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DISEASES AND DISORDERS Copyright © 2019

The Authors, some

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treatment of alcohol use disorder American Association

for the Advancement
of Science. No claim to
, RZ Litten2, L. Leggio3,4,5 *
K. Witkiewitz1
original USGovernment
Works. Distributed
Alcohol is a major contributor to global disease and a leading cause of preventable death, causing approximately under a Creative
88,000 deaths annually in the United States alone. Alcohol use disorder is one of the most common psychiatric Commons Attribution
disorders, with nearly one-third of US adults experiencing alcohol use disorder at some point during their lives. NonCommercial
Alcohol use disorder also has economic consequences, costing the United States at least $249 billion annually. License 4.0 (CC BY-NC).
Current pharmaceutical and behavioral treatments may assist patients in reducing alcohol use or facilitating alcohol
abstinence. Although recent research has expanded understanding of alcohol use disorder, more research is
needed to identify the neurobiological, genetic and epigenetic, psychological, social, and environmental factors
most critical in the etiology and treatment of this disease. Implementation of this knowledge in clinical practice and
training of health care providers is also needed to ensure appropriate diagnosis and treatment of individuals
suffering from alcohol use disorder.

INTRODUCTION Only a small percent of individuals with alcohol use disorder

In most regions of the world, most adults consume alcohol at least contribute to the greatest societal and economic costs (8). For
occasionally (1). Alcohol is among the leading causes of preventable example, in the 2015 National Survey on Drug Use and Health
death worldwide, with 3 million deaths per year attributable to alcohol. survey (total n = 43,561), a household survey conducted across the
In the United States, more than 55% of those aged 26 and older United States, 11.8% met criteria for an alcohol use disorder (n =
consumed alcohol in a given month, and one in four adults in this 5124) (6). Of these 5124 individuals, 67.4% (n = 3455) met criteria
age group engaged in binge drinking (defined as more than four for a mild disorder (two or three symptoms, based on DSM-5), 18.8%
drinks for women and five drinks for men on a single drinking (n = 964) met criteria for a moderate disorder (four or five symptoms,
occasion) (2). Excessive alcohol use costs US society more than based on DSM-5), and only 13.8% (n = 705) met criteria for a severe
$249 billion annually and is the fifth leading risk factor for premature disorder (six or more symptoms) (6). There is a large treatment gap
death and disability (3). for alcohol use disorder, arising from the fact that many individuals
The morbidity and mortality associated with alcohol are largely with alcohol use disorder do not seek treatment. Those with a mild or moderate
due to the high rates of alcohol use disorder in the population. use disorder may be able to reduce their drinking in the absence of
Alcohol use disorder is defined in the Diagnostic and Statistical treatment (9) and have a favorable course; but it is those with more
Manual for Mental Disorders, 5th edition (DSM-5) (4) as a pattern of severe alcohol use disorder who most often seek treatment and who
alcohol consumption, leading to problems associated with 2 or more may experience a chronic relapsing course (10).
of 11 potential symptoms of alcohol use disorder (see Table 1 for criteria).
In the United States, approximately one-third of all adults will meet
criteria for alcohol use disorder at some point during their lives (5), HISTORY OF TREATMENT FOR ALCOHOL USE DISORDER
and approximately 15.1 million US adults meet criteria for alcohol Near the end of the 18th century, the Pennsylvania physician
use disorder in the previous 12 months (6) . The public health Benjamin Rush described the loss of control of alcohol and its
impacts of alcohol use extend far beyond those individuals who drink potential treatments (11). His recommendations for remedies and
alcohol, engage in heavy alcohol use, and/or meet criteria for an case examples included practicing the Christian religion, experiencing
alcohol use disorder. Alcohol use is associated with increased risk guilt and shame, pairing alcohol with aversive stimuli, developing
of accidents, workplace productivity losses, increased medical and other passions in life, following a vegetarian diet, taking an oath to
mental health costs, and greater rates of crime and violence (1). not drink alcohol, and sudden and absolute abstinence from alcohol .
Analyzes that take into account the overall harm due to drugs (harm Through the 1800s and early 1900s, the temperance movement laid
to both users and others) show that alcohol is the most harmful drug (7).the groundwork for mutual help organizations, and the notion of
excessive alcohol use as a moral failing. During the same period,
inebriate asylums emerged as a residential treatment option for
1
Department of Psychology and Center on Alcoholism, Substance Abuse, and excessive alcohol use, although the only treatment offered was forced abstinen
Addictions, University of New Mexico, 2650 Yale Blvd. SE, Albuquerque, NM 87106,
USA.2 Division of Medications Development and Division of Treatment and Recovery The founding of Alcoholics Anonymous (AA) in the 1930s (13) and
Research, National Institute on Alcohol Abuse and Alcoholism, 6700B Rockledge the introduction of the modern disease concept of alcohol use
3
Drive, Bethesda, MD 20892-6902, USA. Section on Clinical Psychoneuroendocrinology disorder (previously called “alcoholism”) in the 1940s (14) laid the
and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism
Division of Intramural Clinical and Biological Research, and National Institute on
groundwork for many of the existing treatment programs that re-
Drug Abuse Intramural Research Program, National Institutes of Health, 10 Center main widely available today. Over the past 80 years, empirical
4
Drive (10CRC/15330), Bethesda, MD 21224 , USES. Medication Development studies have provided support for both mutual support [AA and other
Program, National Institute on Drug Abuse Intramural Research Program, 251
5 support groups, such as SMART (Self-Management and Recovery
Bayview Blvd., Baltimore, MD 21224, USA.for Alcohol and Addiction Studies, Brown
Center
University, Providence, RI 02912, USA. Training)] and medical models of treatment for alcohol use disorder,
*Corresponding author. Email: [email protected] as well as the development of new pharmacological and behavioral

