Promoting Recovery in Alcohol-Dependent Patients
Journal of Substance Abuse Treatment
Volume 36/Number 1, Supplement 1ContentsJanuary 2009
Promoting Recovery in Alcohol-Dependent
An overview of genetic influences in alcoholism
Marc A. Schuckit
S15 The state of pharmacotherapy for the treatment of
James C. Garbutt
S24 CME Posttest
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Promoting Recovery in Alcohol-Dependent Patients
Promoting Recovery in Alcohol-Dependent Patients
Supported by an educational grant from
Alcohol dependence is a complex chronic and relapsing disease with both genetic and environmental origins. Research on the
genetic influences of alcoholism is ongoing. Among other goals, scientists wish to better understand the inheritance of
prominent alcoholism phenotypes and to identify new pharmacotherapeutic targets for development of medications with
improved efficacy and safety. Pharmacotherapies, used in conjunction with psychosocial interventions, are available for the
treatment of alcohol abuse and dependence. Currently, 4 agents are approved by the US Food and Drug Administration
(FDA): disulfiram, acamprosate, oral naltrexone, and extended-release injectable naltrexone. The use of disulfiram, an
aversion-based medication, is limited by the high rates of nonadherence seen with this drug. Acamprosate and oral naltrexone
have both demonstrated an ability to improve outcomes in some clinical trials, but again, adherence issues limit the efficacy of
these agents; behavioral interventions have demonstrated some success toward increased medication adherence and
subsequent improvement in patient outcomes. The development of medications with extended-release dosing formulations,
such as the one available for naltrexone, may also improve patient adherence and thereby outcomes. Further, a number of
medications that act on dopamine and gamma-aminobutyric acid have demonstrated efficacy for the treatment of alcohol
dependence. Ongoing research on these targets and others (eg, neuropeptide Y, cannabinoids) shows promise for delivering
novel agents with better efficacy and tolerability for the treatment of alcohol-dependent patients.
At the conclusion of this educational activity, participants should be better able to:
• Describe the contribution of genetics to an individual's vulnerability to alcohol-related problems
• Evaluate specific gene polymorphisms that are thought to contribute to an individual's vulnerability to alcohol abuse
• Summarize the safety and efficacy of current, FDA-approved pharmacotherapies for the treatment of alcohol dependence
• Appraise ongoing research on the development of novel medications for the treatment of alcohol dependence
This activity has been designed to meet the educational needs of researchers and clinicians involved in the management of
patients with alcohol dependence.
James C. Garbutt, MD
Professor of Psychiatry
University of North Carolina at Chapel Hill
School of Medicine
Chapel Hill, North Carolina
Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S3–S4
0740-5472/09/$ – see front matter
Marc A. Schuckit, MD
Professor of Psychiatry
University of California, San Diego
Director, Alcohol Research Center
Director, Alcohol and Drug Treatment Program
VA San Diego Healthcare System
La Jolla, California
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Marc A. Schuckit, MD
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S4Promoting Recovery in Alcohol-Dependent Patients / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S3–S4
An overview of genetic influences in alcoholism
Marc A. Schuckit, (M.D.)⁎
Department of Psychiatry (116A), University of California, San Diego and the VA San Diego Healthcare System, San Diego, CA 92161-2002, USA
Received 11 January 2008; received in revised form 1 May 2008; accepted 5 May 2008
This review summarizes recent findings from human research regarding genetic influences in alcohol abuse and dependence. Genes
explain about 50% of the vulnerabilities leading to heavy drinking and associated problems. Most genetic influences appear to impact at least
four prominent intermediate characteristics (phenotypes) that interact with environmental events to produce the alcoholism risk: a flushing
response to alcohol; a low level of response to alcohol; personality characteristics that include impulsivity, sensation seeking, and neuronal
and behavioral disinhibition; and through psychiatric symptoms. Polymorphisms potentially related to each phenotype have been identified,
and studies were conducted to evaluate their characteristics in the context of environmental and psychosocial forces. A search is underway to
identify genes that contribute to these phenotypes; the ultimate goals of which are better prediction of how to best prevent heavy drinking and
problems, identifying individuals who may respond best to existing treatments, and development of new therapeutic approaches based on the
biological underpinnings of alcoholism. © 2009 Published by Elsevier Inc.
Keywords: Alcoholism; Genetics; Environment; Phenotypes; Risk factors
Alcoholism, a term referring to alcohol abuse and
dependence, is a typical complex genetically influenced
disorder. Similar to many medical conditions (e.g., diabetes,
hypertension, and most forms of cancer), it is likely that
multiple genes influence a range of intermediate character-
istics that subsequently interact with the environment to
produce the condition (Hyman, 1999; Kendler et al., 1995;
the risk for this condition are likely to vary across families
in others, or levels of blood lipids in yet others (Menzaghi
et al., 2006; Wang & Paigen, 2005). Each of these
vulnerability factors (e.g., hypertension) is also sensitive to
the effects of environmental influences, such as diet and
exercise. Therefore, any gene that affects a specific inter-
mediate characteristic or phenotype, such as hypertension, is
likely to contribute to the vulnerability toward heart disease
but explain only a small proportion of the vulnerability.
The risk for the alcohol use disorders (AUDs; i.e., abuse
and dependence) follows a similar pattern. The steps used in
this article to review how genes contribute to a complex
disorder such as alcoholism include the following: (a)
describing the evidence that supports the influences of genes
overall; (b) presenting the intermediate phenotypes likely to
occur as a consequence of variations (or polymorphisms)
associated with those genes; and (c) highlighting particular
polymorphisms likely to contribute to these intermediate
phenotypes. Although many of the genes of interest have
also been studied in animal models, these will not be
extensively reviewed here, and the reader is referred to
several additional articles (Crabbe, Phillips, Harris, Arends,
& Koob, 2006; Mayfield, Harris, & Schuckit, 2008;
Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
Statement of Conflict of Interest: Dr. Schuckit reports he is on the
Advisory Board of Forest Laboratories, Inc.
Thiswork wassupportedbyfunds provided by theState of Californiafor
medical research on alcohol and substance abuse through the University of
California, San Francisco, and a grant from the CompassPoint Addiction
⁎Department of Psychiatry (116A), University of California, San Diego
and the, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San
Diego, CA 92161-2002, USA. Tel.: +1 858 552 8585 X7978; fax: +1 858
E-mail addresses: firstname.lastname@example.org, email@example.com.
0740-5472/09/$ – see front matter © 2009 Published by Elsevier Inc.
Sommer, Hyytia, & Kiianmaa, 2006). The last part of this
review emphasizes the importance of environmental influ-
ences as they relate to genetic vulnerabilities, with the goal of
developing more focused and effective prevention techni-
ques and treatments.
genetic influences in alcoholism over the past decade was
representative findings from that literature.
3. Evidence that genes impact risk for AUDs
The same steps that might be used in addressing whether
genes contribute to the risk for medical or psychiatric
disorders have been followed in evaluations of AUDs. First,
a review of more than 30 studies revealed strong evidence
that alcoholism runs in families (Cotton, 1979). If a condition
is not familial, it is difficult to view it as having genetic
influences, although running in families does not prove
whether the condition relates to genes, family environment,
Two classical mechanisms are often used to disentangle
the impact of genes versus environment in familial
conditions. The first approach, twin studies, takes advantage
of the fact that pairs of twins are born at the same time and
usually raised together, subsequently experiencing major life
events in childhood at the same ages. However, there are two
kinds of twins: (a) genetically identical, monozygotic or one
egg twins who share 100% of their genes and (b) dizygotic or
two-egg pairs who share 50% of their genes (i.e., the same
proportion as seen for full siblings). Regarding alcoholism,
most studies indicate that whereas dizygotic twins of
alcoholics have approximately the same alcoholism risk as
full siblings, the identical twin of an alcoholic has a
significantly higher risk rate (Kaij, 1960; Kendler, Prescott,
Neale, & Pedersen, 1997; Prescott, Aggen, & Kendler,
1999). Stronger and more consistent evidence supporting
genetic influences for AUDs has been found for males, but
several twin studies support similar conclusions for females
(Cadoret, Troughton, & O'Gorman, 1987; Cadoret, Yates,
Troughton, Woodworth, & Stewart, 1995; Kendler, Heath,
Neale, Kessler, & Eaves, 1992). Overall, investigations of
twins indicate that the proportion of the risk for alcoholism
likely to be explained by genes (also known as the
heritability) is about 50% (McGue, 1999).
The second approach for separating the impact of genes
from that of environment uses adoption studies. Both a
study of half siblings as well as evaluations of adopted-
away children of alcoholics support the conclusion that
genes impact the risk for alcoholism (Goodwin, Schul-
singer, Hermansen, Guze, & Winokur, 1973; Schuckit,
Goodwin, & Winokur, 1972). In fact, a comparison of the
drinking patterns of sons of alcoholic men raised by their
fathers versus those of their full brothers who had been
adopted away indicated that genes may be a more robust
predictor of alcoholism than being raised by an alcoholic
(Goodwin et al., 1974).
The studies of genetic influences in alcoholism are also
notable for the information they offer regarding mechanisms
not likely to contribute to the risk. The fact that the relative
risk for AUDs compared to men and women in the general
population is high in both sons and daughters of alcoholic
men and women does not support a gender-linked mechan-
ism as a major contributor toward these disorders (Cotton,
1979; Eng, Schuckit, & Smith, 2005). Although men overall
carry a high risk for developing AUDs, such gender
differences appear to reflect cultural rather than genetic
mechanisms (Cloninger, Lewis, Rice, & Reich, 1981). In
addition, the family, twin, and adoption studies do not
indicate that simple Mendelian dominant or recessive factors
are major contributors to the AUD risk. Rather, similar to
what was described regarding heart attacks, alcoholism
might be best viewed as a disorder influenced by multiple
genes (i.e., it is polygenic), reflecting multiple characteristics
(i.e., the causes are heterogeneous), and whose causes
include both genes and environment (i.e., it is multifactorial).
4. The importance of multiple intermediate
characteristics of risk: endophenotypes
In the context of AUDs, an intermediate characteristic
might be labeled an endophenotype if the genetically in-
fluenced phenotype is related to alcoholism, can be identified
before the disorder develops, and predicts a high risk for the
condition in the future (Gottesman & Gould, 2003). At least
four such endophenotypes have been identified in alcohol-
ism, with each relating to variations in multiple genes, and
each carrying some response to environmental factors.
One of the most often cited intermediate phenotypes
involves a flush of the skin upon consumption of alcohol,
which is associated with a lower risk for heavy drinking and
alcohol-related problems. This flushing reaction is most
intense among individuals of Asian descent (specifically,
Japanese, Chinese, and Koreans) and is associated with a
lower AUD risk but does not significantly impact on the
vulnerability to problems with other drugs (Li, 2000; Wall &
Ehlers, 1995). The second endophenotype associated with a
higher alcoholism risk is a low level of response (LR) to
alcohol (Schuckit, 2002; Schuckit & Smith, 2000; Schuckit,
Smith, Pierson, Danko, & Beltran, 2006). The low LR
appears to enhance the probability of heavier drinking in
order for the person to achieve the desired effects and thus
increases the risk for AUDs but not other major conditions.
A third intermediate characteristic is associated with a range
of genetically influenced behaviors and neurophysiological
responses variously described as impulsivity, sensation
seeking, behavioral and neuronal disinhibition, behavioral
S6M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
undercontrol, and externalizing behaviors (King, Iacono, &
McGue, 2004; Schuckit & Smith, 2006b; Sher, 1991; Tarter,
Kirisci, Habeych, Reynolds, & Vanyukov, 2004; Zucker,
Ellis, Bingham, & Fitzgerald, 2000). These conditions
increase the risk for a wide range of problematic behaviors
including most substance use disorders and, thus, are not
limited to AUDs (Dick, Bierut, et al., 2006; Slutske et al.,
1998). Finally, although less precisely defined, several
psychiatric conditions, including bipolar disorder, schizo-
phrenia, and several anxiety disorders, can be viewed as
genetically influenced conditions related to an enhanced risk
for substance use disorders in general (D'Souza et al., 2006:
Kessler, Chiu, Demler, & Walters, 2005; Mirin, Weiss,
Griffin, Michael, 1991; Winokur et al., 1996). Additional
mechanisms may operate through genetic variations in
specific neurochemical systems, including opioid receptors
(Barr et al., 2007).
The following sections review the evidence supporting
the importance of alcohol-metabolizing enzymes, the low
LR to alcohol, impulsivity/disinhibition, and some psychia-
tric conditions as relatively independent risk factors for
heavier drinking and alcohol-related problems. For each of
these, as well as for additional mechanisms of enhanced risk,
specific genes potentially related to the phenotypes are
briefly discussed, as is the search for relevant environmental
and cultural factors.
5. Alcohol-metabolizing enzymes and the risk for AUDs
In humans, most of the alcohol consumed is metabolized
by the enzyme alcohol dehydrogenase (ADH) to an active
intermediate metabolite, acetaldehyde, at the rate of about
one standard drink per hour (Li, 2000; Wall & Ehlers, 1995).
At the usual blood alcohol concentrations, the acetaldehyde
is then quickly broken down by the mitochondrial form of
the enzyme aldehyde dehydrogenase (ALDH2).
Between 40% and 50% of Asian individuals have a
is a far less efficient metabolizer of acetaldehyde (Dur-
anceaux et al., 2008; Li, 2000; Wall & Ehlers, 1995). About
10% of Asian men and women have inherited two copies
(alleles) of the deficient gene, and when these homozygous
individuals drink, very high acetaldehyde levels develop,
producing such severe nausea, vomiting, and associated
symptoms that they carry almost no alcoholism risk
(Maezawa, Yamauchi, Toda, Suzuki, & Sakurai, 1995; Wall
& Ehlers, 1995). Thirty percent to 40% of Asians are
heterozygotes for the ALDH2 mutation, carrying both an
an allele with the mutation (Wall & Ehlers, 1995). When they
drink, such heterozygotes experience facial flushing and a
more intense reaction to alcohol, but the alcohol-related
It is hypothesized that the enhanced LR to alcohol may be
associated with fewer drinks per occasion and a lower
alcoholism risk but not the nearly absolute protection seen in
the ALDH2, ALDH2⁎2 homozygotes.
