The effect of naltrexone on alcohols stimulant properties and selfadministration behavior in social drinkers: influence of gender and genotype
The Effect of Naltrexone on Alcohol's Stimulant
Properties and Self-Administration Behavior in Social
Drinkers: Inﬂuence of Gender and Genotype
Elaine Setiawan, Robert O. Pihl, Sylvia M. L. Cox, Christina Gianoulakis,
Roberta M. Palmour, Chawki Benkelfat, and Marco Leyton
Background: Few pharmacological treatments for alcohol dependence are available. Moreover,
the best supported treatment, naltrexone hydrochloride, appears to work for only some.
Methods: To investigate potential predictors of these differential responses, 40 social drinkers
(20 women) were administered 6 days of treatment with naltrexone vs. placebo in a double-blind,counterbalanced, crossover design. At the end of each treatment period, participants received asingle dose of their preferred alcoholic beverage followed by the opportunity to work for addi-tional alcohol units using a progressive ratio (PR) breakpoint paradigm. All subjects but one weregenotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1).
Results: Naltrexone decreased the ethanol-induced ‘euphoria' to a priming dose of alcohol in
two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioidreceptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholicbeverages on the PR task regardless of gender or genotype.
Conclusions: The results add to the evidence that naltrexone decreases positive subjective
effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkersmight decrease alcohol use.
Key Words: Alcohol Dependence, Opioids, Addiction, Individual Differences.
E THANOL ADMINISTRATION INDUCES the reported clinical trials indicate positive effects of naltrexone,
release of endogenous opioids in laboratory rodents
there are also multiple negative reports (Krystal et al., 2001;
(Marinelli et al., 2003, 2005) and in humans (Dai et al., 2002).
Killeen et al., 2004; O'Malley et al., 2007; though, for a
Conversely, administration of the opioid receptor antagonist,
reanalysis of two negative ﬁndings, see Gueorguieva et al.,
naltrexone (Revia), has been reported to decrease alcohol's
2007). Laboratory studies in social drinkers have also yielded
positive subjective effects and drinking behavior. For exam-
inconsistent results; naltrexone failed to decrease ad lib alco-
ple, in alcohol-dependent patients, naltrexone has been found
hol ingestion in two studies (Davidson et al., 1996; Drobes
to decrease alcohol intake and the ability of alcohol exposure
et al., 2003) while the signiﬁcant effects seen in two others
to precipitate binges (Anton et al., 2004; Berglund, 2005;
were proposed to reﬂect nonspeciﬁc sedation and nausea
Drobes et al., 2003; Feinn and Kranzler, 2005; O'Malley
(Davidson et al., 1999; de Wit et al., 1999).
et al., 1992; Oslin et al., 1999; Volpicelli et al., 1992). In labo-
Some of the above discrepant ﬁndings might be explained
ratory studies conducted in heavy social drinkers, naltrexone
by different effects in subpopulations. For example, a retro-
can diminish subjective stimulant effects of alcohol and the
spective analysis of an existing dataset suggested that naltrex-
urge to drink (Davidson et al., 1999; King et al., 1997; Na
one may be clinically more effective in women than men
and Lee, 2002; Peterson et al., 2006; Ray and Hutchison,
(Kiefer et al., 2005). Although this was not replicated in two
2007; Swift et al., 1994). However, although the majority of
subsequent retrospective analyses (Baros et al., 2008; Green-ﬁeld et al., 2010), preferential effects were seen in women inthe one prospective study reported to date (Tidey et al.,
From the Department of Neurology and Neurosurgery (ES,
SMLC, CB, ML); Department of Psychology (ROP, ML); and
Department of Psychiatry (ROP, CG, RMP, CB, ML), McGill
A second potential predictor of differential responses to
University, Montre´al, QC, Canada.
naltrexone is genetic variation of the OPRM1 gene that
Received for publication March 18, 2010; accepted November 23, 2010.