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one of the most common excitatory neurotransmitters. As one of the

Table 1. Alcohol use disorder criteria, as defined by the Diagnostic major inhibitory neurotransmitters, GABA plays a key role in the
and Statistical Manual for Mental Disorders, 5th edition (DSM-5) (4), neurochemical mechanisms involved in intoxication, tolerance, and
and the International Classification of Diseases, 10th edition (ICD-10) (116). withdrawal. This brief review can offer only a very simplified overview
DSM-5 criteria for alcohol use ICD-10 criteria for alcohol of the complex neurobiological basis of alcohol use disorder.
disorder dependence For deeper, more detailed analysis of this specific topic, the reader
Tolerance Tolerance is encouraged to consult other reviews (15, 16).
Withdrawal Withdrawal

Difficulties controlling drinking Difficulties controlling drinking

(unsuccessful in cutting down or (unsuccessful in cutting down CLINICAL MANAGEMENT OF ALCOHOL WITH DRAWAL
stopping drinking) or stopping drinking) SYNDROME
Neglect of activities Neglect of activities Alcohol withdrawal symptoms may include anxiety, tremors, nausea,
insomnia, and, in severe cases, seizures and delirium tremens.
Time spent drinking or recovering Time spent drinking or recovering
from effects of alcohol from effects of alcohol Although up to 50% of individuals with alcohol use disorder present
with some withdrawal symptoms after stopping drinking, only a small
Drinking despite physical/ Drinking despite physical/
psychological problems psychological problems percentage requires medical treatment for detoxification, and some
individuals may be able to reduce their drinking spontaneously.
Craving Craving
Medical treatment may take place either in an outpatient or, when
Alcohol consumed in larger clinically indicated, inpatient setting. In some cases, clinical monitoring
amounts or over longer periods
than was intended may suffice, typically accompanied by supportive care for hydration
and electrolytes and thiamine supplementation. For those patients in
Failure to fulfill major role
obligations
need of pharmacological treatment, benzodiazepines (eg, diazepam,
chlordiazepoxide, lorazepam, oxazepam, and midazolam) are the
Recurrent alcohol use in hazardous
situations most commonly used medications to treat alcohol withdrawal
syndrome. Benzodiazepines work by enhancing the effect of the
Drinking despite social/
GABA neurotransmitter at the GABAA receptor. Notably,
interpersonal problems
benzodiazepines represent the gold standard treatment, as they are
(Two or more criteria met in last (Three or more criteria met in
the only class of medications that not only reduces the severity of
year) last year)
the alcohol withdrawal syndrome but also reduces the risk of
withdrawal seizures and/or delirium tremens. Because of the potential
for benzodiazepine abuse and the risk of overdose, if benzodiazepine
treatment options. In addition, there are several public health policy treatment for alcohol withdrawal syndrome is managed in an
initiatives (eg, taxation, restrictions on advertising, and outlet density) outpatient setting, careful monitoring is required, particularly when
and brief intervention programs (eg, social norms interventions) that combined with alcohol and/or opioid medications (17).
can be effective in reducing prevalence of alcohol use disorder and a-2 agonists (eg, clonidine) and ÿ-blockers (atenolol) are some-
alcohol-related harms. (1). times used as an adjunct treatment to benzodiazepines to control
neuro-autonomic manifestations of alcohol withdrawal not fully
controlled by benzodiazepine administration (18). However, because
NEUROBIOLOGY OF ALCOHOL USE DISORDER of the lack of efficacy of a-2 agonists and ÿ-blockers in preventing
Alcohol use disorder is characterized by loss of control over alcohol severe alcohol withdrawal syndrome and the risk of masking with-
drinking that is accompanied by changes in brain regions related to drawal symptoms, these drugs are recommended not as monotherapy,
the execution of motivated behaviors and to the control of stress and but only as a possible adjunctive treatment.
emotionality (eg, the midbrain, the limbic system, the prefrontal Of critical importance to a successful outcome is the fact that
cortex, and the amygdala). Mechanisms of positive and negative re- alcohol withdrawal treatment provides an opportunity for the patient
inforcement both play important roles with individual drinking behavior and the health care provider to engage the patient in a treatment
being maintained by positive reinforcement (rewarding and desirable program aimed at achieving and maintaining long-term abstinence
effects of alcohol) and/or negative reinforcement mechanisms from alcohol or reductions in drinking. Such a treatment may in-
(negative affective and physiological states that are relieved by clude pharmacological and/or psychosocial tools, as summarized in
alcohol consumption) ( 15 , 16). At the neurotransmitter level, the the next sections.
positive reinforcing effects of alcohol are primarily mediated by
dopamine, opioid peptides, serotonin, ÿ-aminobutyric acid (GABA),
and endo-cannabinoids, while negative reinforcement involves PHARMACOLOGICAL APPROACHES TO THE TREATMENT
increased recruitment of corticotropin-releasing factor and OF ALCOHOL USE DISORDER
glutamatergic systems and down-regulation of GABA transmission US Food and Drug Administration–approved
(16). Long-term exposure to alcohol causes adaptive changes in pharmacological treatments
several neurotransmitters, including GABA, glutamate, and norepinephrine,Development of novel
among many pharmaceutical reagents is a lengthy, costly,
others.
Discontinuation of alcohol ingestion results in the nervous system and expensive process. Once a new compound is ready to be tested
hyperactivity and dysfunction that characterizes alcohol withdrawal for human research use, it is typically tested for safety first via phase
0 and phase 1 clinical studies in a very limited number of individuals.
(15, 16). Acting on several types of brain receptors, glutamate represents

