiological or psychomotor
alcohol effects, or most subjective alcohol effects.
Key Words: Acamprosate, Alcohol, Ethanol, Pharmacokinetics, Human.

CAMPROSATE (CALCIUM ACETYL homotaurinate) has been shown to reduce alcohol consumption
in both preclinical and clinical studies. Preclinical studies in
rodents have established that acamprosate decreases voluntary alcohol intake and preference for alcohol over water
(Boismare et al., 1984; Czachowski et al., 2001; Gewiss et
al., 1991; Heyser et al., 1998; Holter et al., 1997; LeMagnen
et al., 1987b; Olive et al., 2002; Spanagel et al., 1996a).
Several randomized double-blind placebo-controlled clinical trials in detoxified alcoholics have shown that acamprosate increases days to first relapse, cumulative duration of
abstinence, and total abstinence rates (Lhuintre et al., 1985,
1990; Paille et al., 1995; Pelc et al., 1997; Sass et al., 1996;
Whitworth et al., 1996; for review, see Mason, 2001). Since
From the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Received for publication August 26, 2003; accepted March 31, 2004.
Supported by NIAAA Grant R01 AA12394 (EJH).
Reprint requests: Elisabeth J. Houtsmuller, PhD, Johns Hopkins University
School of Medicine, Behavioral Biology Research Center, 5510 Nathan Shock
Drive, Baltimore, MD 21224-6823; Fax: 410-550-0030; E-mail: ehoutsm@
jhmi.edu.
Copyright 2004 by the Research Society on Alcoholism.
DOI: 10.1097/01.ALC.0000130802.07692.29
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the drugs initial approval in France in 1989, acamprosate


has been used to treat more than a million alcoholdependent patients in Europe and other countries, and the
compound is currently under review by the US Food and
Drug Administration for the same indication.
Despite acamprosates established efficacy in the treatment of alcoholism, its mechanism of action remains to be
elucidated. Pharmacological treatments of alcoholism
might increase abstinence by modifying alcohols effects, by
reducing craving, or by some other less direct mechanism.
Pharmacologically, there is evidence that acamprosate may
act by modulating N-methyl-D-aspartate (NMDA) glutamate receptor function. In neurophysiological studies, the
drug has been shown to produce both inhibitory (Zeise et
al., 1993) and excitatory (Berton et al., 1998; Madamba et
al., 1996) effects at this receptor. Recent data suggest that
acamprosate may interact with a polyamine site on the
NMDA receptor complex and differentially modulate the
activity of the receptor on the basis of existing polyamine
levels (al Qatari et al., 1998; Naassila et al., 1998; Popp and
Lovinger, 2000). Acamprosate seems to antagonize or inhibit NMDA receptor activity under conditions of high
polyamine concentrations (high receptor activation) or alcohol dependence (al Qatari et al., 1998; Naassila et al.,
Alcohol Clin Exp Res, Vol 28, No 7, 2004: pp 10741083

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ACAMPROSATE EFFECTS ON ALCOHOL RESPONSES

1998). This property of the drug is consistent with evidence


that acamprosate may reduce neuronal hyperexcitability at
this receptor during alcohol withdrawal in both in vitro and
in vivo rodent models (al Qatari et al., 2001; Koob et al.,
2002). Acamprosates action at the NMDA receptor also
suggests the possibility of an interaction with alcohols
acute inhibitory effects at this receptor.
Preclinical studies examining potential behavioral mechanisms of the action of acamprosate have indicated that acamprosate reduces some signs of alcohol withdrawal in rats (i.e.,
hyperlocomotion: Dahchour and DeWitte, 1999; Gewiss et
al., 1991; Spanagel et al., 1996b) but does not substitute for
alcohol in discrimination testing (Spanagel et al., 1996c) or
alter alcohols hypothermic, motor-impairing, or aversive effects (LeMagnen et al., 1987a). Analyses of alcohol intake
patterns in studies demonstrating acamprosate-induced reductions in drinking behavior have shown that acamprosate
does not reduce the motivation to obtain ethanol or delay the
initiation of drinking, but rather decreases ethanol preference
and continued intake after a normal onset of drinking, i.e.,
after alcohol and acamprosate have been experienced in combination (Czachowski et al., 2001; Heyser et al., 1998; Holter
et al., 1997). Interestingly, it has been reported recently that
part of acamprosates clinical efficacy is due to a reduction in
the severity of, rather than the latency to, relapse in alcoholics
trying to abstain (Chick et al., 2002). Combined, these findings
suggest that acamprosates mechanism of action may involve,
in part, an interaction of the drug with the acute pharmacological effects of alcohol. Although several studies have examined the behavioral and pharmacokinetic properties of acamprosate and its effects on abstinence measures, both alone and
in combination with other treatments (e.g., naltrexone: COMBINE Study Research Group, 2003a,b; Johnson et al., 2003;
Kiefer et al., 2003; Mason, 2001; for review: Mason et al.,
2002; Saivin et al., 1998; Schneider et al., 1998; Soyka et al.,
1998), no published human laboratory studies have examined
the drugs direct pharmacodynamic and pharmacokinetic interactions with alcohol.
The purpose of this double-blind, placebo-controlled,
dose-effect human laboratory study was to examine the
influence of acamprosate on the pharmacokinetics and
direct subjective, psychomotor, and physiologic effects of
alcohol in a sample of heavy-drinking human volunteers.