Similar, but less-consistent, data are available regarding
genetic variations (or polymorphisms) in ADH (Duranceaux
et al., 2006, 2008; Kitson et al., 1996; Li, 2000). Two
specific polymorphisms, the ADH1B⁎2 and the ADH1C⁎1
alleles, produce enzymes capable of slightly faster metabo-
lism of alcohol and a potential modest increase in
acetaldehyde levels, with a subsequent enhanced LR to
alcohol (Carr et al., 2002; Duranceaux et al., 2006). It has
been hypothesized that these ADH gene variations might be
associated with a modest decrease in the alcoholism risk in
Asians, Blacks, Jews, and some Europeans (Ehlers, Gilder,
Harris, & Carr, 2001; Neumark et al., 2004; Whitfield et al.,
2001). In addition, at least one investigation reported that the
impact of ADH polymorphisms on the AUD risk might be
moderated by the level of drinking in the society in which an
individual lives (Higuchi et al., 1994).
In summary, a great deal is known about specific genes
that affect the risk for heavy drinking and alcohol-related
problems through polymorphisms in alcohol-metabolizing
enzymes. This mechanism of risk is most robust through the
impact of ALDH in Asian individuals, but alterations in
ADH-related genes might also diminish the risk for AUDs in
6. The LR to alcohol and the risk for AUDs
A low LR to alcohol is a second intermediate phenotype
related to the alcoholism risk that has been studied relatively
intensively (Eng et al., 2005; Erblich & Earleywine, 1999;
Pollock, 1992; Schuckit, 2002; Schuckit, Smith, & Kalmijn,
2005; Schuckit, Smith, Kalmijn, & Danko, 2005; Schuckit,
Smith, Pierson, et al., 2006). Reports by alcoholics that they
required large amounts of alcohol for the desired effects early
in their drinking careers led to the hypothesis that if
individuals drink for effects and more alcohol is required
to achieve the feelings they want, they are more likely to
drink more heavily per occasion (Schuckit, 2002; Schuckit,
Smith, Anderson, & Brown, 2004; Schuckit, Smith, Danko,
Anderson, et al., 2005). This, in turn, is hypothesized to
encourage association with heavy-drinking peers, alter a
person's expectations of what happens when they drink, and
contribute to subsequent acquired tolerance.
A person's LR to alcohol is established by observing
postdrinking-related changes in cognition, motor perfor-
mance, and physiological effects at a given breath alcohol
concentration (Eng et al., 2005; Schuckit & Gold, 1988;
Schuckit, Smith, Kalmijn, & Danko, 2005) or by asking a
person to report the number of standard drinks required for
various effects early in the drinking career using the Self-
Report of the Effects of Alcohol (SRE) questionnaire
(Schuckit, Tipp, Smith, Wiesbeck, & Kalmijn, 1997;
Schuckit, Smith, Waylen et al., 2006; Schuckit et al.,
2007). The LR to alcohol is genetically influenced, with
S7M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
heritabilities of about 0.6 as measured by comparing alcohol
challenge results in identical versus two-egg twins (Heath et
al., 1999; Viken, Rose, Morzorati, Christian, & Li, 2003).
Similar heritabilities for LR have been estimated from the
retrospective SRE measure through comparisons of correla-
tions among first-degree relatives versus unrelated indivi-
duals (Schuckit et al., 2001; Schuckit, Smith, Danko,
Kuperman, et al., 2005). Low LRs have been seen in several
groups at high risk for the development of AUDs including
children or alcoholics, Native Americans, and Koreans (Eng
et al., 2005; Luczak, Elvine-Kreis, Shea, Carr, & Wall, 2002;
Schuckit & Gold, 1988; Schuckit, Smith, Danko, Kuperman,
et al., 2005). Finally, as relevant to the Gottesman and Gould
(2003) criteria for endophenotypes, both alcohol challenge
and SRE-based LRs predict an elevated risk for future heavy
drinking and alcohol-related problems (Heath et al., 1999;
Schuckit & Smith, 2000; Schuckit, Smith, Pierson, et al.,
2006; Volavka et al., 1996).
Several genes have been implicated as potentially
contributing toward heavier drinking, alcohol-related pro-
blems, and AUDs through the low LR to alcohol (Hu et al.,
2005; Schuckit, Smith, & Kalmijn, 2005; Schuckit, Smith,
gamma-aminobutyric acid (GABA) gene cluster on chromo-
some 5, especially GABRA6 and GABRA1 (Dick, Plunkett,
intense reaction to alcohol could occur in some people as a
consequenceof polymorphisms inrelevantGABA genes that
result in less sensitivity to the effects of alcohol on these
receptors and/or to a more rapid and intense development of
session. A second relevant polymorphism occurs with
variations in a gene that regulates aspects of the serotonin
(Barr et al., 2003; Hu et al., 2005; Nilsson et al., 2005;
Schuckit et al., 1999). In this instance, a lower LR could
reflect less 5-HT in the synaptic space between cells as a
consequence of the faster reuptake of serotonin associated
with the l allele. The l allele has also been reported to interact
with environmental forces in affecting drinking (Barr et al.,
both LR and the alcoholism risk (Hu et al., 2005; Schuckit
et al., 1999). Another polymorphism shown to be closely
linked to LR in animals is an analogue of the potassium
channel-related gene, KCNMA1 in humans (Davies et al.,
2003; Schuckit, Wilhelmsen, et al., 2005). In addition,
although less intensively studied, candidates for LR and the
AUD risk include several polymorphisms related to the
second messenger system, including variations in genes
regulating protein kinases and adenylyl cyclase, as well as
genes related to specific neurotransmitters including endo-
genous opiates, dopamine, adenosine, and cannabinoids
(Schuckit, Smith, & Kalmijn, 2005).
Although recognizing that all of the genes together
explain only about 50% of the variance of risk for AUDs or
for LR itself, it is also important to evaluate how LR and
associated genes relate to a range of environmental and
cultural factors in producing heavy drinking and associated
problems. These include drinking patterns among peers,
levels of stress, attitudes toward alcohol, and ways of coping
with stress (Schuckit & Smith, 2006a; Schuckit et al., 2004;
Schuckit, Smith, Danko, Anderson, et al., 2005; Schuckit,
Smith et al., 2008). Structural equation models (SEMs) can
be used to evaluate how endophenotypes and related genes
might relate to these additional factors, with results
supporting the conclusion that a low LR partially explains,
or mediates, the relationship between a family history of
AUDs and alcohol-related outcomes (Schuckit & Smith,
2000; Schuckit et al., 2004). In these modeling studies, LR
appears to have a direct impact on alcohol-related outcomes,
as do peer influences, expectations of the effects of alcohol,
and ways of coping with stress.
In summary, a low LR to alcohol is one of several
genetically influenced characteristics (or endophenotypes)
through which a family history of alcoholism affects alcohol-
related outcomes. Whereas ADH polymorphisms can
increase the LR to alcohol (thus, decreasing the risk of
heavy drinking and problems), the genes contributing to a
low LR in most persons appear to operate through a range of
polymorphisms that affect the impact of alcohol on GABA,
serotonin systems, and second messenger mechanisms.
7. Impulsivity and disinhibition characteristics and the
The third well-established relevant endophenotype in
alcoholism relates to a broad group of disruptive, or
externalizing, behaviors. These include several personality
characteristics (e.g., impulsivity, sensation seeking, and
behavioral undercontrol), impaired brain executive/cognitive
functioning that affects disinhibition and decision making,
and a range of related physiologic findings such as a low
amplitude of the P300 wave of the event-related potential
(Begleiter & Porjesz, 1999; Sher, 1991; Tarter et al., 2004;
Zucker et al., 2000). These characteristics are all genetically
influenced and are seen in individuals at high risk for future
alcoholism and related conditions, and earlier externalizing
behaviors predict later substance-related problems (Hicks,
Krueger, Iacono, Mcgue, & Patrick, 2004; Tarter et al.,
2004). Externalizing attributes contribute to several psychia-
tric conditions including conduct disorder and oppositional
defiant disorder in childhood and the antisocial personality
disorder in adulthood (Hesselbrock & Hesselbrock, 1992;
King et al., 2004; Slutske et al., 1998). They are also
associated with early onset of AUDs, heavier alcohol intake,
and problems related to alcohol and illicit drug use (Dick,
Bierut, et al., 2006; King et al., 2004; Slutske et al., 1998).
Thus, as opposed to the two endophenotypes discussed
above (the flush related to alcohol-metabolizing enzymes
and the LR to alcohol) that relatively uniquely influence the
S8M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
AUD risk, the externalizing and impulsivity-related pheno-
types enhance the risks for a wide range of substance-related
and additional life problems.
Polymorphisms in a variety of genes have been
potentially linked to externalizing characteristics as partial
mediators of the relationship between a family history of
substance use disorders (including alcoholism) and sub-
stance-related adverse outcomes (Schuckit & Smith, 2006a;
Tarter et al., 2004). A polymorphism coding for the two
subunits of the GABRA receptor has been reported to be
associated with an enhanced risk for both AUDs and other
drug-related disorders (Covault, Gelernter, Hesselbrock,
Nellissery, & Kranzler, 2004; Dick, Bierut, et al., 2006;
Edenberg et al., 2004; Lappalainen et al., 2005). A second
gene variation potentially related to externalizing conditions
and alcoholism occurs with the Taq 1A1 allele of the
dopamine 2 receptor gene (DRD2), although not all studies
agree about the importance of this polymorphism (Blum et
al., 1991; Edenberg et al., 1998; Foley et al., 2004;
Gelernter et al., 1991). The inconsistency of findings across
studies of DRD2 might indicate that the association with
substance use disorders is better explained by the
neighboring gene, ANKK1, or that the association is not
specific for AUDs but reflects more broad-based externaliz-
ing phenomena including conduct disorder, dependence on
illicit substances, and smoking/nicotine dependence (Dick
et al., 2007; Edenberg et al., 1998; Ho & Tyndale, 2007). A
third gene variant potentially associated with externalizing
behaviors is the muscarinic acetylcholine receptor CHRM2,
which has a subsequent impact on disinhibition as reflected
directly in behaviors and the amplitude of the P300 wave
(Jones et al., 2006).
As has been noted for the two additional endophenotypes
discussed above, efforts are underway to understand more
about how the broadly defined externalizing phenotypes and
the related genes combine with environmental forces to
enhance the risk for substance-related behaviors. One recent
SEM analysis carried out with 430 adult Caucasian males
indicated that externalizing conditions were related to the
family history of AUDs in even relatively highly functional
men and appeared to affect alcohol-related outcomes in part
through what a person expects to happen when he or she
drinks alcohol, their ways of coping with stress, and drinking
among peers (Schuckit & Smith, 2006b).
In summary, a third type of endophenotype linked to both
the family history of AUDs and alcohol and drug problems
reflect disinhibition and associated phenomena. These
characteristics appear to develop in the context of a range
of polymorphisms in different genes that are relatively
distinct from those that have an impact on alcohol-
metabolizing enzymes and the LR to alcohol. As is true for
all three of these intermediate phenotypes, genes provide
only part of the explanation, and the true impact of these
phenotypes and the associated genes can be understood only
in the context of correlations and interactions with environ-
8. The Importance of several genetically influenced
psychiatric conditions as intermediate characteristics
influencing the alcoholism risk
The risk for AUDs may also be affected by genes that
influence the vulnerability toward several psychiatric con-
ditions. In addition to the antisocial personality disorder
described above, bipolar disorder and schizophrenia carry a
two- to four-fold higher prevalence of a wide range of
substance use disorders, including alcoholism, although the
mechanisms contributing to this association are not fully
understood (D'Souza et al., 2006; Winokur et al., 1996). It is
possible that substance-related conditions might develop as a
consequence of the poor judgment inherent in these
disorders, could occur as a consequence of temporary
impulsivity associated with manic episodes, might reflect a
crossover in the genes that affect those conditions and
substance-related problems, or could develop as a conse-
quence of the use of alcohol and illicit substances to diminish
some of the psychiatric symptoms or side effects of the
medications used to treat these disorders (Schuckit, 2006;
Schuckit, Kelsoe, Braff, & Whilhelmsen, 2003).
There is also a potential link between major depressive
disorders and AUDs, although the relationship here is less
clear (Schuckit, 2006; Nurnberger et al., 2001). Several large
investigations demonstrated no significant link between
AUDs and major depressive disorders once the analyses
controlled for assortative mating and the influence of
temporary substance-induced mood changes (Schuckit,
Smith et al., 2007), although such a relationship may
characterize a link between independent depressive episodes
and substance-related problems may be characteristic of a
subset of families, and not a more general association
(Nurnberger et al., 2001; Winokur et al., 1996). Mechanisms
similar to those described above for schizophrenia and
bipolar disorder might contribute to an enhanced risk for
AUDs in some alcoholics, and alcoholism might develop as
a consequence of efforts to deal with earlier depressive
episodes, although more research is required before conclu-
sions can be drawn.
Finally regarding this brief review of the potential
importance of genes that influence several psychiatric
disorders on the subsequent risk for AUDs and other
substance-related conditions, a relatively extensive literature
exists regarding anxiety conditions. Although some studies
have speculated a 5- to 10-fold enhanced risk for substance-
related disorders in individuals with prior anxiety conditions
(DiSclafani, Finn, & Fein, 2007; Kushner, Sher, & Erickson,
1999), most studies report a more modest relationship with
perhaps a 2- to 3-fold increased risk for AUDs in the context
of preexisting anxiety conditions. The anxiety conditions
with the strongest support in this context include generalized
social phobia, panic disorder, and posttraumatic stress
disorder (Kessler et al., 2005; Thomas, Randall, Book, &
Randall, 2008; Merikangas et al., 1998; Goodwin, Fergus-
son, et al., 2004; Goodwin, Lieb, et al., 2004; Schuckit, Tipp,
S9 M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
Bucholz, et al., 1997). However, when anxiety conditions
and substance-related problems are carefully defined and
temporary substance-induced conditions and assortative
mating are controlled, several large studies have reported
no significant relationship between anxiety conditions and
AUDs (Gilder, Wall, Ehlers, 2004; Goodwin, Fergusson,
et al., 2004; Goodwin, Lieb, et al., 2004).