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Efficacy and side effects may then be further tested in larger phase although the causal role of acamprosate in giving these side effects
2 clinical studies, which may be followed by larger phase 3 clinical is unclear.
studies, typically conducted in several centers and are focused on A third drug, the opioid receptor antagonist naltrexone, was
efficacy, effectiveness, and safety. If approved for use in clinical approved for the treatment of alcohol dependence by the FDA in
practice, this medication is still monitored from a safety standpoint, 1994. Later, a monthly extended-release injectable formulation of
via phase 4 postmarketing surveillance. naltrexone, developed with the goal of improving patient adherence,
Only three drugs are currently approved by the US Food and was also approved by the FDA in 2006. Naltrexone reduces craving
Drug Administration (FDA) for use in alcohol use disorder. The for alcohol and has been found to be most effective in reducing
acetaldehyde dehydrogenase inhibitor disulfiram was the first heavy drinking (25). The efficacy of naltrexone in reducing relapse
medication approved for the treatment of alcohol use disorder by the to heavy drinking, in comparison to placebo, has been supported in
FDA, in 1951. The most common pathway in alcohol metabolism is numerous meta-analyses (23–25), although there is less evidence
the oxidation of alcohol via alcohol dehydrogenase, which for its efficacy in supporting abstinence (25). Fewer studies have
metabolizes alcohol to acetaldehyde, and aldehyde dehydrogenase, been conducted with the extended-release formulation, but its effects
which converts acetaldehyde into acetate. Disulfiram leads to an on heavy drinking, craving, and quality of life are promising (29, 30).
irreversible inhibition of aldehyde dehydrogenase and accumulation Common side effects of naltrexone may include nausea, headache,
of acetaldehyde, a highly toxic substance. Although additional dizziness, and sleep problems. Historically, naltrexone's package
mechanisms (eg, in-hibition of dopamine ÿ-hydroxylase) may also insert has been accompanied by a risk of hepatotoxicity, a caution
play a role in disulfiram's actions, the blockade of aldehyde primarily due to observed liver toxicity in an early clinical trial with
dehydrogenase activity represents its main mechanism of action. administering a naltrexone dosage of 300 mg per day to obese men
Therefore, alcohol ingestion in the presence of disulfiram leads to (31). However, there is no published evidence of severe liver toxicity
the accumulation of acetaldehyde, resulting in numerous related at the lower FDA-approved dosage of naltrexone for alcohol use
unpleasant symptoms, including tachycardia, headache, nausea, disorder (50 mg per day). Nevertheless, transient, asymptomatic
and vomiting. In this way, disulfiram administration paired with hepatic transaminase elevations have also been observed in some
alcohol causes the aversive reaction, initially proposed as a remedy for alcohol use disorder
clinical trials by postmarketing
and in the Rush (11) in 1784.
period; Therefore, naltrexone
One challenge in conducting a double-blind, placebo-controlled should be used with caution in patients with active liver disease and
alcohol trial of disulfiram is that it is easy to break the blind unless should not be used in patients with acute hepatitis or liver failure.
the “placebo” medication also creates an aversive reaction when
consumed with alcohol, which would then provide the same Additional pharmacological treatments approved
mechanism of action as the medication (eg, the placebo and for alcohol use disorder in Europe
disulfiram would both have the threat of an aversive reaction). Open- Disulfiram, acamprosate, and naltrexone have been approved for
label studies of disulfiram do provide support for its efficacy, as use in Europe and in the United States. Pharmacologically similar to
naltrexone,
compared to controls, with a medium effect size (19), as defined by Cohen's d nalmefene was also approved for the treatment of
effect size ranges of small d = 0.2, medium d = 0.5, and large d = alcohol dependence in Europe in 2013. Nalmefene is an m- and d-
0.8 (20). The efficacy of disulfiram largely depends on patient opioid receptor antagonist and a partial agonist of the k-opioid
motivation to take the medication and/or supervised administration, receptor (32). Side effects of nalmefene are similar to naltrexone;
given that the medication is primarily effective by the potential threat Compared to naltrexone, nalmefene has a longer half-life. Meta-
of an aversive reaction when paired with alcohol (21). analyses have indicated that nalmefene is effective in reducing
The next drug approved for treatment of alcohol use disorder heavy drinking days (32). An indirect meta-analysis of these two
was acamprosate; first approved as a treatment for alcohol drugs concluded that nalmefene may be more effective than
dependence in Europe in 1989, acamprosate has subsequently naltrexone (33), although whether a clinically relevant difference
been approved for use in the United States, Canada, and Japan. between the two medications really exists is still an open question
Although the exact mechanisms of acamprosate action are still not (34). Network meta-analysis and microsimulation studies suggest
fully understood, there is evidence that it targets the glutamate that nalmefene may have some benefits over placebo for reducing total alcoho
system by modulating hyper-active glutamatergic states, possibly The approval of nalmefene in Europe was accompanied by some
acting as an N-methyl-d-aspartate receptor agonist (22). The efficacy controversy (37); a prospective head-to-head trial of nalmefene and
of acamprosate has been evaluated in numerous double-blind, naltrexone could help clarify whether nalmefene has added benefits
randomized controlled trials and meta-analyses, with somewhat to the existing medications available for alcohol use disorder. Last,
mixed conclusions (23–26). Although a meta-analysis conducted in nalmefene was approved in Europe as a medication that can be
2013 (25) indicated small to medium effect sizes in favor of taken “as needed” (ie, on days when drinking was going to occur).
acamprosate over placebo in supporting abstinence, recent large- Prior work has also demonstrated the efficacy of taking naltrexone
scale trials conducted in the United States (27) and Germany (28) only on days that drinking was potentially going to occur (38).
failed to find effects of acamprosate is dis-tinguishable from those of In addition to these drugs, a GABAB receptor agonist used to
a placebo. Overall, there is evidence that acamprosate may be more treat muscle spasms, baclofen, was approved for treatment of
effective in promoting abstinence and preventing relapse in already alcohol use disorder in France in 2018 and has been used off label for alcohol
detoxified patients than in helping individuals reduce drinking (25), use disorder for over a decade in other countries, especially in other
therefore suggesting its use as an important pharmacological aid in European countries and in Australia (39, 40). Recent human
treatment of abstinent patients with alcohol use. disorder. The most common side effect
laboratory with
work suggests that baclofen may disrupt the effects of an
acamprosate is diarrhea. Other less common side effects may initial priming dose of alcohol on subsequent craving and heavy
include nausea, vomiting, stomachache, headache, and dizziness, drinking (41). Meta-analyses and systematic reviews examining the efficacy