(Mini International Neuropsychiatric Interview, version 5.0.0; Sheehan et


al., 1998). Individuals with significant medical or psychiatric conditions or
with physical dependence on alcohol or illicit drugs, as determined by
DSM-IV criteria for alcohol dependence or drug abuse/dependence, were
excluded from the study. Female volunteers were tested for pregnancy and
were excluded from participation if they were pregnant or breast-feeding.
Subject characteristics are presented in Table 1. The participants
ranged in age from 25 to 48 years (mean, 35.3 years). Seven were Caucasian, 2 were African American, and 1 was Hispanic. Six volunteers smoked
cigarettes. On average, subjects reported 3.8 drinking occasions per week
with 6.9 drinks per occasion and reported 18.9 years of alcohol use.
Volunteers were allowed to continue their normal patterns of alcohol
consumption during the study but were told to refrain from any illicit drug
use; random urine drug tests were conducted to ensure compliance. The
study was approved by the Johns Hopkins Bayview Medical Center Institutional Review Board and was conducted in accordance with the Declaration of Helsinki. All subjects provided written, informed consent before
beginning the study and were paid for their participation.
Study Design
Volunteers participated as outpatients in this 6-week within-subject
design. During that time, subjects were maintained on three different
doses of oral acamprosate (0, 2, and 4 g, in counterbalanced order across
subjects) for 11 days at each dose. Acamprosate dosing periods were
separated by 4-day washout periods. Alcohol challenge sessions (0, 0.5,
and 1.0 g/kg, in counterbalanced order) were scheduled on days 7, 9, and
11 during each acamprosate dose condition. The first experimental session
was scheduled on day 7 of each acamprosate treatment period to ensure
steady-state blood levels of acamprosate (Wilde and Wagstaff, 1997). The
half-life of acamprosate after oral administration is 13 hr (Wilde and
Wagstaff, 1997). All acamprosate and alcohol doses were administered
under double-blind conditions.
Procedures
Acamprosate Administration. Acamprosate 500-mg tablets and matching
placebo were provided by Lipha Pharmaceuticals, Inc. (Lyon, France). Daily
doses were administered as eight tablets divided between two administrations,
scheduled 12 hr apart. Subjects came to the laboratory each morning between
9:00 and 10:00 AM to ingest four tablets under supervision by research staff.
A mouth check was performed to ensure that subjects had swallowed the
tablets. An additional four tablets were provided to volunteers in a MEMS
SmartCap bottle (Aprex, San Diego, CA) to take home for evening administration. The cap displayed the number of hours since the bottle was last
opened, informing volunteers of the appropriate time to take their medication and providing a means of monitoring compliance the following morning
when the bottle was returned to the laboratory. At each daily visit, physiologic
measures (heart rate and blood pressure) were collected, and subjects completed brief subjective report measures and psychomotor tasks (see below) to
assess the effects of acamprosate treatment.
Alcohol Challenge Sessions. On session days, subjects completed normal
daily visit procedures, including acamprosate administration, at 9:00 AM

METHODS
Subjects
Participants were 10 adult volunteers (7 men and 3 women) recruited
through local newspaper advertisements and posted flyers. For inclusion
in the study, subjects had to be between the ages of 25 and 50 years and
to report drinking alcohol a minimum of 8 days/month, with five or more
drinks per occasion at least three times per month for men and four or
more drinks per occasion at least three times per month for women.
Before enrollment, volunteers underwent medical, psychiatric, and druguse screening to determine their eligibility for the study. Screening procedures included assessment of medical history, vital signs, self-reported
alcohol and drug use, laboratory tests of blood chemistry and hematology,
urine drug screen, breathalyzer test, and a structured psychiatric interview

Table 1. Subject Characteristics (n 10)

Variable

Data

% Male
% Caucasian
% African American
% Hispanic
% Smokers
Mean age (years)a
Mean years of alcohol usea
Mean drinking occasions/weeka
Mean drinks/occasiona

70
70
20
10
60
35.3 2.5
18.9 2.5
3.8 0.4
6.9 1.7

Mean SEM.

