Annual Review of Pharmacology and Toxicology

Alcohol Use Disorder

Treatment: Problems
and Solutions
George F. Koob
National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA;
email: george.koob@nih.gov

Annu. Rev. Pharmacol. Toxicol. 2024. 64:255–75 Keywords

The Annual Review of Pharmacology and Toxicology is
alcohol use disorder, AUD, AUD treatment, AUD treatment gap, stigma,
online at pharmtox.annualreviews.org
screening, brief intervention and referral to treatment, neurobiology of
https://doi.org/10.1146/annurev-pharmtox-031323-
AUD
115847

This work is licensed under a Creative Commons Abstract

Attribution 4.0 International License, which permits
unrestricted use, distribution, and reproduction in Alcohol use disorder (AUD) afflicts over 29 million individuals and causes
any medium, provided the original author and more than 140,000 deaths annually in the United States. A heuristic frame-
source are credited. See credit lines of images or
work for AUD includes a three-stage cycle—binge/intoxication, withdrawal/
other third-party material in this article for license
information. negative affect, and preoccupation/anticipation—that provides a starting
point for exploring the heterogeneity of AUD with regard to treat-
ment. Effective behavioral health treatments and US Food and Drug
Administration–approved medications are available but greatly underuti-
lized, creating a major treatment gap. This review outlines challenges that
face the alcohol field in closing this treatment gap and offers solutions,
including broadening end points for the approval of medications for the
treatment of AUD; increasing the uptake of screening, brief intervention,
and referral to treatment; addressing stigma; implementing a heuristic def-
inition of recovery; engaging early treatment; and educating health-care
professionals and the public about challenges that are associated with alco-
hol misuse. Additionally, this review focuses on broadening potential targets
for the development of medications for AUD by utilizing the three-stage
heuristic model of addiction that outlines domains of dysfunction in AUD
and the mediating neurobiology of AUD.

255
 SCOPE OF THE PROBLEM
Alcohol misuse constitutes a major source of mortality, social pathology, and burden to the health-
care system in the United States. In the United States, data show that over 29 million individuals
met the criteria for alcohol use disorder (AUD) in 2019, and more than 140,000 deaths were
attributable to alcohol annually from 2015 to 2019 (1, 2). Increases in deaths, hospitalizations,
and liver disease that are attributable to alcohol increased dramatically during the first year of the
coronavirus disease 2019 (COVID-19) pandemic, and 5% of cancer cases are now attributable to
alcohol (3–5).

WHAT IS ALCOHOL USE DISORDER?

Definition
AUD can be defined as a chronically relapsing disorder that is associated with compulsive alcohol
drinking, the loss of control over intake, and the emergence of a negative emotional state when
alcohol is no longer available (6, 7). Alcohol misuse in AUD can range from a pattern of intermit-
tent episodes of binge alcohol intake to a pattern of prolonged heavy drinking over longer periods
of time that progresses to continual drinking for fear of withdrawal.
From a nosology perspective, the diagnosis of AUD is based on positive findings on at least
2 of 11 criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-
5) (8), which provides a framework for the intensity of symptoms with regard to the number of
symptoms that an individual presents. The DSM-5 combines earlier diagnostic criteria for alcohol
abuse and dependence under the new term AUD, with severity modifiers of mild, moderate, and
severe based on the number of criteria that are met. Thus, AUD is now considered a spectrum
disorder as described by the DSM-5.
Consistent with the spectrum framework of the DSM-5, an individual can enter the addiction
cycle at different stages. Classically, individuals with a substance use disorder, such as AUD, may
start with recreational use of the drug during the binge/intoxication stage and progress to the
withdrawal/negative affect stage as negative reinforcement evolves (9) (Figure 1). However, much
of alcohol misuse also develops because negative reinforcement may be the initial starting point
via either self-medication (10) or chronic pain (11).

Neurobiological Framework
A heuristic framework for AUD and addiction in general includes a three-stage cycle—binge/
intoxication, withdrawal/negative affect, and preoccupation/anticipation—that provides a start-
ing point for exploring the heterogeneity of AUD with regard to treatment (10, 12). Under
this addiction framework, stage-related dysregulation occurs in three functional domains (in-
centive salience/pathological habits, negative emotional states, and executive function) that are
mediated by three major neurocircuitry elements (basal ganglia, extended amygdala, and pre-
frontal cortex, respectively) (10, 13, 14). These three stages feed into each other, become
more intense, and ultimately lead to the pathological state of AUD (10) (see the center of
Figure 1).
From a neurobiological perspective, entrance into the three-stage cycle at any stage can
engage neuroadaptations that lead to compulsive-like alcohol consumption. The concept here
is that the excessive engagement of reward system activation by alcohol ultimately triggers a
break from hedonic homeostasis and subsequent compensatory responses in brain reward and
stress systems to generate the negative emotional state of withdrawal (termed hyperkatifeia)
(15) of the withdrawal/negative affect stage (10) (Table 1). As a consequence—and often in

256 Koob
 Molecular
• GABA receptors
Neurochemical • Serotonin receptors
• GABA • Glycine receptors
• Opioid peptides • Glutamate receptors:
• Dopamine NMDA, kainate, AMPA
• Acetylcholine • Potassium M channels
• Serotonin • Potassium BK channels
• Norepinephrine • Calcium channels
• Glycine/taurine • Nucleoside
• Acetaldehyde transporter adenosine
• Glutamate • CREB
• Allopregnanolone • Acetylcholine receptors
• BDNF • G proteins: protein
• Neuroimmune factors kinases: A, C, γ, ε

Binge/
intoxication

ACC Thalamus

dlPFC
DS GP
vlPFC
vmPFC NAc
BN HPC
ST
CeA
OFC Insula
Pr e t i c i p a

e a l/
t
an

ffec
ti v w a
o cc t i

g a d ra
up on

n e it h
at
io

W
n/

Neurochemical Neurochemical
• Dopamine • Dopamine
• Opioid peptides • Serotonin
• GABA Molecular • GABA Molecular
• Glutamate • Dopamine D1, D2 receptors • Glutamate • BK channel
• CRF • Dopamine transporter • CRF • GABAA receptor
• Glucocorticoids • GluN1, GluN2B receptors • Glucocorticoids subunits
• Norepinephrine • NMDA and AMPA receptors • Norepinephrine • NPY receptors
• Dynorphin/κ-opioid • Metabotropic glutamate • Hypocretin (orexin) • cAMP, CREB
receptors receptors • Vasopressin • BDNF
• Hypocretin • Calpain • Substance P • CRF receptors
• Substance P • Casein-1ε/δ • Neuroimmune factors • Protein kinases
• L-type calcium channels • Norepinephrine
• NPY • MTORC1 • NPY transporter
• Nociceptin • ERK1/2 • Nociceptin • microRNA
• Cannabinoids • NF-κB • Endocannabinoids • Histone
• Oxytocin • Histone methyltransferase • Oxytocin dimethyltransferase