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of baclofen have yielded mixed results (35, 39, 42); However, there also smokers (60). Additional details on the FDA-approved
is some evidence that baclofen might be useful in treatment of medications and other medications tested in clinical research settings
alcohol use disorder among individuals with liver disease (43, 44). for the treatment of alcohol use disorder are summarized in Table 2.
Evidence of substantial heterogeneity in baclofen pharmacokinetics The medications and targets described above have shown
among different individuals with alcohol use disorder (41) could promising results in phase 2 or phase 3 medication trials. However,
explain the variability in the efficacy of baclofen across studies. The owing to the development of novel neuroscience techniques, a
appropriate dose of baclofen for use in treatment of alcohol use disordergrowing
remainsand exciting body of data is expanding the armamentarium
a controversial topic, and a recent international consensus statement of targets currently under investigation in animal models and/or in
highlighted the importance of tailoring doses based on safety, early-phase clinical studies. Pharmacological approaches with
tolerability, and efficacy (40). particular promise for future drug development include, but are not
limited to the following [for recent reviews, see, eg, (56, 61–68)]:
Promising pharmacological treatments the antipsy-chotic drug aripiprazole, which has multiple
Numerous other medications have been used off label in the treat- pharmacological actions (mainly on dopamine and serotonin
ment of alcohol use disorder, and many of these have been shown receptors), the antihypertensive alpha-1 blocker drugs prazosin and
to be modestly effective in meta-analyses and systematic reviews doxazosin, neurokinin-1 antagonism, the glucocorticoid receptor
(23, 24, 26, 35). Systematic studies of these medications suggest blocker mifepristone, vasopressin receptor 1b antagonism, oxytocin,
promising findings for topiramate, ondansetron, gabapentin, and ghrelin receptor antagonism, glucagon-like peptide-1 agonism, and
varenicline. The anticonvulsant drug topiramate represents one of pharmacological manipulations of the nociception receptor (We are
the most promising medications in terms of efficacy, based on its intentionally using a general pharmacological terminology for the
medium effect size from several clinical trials [for a review, see (45)], nociceptin receptor, given that it is unclear whether agonism,
including a multisite clinical study (46). One strength of topiramate is antagonism, or both may represent the best approach.). New
the possibility of starting treatment while people are still drinking medications development is particularly important for the treatment
alcohol, therefore serving as a potentially effective treatment to of comorbid disorders that commonly co-occur among individuals
initiate abstinence (or to reduce harm) rather than to prevent relapse with alcohol use disorder, particularly affective disorders, anxiety
in already detoxified patients (45). Although not approved by the disorders, suicidality, and other substance use disorders. This aspect
FDA, it is worth noting that topiramate is a recommended treatment of alcohol use disorder is relevant to the fact that addictive disorders
for alcohol use disorder in the US Department of Veterans Affairs (47). often present with significantly more severe symptoms when they
A concern with topiramate is the potential for significant side effects, coexist with other mental health disorders (69). Likewise, there is
especially those affecting cognition and memory, warranting a slow evidence that pharmacotherapy is most effective when implemented
titration of its dose and monitoring for side effects. Furthermore, in conjunction with behavioral interventions (70), and all phase 2 and
recent attention has been paid on zonisamide, another anticonvulsant phase 3 medication trials, mentioned above, have included a brief
medication, whose pharmacological mechanisms of actions are psychosocial behavioral treatment in combina-tion with medication.
similar to topiramate but with a better tolerability and safety profile
(48). Recently published and ongoing research focuses on a potential
pharmacogenetic approach to treatment in the use of topiramate to BEHAVIORAL/PSYCHOLOGICAL TREATMENTS
treat alcohol use disorder, based on the possibility that both efficacy FOR ALCOHOL USE DISORDER
and tolerability and safety of topiramate may be moderated by a Evidence-based treatments
functional single-nucleotide polymorphism (rs2832407) in GRIK1, A wide range of behavioral and psychological treatments are
encoding the kainate GluK1 receptor subunit (49). Human laboratory available for alcohol use disorder, and many treatments are equally
studies (50) and treatment clinical trials (51) have also used a effective in supporting abstinence or drinking reduction goals (71–
primarily pharmacogenetic approach to testing the efficacy of the 74). Treatments with the greatest evidence of efficacy range from
antinausea drug ondansetron, a 5HT3 antagonist, in alcohol use brief inter-ventions, including motivational interviewing approaches,
disorders. Overall, these studies suggest a potential role for to operant conditioning approaches, including contingency
ondansetron in alcohol use disorder, but only in those individuals management and the community reinforcement approach, to
with certain variants of the genes encoding the serotonin transporter cognitive behavioral treatments, including coping skills training and
5-HTT and the 5-HT3 receptor. The anticonvulsant gabapentin has relapse prevention, and to acceptance- and mindfulness-based
shown promising results in human laboratory studies and clinical approaches. Twelve-step facilitation, which was designed specifically
trials (52–54), although a more recent multisite trial with an extended- to connect individuals with mutual support groups, has also been shown to be e
release formulation of the medication did not have an effect of In addition, harm reduction treatments, including guided self-control
gabapentin superior to that of a placebo (55 ). Although the latter training and controlled drinking interventions, have been successful
findings might be related to potential pharmacokinetic issues in supporting drinking reduction goals (70).
secondary to the specific formulation used, it is nevertheless possible Meta-analyses and systematic reviews have found that brief inter-
that gabapentin may be more effective in patients with more clinically ventions, especially those based on the principles of motivational
relevant alcohol with-drawal symptoms (52). Several human inter-viewing, are effective in the treatment of alcohol use disorder.
laboratory studies support a role for varenicline, a nicotinic These interventions can include self-monitoring of alcohol use,
acetylcholine receptor partial agonist approved for smoking cessation, increasing awareness of high-risk situations, and training in cognitive
in alcohol use disorder [for a review, see (56)], and two of three and behavioral techniques to help clients cope with potential drinking
clinical trials also support its efficacy on alcohol outcomes ( 57–59), situations, as well as life skills training, communication training, and
especially in heavy drinkers who are males (59) and in male and femalecoping
alcohol-dependent individuals
skills training. Cognitivewho are
behavioral treatments can be