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and then remained in the laboratory for the rest of the morning before
commencement of the session at 12:45 PM. Smoking and consumption of
caffeinated beverages were restricted on these days. Smokers were allowed to wear a nicotine patch if they desired; nicotine patches (14 or 21
mg, based on smoking habits) were provided. Before the sessions, subjects
were administered a calorie-controlled lunch at 11:30 AM, which they
were required to finish by noon. A heparinized catheter was then placed
into a forearm vein in the subjects nondominant arm for collection of
blood samples during the session.
Sessions began with baseline assessments of subjective, physiologic, and
psychomotor performance measures (described below) that were part of a
test battery designed to capture alcohol and drug effects. A baseline
breath sample was collected to verify the absence of alcohol. After the
baseline period, subjects ingested the appropriate alcohol dose of alcohol
(0, 0.5, or 1.0 g/kg). Alcohol doses were prepared by mixing the appropriate amount of pure ethanol with juice in three 4-oz drinks. To conceal
the alcohol content of the drinks, a cloth band soaked in ethanol was
placed around each cup to provide an alcohol odor, and 1 ml of ethanol
was floated on top of the drink to deliver an alcohol taste. This latter
volume was included as part of the total alcohol dose. Alcohol doses were
administered at 1:15 PM, and subjects were allowed 15 min to finish the
drinks, with the end of drink administration recorded as time 0. For the
next 3 hr, the test battery was repeated at 30-min intervals (i.e., 30, 60, 90,
120, 150, and 180 min), and breath samples were collected for measurement of alcohol levels. Blood samples were also collected at baseline and
at each postadministration interval for later analysis of neuroendocrine
measures. Neuroendocrine data are not included in this report.

Dependent Measures
Daily Visit Measures. The following measures were collected during
daily visits throughout each acamprosate dosing period to monitor the
effects of the drug on subjective state, behavioral performance, and physiologic function. Unless otherwise indicated, questionnaires and tasks
were administered on a Macintosh computer (Apple Computer Inc.,
Cupertino, CA), and subjects used a mouse or keypad to respond. Subjects
were familiarized with all subjective and performance tasks before initial
completion.
Subject-Rated Measures. The Profile of Mood States was administered
on days 2, 7, and 10 of each acamprosate dosing period to measure current
mood states. Subjects rated 65 adjectives on a 5-point scale from 0 (not at
all) to 4 (extremely). Items comprised a total mood disturbance score and
the following subscales: tension-anxiety, depression-dejection, angerhostility, vigor, fatigue, confusion-bewilderment, and friendly (McNair et
al., 1971).
The Beck Depression Inventory was administered on days 1, 4, and 10
of each acamprosate period. This 21-item instrument measures depressive
symptoms, including ratings of mood, self-image, appetite, and sleep
behavior (Beck et al., 1961). Each item involved choosing one of four
statements (scored from 0 to 3) that best described how the subject felt
that day. Ratings on individual items were summed to produce an overall
Beck Depression Score.
The Hopkins Symptom Checklist was completed on days 2, 4, and 10 to
assess psychological status. Subjects rated 90 items on a 5-point scale from
0 (not at all) to 4 (extremely). This self-report inventory measures psychiatric distress levels across nine subscales (somatization, obsessivecompulsive, depression, anxiety, hostility, interpersonal sensitivity, phobic
anxiety, paranoid ideation, and psychoticism) and three global indices
(Derogatis, 1983).
Alcohol Consumption. Subjects were asked daily about the number of
standard alcoholic drinks they had consumed in the past 24 hr to assess the
effects of acamprosate treatment on self-reported drinking behavior in the
natural environment.
Medication Side Effects. A questionnaire assessing medication side
effects was administered daily. Subjects were asked to indicate whether
they had experienced any of a list of symptoms in the past 24 hr. Symptoms

BRASSER ET AL.