encodes for the mu opioid receptor. The most common vari-
Reprint requests: Marco Leyton, PhD, Department of Psychiatry,
ant is the A118G single nucleotide polymorphism, which
McGill University, 1033 Pine Avenue West, Montreal, Quebec,Canada H3A 1A1. Tel.: 514-398-5804; Fax: 514-398-4866; E-mail:
results in an amino acid substitution of Asn40Asp (Bergen
et al., 1997). This mutation has been reported to enhance
Copyright 2011 by the Research Society on Alcoholism.
alcohol-induced positive subjective effects and craving
responses in nondependent users (Ray and Hutchison, 2004;
Alcohol Clin Exp Res, Vol 35, No 6, 2011: pp 1–8
SETIAWAN ET AL.
van den Wildenberg et al., 2007) and is associated with
Symptom Check List (SCL) including ‘‘headache,'' ‘‘nausea ⁄
greater effects of naltrexone in both social drinkers (Ray and
vomiting,'' ‘‘fatigue,'' and ‘‘abdominal cramps.'' Participants rated
Hutchison, 2007) and alcohol abusers (Oslin et al., 2003;
severity of each symptom on a 5-point rating scale from ‘‘not at all''to ‘‘severe.''
Anton et al., 2008; though, see also Gelernter et al., 2007;
On the sixth day of each treatment, participants arrived at noon at
Tidey et al., 2008).
our Clinical Research Unit for their test day. Participants were asked
To address these issues further under controlled laboratory
to abstain from alcohol for at least 24 hours before the test session
conditions, we tested the effects of naltrexone in a sample of
and to abstain from nicotine and caffeine on the test day A breatha-
male and female social drinkers genotyped for polymor-
lyzer conﬁrmed abstinence from alcohol. Urine screens conﬁrmedcompliance with the treatment regimen (all participants had visually
phisms of the mu opioid receptor. Alcohol self-administration
detectable riboﬂavin under UV light, 366 nm) (Del Boca et al.,
behavior was measured using a progressive ratio (PR) break-
1996). All subjects tested negative on a urine drug screen sensitive to
point paradigm, an objective behavioral measure of motiva-
cocaine, opiates, phencyclidine, barbiturates, D9–tetrahydrocannabi-
tion to seek reward (Barrett et al., 2006, 2008). Positive and
nol, benzodiazepines, and amphetamines (Triage Panel for Drugs of
other subjective effects of alcohol were measured with self-
Abuse; Biosite Diagnostics, San Diego, CA). All women tested nega-tive on a urine hCG test. Crossover occurred after a minimum 7-day
washout period. In women, both drug regimens and test days tookplace during the follicular phase of their cycle or during the placebo
MATERIALS AND METHODS
week of their oral contraceptive pill.
Alcohol Self-Administration Task
Forty-two healthy, medication-free, social drinkers entered the
study. The participants were healthy social drinkers, aged 18–50 who
The alcohol self-administration paradigm followed the same pro-
ingested a minimum of 5 alcoholic units per week (1 unit = 1.5 oz
cedures as used in our previous studies (Barrett et al., 2006, 2008).
of 80-proof alcohol; 12 oz of beer; 5 oz of wine) and scored £5 on
Subjects performed all tasks individually to rule out the social aspect
the MAST. Participants were excluded for any of the following: cur-
of drinking, except for the presence of one of the researchers. At
rent or past dependence on substances other than nicotine or caf-
2:00 pm, subjects received a priming drink (their preferred 80-proof
feine; current major axis I psychiatric disorder; past major axis I
alcohol beverage mixed with caffeine-free soda or juice) to normalize
psychiatric disorders except unipolar mood or anxiety disorders in
drinking in the laboratory setting and to measure the response to a
current, sustained, medication-free remission; cardiovascular, neuro-
standard ethanol unit (males: 12 g; females: 10.4 g). The lower dose
logical, or other disorders that might be aggravated by participation
for women was to compensate for sex differences in ethanol pharma-
in the study or complicate interpretation of the study's results (e.g.,
cokinetics (Baraona et al., 2001). Subjects were then offered the
liver enzymes ‡ 2.5 times above normal, abnormal ECG, body mass
opportunity to work for up to 10 additional drinks, each containing
index £ 19 or >26); acute hepatitis, liver failure, or other liver disor-
half the standard unit of alcohol (males: 6 g; females: 5.2 g) vs.
