Slightly more than half (50.8%) of all Americans older than 12 years of age reported being current consumers of alcohol in the 2019 National Survey on Drug Use and Health [12]. This translates to an estimated 139.7 million people, up from the 2016 estimate of 136.7 million people [12,13]. Nearly one-half (47.1%) of Americans participated in binge drinking at least once in the 30 days prior to the survey. This represents approximately 65.8 million people. Heavy drinking was reported by 35.9% of the population 12 years of age and older (16.0 million people). The 2019 estimates for binge and heavy drinking are substantially higher than the 2016 estimates [12]. Past-month binge and heavy alcohol use for Americans 12 years of age and older are presented in Figure 1.

Binge drinking among various races is 13.4% for Asians, 22.7% for blacks, 20.9% for American Indians or Alaska Natives, 25.8% for persons reporting two or more races, 25.0% for whites, and 24.2% for Hispanics [14].

About 40% of people who drink have experienced an alcohol-related problem [11]. Between 3% and 8% of women and 10% to 15% of men will develop alcohol use disorder at some point in their lives. While alcohol use disorders can develop at any age, repeated intoxication at an early age increases the risk of developing an alcohol use disorder [11]. Usually, dependence develops in the mid-twenties through age forty.

The National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) estimated that the annual economic cost of alcohol and drug abuse was $365.4 billion in 1998 [9]. This estimate represents roughly $1,350 each year for every man, woman, and child living in the United States. Alcohol use disorders generated about half of the estimated costs ($184.6 billion). This figure rose to $249 billion in 2010, representing approximately $807 for every man, woman, and child living in the United States [17].

A Standard Drink: 1.5 ounces of 80-proof distilled spirits, 5 ounces of table wine, or 12 ounces of standard beer [19,20].

Alcohol Intoxication: Clinically significant problematic behavioral or psychologic changes (e.g., inappropriate sexual or aggressive behavior, mood lability, impaired judgment) that developed during, or shortly after, alcohol ingestion [18]. Changes include slurred speech, loss of coordination, unsteady walking or running, impairment of attention or memory, nystagmus, stupor, or coma.

Moderate Drinking: No more than one drink per day for women and no more than two drinks per day for men [20].

Heavy Drinking: Five or more drinks on the same occasion on each of 5 or more days in the past 30 days [17].

Data for health benefits associated with low-to-moderate drinking appear to be common in many medical journals [23]. Light-to-moderate alcohol intake from beer, wine, or spirits is associated with a reduction in all-cause mortality, possibly due to its ability to decrease cardiovascular diseases, especially coronary heart disease (CHD). The relationship between alcohol intake and reduced risk of coronary disease is generally accepted as a U-shaped curve of low-dose protective effect and higher doses producing a loss of protective effects and increased all-cause deaths [25,26,27,28,29,30,31,32]. The World Health Organization (WHO) reported that there is convincing evidence that low-to-moderate alcohol intake decreases risk for heart disease [24].

Cardiovascular protection occurs primarily through blood lipids such as HDL, especially HDL subfraction 2 [1]. Moderate alcohol consumption inhibits platelets, especially after a fatty meal, suggesting an aspirin-like effect for moderate alcohol consumption [35]. Alcohol's effects on clotting appear to be related to the findings that drinking reduces acute heart attack risk. Certain alcoholic beverages, namely red wine, may also have an additional positive antioxidant effect as it contains flavonoids, which possibly slow oxidation of unsaturated fatty acids [36]. Additionally, low amounts of drinking can also enhance insulin sensitivity, reduce fasting insulin, and may also reduce stress.