were selected to include both side effects associated with acamprosate


administration and unrelated symptoms.
Performance Measures
A computerized version of the Digit Symbol Substitution Test
(DSST; McLeod et al., 1982) was administered on day 4 of each
acamprosate period. On each trial, subjects were presented with a
random digit from 1 to 9 on the computer screen. Subjects used a
numeric keypad to replicate the geometric pattern associated with that
digit from 9 digit-symbol codes displayed at the top of the screen.
Measures included the number of trials (patterns) attempted and the
number of trials (patterns) correct within 90 sec.
The Circular Lights task, a reaction time task involving rapid hand-eye
coordinated movements (previously described by Griffiths et al., 1983),
was administered on days 3, 4, and 7 to 11. The apparatus consisted of 16
buttons circularly arranged around a 54-cm diameter. Individual buttons
lit up in random sequence, and subjects were instructed to press each
button to extinguish the associated light. The number of correct responses
during 60 sec was the dependent measure.
The Balance task was performed on the same days as the Circular
Lights task and assessed the subjects ability to stand upright on one foot
with his or her eyes closed and arms extended to the side at shoulder
height. Balance on each foot was measured for a maximum of 30 sec or
until the subject touched the raised foot to the ground. The scores for the
right and left foot were summed for a maximum possible score of 60 sec.
Subjects completed the Digit Recall, a computerized number-recall
task assessing short-term memory (Kirk et al., 1990), on days 2 to 4 and 7
to 11. During each trial, a randomly generated eight-digit number appeared on the computer screen, and subjects were required to reproduce
the displayed number by using a numeric keypad. If the subject entered
the number correctly, the number disappeared from the screen, and the
subject was then required to re-enter the number from memory either
immediately (on five trials) or after a 10-sec delay (on five trials). If the
number was incorrectly entered during the first part of the trial, the trial
was discontinued, and a new eight-digit number was presented. The task
continued until the subject had correctly entered 10 eight-digit numbers
during the first phase of the trials (i.e., 10 valid trials were initiated) or
until 25 incorrect attempts had been made. The total number of 8-digit
numbers (out of 10) correctly recalled was the dependent measure.
Physiologic Measures
At each daily visit, resting systolic and diastolic blood pressure and
heart rate were measured with a Criticare noninvasive patient monitor
(Criticare Systems Inc., Waukesha, WI). After subjects had been seated
for 15 min, three consecutive readings were collected at 3-min intervals,
and the average was used for data analysis.
Session Measures
Unless otherwise specified, the following measures were collected at
baseline and every 30 min after drink administration (up to 180 min)
during each alcohol challenge session. A Visual Analog Craving Questionnaire was administered to assess the level of craving for alcohol. The
scale consisted of two visual analog items for which subjects indicated their
response by positioning a cursor along a 0- to 100-point horizontal line.
These items included How badly do you want an alcoholic drink right
now? (anchored at opposite ends by not at all to extremely) and
Rate your desire for an alcoholic drink right now (anchored from not
at all to very strong).
Subjects completed a six-item Visual Analog Drug Effect Questionnaire (DEQ) every half hour after drink administration to capture the
magnitude, quality, and duration of alcohol effects. Volunteers responded
to each of the following questions on a 0 100 scale from not at all to
extremely: Do you feel any effect of the drinks?, How strong is the
effect of the drinks?, Do you feel good effects from the drinks?, Do

1077

ACAMPROSATE EFFECTS ON ALCOHOL RESPONSES

you feel bad effects from the drinks?, Do you like the effect of the
drinks?, and Do you dislike the effect of the drinks?
The Biphasic Alcohol Effects Scale (BAES; Martin et al., 1993) is
composed of 14 items that measure both sedative (difficulty concentrating,
down, heavy head, inactive, sedated, slow thoughts, and sluggish) and
stimulant (elated, energized, excited, stimulated, talkative, up, and vigorous) effects of alcohol. Subjects rated each adjective on a nine-point scale
from 0 (not at all) to 8 (extremely). Items from each subscale were
summed to produce total sedative and total stimulant scores.
The Subjective High Assessment Scale (SHAS; Schuckit, 1980) comprised 13 brief descriptors of alcohol effects, which subjects rated on a 0
to 100 scale ranging from normal to extremely. Subjects were told to
assume that their ratings were normal before they received the beverage. Items included uncomfortable, high, clumsy, muddled or confused,
slurred speech, dizzy, nauseated, drunk or intoxicated, sleepy, distorted
sense of time, effects of alcohol or drug, difficulty concentrating, and
feelings of floating.
Subjects completed the short form of the Addiction Research Center
Inventory (ARCI; Martin et al., 1971) at baseline and 60, 120, and 180 min
after drink administration. The form consists of 49 true/false items divided
into 5 major subscales sensitive to euphoria (morphine-benzedrine group),
sedation (pentobarbital-chlorpromazine-alcohol group; PCAG), somatic and
dysphoric changes (lysergic acid diethylamide; LSD), and amphetamine-like
effects (benzedrine group and amphetamine).
An Alcohol Hangover Scale (McCaul et al., 1991) was administered at
baseline on session days and the morning after each alcohol challenge
session to assess residual alcohol effects. This scale included 13 visual
analog items (sweating, appetite for food, hands shaky or trembling,
trouble concentrating, heart racing, anxious, alcohol craving, tiredness,
restlessness, irritability, nausea, headache, and loss of appetite) that subjects rated on a 0- to 100-point scale from not at all to extremely.
Performance Measures