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Table 2. FDA-approved medications and other medications tested in clinical research settings (phase 2 or 3 medication trials) for the treatment of alcohol
use disorder. FDA, US Food and Drug Administration; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartate; PO, per os (oral);
IM, intramuscular; HT, serotonin.

FDA-approved medications for alcohol use disorder

Pharmacological mechanism(s) and additional

Daily total dose information

Unclear—it has been suggested that acamprosate is a

Acamprosate (PO) 1998 mg per day modulator of hyperactive glutamatergic states,
possibly as an NMDA receptor agonist
Disulfiram (PO) 250–500 mg per day Inhibition of acetaldehyde dehydrogenase

Naltrexone (PO) 50 mg per day m-opioid receptor antagonist

Naltrexone (IM) 380 mg once a month m-opioid receptor antagonist

Not FDA-approved medications tested for alcohol use disorder

GABAB receptor agonist

Baclofen (PO) 30–80 mg per day Approved in France by the National Agency for the
Safety of Medicines and Healthcare Products

Unclear—the most likely mechanism is blockade of

voltage-dependent Ca2+ channels. Although it is a
Gabapentin (PO) 900–1800 mg per day
GABA analog, gabapentin does not seem to act on
the GABA receptors

m- and d-opioid receptor antagonist and k-opioid

receptor partial agonist
Nalmefene (PO) 18 mg per day
Approved in Europe by the European Medicines
Agency