Research has shown that genetic factors play a strong role in whether a person develops alcohol use disorder, accounting for 40% to 60% of the risk [43,44]. In fact, family transmission of alcohol use disorder has been well established. Individuals who have relatives with alcohol use disorder are at three- to five-times greater risk of developing alcohol use disorder than the general population. The presence of alcohol use disorder in one or both biologic parents is more important than the presence of alcohol use disorder in one or both adoptive parents. The genetic risk of alcohol use disorder increases with the number of relatives with alcohol use disorder and the closeness of the genetic relationship [44]. However, most children of parents with alcohol use disorder do not become alcoholics themselves, and some children from families where alcohol is not a problem develop alcohol use disorders when they get older. Alcohol use disorder is seen in twins from alcoholic parents, even when they are raised in environments where there is little or no drinking. Identical twins adopted into households with an alcoholic stepfather do not show more alcohol use disorders than the general population. Children with close biologic relatives with alcohol use disorder, who are adopted into a never drinking, even religiously opposed family, can readily develop alcohol problems [45].

Genetic factors appear to influence the level of response (LR) to alcohol, as measured by the intensity with which one reacts to a given quantity [53]. The level of response to alcohol varies from individual to individual depending on the tolerance. Low LR at an early age contributes to the risk of alcohol use disorder later in life [53,54].

Studies have found similar results of higher tolerance for alcohol among daughters of parents with alcohol use disorder. One study examined the drinking patterns of 38 daughters of alcoholics compared with 75 family-history-positive men from the same families and 68 men with no family history of alcohol use disorder [58]. Family-history-positive men and women both displayed low reaction to alcohol. This indicates that the degree of genetic influence on alcohol-related behavior is similar for both men and women with family history of alcohol use disorder. In a study of adolescent and young adult offspring from families where alcohol use disorders are prevalent, researchers found both neurophysiologic and neuroanatomical differences, such as reduced right amygdala volume, when comparing these offspring to controls [59]. Another study assessed the relationship between amygdala and orbitofrontal cortex volumes obtained in adolescence and substance use disorder outcomes in young adulthood among high-risk offspring and low-risk controls [60]. A total of 78 participants 8 to 19 years of age (40 high-risk, 38 low-risk) from a longitudinal family study underwent magnetic resonance imaging. Volumes were obtained with manual tracing. Outcomes were assessed at approximately one-year intervals. The ratio of orbitofrontal cortex volume to amygdala volume significantly predicted substance use disorder survival time across the sample. A reduction in survival time was seen in participants with smaller ratios; this was true for both high-risk and low-risk participants [60].

Native Americans and Alaskan Natives have a lower level of response and an increased risk of alcohol use disorder [44]. The alcohol metabolizing enzymes are another important genetic influence, especially for persons of Asian descent. About 50% of Japanese, Chinese, and Korean persons flush and have a more intense response to alcohol because they have a form of alcohol dehydrogenase (ADH) that causes high levels of acetaldehyde. Forms of ADH and aldehyde dehydrogenase (ALDH) (e.g., homozygous or heterozygous) contribute to a higher rate of alcohol metabolism, intensify the response to alcohol, and lower the risk of alcohol use disorder. High levels of impulsivity/sensations seeking/disinhibition are also genetically influenced and may impact alcohol use disorder risk [44].

The effects of alcohol on the electroencephalogram (EEG) of subjects at risk for developing alcoholism are well known [74,75,76]. Researchers found that low EEG response to small amounts of alcohol may be associated with future development of alcohol use disorder. Additionally, differences in EEG response to alcohol may have ethnic variations [76]. Other studies have shown that heavy drinkers had less sedation and cortisol response after alcohol consumption than light drinkers. In addition, heavy drinkers were more sensitive to the positive stimulant-like properties as blood alcohol levels increased [68,77].

With these three models in mind, a review of some of the research findings on genetic and psychosocial risk factors may provide a better understanding of the factors leading to alcohol use disorders [11,78]:

With these three models in mind, a review of some of the research findings on genetic and psychosocial risk factors may provide a better understanding of the factors leading to alcohol use disorders [11,78]:

Alcohol use disorder, also referred to as alcohol abuse and/or alcohol dependence, is defined in the DSM-5 as a problematic pattern of use with two or more of the following criteria over a one-year period [18]:

Alcohol dependence is included in the DSM-5 umbrella definition of alcohol use disorder [18]. The symptoms of withdrawal and tolerance have been the hallmarks of more severe disease, though alone they are neither necessary for nor sufficient to make the diagnosis.

