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ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH
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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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
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.
1077
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
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
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)
***
***
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.
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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.
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
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BRASSER ET AL.
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-
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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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