ders that might be aggravated by alcohol and ⁄ or naltrexone expo-
water, on a computerized PR schedule. The PR breakpoint para-
sure; subjects currently taking opioid analgesics or other opioid
digm was used as an objective, behavioral measure of motivation to
containing medications; and, in women, a positive pregnancy test or
obtain alcohol. Subjects were offered the option of drinking more
not using a reliable method of birth control.
alcohol, water, or neither. To receive one extra drink (water or alco-
Participants were recruited using a three-stage identiﬁcation proce-
hol), participants were required to press keys on a computer key-
dure. (i) Volunteers were initially screened during a semi-structured
board 40 times. To receive a second drink required pressing 60
telephone interview. (ii) Those who were interested and tentatively
times. Up to a maximum of 10 selections from each drink category
met the entry criteria were invited to a face-to-face interview using
(water and alcohol) was permitted (PR = 40, 60, 90, 135, 203, 304,
the Structured Clinical Interview for DSM-IV (SCID, First et al.,
456, 684, 1,026, 1,538 key presses) although participants were not
1995) and the Michigan Alcohol Screen Test (MAST, Pokorny et al.,
informed of the maximum. The maximum alcohol load was
1972) a brief measure of lifetime alcohol problems indicative of possi-
1.25 ml ⁄ kg. The session proceeded as follows:
ble abuse or dependence. (iii) Volunteers underwent a physical exami-
1. Participant ﬁlls in subjective state scales.
nation by a physician at the Medisys clinic, who determined whether
2. Participant exposed to glass of water (sight, smell).
subjects met inclusion ⁄ exclusion criteria, with laboratory tests as
3. Participant ﬁlls in subjective state scales.
deemed appropriate, to ensure that they were medically safe to par-
4. Participant exposed to favorite alcoholic beverage (sight, smell).
ticipate. Two female participants withdrew from the study after com-
5. Participant ﬁlls in subjective state scales.
pleting 1 and 3 days of the ﬁrst week, respectively. Both had been
6. Participant asked to have one drink of favorite alcoholic beverage
taking naltrexone, and both cited nausea and general malaise as the
consumed at their own pace.
reason for discontinuing participation. Follow-up conﬁrmed full
7. Participant rests for 15 min, ﬁlling in subjective state scales.
recovery within 48 hours. The study was approved by the Royal
8. Participant can button press to choose one of 3 possibilities:
Victoria Hospital Research Ethics Board. All participants provided
(i) Another alcoholic beverage, (ii) Water, or (iii) No beverage (if
written informed consent.
option (i) or (ii) chosen, participant was allowed to consume andﬁnish the drink at their own pace but could not begin to button
press for a subsequent drink of the same kind until the previousdrink was completed)
The study was a double-blind, randomized, placebo controlled,
9. Repeat step 8 up to maximum of 10 ‘‘earned'' alcoholic drinks
counter-balanced, crossover design. Participants received oral nal-
OR remain seated to the time limit of 2 hours (neither detail was
trexone (with a 50 mg riboﬂavin marker) or riboﬂavin alone in iden-
disclosed to the participant).
tical capsules for 6 days. On Day 1 of the active treatment phase,subjects took 25 mg of naltrexone. If adverse side effects did not
Participants were required to remain seated in front of the key-
occur, subjects took 50 mg per day for the remaining 5 days. Side
board until they had earned the maximum number of alcoholic
effects of the drug were monitored after the initial dose, midway
drinks or the 2-hour time limit had elapsed, whichever came ﬁrst.
through the regimen and at the start of each test session using a
After completing the procedure, subjects were required to remain
GROUP DIFFERENCES IN NALTREXONE'S EFFECTS
on-site until their blood alcohol level was below 0.04% at which time
they were provided with a taxi home.