In summary, the risk for AUDs may operate, in part,
through genes that impact on the risk for several additional
psychiatric disorders. In addition to the antisocial personality
disorder as described in the section on impulsivity, there is
strong evidence that bipolar disorder and schizophrenia carry
enhanced risks for alcohol and drug use disorders. There is
also suggestive evidence that genes that affect several
anxiety conditions might also carry enhanced risks for AUDs
and other substance-related conditions, with more tenuous
support regarding the impact of genetic influences that relate
to major depressive disorders.
9. Additional genetic influences
As recently reviewed elsewhere regarding both human
and animal studies, polymorphisms that affect additional
brain neurochemical systems are also likely to have a major
impact on the AUD risk (Crabbe et al., 2006; Mayfield
et al., 2008; Schuckit, 2002). Perhaps reflecting the impact
that alcohol has on a wide range of neurochemical
parameters, genetic influences that could affect the quality
of intoxication, alcohol-related euphoria, and aversive
effects of alcohol have been hypothesized to relate to
almost every major transmitter system. This brief review
focuses on interesting findings regarding one specific such
system, opioid receptors.
Acute administration of alcohol in animals and in
humans is associated with specific changes in opioid-related
systems, including the release of beta-endorphin and
dopamine, with the latter subsequently impacting on
endogenous opioid systems in key brain regions (Chang
et al., 2007; Sommer et al., 2006). In addition, mice lacking
mu-opioid receptors exhibit a markedly diminished effect of
alcohol, and mu-opioid receptor antagonists are associated
with lower levels of alcohol consumption (Anton et al.,
2006; Barr et al., 2007; Hall, Sora, & Uhl, 2001; Sommer
et al., 2006). Other studies suggest that the impact of opioid
antagonists such as naltrexone on drinking behaviors may
be enhanced or diminished depending upon specific opioid
receptor polymorphisms (van den Wildenberg et al., 2007;
Oslin et al., 2003).
AUDs are fairly typical of most complex, genetically
influenced disorders in medicine and psychiatry. For
alcohol-related conditions, genes explain about 50% of the
variance of risk and appear to have their major effect through
intermediate characteristics including alcohol-metabolizing
enzymes, a low LR to alcohol, and externalizing or
disinhibited behaviors and several other psychiatric condi-
tions. Efforts are underway to identify genes that contribute
to each of these and other intermediate phenotypes and to
explore the manner in which both the endophenotypes and
multiple related genes correlate and interact with environ-
mental and cultural forces to enhance or diminish the risk for
alcoholism (Schuckit & Smith, 2006a).
One ultimate goal of the work described in this article is
to facilitate the development of more focused and effective
prevention techniques. Knowing more about the biological
mechanisms and genes associated with a specific type of
increased vulnerability toward alcoholism could enhance
prevention in several ways. First, children at high risk,
including offspring of alcoholics, could be screened to
determine if their risk is likely to operate through LR,
externalizing, or other phenomena. Of course, such
knowledge does not indicate who will and will not
develop alcoholism, and the family history of this disorder
may be more generally informative regarding overall risk;
however, the genetic information might be a better
measure of the mechanisms of risk involved. Second,
prospective studies of populations at risk, including those
using SEMs, can better inform us about which specific
environmental or cultural factors enhance the risk for that
specific mechanism and those that diminish the risk.
Armed with these data, more focused and effective
preventative trials can be developed.
A second implication of this work is the enhanced
understanding these data might offer in the evaluation of
existing treatments and the development of new therapeutic
approaches for AUDs. The more we know about the specific
neurochemical systems that contribute to alcoholism, the
better our ability to develop new and more effective
pharmacologic and behavioral approaches to help alcoholics
recover from their disorders. Even today, it might be possible
to understand more about which patients are most likely to
respond to which interventions by evaluating the correlation
between specific genotypes and therapeutic responses to
existing medications (Oslin et al., 2003).
Of course, this brief review has not described all potential
intermediate phenotypes and genes likely to be related to
alcohol-related outcomes. Some additional research has
underscored the potential importance of opioid, adenosine,
and cannabinoid systems (Arolfo, Yao, Gordon, Diamond, &
Janak, 2004; Bart et al., 2005; Schuckit, 2002), and others
have described in much more depth the impact of other
influences including the family and sociocultural forces
(Jessor, Costa, Krueger, & Turbin, 2006; Kendler, Gardner,
& Prescott, 1997; Treno, Grube, & Martin, 2003). In the final
analysis, it is likely that increasing knowledge of these
additional potential mechanisms contributing to the risk for
AUDs will follow much the same general model detailed
herein regarding genes, intermediate phenotypes, and
S10M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
This review was supported by an educational grant from
Cephalon, Inc., and Alkermes.
Anton, R. F., O'Malley, S. S., Ciraulo, D. A., Cisler, R. A., Couper, D.,
Donovan, D. M., Gastfriend, D. R., Hosking, J. D., Johnson, B. A.,
LoCastro, J. S., Longabaugh, R., Mason, B. J., Mattson, M. E., Miller,
W. R., Pettinati, H. M., Randall, C. L., Swift, R., Weiss, R. D., Williams,
L. D., & Zweben, A., for COMBINE Study Research Group. (2006).
Combined pharmacotherapies and behavioral interventions for alcohol
dependence. The COMBINE Study: A randomized controlled trial.
JAMA, 295, 2003−2017.
Arolfo, M., Yao, L., Gordon, A., Diamond, I., & Janak, P. (2004). Ethanol
operant self-administration in rats is regulated by adenosine A2
receptors. Alcoholism: Clinical and Experimental Research, 28,
Barr, C., Schwandt, M., Lindell, S., Chen, S., Goldman, D., Suomi, S.,
Higey, J., & Heilig, M. (2007). Association of a functional polymorph-
ism in the mu-opioid receptor gene with alcohol response and
consumption in male rhesus macaques. Archives of General Psychiatry,
Barr, C. S., Newman, T., Lindell, S., Shannon, C., Champoux, M., Lesch,
K., Suomi, S., Goldman, D., & Higley, J. (2005). Interaction between
serotonin transporter gene variation and rearing condition in alcohol
preference and consumption in female primates. Archives of General
Psychiatry, 61, 1146−1152.
Barr, C. S., Newman, T. K., Becker, M. L., Champoux, M., Lesch, K. P.,
Suomi, S. J., Goldman, D., & Higley, J. D. (2003). Serotonin transporter
gene variation is associated with alcohol sensitivity in rhesus macaques
exposed to early-life stress. Alcoholism: Clinical and Experimental
Research, 27, 812−817.
M. (2005). Increased attributable risk related to a functional mu-opioid
receptor gene polymorphism in association with alcohol dependence in
central Sweden. Neuropsychopharmacology, 30, 417−422.
Begleiter, H., & Porjesz, B. (1999). What is inherited in the predisposition
toward alcoholism? A proposed model. Alcoholism: Clinical and
Experimental Research, 23, 1125−1135.
Blum, K., Noble, E. P., Sheridan, P. J., Finley, O., Montgomery, A., Ritchie,
T., Ozkaragoz, T., Fitch, R. J., Sadlack, F., & Sheffield, D. (1991).
Association of the A1 allele of the D2 dopamine receptor gene with
severe alcoholism. Archives of General Psychiatry, 48, 409−416.
Broeckel, U., Hengstenberg, C., Mayer, B., Holmer, S., Martin, L. J.,
Comuzzie, A. G., Blangero, J., Nurnberg, P., Reis, A., Riegger, G. A.,
Jacob, H. J., & Schunkert, H. (2002). A comprehensive linkage analysis
for myocardial infarction and its related risk factors. Nature Genetics,
Cadoret, R. M., Troughton, E., & O'Gorman, T. W. (1987). Genetic and
environmental factors in alcohol abuse and antisocial personality.
Journal of Studies on Alcohol, 48, 1−8.
Cadoret, R. J., Yates, W. R., Troughton, E., Woodworth, G., & Stewart,
M. A. (1995). Adoption study demonstrating two genetic pathways to
drug abuse. Archives of General Psychiatry, 52, 42−52.
Carr, L. G., Foroud, T. M., Stewart, T., Castelluccio, P., Edenberg, H. J., &
Li, T. -K. (2002). Influence of ADH1B polymorphism on alcohol use
and its subjective effects in a Jewish population. American Journal of
Human Genetics, 112, 138−143.
Chang, G., Karatayev, O., Ahsan, R., Avena, N., Lee, C., Lewis, M., Hoebel,
B., & Leibowitz, S. (2007). Effect of ethanol on hypothalamic opioid
peptides, enkenphalin, and dynorphin: Relationship with circulating
triglycerides. Alcoholism: Clinical and Experimental Research, 31,
Cloninger, C. R., Lewis, C., Rice, J., & Reich, T. (1981). Strategies for
resolution of biological and cultural inheritance. In E. S. Gershon, S.
Matthysse, X. O. Breakefield, & R. D. Ciaranello (Eds.), Genetic
research strategies for psychobiology and psychiatry (pp. 319−331).
New York: The Boxwood Press.
Cotton, N. S. (1979). The familial incidence of alcoholism: A review.
Journal of Studies on Alcohol, 40, 89−116.
Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., & Kranzler, H. R.
(2004). Allelic and haplotypic association of GABRA2 with alcohol
dependence.American Journalof MedicalGenetics: B Neuropsychiatric
Genetics, 129B, 104−109.
Crabbe, J. C., Phillips, T. J., Harris, R. A., Arends, M. S., & Koob, G. F.
(2006). Alcohol-related genes: Contributions from studies with
genetically engineered mice. Addiction Biology, 11, 195−269.
Davies, A. G., Pierce-Shimomura, J. T., Kim, H., VanHoven, M. K., Thiele,
T. R., Bonci, A., Bargmann, C. I., & McIntire, S. L. (2003). A central
role of the BK potassium channel in behavioral responses to ethanol in
C. elegans. Cell, 115, 655−666.
Dick, D. M., Bierut, L., Hinrichs, A., Fox, L., Bucholz, K. K., Kramer, J.,
Kuperman, S., Hesselbrock, V., Schuckit, M., Almasy, L., Tischfield, J.,
Porjesz, B., Begleiter, H., Nurnberger, J., Jr., Xuei, X., Edenberg, H. J.,
& Foroud, T. (2006). The role of GABRA2 in risk for conduct disorder
and alcohol and drug dependence across developmental stages. Beha-
vioral Genetics, 36, 577−590.
Dick, D. M., Plunkett, J., Flury Wetherill, L., Xuei, X., Goate, A.,
Hesselbrock, W., Schuckit, M., Crowe, R., Edenberg, H. J., &
Foroud, T. (2006). Association between GABRA1 and drinking
behaviors in the Collaborative Study on the Genetics of Alcoholism
sample. Alcoholism Clinical and Experimental Research, 30,
Dick, D. M., Wang, J. C., Plunkett, J., Hinrichs, A., Bertelsen, S., Budde,
J. P., Goldstein, E. L., Kaplan, D., Edenberg, H. J., Nurnberger, J., Jr.,
Hesselbrock, V., Schuckit, M., Kuperman, S., Tischfield, J., Porjesz,
B., Begleiter, H., Bierut, L. B., & Goate, A. (2007). Family-based
analyses of alcohol dependence yield association with neighboring
gene ANKK1 rather than DRD2. Alcoholism: Clinical and Experi-
mental Research, 31, 1645−1653.
DiSclafani, V., Finn, P., & Fein, G. (2007). Psychiatric comorbidity in long-
term abstinent alcoholic individuals. Alcoholism: Clinical and Experi-
mental Research, 31, 795−803.
D'Souza, D., Gil, R., Madonick, S., Perry, E., Forselius-Bielen, K., Braley,
(2006). Enhanced sensitivity to the euphoric effects of alcohol in
schizophrenia. Neuropsychopharmacology, 31, 2767−2775.
Duranceaux, N. C. E., Schuckit, M. A., Eng, M. Y., Robinson, S. K., Carr,
L. G., & Wall, T. L. (2006). Association of variations in alcohol
dehydrogenase genes with the level of response to alcohol in non-
Asians. Alcoholism: Clinical and Experimental Research, 30,
Duranceaux, N. C. E., Schuckit, M. A., Luczak, S. E., Eng, M. Y., Carr,
L. G., & Wall, T. L. (2008). Ethnic differences in level of response to
alcohol between Chinese Americans and Korean Americans. Journal
of Studies on Alcohol and Drugs, 69, 227−234.
Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O.,
Crowe, R., Goate, A., Hesselbrock, V., Jones, K. A., Kwon, J., Li, T. -K.,
Nurnberger, J. I., Jr., O'Connor, S. J., Reich, T., Rice, J., Schuckit, M.,
Porjesz, B., Foroud, T., & Begleiter, H. (2004). Variations in GABRA2
encoding the 2 subunit of the GABA-A receptor are associated with
alcohol dependence and with brain oscillations. American Journal of
Human Genetics, 74, 705−714.
Edenberg, H. J., Foroud, T., Koller, D. L., Goate, A., Rice, J., Van
Eerdewegh,P., Reich, T., Cloninger, C. R., Nurnberger, J. I., Kowalczuk,
M., Wu, B., Li, T. -K., Conneally, P. M., Tischfield, J. A., Wu, W.,
Shears, S., Crowe, R., Hesselbrock, V., Schuckit, M., Porjesz, B., &
Begleiter, H. (1998). A family-based analysis of the association of the
dopamine D2 receptor (DRD2) with alcoholism. Alcoholism: Clinical
and Experimental Research, 22, 505−512.
S11M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
Ehlers, C. L., Gilder, D. A., Harris, L., & Carr, L. (2001). Association of the
ADH2*3 allele with a negative family history of alcoholism in African
American young adults. Alcoholism: Clinical and Experimental
Research, 25, 1773−1777.
Eng, M. Y., Schuckit, M. A., & Smith, T. L. (2005). The level of response to
alcohol in daughters of alcoholics and controls. Drug and Alcohol
Dependence, 79, 83−93.
Erblich, J., & Earleywine, M. (1999). Children of alcoholics exhibit
attenuated cognitive impairment during an ethanol challenge. Alcohol-
ism: Clinical and Experimental Research, 23, 476−482.
Foley, P. F., Loh, E. -W., Innes, D. J., Williams, S. M., Tannenberg, A. E. G.,
Harper, C. G., & Dodd, P. R. (2004). Association studies of
neurotransmitter gene polymorphisms in alcoholic Caucasians. Annals
of New York Academy of Sciences, 1025, 39−46.