(Caption appears on following page)

www.annualreviews.org • Alcohol Use Disorder Treatment 257

Figure 1 (Figure appears on preceding page)
Neurochemical and molecular targets of alcohol in the binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation
stages of the addiction cycle. The three stages are hypothesized to be mediated by three key superstructures of motivational circuitry:
basal ganglia for the binge/intoxication stage (blue), extended amygdala for the withdrawal/negative affect stage (red), and prefrontal
cortex for the preoccupation/anticipation stage (green). These stages and corresponding structures are associated with incentive
salience/pathological habits, reward deficits/stress surfeits, and executive function deficits, respectively. Neurochemical targets are listed
in the left-hand box for each stage of the addiction cycle. Molecular targets are listed in the right-hand box for each stage of the
addiction cycle. Abbreviations: ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor; BNST, basal nucleus of the
stria terminalis; CeA, central nucleus of the amygdala; CREB, cyclic adenosine monophosphate response element binding protein;
CRF, corticotropin-releasing factor; dlPFC, dorsolateral prefrontal cortex; DS, dorsal striatum; ERK1/2, extracellular signal-regulated
kinase 1/2; GABA, γ-aminobutyric acid; GluN, glutamine; GP, globus pallidus; HPC, hippocampus; Insula, insular cortex; MTORC1,
mammalian/mechanistic target of rapamycin complex 1; NAc, nucleus accumbens; NF-κB, nuclear factor κB; NMDA,
N-methyl-d-aspartate; NPY, neuropeptide Y; OFC, orbitofrontal cortex; vlPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial
prefrontal cortex. Figure adapted with permission from Reference 7.

parallel—executive function is compromised, thus contributing to deficits that are associated

with the preoccupation/anticipation stage and leading to craving for alcohol and perpetuating
the addiction cycle (13, 14).

THE GOOD NEWS: EFFECTIVE BEHAVIORAL HEALTH

(NONPHARMACOLOGICAL) TREATMENTS FOR ALCOHOL
USE DISORDER
Standards in the field of AUD treatment include behavioral health (i.e., nonpharmacological)
treatments, such as self-help groups and inpatient and outpatient clinical settings. Evidence-based
behavioral health treatments can help patients develop skills to stop or reduce drinking; manage
emotions, stress, and cues that trigger drinking; and establish a framework that will support ul-
timate treatment goals. Evidence-based nonpharmacological treatments, all of which are equally
effective, include cognitive-behavioral therapy, motivational enhancement therapy, acceptance-
and mindfulness-based interventions, contingency management approaches, couples and family
counseling, and 12-step facilitation therapy (16). Although technically not a treatment per se, in-
person or online mutual support groups help many people. Such groups have diverse frameworks
and can be spiritual based (e.g., Alcoholics Anonymous) and also secular (e.g., Secular Alcoholics
Anonymous). Meta-analyses of Alcoholics Anonymous and 12-step facilitation found that they
are as effective as other behavioral health treatments at reducing drinking intensity, promoting
abstinence, and reducing alcohol-related consequences at 12 months (17). Although brief inter-
ventions (see below) can be conducted by primary care physicians and medications for AUD can
be prescribed, licensed professional therapists are recommended for evidence-based behavioral
health treatments for AUD.
Nonpharmacological treatments can also increase the response to medications by modify-
ing attitudes and behaviors that are related to alcohol, increasing healthy life skills, and helping
people stay in treatment. Indeed, most clinical trials that have tested the development of medi-
cations for the treatment of AUD have evaluated a medication that is given in addition to either
the routine AUD treatment that patients would ordinarily receive in that setting or a manual-
guided form of behavioral therapy (e.g., AlcoholFree) (18), motivation enhancement therapy (19),
cognitive behavioral coping skills behavioral therapy (20), and 12-step facilitation therapy (21).
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol Treatment Naviga-
tor (https://alcoholtreatment.niaaa.nih.gov) is a website that is designed to assist in locating
clinicians who provide evidence-based behavioral and/or pharmacological treatments for AUD
(Table 2).

258 Koob
Table 1 Definitions relevant to the three-stage heuristic framework and neurobiology of alcohol use disorder
Term Definition
Anhedonia Anhedonia is generally defined as an inability to experience pleasure in normally pleasurable acts or
markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day
(8). Less pleasure from situations and stimuli that normally induce pleasure or hedonia is a common
element of withdrawal from all drugs of abuse (89) and is considered to be a subset of the hypersensitivity
to negative emotional states that is defined as hyperkatifeia.
Basal ganglia The basal ganglia, or basal nuclei, comprise a group of subcortical nuclei that are situated at the base of the
forebrain and top of the midbrain. Basal ganglia are strongly interconnected with the cerebral cortex,
thalamus, and brainstem in what are known as cortical-striatal-pallidal-thalamic-cortical loops (90). The
basal ganglia are associated with various functions, including the control of voluntary motor movements,
procedural learning, habit learning, conditional learning, and emotion.
Executive function Executive function can be conceptualized as the ability to organize thoughts and activities, prioritize tasks,
manage time, and make decisions. To accomplish such complex tasks in the context of the neurobiology
of addiction, the prefrontal cortex can be divided into two opposing systems: Go system and Stop system.
The Go system engages habit systems, possibly even subconsciously and automatically. The Stop system
inhibits such systems. The interactions between these two system produce the well-known impulsivity
that is associated with the addiction process during both the initiation of drug intake and relapse (14).
Extended amygdala The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the
stria terminalis, the central nucleus of the amygdala, and a transition area in the medial portion (shell) of
the nucleus accumbens. Major neurotransmitters in the extended amygdala that are hypothesized to play
a role in hyperkatifeia, which drives negative reinforcement, include corticotropin-releasing factor,
norepinephrine, dynorphin, vasopressin, orexin (hypocretin), substance P, glucocorticoids, and
neuroimmune factors. Neurotransmitter systems in the extended amygdala that may buffer negative
emotional states include neuropeptide Y, nociceptin (orphanin FQ), endocannabinoids, and oxytocin.
Hyperkatifeia Hyperkatifeia (derived from the Greek katifeia for dejection or negative emotional state) is defined as an
increase in intensity of the constellation of negative emotional or motivational signs and symptoms of
withdrawal from drugs of abuse. Hyperkatifeia can be considered an emotional parallel to the
hyperalgesia (i.e., greater sensitivity to physical pain) that is observed with the repeated administration of
chronic opioids and alcohol (15, 91).
Incentive salience Incentive salience can be defined as motivation for rewards that derive from one’s physiological state and
previously learned associations about a reward cue that is mediated by the mesocorticolimbic dopamine
system.
Pathological habits Pathological habits are hypothesized to result from the pathological coupling of drug-influenced
motivational states and a rigid stimulus response habit system. Drug-seeking and drug-taking habits in
individuals with substance use disorder are also reinforced by Pavlovian conditioning, in which
drug-associated conditioned stimuli in the environment act as conditioned reinforcers and support
protracted sequences of behavior, often in the absence of the outcome.
Prefrontal cortex The prefrontal cortex plays a key role in mediating executive function, such as planning, response selection,
decision making, working memory, personality expression, cognitive flexibility, inhibition, social behavior,
and self-knowledge (92).
Reward deficits Reward deficits refer to the loss of pleasure as reflected in anhedonia or hypohedonia and are measured in
humans and animal models by elevations of intracranial self-stimulation reward thresholds (93) and in
humans by various self-report scales (85) and some operational tasks that reflect anhedonia such as the
monetary incentive delay task (94).
Stress surfeit Stress surfeit refers to hyperactivation of the hypothalamic-pituitary-adrenal axis and brain stress
neurocircuits, resulting in anxiety, irritability, and hyperkatifeia in the context of addiction (91, 95, 96).