For the demographic data, 3-way ANOVAs were performed
(Gender · Gene · Order). The self-administration and subjective
Subjective Desire for Alcohol.
Subjective desire for alcohol was
data were analyzed by four- and ﬁve-way ANOVAs, (Drug ·
assessed throughout the test session. Two visual analogue scales
Gender · Genotype · Order and Drug · Gender · Genotype ·
(VAS), anchored at 1 = ‘‘Least'' to 10 = ‘‘Most,'' were labeled
Time · Order, respectively). In the presence of signiﬁcant main
Want a drink and Desire a Drink. Participants were instructed to
effects or interactions, data were then investigated further using Least
assess how they were feeling at each time referencing the ‘‘least or the
Signiﬁcant Difference post hoc tests, and Bonferroni corrections were
most they could ever imagine feeling that way'' to avoid ceiling or
applied where appropriate. ANCOVAs were performed to rule
out the effects of nausea, side effects, and individual patterns ofalcohol use. Correlations were calculated using Pearson's correlation
Subjective Effects of Alcohol.
Subjective effects induced by
alcohol were measured with the Subjective High Assessment Scale(SHAS, Schuckit et al., 1997), and 11 VAS labeled Like the Drink,Sedated, Intoxicated, Euphoria, Mind Racing, Alert, Energetic,
Excited, Rush, Anxiety, and High. SHAS items were examinedindividually as analogue scales anchored at 0 = ‘‘normal'' to
10 = ‘‘extremely''. Participants' markings were measured in mm andcalculated as a percentage of the whole scale (54 mm). All items were
As summarized in Table 1, subjects were nondependent
assessed individually as the authors wished to examine the stimula-
social drinkers. As a group, the participants averaged
tory and sedative effects of alcohol separately.
15.5 ± 1.5 drinks per week. Men reported signiﬁcantly moredrinks per current drinking episode than women (mean ±
SEM, men: 7.0 ± 0.9; women: 4.8 ± 0.4, p < 0.05). There
was a trend for the OPRM1 - ⁄ G allele carriers to report con-
DNA, extracted from venous blood by the phenol-
suming fewer alcohol units per week during their heaviest per-
chloroform method, was available for 39 participants. The A118G
iod of drinking than individuals with the A ⁄ A genotype
polymorphism of the mu opioid receptor gene (OPRM1) was geno-
(A ⁄ A, 22.0 ± 1.9; - ⁄ G, 14.9 ± 2.6, p < 0.10). There were
typed according to the methods described by Bergen and colleagues
no other group differences when subjects were separated by
(1997). Ampliﬁcation at an annealing temperature of 66C, using for-
gender or genotype.
ward primer 5¢CCTTGGCGTACTCAAGTTGCTC3¢ and reverseprimer 5¢TTCGGACCG CATGGGACGGAC3¢, produced a 95-bpproduct. After overnight digestion with Drd1, samples with a G sub-
Side Effects of Naltrexone
stitution (Asn 40) were cleaved into 22- and 73-bp fragments. Ethidi-um bromide-stained fragments were resolved on 5% polyacrylamide
Side effects of headache, nausea ⁄ vomiting, fatigue, and
gels and photographed under UV. All samples were ampliﬁed and
abdominal cramps ⁄ pain were measured at the beginning of
were typed unambiguously with 100% inter-rater reliability (2 raters).
The allele frequencies of 0.128 G and 0.872 A were not signiﬁcantly
each test session with the SCL. A total side effect score includ-
different from those reported in Caucasian populations (Bergen
ing all four symptoms was calculated. There were no main
et al., 1997; Gelernter et al., 1999) and genotype frequencies were in
effects of naltrexone treatment or any main or interaction
Hardy–Weinberg equilibrium (0.026 GG, 0.205 GA, 0.769 AA).
effects with gender on any of the measures. In comparison,
Because previously characterized control samples were not available,
OPRM1 G-allele carriers reported signiﬁcantly more side
we sequenced 3 samples (1 each AA, AG, GG) bidirectionally withthe expected results. Genotypes were determined after randomization
effects on naltrexone compared to placebo whereas the A ⁄ A
and counterbalancing had occurred. This resulted in 7 ⁄ 9 (4 female)
homozygotes had the opposite pattern at a trend level
participants with the G-substitution in the Placebo-Naltrexone group
(Drug · Gene, F1,28 = 3.5, p < 0.01, - ⁄ G OPRM1: Pbo,
and 2 ⁄ 9 (female) in the Naltrexone-Placebo group.