Gelernter, J., O'Malley, S., Risch, N., Kranzler, H. R., Krystal, J.,
Merikangas, K., Kennedy, J. L., & Kidd, K. K. (1991). No association
between an allele at the D2 dopamine receptor gene (DRD2) and
alcoholism. JAMA, 266, 1801−1807.
Gilder, D. A., Wall, T. L., & Ehlers, C. L. (2004). Comorbidity of select
anxiety and affective disorders with alcohol dependence in Southwest
California Indians. Alcoholism: Clinical and Experimental Research,
Goodwin, D. W., Schulsinger, F., Hermansen, L., Guze, S. B., & Winokur,
G. (1973). Alcohol problems in adoptees raised apart from alcoholic
biological parents. Archives of General Psychiatry, 28, 238−243.
Goodwin, D.W., Schulsinger,F., Moller, N.,Hermansen, L.,Winokur, G.,&
Guze, S. B. (1974). Drinking problems in adopted and nonadopted sons
of alcoholics. Archives of General Psychiatry, 31, 164−169.
Goodwin, R. D., Fergusson, D. M., & Horwood, L. J. (2004). Association
between anxiety disorders and substance use disorders among young
persons: Results of a 21-year longitudinal study. Journal of Psychiatric
Research, 38, 295−304.
Goodwin, R. D., Lieb, R., Hoefler, M., Pfister, H., Bittner, A., Beesdo, K., &
Wittchen, H. -U. (2004). Panic attack as a risk factor for severe
psychopathology. American Journal of Psychiatry, 161, 2207−2214.
Gottesman, I., & Gould, T. D. (2003). The endophenotype concept in
psychiatry: Etymology and strategic intentions. American Journal of
Psychiatry, 160, 636−645.
Hall, P. S., Sora, I., & Uhl, G. R. (2001). Ethanol consumption and reward
are decreased in mu-opiate receptor knockout mice. Psychopharmacol-
ogy, 15, 43−49.
Heath, A. C., Madden, P. A., Bucholz, K. K., Dinwiddie, S. H., Slutske,
W. S., Bierut, L. J., Rohrbaugh, J. W., Statham, D. J., Dunne, M. P.,
Whitfield, J. B., & Martin, N. G. (1999). Genetic differences in alcohol
sensitivity and the inheritance of alcoholism risk. Psychological
Medicine, 29, 1069−1081.
Hesselbrock, M., & Hesselbrock, V. M. (1992). Relationship of family
history, antisocial personality disorder and personality traits in young
men at risk for alcoholism. Journal of Studies on Alcohol, 53, 619−625.
Hicks, B. M., Krueger, R. F., Iacono, W. G., McGue, M., & Patrick, C. J.
(2004). Family transmission and heritability of externalizing disorders:
A twin-family study. Archives of General Psychiatry, 61, 922−928.
Higuchi, S., Matsushita, S., Imazeki, H., Kinoshita, T., Takagi, S., & Kono,
H. (1994). Aldehyde dehydrogenase genotypes in Japanese alcoholics.
The Lancet, 343, 741−742.
Ho, M. K., & Tyndale, R. F. (2007). Overview of the pharmacogenomics of
cigarette smoking. Pharmacogenomics Journal, 7, 81−98.
Hu, X., Oroszi, G., Chun, J., Smith, T. L., Goldman, D., & Schuckit, M. A.
(2005). Expanded evaluation of the relationship of four alleles to the
level of response to alcohol and the alcoholism risk. Alcoholism:
Clinical and Experimental Research, 29, 8−16.
Hyman, S. E. (1999). Introduction to the complex genetics of mental
disorders. Biological Psychiatry, 45, 518−521.
Jessor, R., Costa, F. M., Krueger, P. M., & Turbin, M. S. (2006). A
developmental studyof heavy episodic drinkingamong college students:
The role of psychosocial and behavioral protective and risk factors.
Journal of Studies on Alcohol, 67, 86−94.
Jones, K. A., Porjesz, B., Almasy, L., Bierut, L., Dick, D., Goate, A.,
Hinrichs,A.,Rice,J. P.,Wang,J. C., Bauer,L.O.,Crowe, R., Foroud,T.,
Hesselbrock, V., Kuperman, S., Nurnberger, J., Jr., O'Connor, S. J.,
Rohrbaugh, J., Schuckit, M. A., Tischfield, J., Edenberg, H. J., &
Begleiter, H. (2006). A cholinergic receptor gene (CHRM2) affects
event related oscillations. Behavioral Genetics, 36, 627−639.
Kaij, L. (1960). Alcoholism in twins. Stockholm: Almqvist & Wiksell.
Kendler, K. S., Gardner, C. O., & Prescott, C. A. (1997). Religion,
psychopathology, and substance use and abuse: A multimeasure,
genetic–epidemiologic study. American Journal of Psychiatry, 154,
Kendler, K. S., Heath, A. C., Neale, M. C., Kessler, R. C., & Eaves, L. J.
(1992). A population-based twin study of alcoholism in women. JAMA,
Kendler, K. S., Prescott, C. A., Neale, M. C., & Pedersen, N. L. (1997).
Temperance board registration for alcohol abuse in a national sample of
Swedish male twins, born 1902 to 1949. Archives of General Psychiatry,
Kendler, K. S., Walters, E. E., Neale, M. C., Kessler, R. C., Heath, A. C., &
Eaves, L. J. (1995). The structure of the genetic and environmental risk
factorsfor sixmajorpsychiatricdisordersin women:Phobia,generalized
anxiety disorder, panic disorder, bulimia, major depression, and
alcoholism. Archives of General Psychiatry, 52, 374−383.
Kessler, R. C., Chiu, W. T., Demler, O., & Walters, E. E. (2005). Prevalence,
severity, and comorbidity of 12-month DSM-IV disorders in the National
Comorbidity Survey Replication. Archives of General Psychiatry, 62,
King, S. M., Iacono, W. G., & McGue, J. (2004). Childhood externalizing
and internalizing psychopathology in the prediction of early substance
use. Addiction, 99, 1548−1559.
Kitson, K. E., Bosron, W., Pares, X., Kindros, K., Weiner, H., & Li, T. -K.
(1996). Ethanol and acetaldehyde metabolism: Past, present, and future.
Alcoholism: Clinical and Experimental Research, 20, 82A−92A.
Kushner, M. G., Sher, K. J., & Erickson, D. J. (1999). Prospective analysis
of the relation between DSM-III anxiety disorders and alcohol use
disorders. American Journal of Psychiatry, 156, 723−732.
Lappalainen, J., Krupitsky, E., Remizov, M., Pchelina, S., Taraskina, A.,
Zvartau, E., Somberg, L. K., Covault, J., Kranzler, H. R., Krystal, J., &
Gelernter, J. (2005). Association between alcoholism and gamma-amino
butyric acid alpha2 receptor subtype in a Russian population. Alcohol-
ism: Clinical and Experimental Research, 29, 493−498.
Li, T. -K. (2000). Pharmacogenetics of responses to alcohol and genes that
influence alcohol drinking. Journal of Studies on Alcohol, 61, 5−12.
Luczak, S. E., Elvine-Kreis, B., Shea, S. H., Carr, L. G., & Wall, T. L.
(2002). Genetic risk for alcoholism relates to level of response to alcohol
in Asian-American men and women. Journal of Studies on Alcohol, 63,
Maezawa, Y., Yamauchi, M., Toda, G., Suzuki, H., & Sakurai, S. (1995).
Alcohol-metabolizing enzyme polymorphisms and alcoholism in Japan.
Alcoholism: Clinical and Experimental Research, 19, 951−954.
Mayfield, R. D., Harris, R. A., & Schuckit, M. A. (2008). Genetic factors
influencing alcohol dependence. British Journal of Pharmacology, 154,
McGue, M. (1999). The behavioral genetics of alcoholism. Current
Directions in Psychological Science, 8, 109−115.
Menzaghi, C., Coco, A., Salvemini, L., Thompson, R., DeCosmo, S.,
Doria, T., & Trischitta, V. (2006). Heritability of serum resistin and its
genetic correlation with insulin resistance-related features in non-
diabetic Caucasians. Journal of Clinical Endocrinol Metabolism, 91,
Merikangas, K. R., Stevens, D. S., Fenton, B., Stolar, M., O'Malley, S.,
Woods,S. W.,& Risch, N.(1998). Comorbidityandfamilial aggregation
of alcoholism and anxiety disorders. Psychological Medicine, 28,
Mirin, S. M., Weiss, R. D., Griffin, M. L., & Michael, J. L. (1991).
Psychopathology in drug abusers and their families. Comprehensive
Psychiatry, 32, 36−51.
S12M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
Neumark, Y., Friedlander, Y., Durst, R., Leitersdorf, E., Jaffe, D.,
Ramchandani, V., O'Connor, S., Carr, L., & Li, T. -K. (2004). Alcohol
dehydrogenase polymorphisms influence alcohol-elimination rates in a
male Jewish population. Alcoholism: Clinical and Experimental
Research, 28, 10−14.
Nilsson, K., Sjoberg, R., Damberg, M., Alm, P., Ohrvik, J., Leppert, J.,
Lindstrom, L., & Oreland, L. (2005). Role of the serotonin transporter
gene and family function in adolescent alcohol consumption. Alcohol-
ism: Clinical and Experimental Research, 29, 564−570.
Nurnberger, J. I., Jr., Foroud, T., Flury, L., Su, J., Meyer, E. T., Hu, K.,
Crowe, R., Edenberg, H., Goate, A., Bierut, L., Reich, T., Schuckit, M.,
& Reich, W. (2001). Evidence for a locus on chromosome 1 that
influences vulnerability to alcoholism and affective disorder. American
Journal of Psychiatry, 158, 718−724.
Oslin, D., Berrettini, W., Kranzler, H., Pettinati, H., Gelernter, J., Volpicelli,
J. R., & O'Brien, C. P. (2003). A functional polymorphism of the mu
opioid receptor gene is associated with naltrexone response in alcohol-
dependent patients. Neuropsychopharmacology, 28, 1546−1552.
Pollock, V. E. (1992). Meta-analysis of subjective sensitivity to alcohol in
sons of alcoholics. American Journal of Psychiatry, 149, 1534−1538.
Prescott, C. A., Aggen, S. H., & Kendler, K. S. (1999). Sex differences in the
sources of genetic liability to alcohol abuse and dependence in a
population-based sample of U.S. twins. Alcoholism: Clinical and
Experimental Research, 23, 1136−1144.
Schuckit, M. A. (2002). Vulnerability factors for alcoholism. In K. Davis
(Ed.), Neuropsychopharmacology: The fifth generation of progress,
chapter 98 (pp. 1399−1411). Baltimore: Lippincott Williams & Wilkins
Schuckit, M. A. (2006). Comorbidity between substance use disorders and
psychiatric conditions. Addiction, 101, 78−88.
Schuckit, M. A., & Gold, E. O. (1988). A simultaneous evaluation of
multiple markers of ethanol/placebo challenges in sons of alcoholics and
controls. Archives of General Psychiatry, 45, 211−216.
Schuckit, M. A., & Smith, T. L. (2000). The relationships of a family history
of alcohol dependence, a low level of response to alcohol, and six
domains of life functioning to the development of alcohol use disorders.
Journal of Studies on Alcohol, 61, 827−835.
Schuckit, M. A., & Smith, T. L. (2006). An evaluation of the level
of response to alcohol, externalizing symptoms, and depressive
symptoms as predictors of alcoholism. Journal of Studies on Alcohol,
Schuckit, M. A., & Smith, T. L. (2006). The relationship of behavioral
undercontrol to alcoholism in higher-functioning adults. Drug and
Alcohol Review, 25, 393−402.
Schuckit, M. A., Smith, T. L., Danko, G. P., Pierson, J., Trim, R.,
Nurnberger, J. L., Jr., Kramer, J., Kuperman, S., Bierut, L. J., &
Hesselbrock, V. (2007). A comparison of factors associated with
substance-induced versus independent depressions. Journal of Studies
on Alcohol and Drugs, 68, 805−812.
Schuckit, M. A., Edenberg, H. J., Kalmijn, J., Flury, L., Smith, T. L., Reich,
T., Bierut, L., Goate, A., & Foroud, T. (2001). A genome-wide search for
genes that relate to a low level of response to alcohol. Alcoholism:
Clinical and Experimental Research, 25, 323−329.
Schuckit, M. A., Goodwin, D. W., & Winokur, G. (1972). A study of
alcoholism in half-siblings. American Journal of Psychiatry, 128,
Schuckit, M. A., Kelsoe, J. R., Braff, D. L., & Wilhelmsen, K. C. (2003).
Some possible genetic parallels across alcoholism, bipolar disorder and
schizophrenia. Journal of Studies on Alcohol, 64, 157−159.
Schuckit, M. A., Mazzanti, C., Smith, T. L., Ahmed, U., Radel, M., Iwata,
N., & Goldman, D. (1999). Selective genotyping for the role of 5-HT2A,
Schuckit, M. A., Smith, T. L., Anderson, K. G., & Brown, S. A. (2004).
Testing the level of response to alcohol: Social information processing
model of alcoholism risk—A 20-year prospective study. Alcoholism:
Clinical and Experimental Research, 28, 1881−1889.
Schuckit, M. A., Smith, T. L., Danko, G., Kuperman, S., Bierut, L. J., &
Hesselbrock, V. (2005). Correlations among first-degree relatives for
responses on the Self-Rating of the Effects of Alcohol questionnaire in
teenagers. Journal of Studies on Alcohol, 66, 62−65..
Schuckit, M. A., Smith, T. L., Danko, G. P., Anderson, K. G., Brown, S. A.,
Kuperman, S., Kramer, J., Hesselbrock, V., & Bucholz, K. (2005).
Evaluation of a level of response to alcohol-based structural equation
model in adolescents. Journal of Studies on Alcohol, 66, 174−184.
Schuckit, M. A., Smith, T. L., Danko, G. P., Pierson, J., Hesselbrock, V.,
Bucholz, K. K., Kramer, J., Kuperman, S., Dietiker, C., Brandon, R., &
Chan, G. (2007). The ability of the Self-Rating of the Effects of Alcohol
(SRE) Scale to predict alcohol-related outcomes five years later. Journal
of Studies on Alcohol and Drugs, 68, 371−378.