www.annualreviews.org • Alcohol Use Disorder Treatment 259

Table 2 Online sources for further information
Information Source URL
Excess alcohol deaths Substance Abuse and https://www.samhsa.gov/data/sites/default/files/reports/rpt39441/
Mental Health Services NSDUHDetailedTabs2021/NSDUHDetailedTabs2021/
Administration NSDUHDetTabsSect5pe2021.htm
Centers for Disease https://www.cdc.gov/alcohol/features/excessive-alcohol-
Control and Prevention deaths.html
Interventions available for National Institute on https://alcoholtreatment.niaaa.nih.gov
the treatment of Alcohol Abuse and
alcohol use disorder Alcoholism
Patterns of drinking National Institute on https://www.rethinkingdrinking.niaaa.nih.gov
behavior, effects on Alcohol Abuse and https://www.collegedrinkingprevention.gov/collegeaim/
health, and prevention Alcoholism
Centers for Disease https://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm
Control and Prevention
Guidelines of what to eat US Department of https://www.dietaryguidelines.gov/resources/2020-2025-dietary-
and drink to meet Agriculture guidelines-online-materials
nutrient needs,
promote health, and
help prevent chronic
disease
Symptoms, causes, risk WebMD https://www.webmd.com/mental-health/addiction/what-is-
factors, and diagnosis of alcohol-abuse#1
alcohol use disorder
Drug and device US Food and Drug https://www.fda.gov/patients/learn-about-drug-and-device-
development processes Administration approvals
Overcoming obstacles Foundation for https://www.stopsarcoidosis.org/fsr-dia-2017/
(valleys of death) in Sarcoidosis Research
drug development
Good laboratory practice US Food and Drug https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/
for nonclinical Administration CFRSearch.cfm?CFRPart=58
laboratory studies
Economic costs of Recovery Centers of https://recoverycentersofamerica.com/resource/economic-cost-
substance use disorders America of-substance-abuse-disorder-in-united-states-2019
in the United States Centers for Disease https://www.cdc.gov/alcohol/features/excessive-drinking.html
Control and Prevention
The Healthcare National Institute on https://www.niaaa.nih.gov/health-professionals-
Professional’s Core Alcohol Abuse and communities/core-resource-on-alcohol
Resource for identifying, Alcoholism
managing, and treating
alcohol use disorder

MORE GOOD NEWS: THERE ARE EFFECTIVE US FOOD

AND DRUG ADMINISTRATION–APPROVED MEDICATIONS
FOR THE TREATMENT OF ALCOHOL USE DISORDER
Three medications are currently approved for AUD in the United States and are an effective
and important aid for the treatment of people with this condition (Figure 2). Indeed, they are
as effective for the treatment of AUD as antidepressants are for the treatment of depression
(22). Unfortunately, there is a lack of understanding of their efficacy among the general public,

260 Koob
 Disulfiram Acamprosate Naltrexone
HO

S O
N S HO O OH
S N S N
H
O O N
S
1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide N-acetyl homotaurine O

N-cyclopropylmethylnoroxymorphone
N-cyclopropylmethyl-14-hydroxydihydromorphinone
17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one

Figure 2
Currently approved medications for alcohol use disorder in the United States. Disulfiram is an acetaldehyde dehydrogenase inhibitor
that raises blood acetaldehyde levels if one drinks, resulting in an aversive reaction. This aversive reaction includes flushing, nausea,
vomiting, and multiple physiological symptoms. Acamprosate is a taurine derivative (calcium homotaurine) that blocks craving for
alcohol during abstinence by restoring homeostasis in hyperglutamatergic neurotransmission during acute and prolonged withdrawal
from chronic alcohol drinking that is associated with alcohol use disorder. Naltrexone is an opioid receptor antagonist/inverse agonist
that blocks rewarding effects of alcohol presumably by blocking the alcohol-induced activation of endogenous opioid peptides.

basic scientists, and health-care professionals. As outlined below, there is very poor utilization of
treatment in general and medications in particular.

Disulfiram
Disulfiram, approved by the US Food and Drug Administration (FDA) as a pharmacotherapy
for AUD in 1951, is an aldehyde dehydrogenase inhibitor. If a person is taking disulfiram, then
even small amounts of alcohol produce a buildup of acetaldehyde in the blood and a rapid onset of
an aversive disulfiram-alcohol reaction. This aversive reaction includes flushing, nausea, vomiting,
and multiple cardiac and respiratory symptoms that can be fatal in severe reactions. A person’s fear
of this strong disulfiram-alcohol interaction may comprise the primary mechanism of disulfiram’s
deterrent effect, as opposed to the drug’s pharmacodynamic properties (23). Medication adherence
is a problem with disulfiram (24), and outcomes are optimized with supervised administration (e.g.,
by a spouse or roommate) in compliant patients (25). A meta-analysis of randomized, open-label
trials found a moderate effect of disulfiram relative to various comparison groups; the effect of
disulfiram was found to be large under conditions of supervised administration (23). Disulfiram
has more serious adverse events than comparison treatments (23), and the alcohol-disulfiram in-
teraction has inherent risks, which in some patients can strengthen their motivation to abstain
from alcohol. The potential benefit of disulfiram for appropriately selected patients who prefer
this treatment has been found to outweigh the harms, particularly given the risks of continued
alcohol use (26). Many have found disulfiram to be well tolerated when taken as prescribed (27).