0.9 ± 0.4, Nal, 1.5 ± 0.3, p < 0.05; A ⁄ A OPRM1: Pbo,
Table 1. Breakdown of Participants by Gender and OPRM1 Genotype of A118G Polymorphism
Age of first alcohol intoxication
Current alcohol units ⁄ wk
Heaviest period alcohol units ⁄ wk
Current drinking episodes ⁄ wk
Current alcohol units ⁄ drinking episode*
Lifetime alcohol intoxications
MAST, Michigan Alcoholism Screening Test.
aOne participant homozygous OPRM1 G ⁄ G. Numbers represent mean ± SEM.
bOne participant (male) not genotyped.
*Significant effect of gender, p < 0.05.
SETIAWAN ET AL.
1.3 ± 0.2, Nal, 0.8 ± 0.2, p < 0.10). Based on these obser-
including the covariates of total side effects (from SCL)
vations, the total side effect score was used as a covariate in
and total SHAS ‘‘nauseous'' ratings from the naltrexone
Subjective nausea was also measured with the SHAS item,
For ‘‘euphoria,'' the ANCOVA yielded signiﬁcant Drug ·
‘‘nauseous'' at four times: (1) before any drinks (start); (2)
Gender · Time (F3,81 = 3.0, p < 0.05) and Drug · Gene ·
after seeing the water (see water); (3) after seeing the alcohol
Time interactions (F3,81 = 2.9, p < 0.05). In women, naltrex-
(see alcohol); and (4) after drinking the priming dose of alco-
one decreased ‘‘euphoria'' after both seeing and drinking the
hol (drink alcohol). There was a signiﬁcant Drug · Gene ·
priming dose of alcohol compared to ratings during the pla-
cebo session [Fig. 1A, see alcohol: Pbo, 1.5 ± 0.2 (adjusted
(F3.96 = 3.1, p < 0.05). Here, OPRM1 A ⁄ A women experi-
mean ± SEM); Nal, 1.0 ± 0.2, p < 0.05; drink alcohol:
enced more nausea at the beginning of the naltrexone session
Pbo, 2.1 ± 0.3; Nal, 1.3 ± 0.4, p < 0.05]. Men did not
than the placebo session (start: Pbo, 0.00 ± 0.02; Nal,
report differences in ‘‘euphoria'' between the naltrexone and
0.02 ± 0.02; p < 0.05), while women with the G-allele
placebo sessions at any time (Fig. 1B, p > 0.2). Carriers of
reported feeling more nauseous after consuming the priming
the G-allele also experienced decreased ‘‘euphoria'' during the
dose of alcohol during the naltrexone session when compared
naltrexone session after seeing and drinking the alcohol prim-
ing dose when compared to placebo (Fig. 1C, see alcohol:
0.08 ± 0.05; p < 0.05). Men did not report any signiﬁcant
Pbo, 1.6 ± 0.3; Nal, 0.9 ± 0.3; p < 0.05; drink alcohol:
changes in nausea because of naltrexone at any time over the
Pbo, 2.3 ± 0.3; Nal, 1.1 ± 0.5; p < 0.05), whereas this was
test sessions. Based on these observations, the total SHAS
not seen in the OPRM1 A ⁄ A participants (Fig. 1D, p > 0.2).