0.5 mg per day (fixed dose) or up to

Ondansetron (PO) 5HT3 antagonist
36 mcg/kg per day

Prazosin/doxazosin (PO) Up to 16 mg per day a-1 receptor antagonists

Topiramate is an anticonvulsant with multiple

targets. It increases GABAA-facilitated neuronal
activity and simultaneously antagonizes AMPA
and kainate glutamate receptors. It also inhibits l-
Topiramate (PO) Up to 300 mg per day type calcium channels, limits the activity of
voltage-dependent sodium channels and
facilitates potassium conductance. Furthermore, it is
a weak inhibition of the carbonic anhydrase
isoenzymes, CA-II and CA-IV
Varenicline (PO) 2 mg per day Nicotinic acetylcholine receptor partial agonist

delivered in individual or group settings and can also be extended to was designed to provide psychosocial support (particularly among those
the treatment of families and couples (72, 73). assigned to the placebo medication) and also to increase adherence
Acceptance- and mindfulness-based interventions are increasingly and retention among individuals enrolled in pharmacotherapy trials (80).
being used to target alcohol use disorder and show evidence of Mutual support group (eg, AA and SMART) attendance and
effectiveness in a variety of settings and formats, including brief engagement have been shown to be associated with recovery from
intervention formats (76). Active ingredients include raising present alcohol use disorder, even in the absence of formal treatment (81).
moment awareness, developing a nonjudgmental approach to self and However, selection biases (eg, people selecting to attend these groups)
others, and increasing acceptance of present moment experiences. raise difficulties in assessing whether other factors that are associated
Acceptance- and mindfulness-based interventions are commonly with treatment effectiveness may be the active ingredients for im-
delivered in group settings and can also be delivered in individual therapy contexts.
proving outcomes among those who attend mutual support groups.
Computerized, web-based, and mobile interventions have also been For example, individuals who are highly motivated to change might be
developed, incorporating the principles of brief interventions, behavioral more likely to attend mutual support groups. Likewise, mutual support
and cognitive behavioral approaches, as well as mindfulness and mutual groups often provide individuals with increased social network support
support group engagement; Many of these approaches have for abstinence (82). Motivation to change and having a social network
demonstrated efficacy in initial trials (77–79). For example, the National that supports abstinence (or reductions in drinking) are both factors that
Institute on Alcohol Abuse and Alcoholism (NIAAA) has developed the are associated with greater treatment effectiveness (83).
Take Control computerized intervention that includes aspects of As noted above, most behavioral and psychological treatments are
motivational interviewing and coping skills training and equally effective with small effect size differences [Cohen's d = 2.0 to 0.3