Naltrexone
Naltrexone is an opioid receptor antagonist/inverse agonist that was approved by the FDA for the
treatment of alcohol dependence as an oral preparation in 1995 and as a long-acting injectable
in 2006. The rationale for opioid receptor antagonism as a treatment strategy for AUD is based
on the premise that naltrexone blocks the rewarding effects of alcohol, a hypothesis that is sup-
ported by numerous preclinical and clinical studies (28). A systematic review and meta-analysis

www.annualreviews.org • Alcohol Use Disorder Treatment 261

 that included 53 randomized controlled trials of oral naltrexone (50 mg) for the treatment of AUD
found that the number of people needed to treat was 12 for naltrexone to significantly decrease
the likelihood of returning to heavy drinking (29).
Problems with medication nonadherence with oral naltrexone (30) led to the development of a
long-acting (30-day) injectable formulation. A meta-analysis found a higher risk of discontinuation
due to adverse events with naltrexone compared with placebo. Common side effects included
nausea, vomiting, and dizziness (29). Patients who receive Vivitrol (naltrexone for extended-release
injectable suspension) may also experience injection site reactions. Naltrexone is metabolized in
the liver and is contraindicated in patients with acute hepatitis and liver failure.

Acamprosate
Acamprosate (calcium homotaurine) was developed in France. Its first preclinical study showed
that it decreased dependence-induced drinking in rats (31). The FDA approved acamprosate for
the maintenance of abstinence in detoxified alcoholics in 2004. A meta-analysis of 27 randomized
controlled trials of acamprosate found that the number needed to treat to prevent a return to any
drinking was 12 (29).
One prominent action of acamprosate in AUD is to restore homeostasis in hyperglutamatergic
neurotransmission during acute and prolonged withdrawal (32). Consistent with this hypothe-
sis, acamprosate reversed the increases in brain glutamate in alcohol-dependent rats (33) and in
humans with AUD (34). In a pharmacometabolomic study, serum glutamate was identified as a
biomarker of an acamprosate response in alcohol-dependent patients (35). Additionally, baseline
serum glutamate levels were significantly higher in responders compared with nonresponders, and
serum glutamate levels in responders were normalized after acamprosate treatment, whereas there
was no significant change in glutamate in nonresponders (35). Acamprosate is not metabolized by
the liver and is instead excreted primarily by the kidney. The use of acamprosate is contraindicated
in patients with severe renal impairment (36, 37).

MEDICATIONS REPURPOSED FOR THE TREATMENT OF ALCOHOL

USE DISORDER RECOMMENDED BY THE AMERICAN PSYCHIATRIC
ASSOCIATION PRACTICE GUIDELINE
Topiramate and gabapentin are drugs that were originally developed as antiepileptic medications
and that have therapeutic potential for AUD in patients who (a) seek to decrease or quit drinking,
(b) prefer topiramate or gabapentin, (c) are intolerant to or have not responded to acamprosate
and naltrexone, and (d) have no contraindications to the use of these medications (26).
Topiramate (Topamax and generic) was FDA approved as an oral antiepileptic drug in 1998 and
for migraine prophylaxis in 2004. Topiramate is hypothesized to attenuate alcohol’s reinforcing
effects by facilitating γ-aminobutyric acid (GABA)-ergic function and inhibiting glutamatergic
function (38). A meta-analysis of randomized controlled trials found decreases in heavy drinking
days with topiramate (29). However, patients with AUD who were treated with topiramate had a
higher risk of cognitive dysfunction, paresthesias, and taste abnormalities compared with placebo-
treated patients (29).
Gabapentin (Neurontin and generic) was approved by the FDA as an oral antiepileptic drug
in 1993 and as a treatment for postherpetic neuralgia in 2002. It is a selective inhibitor of calcium
channels (39), which results in multiple antiexcitatory, proinhibitory neurotransmitter actions (40).
Gabapentin has shown efficacy for the treatment of AUD in both human laboratory studies and
clinical trials (41–43). An often-reported secondary benefit of gabapentin for the treatment of
AUD is a beneficial effect on sleep (43).

262 Koob
CURRENT CHALLENGES FOR THE TREATMENT OF ALCOHOL
USE DISORDER
Treatment Gap
The treatment gap refers to the dramatic disconnect between individuals in the United States who
need treatment for AUD and those who receive treatment. Estimates suggest that less than 8% of
adult individuals who need treatment receive any treatment (behavioral or medical) within 1 year
(44). In 2019, less than 2% received one of the FDA-approved medications (45). The reasons for
this treatment gap are numerous and include a lack of knowledge, a lack of screening and brief
intervention, a lack of referral to treatment, a lack of available treatment facilities, and stigma.
The lack of knowledge involves general misconceptions that AUD can only be treated in 28-day
inpatient rehabilitation programs and programs that advocate complete abstinence, such as Alco-
holics Anonymous, when, in fact, AUD is a spectrum disorder that involves levels of engagement
in the disorder, ranging from mild to moderate to severe. It follows that treatments should paral-
lel severity and involve a wide spectrum of interventions (NIAAA Alcohol Treatment Navigator;
https://alcoholtreatment.niaaa.nih.gov; Table 2).
Other knowledge gaps include a general lack of understanding of what constitutes a standard
drink, of what constitutes dietary guidelines for moderate drinking, and that the FDA-approved
medications are effective. Defining a standard drink should be a first step in educating the public
about unhealthy drinking. For example, a standard drink in the United States is considered 12
oz of beer, 5 oz of wine, and 1.5 oz of distilled beverage (46; https://www.rethinkingdrinking.
niaaa.nih.gov). The dietary guidelines for moderate drinking that are outlined by the US De-
partment of Agriculture are 2 drinks per day or 14 drinks per week for males and 1 drink per day
or 7 drinks per week for females (47). Evidence also suggests that few people (public and health-
care professionals) know of the three FDA-approved medications for the treatment of AUD (48)
(Table 2).