‘‘nauseous'' scores over the naltrexone session were also used
Although there were no Gene · Gender interactions, visual
as covariates in subsequent analyses.
comparison of the marginal means suggested that naltrexone-induced reductions in ‘‘euphoria'' were more pronounced inOPRM1 - ⁄ G women than in OPRM1 A ⁄ A women and - ⁄ G
Effects of Naltrexone on Subjective Ratings
men (- ⁄ G women: see alcohol: Pbo, 1.8 ± 0.4; Nal,
Given the imbalance of women in the G-allele group (6 of
0.8 ± 0.3; drink alcohol: Pbo, 2.6 ± 0.4; Nal, 0.9 ± 0.7;
9) as well as a disproportionate number that received placebo
A ⁄ A women: see alcohol: Pbo, 1.3 ± 0.3; Nal, 1.2 ± 0.2,
on the ﬁrst session (7 of 9), we examined subjective ratings in
drink alcohol: Pbo, 1.6 ± 0.3; Nal, 1.6 ± 0.4; - ⁄ G men: see
5-way ANCOVAs (Drug · Gene · Gender · Time · Order).
alcohol: Pbo, 1.3 ± 0.5; Nal, 1.2 ± 0.4, drink alcohol: Pbo,
Means are expressed as the adjusted means (±SEM) after
1.6 ± 0.6; Nal, 1.6 ± 0.9).
score (mean±SEM) 1.50
score (mean±SEM) 1.50
score (mean±SEM) 1.50
Fig. 1. Effects of naltrexone on visual analogue scale (VAS) ‘‘euphoria'' by gender and OPRM1 genotype. Placebo (grey diamonds) vs. naltrexone (black
squares) in women, N = 19a (A), men, N = 17b,c (B), and participants with OPRM1 - ⁄ G, N = 9 (C) or OPRM1 A ⁄ A, N = 27 (D). *Post hoc comparisonp < 0.05 difference from placebo. aOne participant missing ‘‘euphoria'' measure; btwo participants missing Symptom Check List measures; cone participantnot genotyped.
GROUP DIFFERENCES IN NALTREXONE'S EFFECTS
Analysis of SHAS ‘‘high'' ratings resulted in signiﬁcant
alcohol, 2.2 ± 0.2, p < 0.001 for drink alcohol rating com-
Drug · Gender · Gene · Time (F3,84 = 2.8, p < 0.05) and
pared to all other times). There were no signiﬁcant effects of
Drug · Gene · Time · Order (F3,84 = 2.8, p < 0.05) inter-
Drug or Drug interactions on any of the remaining subjective
actions after adjusting for nausea and side effects. Post hoc
comparisons showed a signiﬁcant naltrexone-induced reduc-tion in SHAS ‘‘high'' in G-allele women after consuming the
Effects of Naltrexone on Alcohol Self-Administration
priming dose of alcohol (Fig. 2A, drink alcohol: Pbo,0.04 ± 0.05; Nal, )0.02 ± 0.04; p < 0.01). This decrease
In the group as a whole, the earned alcoholic drinks during
was not signiﬁcant in any other subgroup (at drink alcohol:
the test sessions were related to substance use outside of the
A ⁄ A women, Pbo, 0.07 ± 0.03; Nal, 0.06 ± 0.02; A ⁄ A men,
laboratory. The greater the number of alcoholic drinks
Pbo, 0.08 ± 0.03; Nal, 0.07 ± 0.02; - ⁄ G men, Pbo,
worked for on either session, the greater the lifetime use of
0.02 ± 0.06; Nal, 0.03 ± 0.05), and there were no other
alcohol and the amount of alcohol used during the week prior
signiﬁcant contrasts (Fig. 2B,C,D). However, the Drug ·
to the beginning of each treatment regimen (previous week
Gene · Time · Order interaction indicated that only G-allele
drinking: Pbo, r = 0.402, p < 0.05; Nal, r = 0.503, p <
carriers that received placebo on the ﬁrst day experienced a
0.01; lifetime alcohol: Pbo, r = 0.338, p < 0.05; Nal, r =
reduction in the alcohol-induced ‘‘high'' because of naltrexone
0.365, p < 0.05).