Schuckit, M. A., Smith, T. L., & Kalmijn, J. (2005). The search for genes
contributing to the low level of response to alcohol: Patterns of findings
across studies. Alcoholism: Clinical and Experimental Research, 28,
Schuckit, M. A., Smith, T. L., Kalmijn, J., & Danko, G. P. (2005). A cross-
generational comparison of alcohol challenges at about age 20 in 40
Schuckit, M. A., Smith, T. L., Pierson, J., Danko, G. P., & Beltran, I. (2006).
The relationships among the level of response (LR) to alcohol and the
number of alcoholic relatives in predicting alcohol-related outcomes.
Alcoholism: Clinical and Experimental Research, 30, 1308−1314.
Schuckit, M. A, Smith, T. L., Trim, R., Kreikebaum, S., Hinga, B., & Allen,
R. (2008). Testing the level of response to alcohol-based model of heavy
drinking and alcohol problems in the offspring from the San Diego
Prospective Study. Journal of Studies on Alcohol and Drugs, 69,
Schuckit, M. A., Smith, T. L., Waylen, A., Horwood, J., Danko, G. P.,
Hibbeln, J. R., Davis, J. M., & Pierson, J. (2006). An evaluation of the
performance of the SRE questionnaire in 12- and 35-year-olds. Journal
of Studies on Alcohol, 67, 841−850.
Schuckit, M. A., Tipp, J. E., Bucholz, K. K., Nurnberger, J. I., Jr.,
Hesselbrock, V. M., Crowe, R. R. A., & Kramer, J. (1997). The life-time
rates of three major mood disorders and four major anxiety disorders in
alcoholics and controls. Addiction, 92, 1289−1304.
Schuckit, M. A., Tipp, J. E., Smith, T. L., Wiesbeck, G. A., & Kalmijn, J.
(1997). The relationship between Self-Rating of the Effects of Alcohol
and alcohol challenge results in ninety-eight young men. Journal of
Studies on Alcohol, 58, 397−404.
Schuckit, M. A., Wilhelmsen, K., Smith, T. L., Feiler, H. S., Lind, P., Lange,
L. A., & Kalmijn, J. (2005). Autosomal linkage analysis for the level of
response to alcohol. Alcoholism: Clinical and Experimental Research,
Sher, K. J. (1991). Children of alcoholics: A critical appraisal of theory and
research. Chicago: University of Chicago Press.
Slutske, W., Heath, A., Dinwiddie, S., Madden, P., Bucholz, K., Dunne, M.,
Statham, D., & Martin, N. (1998). Common genetic risk factors for
conduct disorder and alcohol dependence. Journal of Abnormal
Psychology, 107, 363−374.
Sommer, W., Hyytia, P., & Kiianmaa, K. (2006). The alcohol-preferring AA
and alcohol-avoiding ANA rats: Neurobiology of the regulation of
alcohol drinking. Addiction Biology, 11, 289−309.
Tarter, R. E., Kirisci, L., Habeych, M., Reynolds, M., & Vanyukov, M.
(2004). Neurobehavior disinhibition in childhood predisposes boys to
substance use disorder by young adulthood: Direct and mediated
etiologic pathways. Drug and Alcohol Dependence, 73, 121−132.
Thomas, S. E., Randall, P. K., Book, S. W., & Randall, C. L. (2008). A
complex relationship between co-occurring social anxiety and alcohol
use disorders: What effect does treating social anxiety have on drinking?
Alcoholism: Clinical and Experimental Research, 32, 77−84.
Treno, A. J., Grube, J. W., & Martin, S. E. (2003). Alcohol availability as a
predictor of youth drinking and driving: A hierarchical analysis of
survey and archival data. Alcoholism: Clinical and Experimental
Research, 27, 835−840.
S13M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
van den Wildenberg, E., Wiers, R., Dessers, J., Janssen, R., Lambrichs, E.,
Smeets, H., & van Breukelen, G. (2007). A functional polymorphism of
the μ-opiod receptor gene (OPRMI) influences cue-induced craving for
alcohol in male heavy drinkers. Alcoholism: Clinical and Experimental
Research, 31, 1−10.
Viken, R. J., Rose, R. J., Morzorati, S. L., Christian, J. C., & Li, T. -K.
(2003). Subjective intoxication in response to alcohol challenge:
Heritability and covariation with personality, breath alcohol level, and
drinking history. Alcoholism: Clinical and Experimental Research, 27,
Volavka, J., Czobor, P., Goodwin, D. W., Gabrielli, W. F., Jr., Penick,
E. C., Medrick, S. A., Jensen, P., Knope, J., & Schulsinger, F.
(1996). The electroencephalogram after alcohol administration in
high-risk men and the development of alcohol use disorders 10
years later: Preliminary findings. Archives of General Psychiatry,
Wall, T. L., & Ehlers, C. L. (1995). Genetic influences affecting alcohol use
among Asians. Alcohol Health and Research World, 19, 184−189.
Wall, T. L., Johnson, M. L., Horn, S. M., Carr, L. G., Smith, T. L., &
Schuckit, M. A. (1999). Evaluation of the Self-Rating of the Effects of
Alcohol form in Asian-Americans with aldehyde dehydrogenase
polymorphisms. Journal of Studies on Alcohol, 60, 784−789.
Wang, X., & Paigen, B. (2005). Genetics of variation in HDL cholesterol in
humans and mice. Circ Research, 96, 27−42.
Whitfield, J. B., Zhu, G., Duffy, D. L., Birley, A. J., Madden, P. A. F., Heath,
A. C., & Martin, N. G. (2001). Variation in alcohol pharmacokinetics as
a risk factor for alcohol dependence. Alcoholism: Clinical and
Experimental Research, 25, 1257−1263.
Winokur, G., Coryell, W., Endicott, J., Keller, M., Akiskal, H., & Solomon,
D. (1996). Familial alcoholism in manic–depressive (bipolar) disease.
American Journal of Medical Genetics, 67, 197−201.
Zucker, R. A., Ellis, D., Bingham, C. R., & Fitzgerald, H. E. (2000). The
development of alcoholic subtypes risk variation among alcoholic
families during the childhood years. In S. Abbott (Ed.), Children of
alcoholics: Selected readings, Vol. II. (pp. 243−264). Rockville, MD:
National Association of Children of Alcoholics.
S14M.A. Schuckit / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S5–S14
The state of pharmacotherapy for the treatment of alcohol dependence
James C. Garbutt, (M.D.)⁎
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Received 11 January 2008; received in revised form 22 August 2008; accepted 23 August 2008
Pharmacotherapy, in conjunction with psychosocial interventions, is emerging as a valuable tool for alcohol dependence treatment.
Currently, four agents are approved by the Food and Drug Administration for this purpose: disulfiram, acamprosate, oral naltrexone, and the
once-monthly injectable, extended-release naltrexone. All four agents have demonstrated some ability to reduce drinking and/or increase time
spent abstinent, but results have not always been consistent. Except disulfiram, which has an aversive mechanism of action, effective
pharmacotherapies for alcohol dependence are thought to work by blocking the rewards of alcohol or stabilizing systems dysregulated by
chronic alcohol intake. Topiramate and baclofen have also demonstrated some efficacy in treating alcohol dependence. The efficacies of
many of these regimens are modest and are limited by patient nonadherence to treatment and disease heterogeneity. Pharmacotherapeutic
effectiveness could be enhanced through increased knowledge of the pathophysiology of alcohol dependence, through the identification of
predictors of response to specific medications, and by modalities that improve medication adherence. © 2009 Published by Elsevier Inc.
Keywords: Naltrexone; Extended-release naltrexone; Acamprosate; Disulfiram; Pharmacotherapy; Alcohol dependence
Alcohol dependence is a chronic, relapsing disorder with
myriad negative consequences for social, mental, and
physical health. Pharmacotherapy, in conjunction with
psychosocial interventions, is a safe and effective way of
assisting with recovery. Study results and outcome variables
differ, but available Food and Drug Administration (FDA)-
approved agents such as disulfiram, acamprosate, and oral
and extended-release naltrexone can decrease both the
frequency of alcohol consumption and the amount of alcohol
consumed and increase abstinence rates. With the exception
of disulfiram, the effective pharmacotherapies for alcohol
dependence either block the rewarding effects of alcohol or
stabilize systems dysregulated by chronic alcohol intake,
which, in theory, makes it easier for patients to attain
abstinence or greatly reduce alcohol consumption.
Alcohol has diverse effects on the brain. Although these
actions are covered in great detail elsewhere (Chastain, 2006;
Durazzo & Meyerhoff, 2007; Prendergast & Little, 2007), a
basic overview is useful here before discussing pharma-
cotherapies for alcohol dependence. The molecular site(s) of
action of alcohol in the brain is still not clear. However,
alcohol has a multiplicity of acute effects, and because the
central nervous system is exposed to alcohol over time, a
number of neuroadaptational changes occur. Alcohol acutely
facilitates GABAAtransmission, inhibits glutamatergic N-
methyl-D-aspartic acid (NMDA) receptors, and facilitates
noradrenergic, serotonergic, dopaminergic, opioidergic, and
endocannabinoid signaling. Activation of the mesolimbic
and mesocortical dopaminergic pathways via intermediate
neurotransmitters, including endogenous opioids, is thought
to play a key role in mediating acute reinforcing properties of
alcohol, as it does for other drugs of abuse (Kenna, McGeary,
& Swift, 2004). Medications that target the acute rewarding
effects of alcohol, for example, naltrexone, would be
anticipated to disrupt the biochemical processes involved
in these effects. Recently, there has been greater interest in
Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
Statementof Conflictof Interest: Dr Garbutthas receivedgrants/research
support from Alkermes, Inc., Bristol-Myers Squibb Co., and Forest
Laboratories, Inc. He is a Consultant for Alkermes, Inc., Cephalon, Inc.,
and Forest Laboratories, Inc. He is on the Speakers Bureaus of Cephalon,
Inc. and Forest Laboratories, Inc.
This work was supported by an educational grant from Cephalon, Inc.,
⁎Corresponding author. University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA. Tel.: +1 919 966 4652; fax: +1 919 966 5628.
E-mail address: firstname.lastname@example.org.
0740-5472/09/$ – see front matter © 2009 Published by Elsevier Inc.
the role of the negative reinforcing properties of alcohol in
the development of alcohol dependence—a process that
appears to arise over time in response to neuroadaptations to
chronic alcohol (Koob, 2003). These adaptations likely
contribute to the maintenance of dependent-level drinking.
For example, alcohol-dependent patients show evidence of
dysfunction in dopaminergic systems with decreased D2
receptor binding in striatum compared with healthy controls,
suggesting impaired ability to process hedonic stimuli
(Volkow et al., 1996). In addition, in animal models, chronic
ethanol intake alters glutaminergic neurotransmission pre-
and postsynaptically and can alter gene expression and the
protein composition of NMDA receptors in the central
nucleus of the amygdala (Roberto et al., 2004; Roberto,
Bajo, Crawford, Madamba, & Siggins, 2006). Furthermore,
there is evidence that chronic ethanol leads to heightened
activity in central stress-regulating systems, including
corticotrophin-releasing factor (CRF; Koob, 2003). These
changes likely represent part of the pathophysiological
process of alcohol dependence and contribute to the
compulsive use patterns and loss of control over drinking
seen in alcoholism. These neurobiological changes also
represent molecular targets for pharmacotherapy.
2. U.S. FDA-approved medications
Disulfiram, unlike more recently developed pharma-
cotherapies for alcohol dependence, does not primarily
affect neurobiological systems, although its actions on
dopamine-β-hydroxylase affect dopamine and norepinephr-
ine systems and may contribute to its therapeutic actions
(Weinshenker & Schroeder, 2007). The primary action of
disulfiram is its ability to inhibit the action of aldehyde
dehydrogenase, preventing the conversion of acetaldehyde
to acetate. When acetaldehyde accumulates after alcohol
consumption, it causes flushing, throbbing headache,
nausea, vomiting, and chest pain. Thus, the mechanism of
action for disulfiram is aversive, reducing alcohol intake by
producing unpleasant consequences in response to even low
levels of alcohol consumption (Disulfiram (Antabuse)
Prescribing Information, 2005; Swift, 1999).
The landmark disulfiram trial, a Veterans Administration
Cooperative Study of disulfiram, was conducted in the mid
1980s. Prior to that, few controlled, and even fewer blinded,
studies had been conducted to assess the efficacy of
disulfiram in alcohol-dependent patients. Disulfiram posed
a unique challenge to study design because disulfiram is
thought to work as much by the threat of adverse
consequences as by their actual occurrence following
ingestion of alcohol. For this reason, participants were
assigned to receive either an active dose of disulfiram (250
mg, n = 202), a dose of disulfiram so low as to be inactive (1
mg, n = 204), or the vitamin riboflavin (n = 199). Patients
were told what they were receiving (“vitamin” or “dis-
ulfiram”), but not which disulfiram dose. Researchers were
also blinded to the dose of disulfiram. Disulfiram 250 mg
had no effect on the number of patients who maintained
abstinence or the time to first drink, but among patients who
were nonabstinent, those who had a complete set of
assessment interviews and who received disulfiram 250 mg
had significantly fewer drinking days than those who
received 1 mg disulfiram or riboflavin (p = .05). This
positive finding on drinking frequency, however, was
appropriately interpreted with caution because it was based
on a subset of the study population; additionally, it was
obtained in a context of multiple statistical comparisons for
which the significance standard was not adjusted, suggesting
it could have been a Type I error (Fuller et al., 1986).
Efficacy of disulfiram may have been undermined by the
high rate of nonadherence—80%—seen in this trial. Patients
who were medication adherent were significantly more
likely to be abstinent than patients who were not adherent,
but even among the adherent individuals, there were no
significant differences in the rate of abstinence among any of
the treatment groups (Fuller et al., 1986). Other studies
further emphasize the association between treatment adher-
ence and positive outcomes with disulfiram. One trial
evaluated a disulfiram compliance program that was added
to the Community Reinforcement Approach, a behavioral
substance abuse treatment. The compliance program uses a
supportive family member or friend to administer the drug
and monitor patient adherence. When compared to tradi-
tional 12-step counseling plus disulfiram, patients who also
participated in the disulfiram compliance program showed
greater progress toward recovery—at 6 months follow-up,
74% of patients were abstinent with the monitor compared to
45% of those who did not receive the supervised program
(Meyers, Smith, & Lash, 2003). A review of seven
controlled clinical trials also concluded that disulfiram
treatment is more successful under supervised conditions
and that the monitor needs to be trained in supervisory
techniques and educated on evasion behaviors common in
patients with alcohol dependence (Brewer, 1992).