Individuals with alcohol use disorder often experience a severe, potentially fatal withdrawal syndrome when they either abruptly discontinue or sharply reduce their alcohol consumption. The symptoms may include sweating, rapid heartbeat, hypertension, tremors, anorexia, insomnia, agitation, anxiety, nausea, and vomiting. Tremors of the hands are usually the earliest symptom of alcohol withdrawal. Hallucinosis, seizures, and delirium tremens (DTs) are the most severe form of alcohol withdrawal. Hallucinosis, when it occurs, occurs one to two days after decreasing or abstaining from alcohol. While the effects of DTs can be life threatening, all other symptoms, with or without treatment, usually resolve several hours or days after appearance. Alcohol withdrawal in tolerant individuals can occur before the BAC has dropped below the established legal limit for intoxication. Some persons with alcohol use disorder have symptoms of irritability, emotional lability, insomnia, and anxiety that persist for weeks to months after alcohol withdrawal. The symptoms may be due to the residual effects of alcohol toxicity on the central nervous system and can be post-acute withdrawal symptoms; members of Alcoholics Anonymous (AA) refer to this as being a "dry drunk." AA considers alcoholics who are only abstaining from alcohol but who are not working a recovery program and remaining in essentially the same emotional state as they were when they were drinking to be "dry drunks."

Impaired control over drinking means that a person is consistently unable to limit the number of occasions when alcohol is used or the amount of alcohol ingested on those occasions. Often, because of the damage alcohol causes in their lives, people with alcohol use disorder will express a strong and persistent desire to cut down or stop drinking. Often they may be able to do so, sometimes for a matter of weeks, a month, or even longer. One does not need to be a daily drinker to meet criteria for alcohol use disorder, as even those who go weeks or months without a drink may binge and meet diagnostic criteria. However, because alcohol use disorder is a chronic progressive disease, once patients with alcohol use disorder resume drinking, even after years of sobriety, they typically return to the previous quantities of consumption, with worsening adverse consequences.

While a strong attachment to alcohol is the hallmark of early dependency, if the patient refuses to acknowledge a problem and no one from home or work helps to confirm the diagnosis, healthcare professionals are often left with nothing more than clinical intuition, resulting in a missed diagnosis. However, late in the course of alcohol use disorder, physical clues typically become increasingly apparent and suggestive of alcohol abuse and/or dependence. Alcohol abuse and dependence are often referred to as the "Great Masquerader" because many of the signs and symptoms are also commonly found in other conditions [90].

Elevated Laboratory Findings

Gastrointestinal Signs/Symptoms

Cardiopulmonary Signs/Symptoms

Central Nervous System (CNS) Signs/Symptoms

Behavioral Clues

Miscellaneous Signs/Symptoms

The liver is a particularly vulnerable organ to alcohol consumption, in large part because it is where alcohol is metabolized prior to elimination from the body. As few as six drinks a day for men have been found to be associated with liver damage. The most common manifestation among persons with alcohol use disorder is called "fatty liver." Among heavy drinkers, the incidence of fatty liver is almost universal. For some, a fatty liver may precede the onset of alcoholic cirrhosis. Fatty deposits have been associated with men who have six or more drinks a day and women who have only one or two drinks daily.

Alcoholic hepatitis is a condition that, when severe, is characterized by jaundice, fever, anorexia, and right upper-quadrant pain. Between 10% and 35% of heavy drinkers (those drinking five or six standard drinks a day or more) develop alcoholic hepatitis and 10% to 20% develop cirrhosis [91,92]. More than 60% of persons who develop both alcoholic hepatitis and cirrhosis will die within four years. Drinking 12 beers a day for 20 years has been associated with a 50% incidence of cirrhosis. It is not known which individuals will develop cirrhosis. Studies have shown that women develop liver disease faster and at lower levels of alcohol consumption than men [92,93]. Women also have a higher incidence of alcoholic hepatitis and higher mortality rate from cirrhosis [94].