(drink alcohol: Pbo, 0.07 ± 0.04; Nal, 0.02 ± 0.03; p <
Analyses of alcohol self-administration on the PR task did
0.01). Taken together, this would suggest that primarily the
not yield any signiﬁcant effects of naltrexone on breakpoints
OPRM1 - ⁄ G women who received naltrexone on the second
or total number of presses for alcoholic drinks. Covarying
session experience a reduced ‘‘high'' after consuming the
nausea, side effects, and variations in individual alcohol use
alcohol. However, this decrease in alcohol-induced ‘‘high''
(current drinks per drinking episode, current drinks per week,
was not observed in any other gene by gender combination
heaviest period drinks per week, lifetime alcohol intoxica-
that received naltrexone on the second day, suggesting the
tions) did not reveal any signiﬁcant effects. There were no sig-
preferential effect in the G-allele women was not merely an
niﬁcant interactions with either gender or genotype (p ‡ 0.3).
artefact of order.
Consumption of the alcohol priming dose increased subjec-
tive intoxication without any signiﬁcant main effects or inter-actions because of naltrexone, gender, or genotype (VAS
The present study has three main ﬁndings. First, it repli-
‘‘intoxicated'': main effect of Time, F3 = 4.3, p < 0.01; start,
cates a now fairly consistent ﬁnding that naltrexone can
1.2 ± 0.1; see water, 1.2 ± 0.1; see alcohol, 1.2 ± 0.1; drink
diminish stimulant and euphorigenic effects of alcohol.
Women OPRM1 -/G
Men OPRM1 -/G
SHAS "high" score (mean±SEM)
SHAS "high" score (mean±SEM)
Women OPRM1 A/A
Men OPRM1 A/A
SHAS "high" score (mean±SEM) -0.08
SHAS "high" score (mean±SEM)
Fig. 2. Effects of naltrexone on Subjective High Assessment Scale (SHAS) ‘high' by gender and genotype. Placebo (grey diamonds) vs. naltrexone
(black squares) in women with OPRM1 - ⁄ G, N = 6 (A), women with OPRM1 A ⁄ A, N = 14 (B), men with OPRM1 - ⁄ G, N = 3 (C), and men with OPRM1A ⁄ A, N = 14a (D). **Post hoc comparison p < 0.01 difference from placebo. aTwo participants missing Symptom Check List measures.
SETIAWAN ET AL.
Second, it adds to a smaller literature suggesting that these
further suggests that naltrexone does not diminish self-admin-
effects occur preferentially in women and carriers of the G-
istration behavior in social drinkers and extends the ﬁndings
allele for the mu opioid receptor gene, OPRM1; those with
to the use of a PR breakpoint paradigm.
both of these traits might be the most sensitive. Third, the
Like all studies, this one is not without limitations. First,
results do not support the hypothesis that these decrements in
some of the subjects experienced naltrexone-induced nausea,
subjective effects translate to decreased self-administration
particularly those carrying the G-allele. However, only 5% of
behavior in moderate social drinkers.
participants withdrew from the study, and neither nausea nor
The majority of clinical trials with mu opioid receptor
other side effects accounted for signiﬁcant variance in the
antagonists ﬁnd evidence of decreased alcohol use; however,
observed changes in subjective response to alcohol. Second,
the group effects have been weak, seeming to occur in some
the G-allele subgroup was small and not counterbalanced.
patients only (Bouza et al., 2004; Gueorguieva et al., 2007;
However, the population frequency was as seen in other sam-
Kranzler and Van Kirk, 2001; Srisurapanont and Jarusurai-
ples (Gelernter et al., 1999; Oslin et al., 2003), and including
sin, 2005; Streeton and Whelan, 2001). Preliminary evidence
order in the statistical model still yielded preferential effects in
suggests that some of this variability is attributable to genetic
the G-allele carriers. Indeed, the results replicate quite closely
variation of the OPRM1 gene (Anton et al., 2008; Oslin et al.,
Ray and Hutchison's (2007) report that naltrexone reduces
2003). This possibility was supported by an initial laboratory
alcohol's stimulatory and positive subjective effects preferen-
study in moderate to heavy social drinkers; G-allele carriers
tially in social drinkers who carry the G-allele (n = 40, 15 G-
exhibited a greater naltrexone-induced reduction in alcohol's
allele carriers). Third, the PR breakpoint paradigm has been
stimulant and pleasurable effects (Ray and Hutchison, 2007).
used by us successfully before (Barrett et al., 2006, 2008;
The present study provides a ﬁrst laboratory replication.