The most common side effects reported more frequently


during acamprosate treatment than during placebo treatment were gastrointestinal upset, diarrhea, nausea, drowsiness, and tiredness. Gastrointestinal upset, diarrhea, and
nausea occurred more often for the high (4-g) acamprosate
dose than for the lower (2-g) dose. The frequencies of these
events across all subjects by acamprosate condition are
presented in Table 2.
Daily Visit Measures
Acamprosate did not substantially affect subjective, psychomotor, or physiologic measures during chronic 11-day
maintenance periods at each dose. The only exception was
ratings of the item exhausted [Profile of Mood States;
F(2,18) 5.00; p 0.05]. These ratings were significantly
higher during acamprosate (4-g) treatment than during
placebo treatment [Tukeys honestly significant difference
(HSD); p 0.05]. However, ratings overall were low on this
item (scale, 0 4: placebo, 0.17 0.13; acamprosate 2 g,
0.31 0.12; acamprosate 4 g, 0.53 0.13).
Alcohol Challenge Sessions
Physiologic Effects. Alcohol dose-dependently increased
blood alcohol levels [BAL; Fig. 1; interaction of ethanol
time; F(12,108) 121.80; p 0.001]. Alcohol (0.5 g/kg)
Table 2. Frequencies of Acamprosate Side Effects

Volunteers completed the DSST, Digit Recall, Circular Lights, and


Balance tasks (described previously) at each session interval to assess
psychomotor performance.
Physiologic Measures
Resting systolic and diastolic blood pressure and heart rate were recorded at 3-min intervals throughout each session by a Criticare monitor
interfaced with an Apple Macintosh computer. Breath alcohol readings
were taken with an Intoxilyzer 5000 (CMI, Inc., Owensboro, KY).

Effect

Placebo

2g

4g

Gastrointestinal upset
Diarrhea
Nausea
Drowsiness
Tiredness

7
5
3
17
1

12
8
2
21
6

23
13
12
22
4

Data Analysis
Raw scores were analyzed by using ANOVA with alcohol dose and
acamprosate dose as within-subjects factors and time point (including
baseline) as a repeated-measures factor. Repeated-measures data were
adjusted for sphericity by using Huynh-Feldt corrections. Tukey post hoc
tests were performed when appropriate. The session subjective data for
one subject were eliminated due to failure to respond appropriately to
questionnaires; this subjects psychomotor and physiologic data were
retained.

RESULTS

Medication Compliance and Side Effects of Acamprosate


Data regarding subject compliance with evening medication administration obtained from SmartCap bottles (hours
since last opened) indicated that overall, 0.7% of the total
evening doses were missed, 4% were administered late
(defined as 1 hr late), and 0.7% were administered early
(defined as 1 hr early), indicating good compliance. All
morning doses were administered under supervision.

Fig. 1. Mean SEM blood alcohol levels (g/dl) at baseline (30 min) and for
3 hr after the administration of 0, 0.5, and 1.0 g/kg alcohol doses under each
acamprosate dose condition.

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BRASSER ET AL.
Table 3. Summary of Significant EffectsAlcohol Challenge Sessions
Variable
Subjective High Assessment Scale
High
Dizzy
Drunk or intoxicated
Sleepy
Effects of alcohol
Biphasic Alcohol Effects Scale
Total stimulant
Total sedative
Addiction Research Center
Inventory
PCAG (sedation)
BG (stimulant)
LSD (dysphoria)
Drug Effect Questionnaire
Feel effect
Strong effect
Good effects
Bad effects
Like effects
Dislike effects
Craving Questionnaire
Desire to Drink
Digit Symbol Substitution Task
Trials attempted
Trials correct
Circular Lights
Balance
Blood alcohol level
Heart rate

Acamprosate
(A)

Ethanol
(E)

Time
(T)

** (1)

***

**

* (1)
* (1)
** (1)

***
*
***

**

***
*

**

* (1)

** (1)
** (2)
* (1)

**

***(1)
** (1)
***(1)
* (1)
** (1)
* (1)

***
***
***

***
**
***

***

***

** (2)
***(2)
** (2)
** (2)
***(1)
***(1)

*
**
**

**
**
**
*
***

AE

AT

ET

AET

***

* (1)

***
***

Arrows denote the direction of effect.