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(20)] between active treatments (84–88). Behavioral interventions Factors contributing to the effectiveness of treatments
have also been shown to be as effective as pharmacotherapy Numerous models have examined factors that predict treatment
options, with a 16-week cognitive behavioral intervention shown to readiness, treatment engagement, and treatment outcomes for
be statistically equivalent to naltrexone in reducing heavy drinking alcohol use disorder. The transtheoretical model of changes proposes
days in a large randomized trial (27). One of the challenges of that an individual's own readiness to change his or her drinking
examining behavioral interventions in randomized trials is that intervention behavior may have an impact on treatment engagement and
blinding and placebo controls cannot be implemented in most effectiveness (93). The dynamic model of relapse proposes the
contexts, other than in computerized interventions. Furthermore, the involvement of multiple interacting biological, psychological, cognitive,
general therapeutic factors common to most behavioral interventions emotional, social, and situational risk factors that are static and
(eg, therapist empathy and supportive therapeutic relationship) in dynamic in their association with treatment outcomes (83).
treatment of alcohol use disorder are as powerful as the specific Neurobiological models of addiction focus on the brain reward and
therapeutic targets of specific behavioral interventions (eg, teaching stress system dysfunction that contributes to the development and
skills in a cognitive behavioral treatment) in facilitating behavioral changemaintenance
(89). of alcohol use disorder, that is, the “addiction cycle”
(15, 16). The alcohol and ad-diction research domain criteria
Promising future behavioral treatments (AARDoC) (92), which have been operationalized in the addictions
and neuromodulation treatments neuroclinical assessment (94), focus on the following three domains
With respect to behavioral treatments, there are numerous opportu- that correspond to particular phases in the addiction cycle: incentive
nities for the development of novel mobile interventions that could salience in the binge /intoxication phase, negative emotionality in
provide treatment and recovery support in near real time. This mobile the withdrawal/negative affect phase, and executive function in the preoccupat
technology may also extend the reach of treatments to individuals Within each domain of the AARDoC, the addictions neuroclinical
with alcohol use disorder, particularly in rural areas. On the basis of assessment proposes constructs that can be measured at multiple
a contextual self-regulation model of alcohol use (90), it is critical to levels of analysis, such as craving in the incentive salience domain,
address the immediate situational context alongside the broader negative affect and emotion dysregulation in the negative emotionality
social, environmental, and familial context in which an individual domain, and cognitive impairment and impulsivity in the executive
experiences the world and engages in momentary decision-making . function domain. The AARDoC recognizes that environmental and
Ambulatory assessment, particularly tools that require only passive con-textual factors play a role in alcohol use disorder and treatment
monitoring (eg, GPS, heart rate, and skin conductance) and real- out-comes. Furthermore, because of the heterogeneity of alcohol
time support via mobile health, could provide immediate environmental use disorder, the significance of these domains in causing alcohol
supports and could extend the reach of medications and behavioral treatments use disorder and alcohol-related problems will vary among individuals.
for alcohol use disorder. For example, a mobile device could Each of the abovementioned theoretical models proposes factors
potentially signal a high-risk situation by indicating the geographic that may affect treatment effectiveness; However, many of the con-
location (near a favorite drinking establishment) and the heart rate structs proposed in each of these models are overlapping and likely
(increased heart rate when approaching the establishment). The contribute to the effectiveness of alcohol use disorder treatment.
device could provide a warning either to the individual under across a range of populations and settings. A heuristic model com-
treatment and/or to a person supporting that individual's recovery. bining components from each of these models is shown in Fig. 1.
In addition, de-developments in alcohol sensing technology (eg, Specifically, this model highlights the precipitants of alcohol use that
transdermal alcohol sensors) could greatly increase rigor of research are influenced by the neurobiological adaptations proposed in the
on alcohol use dis-order and also provide real-time feedback on addiction cycle (indicated by bold font) and additional contextual
alcohol consumption levels to individuals who are attempting to factors (regular font) that decrease or increase the likelihood of
moderate and/or reduces their alcohol use. drinking in context, depending on whether an individual uses effective
Recent advances in neuromodulation techniques may also hold coping regulation at the moment. The domains supporting alcohol
promise for the development of novel treatments for alcohol use use/coping regulation (negative emotionality, executive function,
disorder. Deep brain stimulation, transcranial magnetic stimulation, incentive salience, and social environment) may interact to predict
transcranial electrical stimulation (including transcranial direct current alcohol use or coping regulation in the moment. For example,
stimulation and transcranial alternating current stimulation), and real- network support for abstinence could improve decision-making and
time neurofeedback have recently been tested as potential treatments decrease likelihood of drinking. Conversely, experiences of physical
for addiction, although evidence in favor of these treatments is pain are associated with increases in negative affect and poorer
currently uncertain and focused mostly on intermediate targets (eg, executive function, which could both increase likelihood of drinking.
alcohol craving) (91). These techniques attempt to directly target Both of these examples require environmental access to alcohol and
spec-cific brain regions and addiction-related cognitive processes a desire to drink alcohol. Treatment effectiveness will depend on the
via surgically implanted electrodes (deep brain stimulation), electrical extent to which a particular treatment targets those risk factors that
currents or magnetic fields applied to the scalp (transcranial electrical are most likely to increase or decrease the likelihood of drinking for
and magnetic stimulation, respectively), or individual self- generated each individual, as well as the personal resources that each individual
modulation via feedback (neurofeedback). Although robust large brings to treatment and/or that could be enhanced in treatment.
scale trials with double-blind, sham controls, and long-term follow- A functional analysis of contextual risk and protective factors can be
ups of alcohol behavior change and relapse have not been conducted critically important in guiding treatment.
(91), the heterogeneity of alcohol use disorder suggests that targeting For example, there is considerable heterogeneity in treatment
one specific neural region may be insufficient to treat such a complex response to naltrexone, which may vary in efficacy in some
disorder, with its multiple etiologies and diverse clinical courses (92). individuals. Recent studies conducted to determine whether certain patients

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(2). Very little is known about factors, particularly neurobiological,