Venugopalan et al., 2009) but it remains a laboratory model
Gender has also recently emerged as a possible moderator
with attendant artiﬁcial aspects (Davidson et al., 1999).
of naltrexone's effects. The possibility that naltrexone might
Despite this, individual differences in alcohol ingestion were
be more efﬁcacious in women than men was ﬁrst suggested by
well predicted by alcohol use on the street, suggesting that the
a retrospective analysis of clinical trial data (Kiefer et al.,
PR breakpoint measure has validity, demonstrating good sen-
2005). In support, a subsequent prospective study in nontreat-
sitivity to individual differences in substance use patterns. The
ment seeking heavy drinkers suggested that naltrexone
ability to detect naltrexone-induced reductions in alcohol con-
decreased alcohol's stimulant effects in women only (Tidey
sumption may be limited to a heavier drinking population
et al., 2008). In comparison, other clinical trials (Baros et al.,
(Drobes et al., 2003). Fourth, changes in subjective effects
2008; Greenﬁeld et al., 2010) and laboratory studies (David-
were primarily detected post consumption of the priming dose
son et al., 1996; Drobes et al., 2003) suggest that naltrexone is
of alcohol. These results were not unexpected; naltrexone
equally effective in both men and women, although most
may be diminishing the effects of ethanol-induced opioid
studies seem not to have tested for gender differences. Gender
release (Dai et al., 2002; Marinelli et al., 2003, 2005). In previ-
differences, the present study suggests, still warrant further
ous studies, naltrexone affected responses to alcohol but not
placebo beverages or pre-alcohol measures (Ray and Hutchi-
The observation that women with the A118G polymor-
son, 2007; Swift et al., 1994).
phism appear the most sensitive to naltrexone's effects should
In conclusion, the present laboratory study in moderate
be considered preliminary. The subsamples were small, and
social drinkers supports the evidence from heavy and depen-
the interaction was inﬂuenced by an order effect in the case of
dent drinking populations that naltrexone reduces alcohol's
SHAS ‘‘high''. This noted, visual inspection of the ‘‘euphoria''
positive subjective effects and that gender and OPRM1 geno-
data also suggested that the naltrexone-induced reductions
type moderate these effects. These naltrexone-induced
occurred primarily in women with the OPRM1 - ⁄ G polymor-
changes in subjective experience, though, did not translate to
phism. Replication in future studies with larger samples of
decreased alcohol self-administration in this population.
men and women G-allele carriers is required but may help
Additional studies in large, prospectively genotyped, heavier
explain, in part, negative ﬁndings in clinical trials when gender
drinking populations may elucidate further naltrexone's
or genotype effects were examined separately.
effects on motivation to obtain alcohol as well as the inﬂuence
Finally, our results do not support the proposition that nal-
of gender and OPRM1 genotype.
trexone can decrease alcohol self-administration in socialdrinkers, even in subgroups that reported diminished positive
subjective effects. Previous work is consistent with this obser-vation. For example, Drobes and colleagues (2003) reported
This work was supported by operating funds from Glaxo-
that naltrexone decreased ad lib drinking in alcohol-depen-
SmithKline to M.L. Both M.L. and C.B. are recipients of
dent subjects but not in social drinkers. Similarly, naltrexone
research chairs from McGill University. E.S. received scholar-
failed to decrease ad lib alcohol ingestion in Davidson et al.
ships from the Canadian Institutes of Health Research
(1996) while the signiﬁcant effects seen in two other studies
and McGill University Health Centre. We thank Li Bai,
were thought to reﬂect nonspeciﬁc sedation and nausea
Dominique Allard, and Kathleen Auclair for their excellent
(Davidson et al., 1999; de Wit et al., 1999). The present study
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