Lack of Uptake of Screening, Brief Intervention, and Referral to Treatment

Another common reason why individuals with AUD do not seek treatment is that they do not
consider themselves to have a drinking problem or may never have been told they have AUD
(49). The fact that individuals do not consider themselves to have a drinking problem highlights
the importance of adequate screening and accurate diagnosis as a first step in treating AUD. The
screening, brief intervention, and referral to treatment (SBIRT) (50) model is an evidence-based
approach to early detection and intervention for those at risk of developing AUD. The US Pre-
ventive Services Task Force (USPSTF) recommends alcohol SBIRT or counseling in primary care
settings for adults 18 years of age and older (51).
For example, Mintz et al. (52) used 2015–2019 National Survey on Drug Use and Health data to
examine very basic screening, advice, and referral for people with AUD. In their sample of 214,505
people, there was a weighted prevalence of AUD of 7.8%. Examining cascades of care, 81.4% of
people with AUD saw a clinician in the past year, and 69.9% were asked at least one question
about their alcohol consumption, most likely on an intake form (screening). However, among
people who were screened, only 11.6% were offered advice/information (brief intervention), and
only 5.1% were advised about treatment options or other resources (referral to treatment) (52).
People with severe AUD were more likely to receive advice (23%) and/or referral (12.5%), but
these levels are quite low. Importantly, screening for alcohol misuse can also help clinicians spot
other health-related issues, and primary care settings represent a key place and opportunity for
the implementation of AUD treatment.

www.annualreviews.org • Alcohol Use Disorder Treatment 263

 The SBIRT model requires little effort by a health-care clinician. Although simple quantity-
frequency questions do not provide a diagnosis of AUD, a single standardized screening question
was found to effectively detect unhealthy alcohol use: “How many times in the past year have
you had X or more drinks in a day?” where X is 5 for men and 4 for women, and a response of 1
or greater is considered positive (53). The SBIRT model also includes a brief intervention using
motivational interviewing. Brief interventions were effective in reducing alcohol consumption
compared with controls at 1-year follow-up with comparable efficacy in men and women (54). If
clinical follow-up shows that the brief intervention was ineffective in reducing alcohol use, then
evidence-based pharmacological and behavioral treatments for AUD should be provided (referral
to treatment).
Finally, the treatment gap is perpetuated by the lack of treatment facilities in the United States
for addiction and psychiatric disorders in general (55). An inadequate capacity for the treatment
of substance use disorders in general continues to be an issue, and evidence suggests that long
waiting lists remain a major impediment to treatment (56, 57). In general, outpatient treatment is
inadequate, and more inpatient hospital beds are needed (58).

Challenges for Medication Development

One major challenge is the long process between identifying possible treatment targets for AUD
and the approval of a medication by the FDA. For example, the search for naltrexone began in 1980
with a preclinical study in an animal model (59). Naltrexone was approved by the FDA 15 years
later (in 1995). The search for acamprosate began in 1987 with a preclinical study in an animal
model (31) and was approved by the FDA 17 years later (in 2004).
Research on the neurobiology of AUD has identified numerous potential targets for the treat-
ment of AUD within the framework of the three-stage cycle of addiction and three major domains
of dysfunction (see Figure 1). However, there remain many challenges for medication develop-
ment. These include valleys of death on the way to FDA approval and ultimate marketing of
the drug, stigma, and pharmaceutical industry commitment (60; https://www.fda.gov/patients/
learn-about-drug-and-device-approvals) (Table 2). Valleys of death are the obstacles that block
innovative medical research discoveries (in this case, medications) from becoming new therapies or
even the initiation of clinical trials (https://www.stopsarcoidosis.org/fsr-dia-2017/), and these
valleys of death follow the FDA approval process.
The first step in the FDA approval process for a drug involves research and development,
comprising investigational processes in the identification of new drugs that interface with neuro-
functional domains of the three cycles of AUD. Information is then gathered on pharmacokinetics,
effectiveness in animal models, and initial studies of toxicity.
The second step in the FDA approval process requires studies of potential toxicity. Before
testing a drug in people, the potential of the drug to cause toxicity is studied using both in vitro
and in vivo testing of serious harm, also called toxicity, using good laboratory practices (61).
The third step in the FDA approval process involves clinical research with humans. Here, the
sponsor must submit an investigational new drug (IND) application to the FDA before beginning
clinical research. The IND application includes animal efficacy and toxicity data, manufacturing
information, clinical protocols for studies to be conducted, data from any prior human research,
and information about the investigator (Table 2). There are then four phases of clinical trials.
Phase I is primarily for safety and dosage determination. Approximately 70% of drugs move to
the next phase. Phase II trials test efficacy and side effects. Approximately 33% of drugs move to
the next phase. Phase III trials are designed to test efficacy and monitor adverse reactions, and only
3–25% move to the next phase. The fourth step involves FDA approval. At this point, the drug
developer has established from preclinical and clinical research that the drug is safe and effective
264 Koob
for its intended use, which is all outlined in the new drug application (NDA). The NDA must
include everything that is known about the drug from preclinical to Phase III clinical trials. The
NDA is then reviewed by an FDA advisory committee, a process that can take up to 6–10 months.

Pharmaceutical Industry Commitment

A 34% increase in the number of drug development programs comprising the clinical pipeline for
addiction pharmacotherapies occurred over the past 5 years (29 programs in 2018 versus 39 pro-
grams in 2022; 8 programs in 2019 versus 9 programs in 2023), but this is very low compared with
other major diseases and disorders (62). A 2021 report showed that despite a surge in biotechnol-
ogy industry funding, the amount of venture capital funding for novel addiction drug programs
was $130 million over the past 10 years, 270 times less than for oncology (62). The estimated
economic cost in the United States for substance use disorders was $500 billion in 2019 according
to the Recovery Centers of America (63) and $249 billion for AUD specifically (64). These costs
include indirect costs that are attributable to job losses, early deaths, and other social impacts (e.g.,
criminal activity), in addition to direct health-care costs (Table 2).
Several factors appear to contribute to this lack of funding by industry, including the lack of
novel chemical entities in the clinical pipeline as exemplified by only one new chemical entity
being FDA approved in the past 5 years (i.e., lofexidine for opioid use disorder) (62, 65). Novel
addiction treatments also have one of the lowest Phase II success rates (14 of 15 programs failed
in the last decade) (62). Thus, for addiction and particularly AUD, venture capital funding is very
low, the number of companies that engage in developing addiction therapies is very small, most
of the targets are not novel identities (as defined by no FDA approval history: only 9 of 39), and
the approval rate for medications is very low (62).
Why is there so little interest in, and pursuit of, medications for addiction, particularly for
AUD? Some factors are inherent to the process (e.g., cost, success rate of trials, and perceived
return on investment). Other issues are that policy decisions have not incentivized innovation,
instead favoring reimbursement with existing generic addiction treatments and coverage, and the
need to change reimbursement policies to increase investment in new entities (62). One contri-
bution to the lack of a perceived return on investment involves negative perceptions about AUD
as a treatable disorder and the stigma that AUD is a moral problem and not a brain disorder (66).