* p 0.05; ** p 0.01; *** p 0.001.

produced significant increases in BAL 30 to 150 min after


administration, with peak levels at 30 min, followed by a
steady decline across the remainder of the session. Alcohol
(1.0 g/kg) significantly increased BAL at all time points
after consumption, with a peak 30 to 90 min after administration and a gradual decline thereafter (Tukeys HSD; p
0.05). Alcohol pharmacokinetics were unaffected by
acamprosate.
Alcohol (0.5 and 1.0 g/kg) produced tachycardic effects
that were comparable in degree at both active alcohol doses
[ethanol effect: F(2,18) 16.20, p 0.001; mean heart
rate: placebo, 75.98 2.38; alcohol 0.5 g/kg, 81.48 1.91;
alcohol 1.0 g/kg, 82.44 2.08]. Acamprosate did not significantly alter alcohol-induced tachycardia.
Subjective Effects. Alcohol produced dose- and timerelated increases on most subjective measures (SHAS:
drunk, high, and effects of alcohol or drug; DEQ: feel
effect, strong effect, good effects, and like effects; BAES:
composite stimulant subscale; ARCI: PCAG (sedation)
subscale; see Table 3 and Figs. 2 and 3). In general, alcohol
effects on these measures peaked during the first hour after
administration and declined thereafter. The lower (0.5
g/kg) alcohol dose produced significant increases in subjective measures during the first 30120 min after administration, whereas the effects of the high (1.0 g/kg) alcohol dose
remained significantly different from both baseline levels
and placebo during the entire 3-hr session (Tukeys HSD; p
0.05). The only exception was alcohol-induced stimulant

Fig. 2. Mean SEM subject ratings on the visual analog item drunk or
intoxicated (Subjective High Assessment Scale) at baseline (30 min) and for 3
hr after the administration of 0, 0.5, and 1.0 g/kg alcohol doses under each
acamprosate dose condition.

effects (BAES), which were significantly increased only at


30 min for the 0.5 g/kg dose and at 30 to 60 min for the 1.0
g/kg dose. Alcohol (1.0 g/kg) significantly increased ratings
on measures of sedative or negative effects [SHAS, sleepy;
DEQ, bad effects and dislike effects; BAES, composite

ACAMPROSATE EFFECTS ON ALCOHOL RESPONSES

1079

Fig. 4. Mean SEM number of correct responses on the Circular Lights task
at baseline (30 min) and for 3 hr after the administration of 0, 0.5, and 1.0 g/kg
alcohol doses under each acamprosate dose condition.

Fig. 3. Mean SEM subject ratings on the visual analog items like effects
and dislike effects for 3 hr after the administration of 0, 0.5, and 1.0 g/kg alcohol
doses under each acamprosate dose condition.

sedative subscale; ARCI, LSD (dysphoria) subscale] and


decreased ratings of stimulant effects [benzedrine group
(ARCI)] as compared with placebo (Tukeys HSD; p
0.05).
Acamprosate did not affect alcohol-induced changes on
most subjective measures (Table 3). There was, however, a
trend for both active doses of acamprosate to increase
subjective ratings of alcohol intoxication [drunk (SHAS)]
at the lower (0.5 g/kg), but not higher (1.0 g/kg), alcohol
dose (Fig. 2; main effect of acamprosate, p 0.06; acamprosate ethanol time interaction, p 0.10). The trend
for a three-way interaction resulted from enhanced subjective ratings of intoxication during the peak phase of the
alcohol effect curve (3090 min after administration) at the
0.5 g/kg alcohol dose under both active acamprosate doses
relative to placebo. This effect of acamprosate was reflected in non-significantly increased scores on the sedative,

but not the stimulant, items of the BAES and the PCAG
(sedation) subscale of the ARCI at the same time points,
suggesting a specific enhancement of alcohols sedative
effects. In order to further examine the trend for alcohol
intoxication, separate repeated measures ANCOVAs were
conducted with alcohol dose, acamprosate dose, and timepoint as within-subjects factors and peak BAL or time to
peak BAL as covariates. Both analyses revealed significant
interactions of Ethanol by Time [Fs (12, 96) 10.23, ps
.001], but no effect of acamprosate or interaction of
acamprosate with other factors (Fs 1). Thus, adjusting
for differences in blood alcohol level eliminated the initially
observed trend for acamprosate-induced potentiation of
intoxication, suggesting the latter trend is not due to a
central pharmacodynamic interaction. A significant interaction among acamprosate, ethanol, and time was observed
for dizzy [SHAS; F(24,192) 2.57; p 0.05]. Post hoc
tests revealed that this interaction resulted from subjects
reporting less dizziness under active acamprosate compared with placebo at the high alcohol dose (60 min;
Tukeys HSD; p 0.05).
An interaction between acamprosate and time was observed for the LSD (dysphoria) subscale of the ARCI
[F(6,48) 3.06; p 0.05]. Post hoc tests indicated that
dysphoria scores were significantly increased from baseline
for both placebo and acamprosate (4 g) at 60 and for the
2-g dose at 120. Although there was no statistically significant three-way interaction with alcohol dose, a somewhat prolonged alcohol-induced dysphoria at the lower
acamprosate dose seemed to contribute to the effect.
Finally, the higher (4-g) acamprosate dose was associated with a significant increase in desire to drink now
compared with placebo (Alcohol Craving Questionnaire;
Tukeys HSD; p 0.05). The mean values for placebo and

1080

BRASSER ET AL.