Acamprosate appears to modulate glutamate hyperactiv-
ity, which suggests that it could reduce a hyperglutaminergic
state that may characterize some alcohol-dependent indivi-
duals (Heilig & Egli, 2006). Numerous trials have demon-
strated the ability of acamprosate to maintain abstinence in
patients with alcohol dependence. In a comprehensive meta-
analysis of 20 randomized controlled trials (19 published, 1
unpublished), 36.1% of patients receiving acamprosate had
achieved continuous abstinence at 6-month follow-up, as
opposed to 23.4% of the patients who received placebo.
Three-month and 12-month abstinence rates were also
greater in patients who had received acamprosate (Mann,
Lehert, & Morgan, 2004). These outcomes were achieved in
S16J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
patients who had recently been detoxified, a use in
accordance with the FDA indication for acamprosate in
maintenance of patients abstinent at treatment initiation
(Acamprosate PI, 2005). However, there is some research to
suggest that acamprosate may be efficacious in patients who
have not yet become abstinent. Gual and Lehert (2001)
reported that when prescribed from the beginning of alcohol
detoxification, acamprosate was associated with a greater
(cumulative) period of abstinence compared to placebo.
Of note, all of the studies discussed above—and most of
the research on acamprosate—were conducted outside the
United States, primarily in Europe. Two randomized,
placebo-controlled studies have been completed in the
United States (Anton et al., 2006; Mason, Goodman,
Chabac, & Lehert, 2006). Neither demonstrated a significant
effect for acamprosate on the primary outcome measure. In
the Anton et al. (2006) Combined Pharmacotherapies and
Behavioral Interventions (COMBINE) trial, results of a main
effects analysis of patients who received acamprosate (n =
608) versus those who received placebo (n = 618)
demonstrated that the proportion of time spent abstinent
and time to first heavy drinking day—the specified primary
outcome measures—were similar in both groups. Adverse
events that occurred more commonly with acamprosate than
with placebo were diarrhea (65% vs. 35%, p b .001),
somnolence (31% vs. 24%, p b .01), and a need for alcohol
detoxification (4% vs. 1%, p b .05; Anton et al., 2006).
The Mason et al. (2006) trial studied placebo (n = 260),
acamprosate 2 g (n = 258), or acamprosate 3 g (n = 83) with
brief counseling over 24 weeks, with percent days abstinent
as the primary outcome measure. No significant differences
were noted in rates of percent days abstinent across the three
groups (54.3%, placebo; 56.1%, 2 g; 60.7%, 3 g). In a post
hoc analysis, when baseline covariates were controlled for
and patients who were motivated for abstinence were
examined as a separate group, a significant acamprosate
effect was reported with percent abstinent days of 58.1% for
placebo, 70.0% for 2 g acamprosate, and 72.5% for 3 g
acamprosate (p = .02). Gastrointestinal adverse events,
particularly diarrhea (18%, 33%, and 40%, respectively),
were more common with acamprosate (Mason et al., 2006).
An important point to note with the U.S. trials compared
with the European trials is that the U.S. trials limited the
extent of abstinence prior to starting acamprosate to no more
than 21 days for the Anton et al. (2006) trial, and 66% of
patients were abstinent for 7 days or less. In the Mason et al.
(2006) trial, patients could not be abstinent for more than 10
days prior to randomization. The shorter periods of
abstinence in the U.S. trials may be an important factor in
the failure to detect an acamprosate effect, although this
efficacy of acamprosate for the treatment of alcohol
dependence in Germany, a significantly greater percentage
of patients taking acamprosate remained continuously
abstinent during the 48 weeks of treatment (44.8% for
acamprosate vs. 25.3% for placebo, p = .005) and during the
48 weeks of follow-up (39.9% for acamprosate vs. 17.3% for
placebo, p = .003) relative to placebo (Fig. 1; Sass, Soyka,
Mann, &Zieglgänsberger,1996).Patients hadtobe abstinent
and free of withdrawal symptoms for at least 14 days and no
more than 28 days prior to entering the study. However, it
should be noted that almost half of the patients in the
acamprosate group (41.9%) and more than half of the
patients taking placebo pills (59.6%) withdrew from the
study within the first year.
2.3. Oral naltrexone
causes the release of endogenous opioids and this likely
contributes to its reinforcing effects. Naltrexone, by blocking
endogenous opioids, reduces the rewarding properties of
alcohol (Kenna et al., 2004), thereby counteracting this
important component of the behavioral response to alcohol.
In fact, in the initial human studies of naltrexone for alcohol
dependence, it was reported that patients who consumed
likely to experience their usual “high” or level of intoxication
King, Sherman, & O'Brien, 1995). In addition, naltrexone has
trials. (Brown, Beard, Dobbs, & Rush, 2006; Huang, Chen,
Yu, & Chen, 2005; Petrakis et al., 2005).
Oral naltrexone has now been studied in more than
20 clinical trials in the United States, Europe, Asia, and
Australia, involving approximately 4,000 patients. Meta-
analyses of these trials (Bouza, Angeles, Muñoz, & Amate,
2004; Kranzler & Van Kirk, 2001) reveal several key
findings: (a) there is convincing evidence that oral naltrexone
reduces the likelihood of relapse to heavy drinking; (b) there
is some evidence that oral naltrexone can enhance rates of
complete abstinence; (c) the efficacy of oral naltrexone is
modest; (d) the overall tolerability of naltrexone in the
alcohol-dependent population is acceptable. Although the
average effect of naltrexone may be modest, clinicians,
including the author, note that some patients with alcohol
dependence appear to have a strong therapeutic response.
Fig. 1. Kaplan-Meier survival analysis (survival function estimate).
Continuous abstinence for the treatment and follow-up periods for
acamprosate (shaded squares) versus placebo (open circles). Reproduced
from Sass et al. (1996).
S17J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
The recent results of the largest medication treatment
trial of alcoholism completed to date (n = 1,383), The
COMBINE Study (Anton et al., 2006), supported the meta-
analyses findings by reporting a main effect for naltrexone.
Oral naltrexone 100 mg/day reduced the risk of heavy
drinking and showed evidence of increased days abstinent.
Furthermore, patients who received naltrexone plus medical
management were more likely (74%) to have a predefined
positive outcome (abstinent or moderate drinking without
problems) than patients who received placebo plus medical
management (58%). Patients who received oral naltrexone
were significantly more likely than patients who received
placebo to experience vomiting, diarrhea, somnolence, and
aspartate aminotransferase (AST) or alanine aminotransfer-
ase (ALT) levels more than five times the upper limit of
normal. AST or ALT elevations occurred in 2% of patients
receiving oral naltrexone and generally returned to normal
upon medication discontinuation. It should be noted that the
100-mg dose of oral naltrexone in COMBINE was higher
than the standard 50-mg dose. Oral naltrexone does carry a
dose-limiting hepatic warning (Naltrexone PI, 2001;
Naltrexone PI, 2006).
Oral naltrexone has been available for clinical use in the
United States for over 10 years. However, its use has been
limited, and efforts to identify the reasons for this have been
reported (Mark, Kranzler, & Song, 2003). One reason has
been clinician concerns about efficacy. As mentioned earlier,
the overall naltrexone literature indicates that the efficacy of
oral naltrexone is modest. Therefore, it is not surprising that
some clinicians will fail to see a robust clinical response if
theyprescribe oral naltrexone toa limited numberofpatients.
The ability to enhance the response to oral naltrexone would
be an important clinical development. One approach is to
identify characteristics of patients that predict a positive
naltrexone response. Several predictors have been identified
including a positive family history of alcoholism and higher
rates ofbaseline craving foralcohol(Monterossoetal.,2001)
as well as a polymorphism in the μ-opioid receptor (Oslin
et al., 2003; Anton et al., 2008; although not confirmed by
Gelernter et al., 2007). To date, the practical clinical utility of
these putative predictors has not been demonstrated.
Another approach to enhance efficacy is to improve the
bioavailability of naltrexone. Several studies have shown
that patients who are adherent to medication show an
advantage with oral naltrexone over placebo that is not seen
in nonadherent patients (Chick et al., 2000; Monti et al.,
2001; Volpicelli et al., 1997). For example, one multisite,
placebo-controlled study found no significant difference
between patients with alcohol dependence or abuse taking
oral naltrexone versus placebo in drinking outcomes for the
total sample. However, analyses with a subsample of patients
who were treatment adherent (defined as consuming at least
80% of the medication and attendance at all psychosocial
treatment sessions) revealed that patients who received oral
naltrexone consumed significantly less alcohol relative to
patients who were given placebo pills (Fig. 2; Chick et al.,
2000). Formulations of extended-release naltrexone repre-
sent methods to enhance the bioavailability of naltrexone and
thereby minimize the adherence problems inherent with
daily dosing of oral naltrexone.
2.4. Extended-release naltrexone
Extended-release naltrexone is designed to be adminis-
tered as a long-acting intramuscular injection providing
opioid blockade for 1 month or possibly longer. Extended-
release formulations reduce the frequency of occasions on
which a patient may forget or choose not to take his or her
medication, assuring that once the patient receives an
injection, he or she will be “adherent” for the next month
(Galloway, Koch, Cello, & Smith, 2005).
Two randomized controlled trials have been published,
establishing the efficacy and safety of extended-release
naltrexone. In the first, a depot formulation of naltrexone
that is not commercially available was studied in alcohol-
dependent individuals who wished to stop drinking. Patients
were randomly assigned to receive either extended-release
naltrexone (n = 158) or placebo (n = 157) monthly for 3
many trials of acamprosate, patients were not required to be
number of heavy drinking days. However, extended-release
naltrexone was associated with a significantly longer time to
first drink than was placebo (median time = 5 vs. 3 days, p =
.003) and a higher rate of abstinence (18% vs. 10%, p = .048).
Overall, injection site reactions were more common in the
group treated with naltrexone compared to those receiving
placebo (Kranzler, Wesson, & Billot, 2004).
patients investigated the effects of two different doses of
extended-release naltrexone (the FDA-approved dose of
380 mg and an unapproved and commercially unavailable
dose of 190 mg) over 6 months. Patients (N = 627) were
randomly assigned to receive extended-release naltrexone
low-intensity psychosocial intervention. A total of 624
received their first injection and formed the intent-to-treat
population. The primary outcome variable was the event rate
of heavy drinking, which proved to be 25% lower among
patients who received 380 mg extended-release naltrexone
Fig. 2. Alcohol consumption among treatment-adherent patients taking oral
naltrexone versus placebo. Reproduced from Chick et al. (2000).
S18J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
compared with patients who received placebo (p = .03), and
17% lower among patients receiving 190 mg extended-
release naltrexone compared with those receiving placebo
(p = .07); the median rate of heavy drinking was 48% lower
among patients receiving 380 mg extended-release naltrex-
one compared with placebo. The median number of heavy
drinking days decreased relative to pretreatment in all three
groups, although the overall decrease was greatest in patients
who received the higher dose of extended-release naltrexone
(Fig. 3; Garbutt et al., 2005).
Extended-release naltrexone was most effective in men
and in patients who entered the study with at least 7 days of
abstinence. Among patients receiving 380 mg extended-
release naltrexone, the hazard ratio (HR) for heavy drinking
was 0.56 for men compared with 0.75 for the group as a
whole (Garbutt et al., 2005). In the subset of patients who
remained abstinent for at least 7 days prior to the onset of
treatment (n = 53, 8% of sample), those who received
extended-release naltrexone werenumericallyfarmorelikely
to remain abstinent over the course of the study relative to
participants who received placebo treatment and had a
significantly lower HR for heavy drinking (HR = 0.20, p =
Kranzler (2007) have extended this analysis to patients who
were abstinent for 4 or more days and have shown a
significantly higher likelihood of abstinence in individuals
who received their first injection with at least four days of
abstinence compared to individuals without this length of
abstinence (32% vs. 11% continuous abstinence, p = .02).
Additional analyses from the 6-month trial of extended-
release naltrexone suggest that individuals who use
extended-release naltrexone are no less likely to avail
themselves of psychosocial therapies than are patients who
received placebo and are numerically more likely to attend
all 12 study-provided counseling sessions and to attend
extramural psychosocial treatments (Zweben, Gastfriend,
Loewy, Silverman, & Ehrich, 2005).
Extended-release naltrexone is generally safe and well
tolerated.Of thecommonadverse events in the Kranzleret al.
(2004) study, upper abdominal pain was significantly more
common among patients receiving extended-release naltrex-
one, but chest pain and irritability were significantly more
common among the placebo group (Kranzler et al., 2004). In
the Garbutt et al. (2005) study, nausea, decreased appetite,
dizziness, and injection-site pain were significantly more
common among patients receiving 380 mg extended-release
naltrexone than those receiving placebo; decreased appetite
was significantly more common in the 380-mg group than in
the 190-mg group, as well (Garbutt et al., 2005). Postmarket-
ing reports with extended-release naltrexone have noted risk
for injection site reactions that may require medical interven-
tion, although the frequency of such reactions appears low
and possibly related to poor injection technique. Extended-
placebo (Lucey, Silverman, Illeperuma, & O'Brien, 2008).
3. Medications under investigation for the treatment of
3.1. Dopaminergic agents
Dopamine antagonists that block dopamine actions in the
nucleus accumbens have been shown to reduce craving and
alcohol consumption in a human laboratory setting (Modell,
Mountz, Glaser, & Lee, 1993). However, clinical trials with
traditional dopamine antagonists in alcohol dependence have
been limited, perhaps because of concern over the acute and
long-term side effects of this class of medications.
Tiapride, a D2dopamine antagonist approved for use in
France, has demonstrated some efficacy in the treatment of
alcohol dependence. Patients (n = 100) were randomly
assigned to 3-months' treatment with either tiapride or
placebo. Study dropout was greater than 50%. In both the
associated with increased abstinence and decreased alcohol
consumption compared with placebo (Shaw et al., 1994).