Stigma
Words matter when it comes to the widespread stigma regarding people who struggle with alcohol
misuse. Research on stigma for AUD in various countries found that people with AUD were more
likely to be deemed as at fault for their condition than people with a range of mental disorders
and dementia (67). Stigma is also associated with decisions to pursue care in mental health (68).
As noted above, fewer than 1 in 10 people with AUD get help each year, and 20% of people who
do not receive care indicate concern that it might cause neighbors or their community to have a
negative opinion of them (69). Stigma also impacts the care of those in need of liver transplants due
to long-term excessive alcohol consumption (70). Indeed, in the context of clinical trials, personal
stigmas about addiction are viewed as constraining clinical trial enrollment because many patients
are reluctant to seek help (62).

NOVEL SOLUTIONS FOR THE TREATMENT OF ALCOHOL

USE DISORDER: CLOSING THE TREATMENT GAP
Given the diverse biological processes that contribute to AUD, new treatments are needed to
provide a broader spectrum of therapeutic options (58). Some people may respond to a behavioral

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 or medication treatment that helps with craving. Others may respond to a medication that
relieves impulsivity. Still others may respond to agents that reverse the negative emotional state
of withdrawal or protracted withdrawal. As with other medical conditions, people with substance
use disorders should have a range of treatment options. Scientists are working to develop a larger
menu of therapeutics that could be tailored to individual needs.

Broadening End Points for the Approval of Medications for the Treatment
of Alcohol Use Disorder
Reductions of drinking can be clinically meaningful, and the FDA accepts abstinence and no heavy
drinking days as primary outcomes for Phase III trials of AUD pharmacotherapy (71). A heavy
drinking day is defined as 4 or more (in women) or 5 or more (in men) drinks in a day. How-
ever, studies showed that World Health Organization (WHO) 1- and WHO 2-level reductions of
risk levels are associated with clinically meaningful benefits, reductions of alcohol-related conse-
quences, and improvements in mental health (72, 73). WHO risk levels are defined by the amount
of alcohol consumed per day (low risk: 1–40 g for males, 1–20 g for females; medium risk: 41–60 g
for males, 21–40 g for females; high risk: 61–100 g for males, 41–60 g for females; very high risk:
≥101 g for males, ≥61 g for females) (74).
A secondary analysis of three multisite AUD pharmacotherapy trials to evaluate WHO 1- and
2-level reductions of drinking as AUD treatment outcome measures showed that the WHO drink-
ing risk level reduction was equally or more sensitive to treatment compared with FDA-accepted
outcomes, implying that this measure could be an outcome indicator of treatment efficacy in AUD
therapeutic trials (75). Additionally, using a secondary data analysis with logistic regression of indi-
viduals with AUD in a large, multisite, randomized, placebo-controlled clinical trial, 1- and 2-level
reductions of WHO risk levels during alcohol treatment were maintained after treatment and as-
sociated with better functioning over time (76). Both studies suggest that the use of WHO risk
level reductions as an outcome measure that may reflect clinically significant improvement in how
individuals who seek treatment for AUD feel and function may make Phase III clinical trials more
attractive for medication development by the pharmaceutical industry.

Engaging Screening, Brief Intervention, and Referral to Treatment

As noted above, research has shown that screening and brief intervention are cost effective in
primary care settings, can reduce alcohol use, and prevent the burden of pathology in individuals
who are engaged in alcohol misuse (77–79).
For the screening of adults, the USPSTF recommends the Alcohol Use Disorders Identifica-
tion Test–Consumption (51). The USPSTF also recommends the NIAAA single alcohol screening
question, which asks, “How many times in the past year have you had X or more drinks in a
day?” where X is 5 for men or 4 for women. Brief interventions in health-care settings and visits
to primary care can include feedback on patients’ current level of alcohol use risk and potential
health-related harms, the identification of common situations in which they drink at risky levels,
clear advice to reduce drinking, and agreement on a plan to reduce drinking (80; see below). For
individuals with major alcohol problems or moderate to severe AUD, more intensive therapy that
is provided by licensed therapists with a specialty in addiction, including the use of FDA-approved
medications for AUD that are provided in primary care or by addiction-specialist physicians, will
likely be required (referral to treatment) (81).

Addressing Stigma
The stigma of addiction in general and alcohol in particular requires a change in language usage
(62, 82). When clinicians are provided with vignettes that use such terms as “alcohol abuser” rather

266 Koob
than “a person with an alcohol use disorder,” they are more likely to view patients in a negative
light. The recommendation now is to change the terminology physicians use to “alcohol use disor-
der” rather than “alcoholism” and to “alcohol-associated liver disease” rather than “alcoholic liver
disease” (70, 82). Modifying language reduces stigma, mitigates shame and guilt about problems
with alcohol, increases the likelihood a person with an AUD will seek treatment, and facilitates
the belief that recovery is possible.

Implementing a Heuristic Definition of Recovery

An operational definition of recovery for AUD was developed based on qualitative feedback from
key recovery stakeholders (e.g., researchers, clinicians, and recovery specialists) to facilitate re-
search on recovery (83). Here, recovery is viewed as both a process of behavioral change and an
outcome that incorporates time periods for two key components: remission from DSM-5 AUD
and cessation from heavy drinking (a nonabstinent recovery outcome). This definition of recovery
also emphasizes the importance of biopsychosocial functioning and quality of life in enhancing re-
covery outcomes. Such a definition will hopefully increase consistency in recovery measurement,
stimulate research to better understand recovery, facilitate the process of recovery, and ultimately
contribute to closing the treatment gap.

Considering a Conceptual Framework Embracing Earlier Treatment

of Addiction
As noted above, treatment penetration rates for AUD are disappointing. One observation is that a
significant proportion of the larger population of those who regularly misuse substances is likely
to meet the criteria for mild AUD and then often transition to moderate or severe AUD, a pro-
gression that has largely been ignored (84). A conceptual framework to provide an operational
definition of early-stage AUD has been proposed (84). In this formulation, the DSM-5 diagnostic
categories of mild to moderate substance use disorder formed a starting operational definition for
preaddiction, which was proposed to engender broader clinical efforts to effect early treatment.