genetic, and epigenetic factors, that predict the transition from
alcohol use to alcohol use disorder, although basic science models
suggest that a cycle of neuroadaptations could be at play (15, 16).
We also lack a basic understanding of how individuals recover from
alcohol use disorder in the absence of treatment and what
neurobiological, psychological, social, and environmental factors are
most important for supporting recovery from alcohol use disorder.
Gaining a better understanding of recovery in the absence of
treatment, particularly modifiable psychological, neurobiological, and
epigenetic factors, could provide novel insights for medications and
behavioral treatment development. Among many other factors,
special attention is needed in future studies to shed light on the role
of sex and gender in the development and maintenance of alcohol
use disorder and on the response to pharmacological, behavioral, and other tre
The heterogeneity of alcohol use disorder presents a major
challenge to scientific understanding and to the development of
effective treatments for prevention and intervention (92). For
example, a DSM-5 diagnosis of alcohol use disorder requires 2 or
more symptoms, out of 11, over the past year. That requirement
equates to exactly 2048 potential symptom combinations that would
meet the criteria of alcohol use disorder. An individual who only
meets criteria for tolerance and withdrawal (ie, physiological
Fig. 1. Conceptual model of factors that affect treatment effectiveness. Risk dependence) likely requires a very different course of treatment from
factors proposed in the AARDoC, including incentive salience, negative emotionality, an individual who only meets the criteria for failure to fulfill role
executive function, and social environmental factors, are shown in black bold font obligations and use of alcohol in hazardous situations. Gaining a
encircling alcohol use. Contextual risk factors, including decision-making, self- better understanding of the etiology and course of alcohol use
efficacy, pain, craving, etc., are shown in black font in colored boxes. Risk and disorder, as well as identifying whether different subtypes of
protective factors overlap with alcohol use and interact in predicting coping drinkers may respond better to certain treatments (103, 104), is
regulation and alcohol use among individual patients. critical for advancing the science of alcohol use disorder prevention
and treatment . Alternative conceptualizations of alcohol use disorder
may benefit more from naltrexone have yielded mixed findings (95). may also aid in improving our understanding of the disorder and
Promising evidence suggests that individuals with the OPRM1 reducing heterogeneity. For example, the pending International
A118G G (Asp40) allele may have a better response to naltrexone Classification of Diseases, 11th edition, will simplify the diagnosis of
(96–98); However, a prospective study of medication response alcohol dependence to requiring only two of three criteria in the past
among individuals stratified by presence of the Asp40 allele did not 12 months: (i) impaired control over alcohol use; (ii) alcohol use that
provide support for the genotype by treatment interaction (99), and dominates over other life activities; and (iii) persistence of alcohol
recent human laboratory studies have not confirmed the hypothesized use despite consequences. The diagnosis will be made with or
mechanisms underlying the pharmacogenomic effect (100). Initial without physiological dependence, as characterized by tolerance,
evidence suggests that naltrexone may be more effective in withdrawal, or repeated use to prevent or alleviate withdrawal (105).
reducing heavy drinking among smokers (101) and among those It remains to be seen whether simplification of the criteria set will
with a larger number of heavy drinkers in their social networks (102). narrow our conceptualization or potentially increase heterogeneity
With respect to reinforcement typologies, recent work has found that of this disorder among those diagnosed with alcohol dependence.
naltrexone may be more effective among those who tend to drink
alcohol for rewarding effects (103), and acamprosate may also be Placebo effect
more effective for individuals who drink to relieve negative affect (104). An additional challenge to development of pharmacological
treatments for alcohol use disorder is the high placebo response
rates seen in drug trials (106). The tendency for individuals to have
GAPS INSCIENTIFIC KNOWLEDGE ANDNEW RESEARCH a good treatment response when assigned to placebo medication
DIRECTIONS reflects both the high probability of recovery without treatment and
Heterogeneity of individuals with alcohol use disorder the hetero-geneity in the disorder itself. Many people who enter
This review has briefly summarized the treatments currently treatment are already motivated to change behavior, and receiving
available for alcohol use disorder that are relatively effective, at least a placebo medication can help these individuals continue the process
in some patients. Many new treatments are also being developed, of change. Gaining a better understanding of which kinds of
and some of them seem promising. However, numerous gaps in individuals respond to placebo and of the overall physiological and
sci-entific knowledge remain. Notably, most people who drink alcohol behavioral complexities in the placebo response is critical to
do not develop an alcohol use disorder, most people with alcohol identifying those individuals who will benefit the most from active
use disorder do not seek treatment, and most of those who do not medication. More generally, very little is understood about how
seek treatment “recover” from alcohol use disorder without treatment motivation to change drinking behavior may influence the efficacy of active me

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via adherence mechanisms. Additional research on targeted (ie, as and medication in primary care and other clinical settings, as well as
needed) dosing of medications, such as nalmefene and naltrexone research on best methods for implementation, has great potential for
(32, 38), would be promising from the perspective of increasing expanding access to effective treatment options (115). Because the
adherence to medications and also raising awareness of potentially heterogeneity of alcohol use disorder makes it highly unlikely that one
heavy drinking occasions. single treatment will work for all individuals, it is important to provide a
menu of options for pharmacological and behavioral therapies to both
Recent developments in pharmacological clinicians and patients. Reducing the stigma of alcohol use disorder
and behavioral approaches and moving toward a public health approach to addressing this
In addition to gaining a better understanding of the disorder and who problem may further increase the range of acceptable-able treatment
benefits from existing treatments, the examination of molecular targets options.
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change and sustain talk subtypes in motivational interviewing. Psychother. Res. 2018, 1–10 necessarily represent the official views of the founders. Author contributions: KW wrote the first draft of
(2018). the manuscript. KW, RZL, and LL provided additional text and edits. All authors approved the final draft.
114. Department of Health and Human Services (HHS), Facing Addiction in America: The Surgeon Competing interests: The authors declare that they have no competing interests. Data and
General's Report on Alcohol, Drugs, and Health (HHS, 2016). materials availability: All data needed to evaluate the conclusions in the paper are present in the

115. J. Rehm, P. Anderson, J. Manthey, KD Shield, P. Struzzo, M. Wojnar, A. Gual, Alcohol use disorders paper and/or in the materials cited here.

in primary health care: What do we know and where do we go? Alcohol Alcohol Additional data related to this paper may be requested from the authors.
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116. World Health Organization, ICD-10: International Statistical Classification of Diseases and Submitted March 20, 2019
Related Health Problems, 10th revision (World Health Organization, 2004). Accepted August 28, 2019
Published 25 September 2019
Acknowledgment 10.1126/sciadv.aax4043
Funding: This research was supported by a grant from NIAAA (R01 AA022328) awarded to KW
(principal investigator). RZL is funded by NIAAA. LL is jointly funded by NIAAA and the National Institute Citation: K. Witkiewitz, RZ Litten, L. Leggio, Advances in the science and treatment of alcohol use disorder.
on Drug Abuse (NIDA) (ZIA-AA000218). The content of this review does not Sci. Adv. 5, eaax4043 (2019).

Witkiewitz et al., Sci. Adv. 2019; 5 : eaax4043 25 September 2019 11 of 11