4-g doses, respectively, were 12.33 3.55 and 21.88 5.98


on a scale of 0 to 100 units.
Psychomotor Performance
Alcohol produced dose-related impairment of performance on the Circular Lights task (Fig. 4), DSST, and
Balance task. Significant alcohol effects were observed for
both the number of attempted trials and the number of
correct trials on the DSST, correct responses on the Circular Lights task, and total Balance scores (Table 3). The
high (1.0 g/kg) alcohol dose produced significant decreases
in both Circular Lights and total Balance scores 30 to 150
min after administration and in DSST trials correct
throughout the entire 3-hr session (Tukeys HSD; p
0.05). In general, impairment at the 1.0 g/kg alcohol dose
was most pronounced 30 to 90 min after administration,
with some recovery in performance thereafter. The only
significant psychomotor impairment at the lower (0.5 g/kg)
alcohol dose was a decrement in Circular Lights (reaction
time) performance 30 min after alcohol administration
(Tukeys HSD; p 0.05). Acamprosate did not affect
performance on any of these measures and did not alter
alcohol effects on these measures.
Next-Day Measures
Alcohol (1.0 g/kg) significantly increased ratings of headache (Alcohol Hangover Scale) the morning after the sessions [ethanol effect: F(2,18) 5.41, p 0.05; Tukeys
HSD; p 0.05]. Subjects reported less tiredness the day
after the 0.5 g/kg alcohol dose than after both placebo and
high-dose alcohol [ethanol effect: F(2,18) 6.25; p 0.01).
Finally, alcohol (0.5 and 1.0 g/kg) significantly increased
ratings of appetite for food the morning after sessions
under the high (4-g) acamprosate dose, but not under
placebo or acamprosate (2-g) conditions [acamprosate
ethanol interaction; F(4,36) 3.24; p 0.05; Tukeys
HSD; p 0.05].
DISCUSSION

This laboratory study evaluated the effects of acamprosate on the pharmacokinetics and acute pharmacodynamic
effects of alcohol in heavy drinkers. A broad dose range for
both drugs and a variety of dependent measures were used
to allow for a comprehensive assessment of potential interaction effects. Results confirm previous clinical findings
that acamprosate alone does not produce marked physiologic, subjective, or psychomotor effects, and they additionally show that acamprosate does not alter alcohol pharmacokinetics, alcohol-induced psychomotor impairment, or
physiologic alcohol effects (i.e., tachycardia) and most subjective effects.
The present findings that acamprosate did not interact
with the pharmacokinetic profile of alcohol (rate or magnitude of increase in BAL) or alcohols psychomotor-

impairing effects on several indices of performance (DSST,


Circular Lights task, Balance task) are in agreement with
preclinical data (Daoust et al., 1992; Gewiss et al., 1991;
LeMagnen et al., 1987a). That acamprosate does not alter
the disposition of alcohol is consistent with the fact that
acamprosate is not metabolized by the liver (Saivin et al.,
1998) and therefore does not interact with the hepatic
enzymes involved in alcohol metabolism. In humans it has
been shown previously that acamprosate alone does not
affect psychomotor performance (Schneider et al., 1998;
Soyka et al., 1998). Our data confirm these findings and
show in addition that acamprosate does not alter alcoholinduced psychomotor impairment. This is important because the clinical population targeted for treatment with
this compound is, by definition, at risk for alcohol abuse
during treatment.
Acamprosate did not affect most subjective alcohol effects at peak levels and across the descending limb of a
moderate (0.5 g/kg) and high (1.0 g/kg) dose of alcohol.
Alcohol dose-dependently increased typical subjective effects, such as good effect, liking, and stimulant effects, and
at the high dose it also increased unpleasant effects (bad
effect and disliking), but these measures were unaltered by
acamprosate. Although an initial trend appeared for acamprosate to increase ratings of drunk after the lower (0.5
g/kg) alcohol dose, subsequent ANCOVAs adjusting for
individual differences in peak BAL eliminated this trend,
suggesting that any effect of acamprosate on subjective
intoxication may be non-pharmacodynamic in nature. It is
possible that some modest potentiation of subjective intoxication is due to subtle effects of acamprosate on individual
blood alcohol curves (e.g., increased or delayed peak BALs
in some individuals due to gastrointestinal effects of acamprosate on alcohol absorption), albeit such differences were
not robust and were thus undected in the overall pharmacokinetic analysis. Further research using a larger subject
sample will be necessary to fully evaluate such hypotheses.
Alcohol was administered as a bolus dose in this study,
and effects were measured for 3 hr after administration.
This procedure has been used extensively in studies examining alcohol effects, and in this study it allowed for careful
characterization of acamprosate/alcohol interactions at
peak alcohol levels and across the descending limb of the
alcohol-concentration curve. It is possible that additional or
more robust effects of acamprosate would be observed
during the ascending limb of the alcohol-concentration
curve.
Acamprosate has been described often as a putative
anticraving agent, in part related to its ability to suppress
some behavioral and physiologic signs of withdrawal in
rodents (Cole et al., 2000; Dahchour and DeWitte, 1999;
Gewiss et al., 1991; Littleton, 1995; Putzke et al., 1996;
Spanagel et al., 1996b). Although a recent open-label study
suggested craving reduction after 6 weeks of acamprosate
treatment (Weinstein et al., 2003), most evidence from
clinical trials has failed to support an effect of acamprosate