Educating Health Professionals: The Healthcare Professional’s Core Resource

on Alcohol
The Healthcare Professional’s Core Resource on Alcohol (80) was developed to provide health-care pro-
fessionals everything they need to know about alcohol. It consists of 14 concise, user-friendly
articles and provides a means of gaining continuing education credit. It is organized into three
sections: “Foundational Knowledge,” “Alcohol’s Clinical Impacts,” and “Strategies for Preven-
tion and Treatment.” In the “Foundational Knowledge” section, one can find “The Basics,” “Risk
Factors,” “Neuroscience,” and “Stigma.” In the “Alcohol’s Clinical Impacts” section, one can find
“Medical Complications,” “Alcohol-Medication Interactions,” “Mental Health Issues,” and “Alco-
hol Use Disorder.” In the “Strategies for Prevention and Treatment” section, one can find “Screen
and Access,” “Conduct a Brief Intervention,” “Recommend Evidence-Based Treatment,” “Make
Referrals,” and “Support Recovery.” Finally, there is the additional article “Promote Practice
Change.”

Educating the Public

A number of resources are now available for the general public to understand what consti-
tutes unhealthy drinking, to understand individual differences in vulnerability to pathology that
is associated with drinking, and to help individuals find treatment options for alcohol misuse

www.annualreviews.org • Alcohol Use Disorder Treatment 267

 and AUD. Rethinking Drinking (https://www.rethinkingdrinking.niaaa.nih.gov) is a website
and print publication to help individuals assess their drinking habits and find ways to make a
change. Similarly, the Centers for Disease Control and Prevention has the website Alcohol Use
and Your Health (https://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm). College Aim
(https://www.collegedrinkingprevention.gov/collegeaim/) provides comprehensive informa-
tion regarding prevention approaches that are found to be effective in college environments.
The NIAAA Alcohol Treatment Navigator (https://alcoholtreatment.niaaa.nih.gov) is an on-
line resource to help people understand treatment options and locate nearby treatment, including
telehealth options.

Broadening Targets Based on the Heuristic Three-Stage Addiction Model

In AUD, as predicted by the three-stage cycle framework and three domains of dysfunction dis-
cussed above (see Figure 1), a broad spectrum of drug misuse is manifest that can range from
binges of alcohol intake to daily episodes or prolonged days of heavy drinking, constant drinking
for fear of withdrawal, episodic recovery, craving, and relapse.
A framework and rationale for the Addictions Neuroclinical Assessment (ANA) were estab-
lished using knowledge of the neurobiological basis of addiction in humans and model organisms
(85). Three domains—executive function, incentive salience, and negative emotionality—that are
linked to the three stages of the addiction cycle form the core functional elements of addictive
disorders. The ANA framework proposes that measurements of these domains in epidemio-
logical, genetic, clinical, and treatment studies will provide underpinnings for understanding
cross-population and temporal variations in addictions in general. The ANA also provides a basis
for understanding shared mechanisms in addictive disorders, the impact of changing environ-
mental influences, and gene identification. Ultimately, such a deep assessment was hypothesized
to involve a combination of neuroimaging and performance measures and was thought to be a key
to reconceptualizing the nosology of addictive disorders on the basis of process and etiology, an
advance that can lead to better prevention and treatment (85).
Subsequently, several lines of evidence, including a factor analysis of responses on self-reported
measures and neuropsychological tests in humans with AUD, have validated the importance of the
three-stage cycle/three-domain dysfunction in AUD. These factor analyses showed that measures
of three heuristically defined functional domains (incentive salience, negative emotionality, and
executive function; Table 1) captured many of the effects of genetics and environment that lead
to trait vulnerability that is shared across different addictive disorders. In one study, clinical, be-
havioral, and self-report measures of addiction, personality, cognition, behavior, and exposure to
early-life stress were collected as part of a screening and natural history study of AUD in 454 indi-
viduals who represented the spectrum of alcohol use and AUD (86). A three-factor model generally
demonstrated a good fit with the assessment measures, and the factors closely aligned with ANA
domains of incentive salience, negative emotionality, and executive function. Subsequent studies
have confirmed the original factor analysis (87).
One potential benefit of this approach is that measures of these domains in a general frame-
work of an ANA may ultimately transform the assessment and nosology of addictive disorders and
may be informative for staging disease progression. Another potential benefit is that a focus on
the three domains may serve as a bridge to a reformulation of addiction nosology to better capture
individual differences among patients for whom the withdrawal/negative affect stage drives com-
pulsive drug taking (88). An analysis using self-report measures from the Matching Alcoholism
Treatments to Client Heterogeneity (Project MATCH) and Combined Pharmacotherapies and
Behavioral Interventions (COMBINE) studies also showed the utility of domains that are relevant
to the addiction cycle in predicting AUD treatment outcomes and recovery. Among individuals

268 Koob
who sought treatment for AUD, negative emotional states and incentive salience were signifi-
cantly associated with outcomes 1 and 3 years posttreatment, and executive functioning predicted
nonabstinent recovery at year 3 (87).
Given the clinical validation of the three domains of dysfunction that are associated with AUD,
data from animal models that are relevant to the three stages of the addiction cycle can also be
used to identify novel targets for drug development (see Figure 1). Compiled from an exten-
sive review of the neurobiology of alcohol addiction (7), this large number of targets emphasizes
the gap between basic research and translation to the clinical domain and provides promise for
future studies if some of the obstacles that are associated with industry can be overcome.