Some antipsychotics have demonstrated efficacy in
alcohol-dependent patients with comorbid schizophrenia or
bipolar disorder. In a naturalistic study, patients with
comorbid schizophrenia and alcohol abuse had fewer
drinking days while on clozapine, an atypical antipsychotic
with a wide variety of neuropharmacological effects, than
while off (Drake, Green, McHugo, & Xie, 2000). In another
open-label, naturalistic study, patients with comorbid
schizophrenia or bipolar disorder and alcohol dependence
(n = 17) were switched from their current antipsychotic to
open-label aripiprazole, a partial dopamine agonist with a
high affinity for D2receptors, and a significant reduction in
craving for alcohol and in dollars spent on alcohol was
observed (Brown, Jeffress, Liggin, Garza, & Beard, 2005).
Olanzapine, a D2antagonist, has been shown to reduce
craving for alcohol in nonschizophrenic, alcohol-dependent
polymorphism, but not the shorter form version, suggesting
that genetic variables may mediate the efficacy of some
Fig. 3. Median heavy-drinking days per month: extended-release naltrexone
(190, 380 mg) versus placebo. The bars represent interquartile range.
Reproduced from Garbutt et al. (2005).
S19J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
The development of new D2 antagonists with other
neuropharmacological properties, for example, 5-HT2antagon-
ism, and improved neurological side effects have led to a
resurgence of interest in the use of dopamine antagonists in
alcohol dependence. It will be important to assess the efficacy
3.2. Anticonvulsants and mood-stabilizing agents
Anticonvulsants exhibit a range of neuropharmacologic
effects, although two prominent actions—facilitating GABA
or impeding glutaminergic function—would be predicted to
dampen the hypothesized hyperglutaminergic state seen in
alcohol-dependent individuals (Heilig & Egli, 2006). This,
combined with the developing evidence of efficacy of these
agents in detoxification protocols, suggests that these agents
may be of use in the treatment of alcohol dependence.
Topiramate, an anticonvulsant that augments GABA by
binding to a nonbenzodiazepine site on GABAAreceptors,
antagonizes the AMPA/kainate subtype of the glutamate
receptor, and inhibits carbonic anhydrase has demonstrated
efficacy in the treatment of alcohol dependence in two
placebo-controlled trials (Johnson et al., 2003; Johnson et al.,
2007). Patients with alcohol dependence (n = 150) were
adherence management plus either topiramate (25–300 mg/
day, escalating dose) or placebo. Approximately 25% of
topiramate-treated patients and more than 33% of placebo-
treated patients discontinued study prior to completion.
Patients who received topiramate had significantly fewer
drinking days, fewer drinks per day, and fewer drinks per
drinking day than did patients who received placebo and
spent a greater proportion of days abstinent. Topiramate
users, however, also experienced significantly more dizzi-
ness, paresthesias, psychomotor slowing, memory or con-
centration impairment, and weight loss; some of these
adverse events occurred in almost 60% of patients receiving
active drug (Johnson et al., 2003). Results were similar in a
larger (n = 371) 14-week multisite study of patients with
alcohol dependence. Compared with placebo, topiramate-
treated patients (up to 300 mg/day) demonstrated a
significantly lower percentage of self-reported heavy drink-
ing days, the primary efficacy measure. There was also a
significant decrease in the following measures in topiramate-
treated individuals compared to those in the placebo group:
percentage of days abstinent, drinks per drinking day, and
laboratory measures of plasma γ-glutamyltransferase (a
marker for alcohol consumption). Adverse events more
common in the topiramate compared to placebo group
included paresthesia (51% vs. 11%), taste perversion (23%
vs. 5%), anorexia (20% vs. 7%), and concentration impair-
ment (15% vs. 3%; Johnson et al., 2007).
Other anticonvulsants have demonstrated lesser degrees
of efficacy in smaller trials. In an open-label trial of
oxcarbazepine and acamprosate, patients receiving oxcarba-
zepine fared similarly to those on acamprosate in terms of
time to relapse and time to first consumption (Croissant
et al., 2006); given the wide variation in the reported efficacy
of acamprosate, it is difficult to interpret these results.
Divalproex was studied in one 12-week, placebo-
controlled trial with only 29 patients forming the analyzable
population (Brady, Myrick, Henderson, & Coffey, 2002).
Although there was a trend toward fewer patients who
received divalproex to relapse to heavy drinking, this was
noted by the authors to represent a small effect size (Brady
et al., 2002). Divalproex and lamotrigine have demonstrated
some ability to decrease drinking and craving in patients with
bipolar disorder—for which these and other anticonvulsants
are frequently prescribed—and comorbid alcohol depen-
dence (Rubio, López-Muñoz, Alamo, 2006; Salloum et al.,
2005). Further research is needed to determine whether
lamotrigine would be useful in alcohol-dependent patients
who do not have comorbid bipolar disorder.
Baclofen is a GABA-B receptor agonist that, in animal
models, has demonstrated an ability to reduce alcohol intake
under baseline as well as alcohol-deprived conditions. Three
placebo-controlled trials have been completed with baclofen,
30 mg per day, in alcohol-dependent patients (Addolorato
et al., 2002, 2007; Garbutt et al., 2007). Addolorato et al.
(2002, 2007) found that baclofen significantly increased
continuous abstinence rates in both noncirrhotic and cirrhotic
alcohol-dependent patients. Garbutt et al. (2007) did not find
an effect for baclofen on either heavy drinking days or
abstinent days. Similar to what has been reported with
acamprosate, differences in patient populations and recruit-
ment methods in the European versus United States trials
may have contributed to the differences in outcome.
3.4. Other potential pharmacotherapies for treating alcohol
Several new agents utilizing novel mechanisms of action
have demonstrated efficacy in rodent models of alcohol
dependence. These include kudzu root extract, which
reduces alcohol consumption (Benlhabib, Baker, Keyler, &
Singh, 2004); the cannabinoid receptor antagonist rimona-
bant (SR141716A; Cippitelli et al., 2005); the neuropeptide-
Y receptor antagonist L-152,804 (Schroeder, Overstreet, &
Hodge, 2005); and the CRF antagonists antalarmin and
R121919 (Funk, Koob, Lee, Rice, & Zorrilla, 2007), which
all reduced alcohol self-administration in operant paradigms.
4. Combined pharmacotherapy
If two medications with different mechanisms of action
are combined, the effect of the combination may be greater
than that of the components in isolation. One trial assessed
the combination of acamprosate and open-label disulfiram,
S20J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
whereas two randomized controlled trials assessed the
efficacy of a combination of naltrexone and acamprosate.
Among patients randomly assigned to acamprosate or
placebo, some of whom were voluntarily taking open-label
disulfiram, patients who received acamprosate and disul-
firam had a greater cumulative duration of abstinence than
did patients who received only acamprosate, only disulfiram,
or placebo (Besson, Aeby, Kasas, Lehert, & Potgieter, 1998).
Further controlled study of this combination is needed,
especially given disulfiram's lack of effect on abstinence in a
blinded trial (Fuller et al., 1986).
The combination of oral naltrexone and acamprosate was
assessed by Kiefer et al. (2003), who randomized alcohol-
dependent patients (n = 160) to receive weekly psychother-
apy and either placebo, oral naltrexone, acamprosate, or oral
naltrexone plus acamprosate for 12 weeks. Of note, less than
half of participants completed the study. Nonrelapse rates
were significantly greater in all three active treatment groups
than in the placebo group. The patients who received oral
naltrexone and acamprosate fared significantly better than
patients who received acamprosate alone but not better than
patients who received oral naltrexone alone. Results were
similar for time to first drink, again demonstrating efficacy
for all active interventions and superiority of combined
treatment to acamprosate alone (Kiefer et al., 2003).
More recently, in the COMBINE trial, alcohol-dependent
patients (n = 1,383) were randomly assigned to receive
medical management in addition to placebo, oral naltrexone,
acamprosate, or oral naltrexone plus acamprosate, with and
without an additional behavioral intervention (combined
behavioral intervention [CBI]; Anton et al., 2006). Oral
naltrexone, but not acamprosate, extended time to first
heavy-drinking day. Oral naltrexone and CBI also signifi-
cantly led to more patients having an a priori measure of
good clinical outcome (Cisler & Zweben, 1999) as assessed
by drinking patterns and consequences The combination of
oral naltrexone and acamprosate, although safe, offered no
advantages over naltrexone alone (Anton et al., 2006). There
have been suggestions that the failure to detect an effect for
acamprosate in COMBINE, as opposed to the positive
effects seen in the European trials, is related to study design
issues (Kranzler, 2006). Study design issues of interest
include differences in the length of abstinence prior to
starting medication, variations in psychosocial interventions,
and variations in subject characteristics.
injectable forms of naltrexone are currently FDA approved for
the treatment of alcohol dependence. The efficacy of disulfiram
is undermined by high rates of medication nonadherence,
leading to the suggestion that it should be taken under some
form of supervision. Acamprosate has a well-established record
of efficacy in Europe, although studies conducted in the United
States have failed to show superiority over placebo—perhaps
because of methodological issues. Both oral and extended-
release naltrexone have been shown to reduce heavy drinking
rates and enhance abstinence. Extended-release naltrexone
offers the opportunity to enhance bioavailability of medication
medications have been studied for alcohol dependence with
topiramate having the most evidence for efficacy. The efficacy
of other promising agents, for example, baclofen, awaits the
example, CRF antagonists, neuropeptide Y antagonists, are in
development based on an expanded understanding of the
pathophysiology of alcohol dependence.
Clearly, the range of options available to health care
professionals wishing to supplement psychotherapy for their
studies available suggesting which medication would be most
efficacious in a particular patient, although genetic studies
certainly raise the possibility that someday, pharmacogenetics
will allow medication therapy to be tailored to a patient's
particular genotype. At the moment, however, pharmacother-
for patients with alcohol dependence—a component that all
patients should have the opportunity to benefit from.
Acamprosate calcium (Campral) Prescribing Information. (2005). St Louis,
Addolorato, G., Caputo, F., Capristo, E., Domenicali, M., Bernardi, M.,
Janiri, L., et al. (2002). Baclofen efficacy in reducing alcohol craving
and intake: A preliminary double-blind randomized controlled study.
Alcohol Alcohol, 37, 504−508.
Addolorato, G., Leggio, L., Ferrulli, A., Cardone, S., Vonghia, L.,
Mirijello, A., et al. (2007). Effectiveness and safety of baclofen for
maintenance of alcohol abstinence in alcohol-dependent patients with
liver cirrhosis: Randomised, double-blind controlled study. Lancet,
Anton, R. F., O'Malley, S. S., Ciraulo, D. A., Cisler, R. A., Couper, D.,
Donovan, D. M., et al. (2006). Combined pharmacotherapies and
behavioral interventions for alcohol dependence: The COMBINE Study:
A randomized controlled trial. Journal of the American Medical
Association, 295, 2003−2017.
Anton, R. F., Oroszi, G., O'Malley, S., Couper, D., Swift, R., Pettinati, H.,
et al. (2008). An evaluation of μ-opioid receptor (OPRM1) as a predictor
of naltrexone response in the treatment of alcohol dependence. Results
from the Combined Pharmacotherapies and Behavioral Interventions for
Alcohol Dependence (COMBINE) Study. Archives of General Psychia-
try, 65, 135−144.
Benlhabib, E., Baker, J. I., Keyler, D. E., & Singh, A. K. (2004). Kudzu root
extract suppresses voluntary alcohol intake and alcohol withdrawal
symptoms in P rats receiving free access to water and alcohol. Journal of
Medicinal Food, 7, 168−179.
Besson, J., Aeby, F., Kasas, A., Lehert, P., & Potgieter, A. (1998). Combined
efficacy of acamprosate and disulfiram in the treatment of alcoholism: A
controlled study. Alcoholism, Clinical and Experimental Research, 22,
Bouza, C., Angeles, M., Muñoz, A., & Amate, J. M. (2004). Efficacy and
safety of naltrexone and acamprosate in the treatment of alcohol
dependence: A systematic review. Addiction, 99, 811−828.
S21J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
Brady, K. T., Myrick, H., Henderson, S., & Coffey, S. F. (2002). The use of
divalproex in alcohol relapse prevention: A pilot study. Drug and
Alcohol Dependence, 67, 323−330.
Brewer, C. (1992). Controlled trials of antabuse in alcoholism: The
importance of supervision and adequate dosage. Acta Psychiatrica
Scandinavica Supplementum, 369, 51−58.
Brown, E. S., Beard, L., Dobbs, L., & Rush, A. J. (2006). Naltrexone in
patients with bipolar disorder and alcohol dependence. Depression and
Anxiety, 23, 492−495.
Brown, E. S., Jeffress, J., Liggin, J. D., Garza, M., & Beard, L. (2005).
Switching outpatients with bipolar or schizoaffective disorders and
substance abuse from their current antipsychotic to aripiprazole. Journal
of Clinical Psychiatry, 66, 756−760.
Chastain, G. (2006). Alcohol, neurotransmitter systems, and behavior.
Journal of General Psychology, 133, 329−335.
Chick, J., Anton, R., Checinski, K., Croop, R., Drummond, D. C., Farmer,
R., et al. (2000). A multicentre, randomized, double-blind, placebo-
controlled trial of naltrexone in the treatment of alcohol dependence or
abuse. Alcohol, 35, 587−593.
Cippitelli, A., Bilbao, A., Hansson, A. C., del Arco, I., Sommer, W., Heilig,
M., et al. (2005). Cannabinoid CB1 receptor antagonism reduces
conditioned reinstatement of ethanol-seeking behavior in rats. European
Journal of Neuroscience, 21, 2243−2251.
Cisler, R. A., & Zweben, A. (1999). Development of a composite measure
for assessing alcohol treatment outcome: Operationalization and
validation. Alcoholism, Clinical and Experimental Research, 23,
Croissant, B., Diehl, A., Heinz, A., Klein, O., Mann, K., Nakovics, H., et al.
(2006). A pilot study of oxcarbazepine versus acamprosate in alcohol-
dependent patients. Alcoholism, Clinical and Experimental Research,
Disulfiram (Antabuse) Prescribing Information. (2005). Florham Park, NJ.
Drake, R. E., Green, A. I., McHugo, G. J., & Xie, H. (2000). The effects of
clozapine on alcohol and drug use disorders among patients with
schizophrenia. Schizophrenia Bulletin, 26, 441−449.
Durazzo, T. C., & Meyerhoff, D. J. (2007). Neurobiological and
neurocognitive effects of chronic cigarette smoking and alcoholism.