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ACAMPROSATE EFFECTS ON ALCOHOL RESPONSES

on alcohol craving [see Mason (2001) for review]. These


data showed no effect of acamprosate on measures of
craving at a clinically relevant dose (2 g), suggesting that
acamprosate does not reduce craving in heavy drinkers who
are not restricting their alcohol intake. A small but significant increase in the desire to drink was observed for the
4-g acamprosate dose (average of 22 vs. 13 on a 100-point
scale), suggesting that doubling the currently accepted therapeutic dose may actually produce undesirable effects on
craving. High (3-g) acamprosate doses have previously
been reported to increase nervousness (Johnson et al.,
2003), which might account for some increase in desire to
drink at the 4-g dose in this study. The higher acamprosate
dose was also associated with increased ratings of exhaustion and a greater incidence of side effects. With regard to
overall drug tolerability, however, it should be noted that
acamprosate had minimal to no effects on subjective, performance, or physiologic measures during chronic dosing
cycles; the most common side effects were gastrointestinal
disturbances and diarrhea.
This study was conducted with a sample of heavy drinkers, similar to previous studies elucidating mechanisms of
action of medications for alcoholism (e.g., Davidson et al.,
1999; McCaul et al., 2000; Palfai et al., 1999). The use of
heavy drinkers allows for evaluation of medication effects
in individuals who frequently self-administer large doses of
alcohol, without the logistical complications of alcohol
withdrawal during placebo sessions or the ethical complications of alcohol administration to alcohol-dependent individuals. The relatively high levels of alcohol use and long
history of heavy drinking in our subjects (an average of
seven drinks four times a week for 19 years) renders this
group appropriate for characterization of effects of medications for alcoholism. The effects reported here should
nevertheless be investigated in alcohol-dependent subjects
to determine the clinical generalizability of these findings.
Mechanisms of action of acamprosate are likely distinct
from those of the two current US approved medications for
alcoholism: naltrexone and disulfiram. Naltrexone, a nonselective opioid receptor antagonist, is hypothesized to reduce drinking primarily by decreasing the positivereinforcing euphoric effects of alcohol and desire to drink
(Davidson et al., 1999; King et al., 1997; McCaul et al.,
2000; OMalley et al., 2002; Palfai et al., 1999; Swift et al.,
1994). Disulfiram acts as an aversive agent by blocking
enzymatic metabolism of alcohol via inhibition of aldehyde
dehydrogenase, resulting in increases in levels of acetaldehyde and its associated toxic effects (Johansson, 1992; Petersen, 1992). Acamprosate, which exerts NMDA receptor
antagonist effects under conditions of chronic alcohol exposure (al Qatari et al., 1998; Naassila et al., 1998), may
facilitate abstinence by attenuating withdrawal hyperexcitability (al Qatari et al., 2001; Dahchour and DeWitte, 1999;
Gewiss et al., 1991; Koob et al., 2002; Spanagel et al.,
1996b) and counteracting conditioned alcohol effects (Cole
et al., 2000; Quertemont et al., 2002).

In summary, this controlled human laboratory investigation corroborates previous research showing that acamprosate alone does not have substantial effects on physiologic,
subjective, or psychomotor measures. This study extends
these findings by showing that acamprosate does not alter
alcohol pharmacokinetics, physiologic effects, alcoholinduced behavioral impairment, or most typical subjective
alcohol effects. The observation of a modest trend for
increased alcohol intoxication during acamprosate treatment may be non-pharmacodynamic in origin and requires
further investigation before being considered in the context
of potential mechanisms of action of acamprosate.
ACKNOWLEDGMENTS
The authors thank Abigail Kendrick, Erin Moffet, Paul Nuzzo,
Tim Mudric, and John Yingling for their contributions to this
project. The authors also thank Lipha Pharmaceuticals, Inc., for
supplying the acamprosate.
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