Abnormally high plasma levels of the amino acid homocysteine have been shown in studies to increase the risk for cardiac and other vascular diseases [110]. Even small increases in homocysteine appear to increase the risk of heart disease. Vitamins like folate, B12, and B6 are required for homocysteine disposal within cells. The lower the concentration of these and other vitamins, the greater the concentration of homocysteine. A number of nutritional problems have been reported in people with alcohol use disorder. Malnourished persons with alcohol use disorder and liver diseases have been found to have B6 and folate deficiencies. In addition, average homocysteine levels are twice as high in patients with chronic alcohol use disorder when compared to nondrinking controls. Thus, homocysteine may contribute to the cardiovascular complications experienced by many with chronic alcohol use disorder. Lowering homocysteine with B vitamin supplementation may reduce cardiovascular risk [111,112]. Further research is necessary to determine whether abstinence and recovery reverses the risk of cardiovascular disease, and whether folate and vitamins B12 and B6 should be considered as appropriate nutritional supplements for patients with alcohol use disorder [113].

Although alcohol has a relatively high caloric value, 7.1 calories per gram (1 gram of fat contains 9 calories), alcohol consumption does not necessarily result in increased body weight. Moderate, regular doses of alcohol added to the diets of lean men and women do not seem to lead to weight gain. However, in some studies obese patients have gained weight when alcohol is added to their diets.

An analysis of data collected from the first National Health and Nutrition Examination Survey (NHANES I) found that although drinkers had significantly higher intakes of total calories than nondrinkers, drinkers were not more obese than nondrinkers. In fact, women drinkers had significantly lower body weight than nondrinkers. As alcohol intake among men increased, their body weight decreased. An analysis of data from the second National Health and Nutrition Examination Survey (NHANES II) and other large U.S. studies found similar results for women [129]. When chronic heavy drinkers substitute alcohol for food in their diets, they typically lose weight and weigh less than their nondrinking counterparts [130].

Many older studies, such as those discussed, have focused on total volume of alcohol based on intake over time (e.g., number of drinks per week), an average that reveals little about the actual drinking habits of individuals. This has led to a very inconsistent array of data on the relationship of drinking and body mass index (BMI). One study sought a better understanding of the relationship between BMI and regular/moderate versus infrequent binge drinking [131]. Researchers found that although individuals of similar height might consume the same weekly average of alcohol (e.g., 14 drinks per week), individuals who consume two drinks each day of the week typically have low BMIs and individuals who consume seven drinks on each of two days of the week typically have high BMIs. A 2018 study examined the associations of alcoholic beverage consumption with dietary intake, waist circumference, and BMI [132]. A total of 7,436 men and 6,939 women 20 to 79 years of age were included in the study. By average daily drinking volume, the differences in waist circumference and BMI between former and moderate drinkers were +1.78 cm and +0.65, respectively, in men and +4.67 cm and +2.49, respectively, in women. Compared with moderate drinking, heavier drinking volume (three drinks/day or more in men, two drinks/day or more in women) was not associated with higher waist circumference or BMI, whereas drinking five or more drinks/day was associated with higher waist circumference and BMI in men. There were no significant differences in women who consumed four or more drinks/day compared with women who consumed one drink/day [132].

It is also important to note those individuals who have undergone bariatric surgery. According to a research study conducted at a substance abuse treatment facility, bariatric surgery patients were more likely to be diagnosed with alcohol withdrawal than those who had not had the surgery [133]. In another study of patients in active weight management being considered for bariatric surgery, an inverse relationship was found between BMI and alcohol consumption—the more overweight the patient, the less alcohol was consumed [134]. Past-year alcohol consumption actually decreased as BMI increased. Surgeons felt it rare to have a patient excluded for bariatric surgery due to excessive alcohol consumption. The authors concluded that it is likely that food and alcohol compete at brain reward sites.

Excessive drinking may interfere with the absorption, digestion, metabolism, and utilization of nutrients, particularly vitamins. