Alcohol is a major contributor to global disease and a leading cause of preventable death, causing approximately 88,000 deaths annually in the United States alone. Alcohol use disorder is one of the most common psychiatric disorders, with nearly one-third of U.S. adults experiencing alcohol use disorder at some point during their lives. Alcohol use disorder also has economic consequences, costing the United States at least $249 billion annually. 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.

Only a small percent of individuals with alcohol use disorder contribute to the greatest societal and economic costs ( 8 ). For example, in the 2015 National Survey on Drug Use and Health survey (total n = 43,561), a household survey conducted across the United States, 11.8% met criteria for an alcohol use disorder (n = 5124) ( 6 ). Of these 5124 individuals, 67.4% (n = 3455) met criteria for a mild disorder (two or three symptoms, based on DSM-5), 18.8% (n = 964) met criteria for a moderate disorder (four or five symptoms, based on DSM-5), and only 13.8% (n = 705) met criteria for a severe disorder (six or more symptoms) ( 6 ). There is a large treatment gap for alcohol use disorder, arising from the fact that many individuals with alcohol use disorder do not seek treatment. Those with a mild or moderate alcohol use disorder may be able to reduce their drinking in the absence of treatment ( 9 ) and have a favorable course; but it is those with more severe alcohol use disorder who most often seek treatment and who may experience a chronic relapsing course ( 10 ).

The morbidity and mortality associated with alcohol are largely due to the high rates of alcohol use disorder in the population. Alcohol use disorder is defined in the Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5) ( 4 ) as a pattern of alcohol consumption, leading to problems associated with 2 or more 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 ), and approximately 15.1 million of U.S. adults meet criteria for alcohol use disorder in the previous 12 months ( 6 ). The public health impacts of alcohol use extend far beyond those individuals who drink alcohol, engage in heavy alcohol use, and/or meet criteria for an alcohol use disorder. Alcohol use is associated with increased risk of accidents, workplace productivity losses, increased medical and mental health costs, and greater rates of crime and violence ( 1 ). Analyses that take into account the overall harm due to drugs (harm to both users and others) show that alcohol is the most harmful drug ( 7 ).

In most regions of the world, most adults consume alcohol at least occasionally ( 1 ). Alcohol is among the leading causes of preventable death worldwide, with 3 million deaths per year attributable to alcohol. In the United States, more than 55% of those aged 26 and older consumed alcohol in a given month, and one in four adults in this age group engaged in binge drinking (defined as more than four drinks for women and five drinks for men on a single drinking occasion) ( 2 ). Excessive alcohol use costs U.S. society more than $249 billion annually and is the fifth leading risk factor for premature death and disability ( 3 ).

Near the end of the 18th century, the Pennsylvania physician Benjamin Rush described the loss of control of alcohol and its potential treatments ( 11 ). His recommendations for remedies and case examples included practicing the Christian religion, experiencing guilt and shame, pairing alcohol with aversive stimuli, developing other passions in life, following a vegetarian diet, taking an oath to not drink alcohol, and sudden and absolute abstinence from alcohol. Through the 1800s and early 1900s, the temperance movement laid 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 excessive alcohol use, although the only treatment offered was forced abstinence from alcohol ( 12 ). The founding of Alcoholics Anonymous (A.A.) in the 1930s ( 13 ) and the introduction of the modern disease concept of alcohol use disorder (previously called “alcoholism”) in the 1940s ( 14 ) laid the groundwork for many of the existing treatment programs that remain widely available today. Over the past 80 years, empirical studies have provided support for both mutual support [A.A. and other support groups, such as SMART (Self-Management and Recovery Training)] and medical models of treatment for alcohol use disorder, as well as the development of new pharmacological and behavioral treatment options. In addition, there are several public health policy initiatives (e.g., taxation, restrictions on advertising, and outlet density) and brief intervention programs (e.g., social norms interventions) that can be effective in reducing prevalence of alcohol use disorder and alcohol-related harms ( 1 ).

Alcohol use disorder is characterized by loss of control over alcohol drinking that is accompanied by changes in brain regions related to the execution of motivated behaviors and to the control of stress and emotionality (e.g., the midbrain, the limbic system, the prefrontal cortex, and the amygdala). Mechanisms of positive and negative reinforcement both play important roles with individual drinking behavior being maintained by positive reinforcement (rewarding and desirable effects of alcohol) and/or negative reinforcement mechanisms (negative affective and physiological states that are relieved by alcohol consumption) ( 15 , 16 ). At the neurotransmitter level, the positive reinforcing effects of alcohol are primarily mediated by dopamine, opioid peptides, serotonin, γ-aminobutyric acid (GABA), and endocannabinoids, while negative reinforcement involves increased recruitment of corticotropin-releasing factor and glutamatergic systems and down-regulation of GABA transmission ( 16 ). Long-term exposure to alcohol causes adaptive changes in several neurotransmitters, including GABA, glutamate, and norepinephrine, among many others. Discontinuation of alcohol ingestion results in the nervous system hyperactivity and dysfunction that characterizes alcohol withdrawal ( 15 , 16 ). Acting on several types of brain receptors, glutamate represents one of the most common excitatory neurotransmitters. As one of the major inhibitory neurotransmitters, GABA plays a key role in the neurochemical mechanisms involved in intoxication, tolerance, and withdrawal. This brief review can offer only a very simplified overview of the complex neurobiological basis of alcohol use disorder. For deeper, more detailed analysis of this specific topic, the reader is encouraged to consult other reviews ( 15 , 16 ).

a-2 agonists (e.g., clonidine) and β-blockers (atenolol) are sometimes used as an adjunct treatment to benzodiazepines to control neuro-autonomic manifestations of alcohol withdrawal not fully controlled by benzodiazepine administration ( 18 ). However, because of the lack of efficacy of a-2 agonists and β-blockers in preventing severe alcohol withdrawal syndrome and the risk of masking withdrawal symptoms, these drugs are recommended not as monotherapy, but only as a possible adjunctive treatment.

Alcohol withdrawal symptoms may include anxiety, tremors, nausea, insomnia, and, in severe cases, seizures and delirium tremens. Although up to 50% of individuals with alcohol use disorder present with some withdrawal symptoms after stopping drinking, only a small percentage requires medical treatment for detoxification, and some individuals may be able to reduce their drinking spontaneously. Medical treatment may take place either in an outpatient or, when clinically indicated, inpatient setting. In some cases, clinical monitoring may suffice, typically accompanied by supportive care for hydration and electrolytes and thiamine supplementation. For those patients in need of pharmacological treatment, benzodiazepines (e.g., diazepam, chlordiazepoxide, lorazepam, oxazepam, and midazolam) are the most commonly used medications to treat alcohol withdrawal syndrome. Benzodiazepines work by enhancing the effect of the GABA neurotransmitter at the GABA A receptor. Notably, benzodiazepines represent the gold standard treatment, as they are the only class of medications that not only reduces the severity of 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 for alcohol withdrawal syndrome is managed in an outpatient setting, careful monitoring is required, particularly when combined with alcohol and/or opioid medications ( 17 ).

PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF ALCOHOL USE DISORDER

U.S. Food and Drug Administration–approved pharmacological treatments Development of novel pharmaceutical reagents is a lengthy, costly, and expensive process. Once a new compound is ready to be tested 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. Efficacy and side effects may then be further tested in larger phase 2 clinical studies, which may be followed by larger phase 3 clinical studies, typically conducted in several centers and are focused on efficacy, effectiveness, and safety. If approved for use in clinical practice, this medication is still monitored from a safety standpoint, via phase 4 postmarketing surveillance. Only three drugs are currently approved by the U.S. Food and Drug Administration (FDA) for use in alcohol use disorder. The acetaldehyde dehydrogenase inhibitor disulfiram was the first medication approved for the treatment of alcohol use disorder by the FDA, in 1951. The most common pathway in alcohol metabolism is the oxidation of alcohol via alcohol dehydrogenase, which metabolizes alcohol to acetaldehyde, and aldehyde dehydrogenase, which converts acetaldehyde into acetate. Disulfiram leads to an irreversible inhibition of aldehyde dehydrogenase and accumulation of acetaldehyde, a highly toxic substance. Although additional mechanisms (e.g., inhibition of dopamine β-hydroxylase) may also play a role in disulfiram’s actions, the blockade of aldehyde dehydrogenase activity represents its main mechanism of action. Therefore, alcohol ingestion in the presence of disulfiram leads to the accumulation of acetaldehyde, resulting in numerous related unpleasant symptoms, including tachycardia, headache, nausea, and vomiting. In this way, disulfiram administration paired with alcohol causes the aversive reaction, initially proposed as a remedy for alcohol use disorder by Rush (11) in 1784. One challenge in conducting a double-blind, placebo-controlled alcohol trial of disulfiram is that it is easy to break the blind unless the “placebo” medication also creates an aversive reaction when consumed with alcohol, which would then provide the same mechanism of action as the medication (e.g., the placebo and disulfiram would both have the threat of an aversive reaction). Open-label studies of disulfiram do provide support for its efficacy, as compared to controls, with a medium effect size (19), as defined by Cohen’s d effect size ranges of small d = 0.2, medium d = 0.5, and large d = 0.8 (20). The efficacy of disulfiram largely depends on patient motivation to take the medication and/or supervised administration, given that the medication is primarily effective by the potential threat of an aversive reaction when paired with alcohol (21). The next drug approved for treatment of alcohol use disorder was acamprosate; first approved as a treatment for alcohol dependence in Europe in 1989, acamprosate has subsequently been approved for use in the United States, Canada, and Japan. Although the exact mechanisms of acamprosate action are still not fully understood, there is evidence that it targets the glutamate system by modulating hyperactive glutamatergic states, possibly acting as an N-methyl-d-aspartate receptor agonist (22). The efficacy of acamprosate has been evaluated in numerous double-blind, randomized controlled trials and meta-analyses, with somewhat mixed conclusions (23–26). Although a meta-analysis conducted in 2013 (25) indicated small to medium effect sizes in favor of acamprosate over placebo in supporting abstinence, recent large-scale trials conducted in the United States (27) and Germany (28) failed to find effects of acamprosate distinguishable from those of a placebo. Overall, there is evidence that acamprosate may be more effective in promoting abstinence and preventing relapse in already detoxified patients than in helping individuals reduce drinking (25), therefore suggesting its use as an important pharmacological aid in treatment of abstinent patients with alcohol use disorder. The most common side effect with acamprosate is diarrhea. Other less common side effects may include nausea, vomiting, stomachache, headache, and dizziness, although the causal role of acamprosate in giving these side effects is unclear. A third drug, the opioid receptor antagonist naltrexone, was approved for the treatment of alcohol dependence by the FDA in 1994. Later, a monthly extended-release injectable formulation of naltrexone, developed with the goal of improving patient adherence, was also approved by the FDA in 2006. Naltrexone reduces craving for alcohol and has been found to be most effective in reducing heavy drinking (25). The efficacy of naltrexone in reducing relapse to heavy drinking, in comparison to placebo, has been supported in numerous meta-analyses (23–25), although there is less evidence for its efficacy in supporting abstinence (25). Fewer studies have been conducted with the extended-release formulation, but its effects on heavy drinking, craving, and quality of life are promising (29, 30). Common side effects of naltrexone may include nausea, headache, dizziness, and sleep problems. Historically, naltrexone’s package insert has been accompanied by a risk of hepatotoxicity, a precaution primarily due to observed liver toxicity in an early clinical trial with administrating a naltrexone dosage of 300 mg per day to obese men (31). However, there is no published evidence of severe liver toxicity at the lower FDA-approved dosage of naltrexone for alcohol use disorder (50 mg per day). Nonetheless, transient, asymptomatic hepatic transaminase elevations have also been observed in some clinical trials and in the postmarketing period; therefore, naltrexone should be used with caution in patients with active liver disease and should not be used in patients with acute hepatitis or liver failure.

Additional pharmacological treatments approved for alcohol use disorder in Europe Disulfiram, acamprosate, and naltrexone have been approved for use in Europe and in the United States. Pharmacologically similar to naltrexone, nalmefene was also approved for the treatment of alcohol dependence in Europe in 2013. Nalmefene is a m- and d-opioid receptor antagonist and a partial agonist of the k-opioid receptor (32). Side effects of nalmefene are similar to naltrexone; compared to naltrexone, nalmefene has a longer half-life. Meta-analyses have indicated that nalmefene is effective in reducing heavy drinking days (32). An indirect meta-analysis of these two drugs concluded that nalmefene may be more effective than naltrexone (33), although whether a clinically relevant difference between the two medications really exists is still an open question (34). Network meta-analysis and microsimulation studies suggest that nalmefene may have some benefits over placebo for reducing total alcohol consumption (35, 36). The approval of nalmefene in Europe was accompanied by some controversy (37); a prospective head-to-head trial of nalmefene and naltrexone could help clarify whether nalmefene has added benefits to the existing medications available for alcohol use disorder. Last, nalmefene was approved in Europe as a medication that can be taken “as needed” (i.e., on days when drinking was going to occur). Prior work has also demonstrated the efficacy of taking naltrexone only on days that drinking was potentially going to occur (38). In addition to these drugs, a GABA B receptor agonist used to treat muscle spasms, baclofen, was approved for treatment of alcohol use disorder in France in 2018 and has been used off label for alcohol use disorder for over a decade in other countries, especially in other European countries and in Australia (39, 40). Recent human laboratory work suggests that baclofen may disrupt the effects of an initial priming dose of alcohol on subsequent craving and heavy drinking (41). Meta-analyses and systematic reviews examining the efficacy of baclofen have yielded mixed results (35, 39, 42); however, there is some evidence that baclofen might be useful in treatment of alcohol use disorder among individuals with liver disease (43, 44). Evidence of substantial heterogeneity in baclofen pharmacokinetics among different individuals with alcohol use disorder (41) could explain the variability in the efficacy of baclofen across studies. The appropriate dose of baclofen for use in treatment of alcohol use disorder remains a controversial topic, and a recent international consensus statement highlighted the importance of tailoring doses based on safety, tolerability, and efficacy (40).