Binge/Intoxication Stage Targets

In the binge/intoxication stage, the neurobiological mechanism of action of the acute reinforc-
ing effects of alcohol involves the activation of some of the same reward neurocircuitry and
neurotransmitters that are implicated in the actions of psychostimulants and opioids, including
dopamine and opioid peptides, with a focus on the nucleus accumbens and central nucleus of
the amygdala (7, 9, 14). Other neurotransmitters/neuromodulators that interact with these key
elements of basal forebrain neurocircuitry to drive incentive salience and pathological habits in-
clude GABA, glutamate, acetylcholine, serotonin, norepinephrine, glycine/taurine, acetaldehyde,
neurosteroids, growth factors, and neuroimmune factors (see Figure 1; Table 1).
In addition to the neurochemical systems that play a functional role in mediating the acute
rewarding effects of alcohol, the molecular entities as illustrated in Figure 1 provide potential
targets to block the initial actions of alcohol. For example, although alcohol does not bind to any
particular receptor, it is hypothesized to act at ethanol-receptive elements, particularly in water-
filled pockets of ion receptor proteins. Thus, low-dose alcohol (<10 mM) interacts allosterically
with the following molecular entities: N-methyl-d-aspartate receptor 2B (NR2B)-containing
N-methyl-d-aspartate receptors, α1-glycine receptors, α7 nicotinic acetylcholine receptors,
δ-containing GABAA receptors, BK channels, and T-type calcium channels. These initial actions
are then translated via various transduction systems, such as protein kinases, or by the activation
of gene transcription via the adenosine-induced activation of cyclic adenosine monophosphate
(cAMP)-protein kinase A and, ultimately, cAMP response element binding protein (CREB)
systems, making them all potential targets for blocking the acute rewarding effects of alcohol
(7). Note that molecular genetic studies, including knockout studies, have confirmed some of the
more powerful neuropharmacological effects of alcohol, such as on the µ-opioid receptor and
neuropeptide Y (NPY) systems (7).

Withdrawal/Negative Affect Stage Targets

In the withdrawal/negative affect stage, withdrawal from chronic alcohol, similar to other addic-
tive drugs, disrupts reward neurotransmitter function (dopamine, opioid peptides, glutamate, and
GABA), recruits the brain stress systems [corticotropin-releasing factor (CRF), glucocorticoids,
dynorphin, norepinephrine, hypocretin, vasopressin, substance P, and neuroimmune function],
and dysregulates the brain antistress systems (NPY, nociceptin, oxytocin, and endocannabi-
noids), all of which contribute to negative emotional states of withdrawal, termed hyperkatifeia,
and excessive drinking during dependence, mediated by negative reinforcement (7, 9, 14) (see
Figure 1).
In addition to the neurochemical systems that play a functional role in mediating the tol-
erance and hyperkatifeia that are associated with chronic alcohol use and alcohol withdrawal,
the molecular entities as illustrated in Figure 1 provide potential targets to reset neuroadaptive

www.annualreviews.org • Alcohol Use Disorder Treatment 269

 actions that are altered by alcohol and return these neuroadaptations to homeostasis. For example,
a role for BK channels in tolerance to alcohol can be seen in the worm Caenorhabditis elegans, the
fruit fly Drosophila, and mice, suggesting an evolutionarily conserved mechanism. Other low-dose
molecular targets that play a role in tolerance include GABAA receptors and NPY, both of which
are involved in acute withdrawal, thus reflecting the mechanistic interaction between acute with-
drawal and tolerance. Molecular mechanisms that are involved in acute withdrawal and protracted
withdrawal include neuroadaptations in GABA receptors, cAMP/CREB systems, brain-derived
neurotrophic factor, CRF receptors, protein kinases, and histone acetylation, all of which can con-
tribute to molecular loading on within- and between-system neurocircuitry adaptations and may
be targets for medication development (7).

Preoccupation/Anticipation Stage Targets

In the preoccupation/anticipation stage, protracted abstinence studies have shown changes in
neurotransmitter systems that reflect extensions of changes that are observed in the withdrawal/
negative affect stage. Increases in dopamine, opioid peptide, and glutamate function are associ-
ated with animal models of craving, such as cue- and context-induced reinstatement (7, 9, 14).
Increases in CRF, glucocorticoid, norepinephrine, dynorphin/κ-opioid receptor, hypocretin, sub-
stance P, and neuroimmune function and decreases in NPY, nociceptin, endocannabinoid, and
oxytocin function in the antistress domain are associated with protracted stress-like effects (7)
(see Figure 1).
In addition to the neurochemical systems that play a functional role in mediating craving that
is associated with the preoccupation/anticipation stage of the addiction cycle, molecular entities
as illustrated in Figure 1 provide potential targets to block animal model surrogates for craving
(7). For example, cue- and context-induced reinstatement reflect dopamine transporter overex-
pression in the nucleus accumbens and extracellular signal–regulated kinase 1/2 overexpression in
the basolateral amygdala, and GluR-C α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor subunit–knockout mice exhibit a blunted cue-induced reinstatement response.
Stress-induced reinstatement is associated with the activation of neuroimmune molecular targets,
with a prominent role for nuclear factor κB and other proinflammatory factors in the frontal cor-
tex and hippocampus. Mammalian/mechanistic target of rapamycin complex 1 plays a key role in
the dendritic translation of synaptic proteins that are associated with alcohol-related memories.

SUMMARY
In summary, AUD imposes a significant burden on society that inflicts significant medical and
social costs. In the United States, most afflicted individuals do not receive treatment, and clos-
ing this treatment gap is an ongoing challenge. Effective behavioral health treatments and
FDA-approved medications are available but greatly underutilized, contributing to a major treat-
ment gap. Given the diverse biological processes that contribute to AUD, new medications
are needed to provide a broader spectrum of treatment options. A starting point for exploring
the heterogeneity of AUD with regard to treatment includes engaging a heuristic framework
for AUD that includes a three-stage cycle—binge/intoxication, withdrawal/negative affect, and
preoccupation/anticipation—with three domains of dysfunction that parallel each stage and have
been validated and replicated. This review outlined challenges that face the alcohol field in closing
the treatment gap, and it offered solutions, including broadening end points for the approval of
medications for the treatment of AUD; increasing the uptake of screening, brief intervention, and
referral to treatment; addressing stigma; implementing a heuristic definition of recovery; engag-
ing the concept of early treatment; and educating health-care professionals and the public about

270 Koob
challenges that are associated with alcohol misuse. Additionally, broadening potential targets for
the development of medications for AUD, based on the three-stage heuristic model, will pro-
vide a neuroscience- and neurocircuit-based rationale for reestablishing homoeostatic function
in reward, stress, and executive function domains, now known to be the root cause that perpetu-
ates AUD. Such a neuroscientific approach will require a scaling up of the current reductionistic
molecular-microcircuit targets under intense investigation in addiction research today but, ulti-
mately, will allow individualized medicinal treatments for AUD that account for diversity in all
domains, from gender to culture to individual makeup.

DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
The author thanks Michael Arends for his assistance with manuscript preparation; Dr. Barbara
Mason for her help with the clinical framework, clinical literature, and clinical expertise; Dr. Aaron
White for his help with the statistics regarding alcohol misuse and pathology; and National
Institute on Alcohol Abuse and Alcoholism staff for discussions and insights.

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