Frontiers in Bioscience: A Journal and Virtual Library, 12,
Fuller, R. K.,Branchey, L.,Brightwell,D. R., Derman, R. M., Emrick,C. D.,
Iber, F. L., et al. (1986). Disulfiram treatment of alcoholism. AVeterans
Administration cooperative study. Journal of the American Medical
Association, 256, 1449−1455.
Funk, C. K., Koob, G. F., Lee, M. J., Rice, K. C., & Zorrilla, E. P. (2007).
Corticotropin-releasing factor 1 antagonists selectively reduce ethanol
self-administration in ethanol-dependent rats. Biological Psychiatry, 61,
Galloway, G. P., Koch, M., Cello, R., & Smith, D. E. (2005).
Pharmacokinetics, safety, and tolerability of a depot formulation of
naltrexone in alcoholics: An open-label trial. BMC Psychiatry, 61,
Garbutt, J. C., Kranzler, H. R., O'Malley, S. S., Gastfriend, D. R., Pettinati,
H. M., Silverman, B. L., et al. (2005). Efficacy and tolerability of long-
acting injectable naltrexone for alcohol dependence: A randomized
controlled trial. Journal of the Medical Association, 293, 1617−1625.
Garbutt, J. C., Kampov-Polevoy, A., Flannery, B., Kalka-Juhl, L., & Gallop,
R. (2007). Placebo-controlled trial of baclofen in alcohol dependence.
Research Society on Alcoholism Annual Meeting, Chicago, Illinois,
Gelernter, J., Gueorguieva, R., Kranzler, H. R., Zhang, H., Cramer, J.,
Rosenheck, R., et al. (2007). Opioid receptor gene (OPRM1, OPRK1,
and OPRD1) variants and response to naltrexone treatment for alcohol
dependence: Results from the VA Cooperative Study. Alcohol Clin Exp
Res, 31, 555−563.
Gual, A., & Lehert, P. (2001). Acamprosate during and after acute alcohol
withdrawal: A double-blind placebo-controlled study in Spain. Alcohol,
Heilig, M., & Egli, M. (2006). Pharmacological treatment of alcohol
dependence: Target symptoms and target mechanisms. Pharmacology &
Therapeutics, 111, 855−876.
Huang,M. C., Chen, C. H., Yu, J. M., & Chen, C. C. (2005). A double-blind,
placebo-controlled study of naltrexone in the treatment of alcohol
dependence in Taiwan. Addiction Biology, 10, 289−292.
Hutchison, K. E., Ray, L., Sandman, E., Rutter, M. C., Peters, A., Davidson,
D., et al. (2006). The effect of olanzapine on craving and alcohol
consumption. Neuropsychopharmacology, 31, 1310−1317.
Johnson, B. A., Ait-Daoud, N., Bowden, C. L., Diclemente, C. C., Roache,
J. D., Lawson, K., et al. (2003). Oral topiramate for treatment of alcohol
dependence: A randomised controlled trial. Lancet, 361, 1677−1685.
Johnson, B. A., Rosenthal, N., Capece, J. A., Wiegand, F., Lian Mao, L.,
Beyers, K., et al., for the Topiramate for Alcoholism AdvisoryBoard and
the Topiramate for Alcoholism Study Group. (2007). Topiramate for
treating alcohol dependence: A randomized controlled trial. Journal of
the American Medical Association, 298, 1641−1651.
Kenna, G. A., McGeary, J. E., & Swift, R. M. (2004). Pharmacotherapy,
pharmacogenomics, and the future of alcohol dependence treatment, part
1. American Journal of Health-System Pharmacy, 61, 2272−2279.
Kiefer, F., Jahn, H., Tarnaske, T., Helwig, H., Briken, P., Holzbach, R., et al.
(2003). Comparing and combining naltrexone and acamprosate in
relapse prevention of alcoholism: A double-blind, placebo-controlled
study. Archives of General Psychiatry, 60, 92−99.
Koob, G. F. (2003). Alcoholism: Allostasis and beyond. Alcoholism,
Clinical and Experimental Research, 27, 232−243.
Kranzler, H. R. (2006). Evidence-based treatments for alcohol dependence:
New results and new questions. Journal of the American Medical
Association, 295, 2075−2076.
Kranzler, H. R., & Van Kirk, J. (2001). Efficacy of naltrexone and
acamprosate for alcoholism treatment: A meta-analysis. Alcoholism,
Clinical and Experimental Research, 25, 1335−1341.
Kranzler, H. R., Wesson, D. R., & Billot, L. (2004). Naltrexone depot for
treatment of alcohol dependence: A multicenter, randomized, placebo-
controlled clinical trial. Alcoholism, Clinical and Experimental
Research, 28, 1051−1059.
Lucey, M. R, Silverman, B. L., Illeperuma, A., & O'Brien, C. P. (2008).
Hepatic safety of once-monthly injectable extended-release naltrexone
administered to actively drinking alcoholics. Alcoholism, Clinical and
Experimental Research, 32, 498−504.
Mann, K., Lehert, P., & Morgan, M. Y. (2004). The efficacy of acamprosate
in the maintenance of abstinence in alcohol-dependent individuals:
Results of a meta-analysis. Alcoholism, Clinical and Experimental
Research, 28, 51−63.
Mark, T. L., Kranzler, H. R., & Song, X. (2003). Understanding US
addiction physicians' low rate of naltrexone prescription. Drug and
Alcohol Dependence, 71, 219−228.
Mason, B. J., Goodman, A. M., Chabac, S., & Lehert, P. (2006). Effect of
oral acamprosate on abstinence in patients with alcohol dependence in a
double-blind, placebo-controlled trial: The role of patient motivation.
Journal of Psychiatric Research, 40, 383−393.
Meyers, R. J., Smith, J. E., & Lash, D. N. (2003). The community
reinforcement approach. Recent Developments in Alcoholism, 16,
Modell, J. G., Mountz, J. M., Glaser, F. B., & Lee, J. Y. (1993). Effect of
haloperidol on measures of craving and impaired control in alcoholic
subjects. Alcoholism, Clinical and Experimental Research, 17,
Monterosso, J. R., Flannery, B. A., Pettinati, H. M., Oslin, D. W., Rukstalis,
M., O'Brien, C. P., et al. (2001). Predicting treatment response to
naltrexone: The influence of craving and family history. American
Journal on Addictions, 10, 258−268.
Monti, P. M., Rohsenow, D. J., Swift, R. M., Gulliver, S. B., Colby, S. M.,
Mueller, T. I., et al. (2001). Naltrexone and cue exposure with coping
and communication skills training for alcoholics: Treatment process and
1-year outcomes. Alcoholism, Clinical and Experimental Research, 25,
S22J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
Naltrexone hydrochloride (Depade) Prescribing Information. (2006). St
Naltrexone for extended-release injectable suspension (Vivitrol) Prescribing
Information. (2001). Cambridge, MA.
O'Malley, S. S., Jaffe, A. J., Rode, S., & Rounsaville, B. J. (1996).
Experience of a “slip” among alcoholics treated with naltrexone or
placebo. American Journal of Psychiatry, 153, 281−283.
O'Malley, S. S., Garbutt, J. C., Gastfriend, D. R., Dong, Q., & Kranzler, H. R.
(2007). Efficacy of extended-release naltrexone in alcohol-dependent
patients who are abstinent before treatment. J Clin Psychopharmacol, 27,
Oslin, D. W., Berrettini, W., Kranzler, H. R., Pettinati, H., Gelernter, J.,
Volpicelli, J. R., et al. (2003). A functional polymorphism of the mu-
opioid receptor gene is associated with naltrexone response in alcohol-
dependent patients. Neuropsychopharmacology, 28, 1546−1552.
Petrakis, I. L., Poling, J., Levinson, C., Nich, C., Carroll, K., Rounsaville,
B., et al. (2005). Naltrexone and disulfiram in patients with alcohol
dependence and comorbid psychiatric disorders. Biological Psychiatry,
Prendergast, M. A., & Little, H. J. (2007). Adolescence, glucocorticoids
and alcohol. Pharmacology, Biochemistry, and Behavior, 86,
Roberto, M., Bajo, M., Crawford, E., Madamba, S. G., & Siggins, G. R. (2006).
Chronic ethanol exposure and protracted abstinence alter NMDA receptors
in central amygdala. Neuropsychopharmacology, 31, 988−996.
Roberto,M.,Schweitzer,P.,Madamba,S. G.,Stouffer,D. G.,Parsons,L.H.,
& Siggins, G. R. (2004). Acute and chronic ethanol alter glutamatergic
transmission in rat central amygdala: An in vitro and in vivo analysis.
European Journal of Neuroscience, 24, 1594−1603.
Rubio, G., López-Muñoz, F., & Alamo, C. (2006). Effects of lamotrigine in
patients with bipolar disorder and alcohol dependence. Bipolar
Disorders, 8, 289−293.
Salloum, I. M., Cornelius, J. R., Daley, D. C., Kirisci, L., Himmelhoch, J.
M., & Thase,M. E. (2005).Efficacy of valproatemaintenancein patients
with bipolar disorder and alcoholism: A double-blind placebo-controlled
study. Archives of General Psychiatry, 62, 37−45.
Sass, H., Soyka, M., Mann, K., & Zieglgänsberger, W. (1996). Relapse
prevention by acamprosate. Results from a placebo-controlled study
on alcohol dependence. Archives of General Psychiatry, 53,
Schroeder, J. P., Overstreet, D. H., & Hodge, C. W. (2005). The neuropeptide-Y
Y5 receptor antagonist L-152,804 decreases alcohol self-administration in
inbred alcohol-preferring (iP) rats. Alcohol, 36, 179−186.
Shaw, G. K., Waller, S., Majumdar, S. K., Alberts, J. L., Latham, C. J., &
Dunn, G. (1994). Tiapride in the prevention of relapse in recently
detoxified alcoholics. British Journal of Psychiatry: The Journal of
Mental Science, 165, 515−523.
Swift, R. M. (1999). Drug therapy for alcohol dependence. New England
Journal of Medicine, 340, 1482−1490.
Volkow, N. D., Wang, G. J., Fowler, J. S., Logan, J., Hitzemann, R., Ding, Y.
S., et al. (1996). Decreases in dopamine receptors but not in dopamine
transporters in alcoholics. Alcoholism, Clinical and Experimental
Research, 20, 1594−1598.
Volpicelli, J. R., Rhines, K. C., Rhines, J. S., Volpicelli, L. A.,
Alterman, A. I., & O'Brien, C. P. (1997). Naltrexone and alcohol
dependence. Role of subject compliance. Archives of General
Psychiatry, 54, 737−742.
(1995). Effect of naltrexone on alcohol “high” in alcoholics. American
Journal of Psychiatry, 152, 613−615.
Weinshenker, D., & Schroeder, J. P. (2007). There and back again: A tale of
norepinephrine and drug addiction. Neuropsychopharmacology, 32,
Zweben, A., Gastfriend, D., Loewy, J., Silverman, B., & Ehrich, E. (2005,
December). Participation in counseling and recovery activities during
pharmacotherapy with injectable long-acting naltrexone. Presented at
American Academy of Addiction Psychiatry 16th Annual Meeting,
Scottsdale, Arizona (Poster #19).
S23J.C. Garbutt / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S15–S23
Genetics of Alcoholism
1. Approximately what percentage of an individual's vulnerability to heavy drinking and associated problems can be attributed
2. Which of the following statements applies to the genetics of alcohol abuse and dependence?
a. The complex relationship of multiple genes and environmental factors is similar to that of other genetically influenced
b. Polymorphism of a single gene is thought to be responsible for an individual's risk for alcoholism
c. Phenotypes like skin flushing response to alcohol, low levels of response to alcohol, and impulsivity and sensation-seeking
behaviors do not offer clues to identification of genes implicated in alcoholism
d. Polymorphisms in genes for alcohol dehydrogenase, but not aldehyde dehydrogenase have been implicated in alcoholism
e. Genetics of the opioid, adenosine, and cannabinoid systems are unlikely to influence an individual's risk of alcoholism
3. Polymorphism of which of the following genes is thought to be related to externalizing and impulsivity-related phenotypes
associated with alcohol use disorders?
b. DRD2 (dopamine 2 receptor)
c. CHRM2 (muscarinic acetylcholine receptor M2)
e. All of the above
Therapies for Alcohol Dependence
4. Which of the following is among the FDA-approved medications for treatment of alcohol dependence?
a. Oral naltrexone
d. Injectable extended-release naltrexone
e. All of the above
5. The molecular target of naltrexone is ________________
a. Aldehyde dehydrogenase
b. Alcohol dehydrogenase
c. An opioid receptor
d. A GABA receptor
e. A cannabinoid receptor
Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S24–S25
0740-5472/09/$ – see front matter
6. Which alcohol dependence pharmacotherapy listed below has an aversive mechanism of action that contributes to poor
d. Mood stabilizers
e. Anticonvulsive agents
S25 CME Posttest / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S24–S25
EVALUATION FORM – SCI-ALC-0245
Promoting Recovery in Alcohol-Dependent Patients
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EXTENT TO WHICH ACTIVITY MET THE IDENTIFIED OBJECTIVES
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• Describe the contribution of genetics to an individual's
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pharmacotherapies for the treatment of alcohol dependence
• Appraise ongoing research on the development of novel
medications for the treatment of alcohol dependence
5 4 3 2 1
5 4 3 2 1
5 4 3 2 1
5 4 3 2 1
OVERALL EFFECTIVENESS OF THE ACTIVITY
The content presented:
Was timely and will influence how I practice
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5 4 3 2 1
5 4 3 2 1
5 4 3 2 1
If you rated “1" or “2" regarding commercial bias, please provide comment(s).
The format and materials were useful 5 4 3 2 1
What was the most positive part of this activity?
Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S26–S28
0740-5472/09/$ – see front matter
IMPACT OF THE ACTIVITY
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Please describe any change(s) you plan to make in your practice as a result of this activity.
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S27EVALUATION FORM – SCI-ALC-0245 / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S26–S28
REQUEST FOR CREDIT Download full-text
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form can be faxed to 212-661-8338, Attn: CME Department.
POSTTEST ANSWER KEY (Enter answers to posttest questions in the spaces below)
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S28EVALUATION FORM – SCI-ALC-0245 / Journal of Substance Abuse Treatment 36 (Suppl 1) (2009) S26–S28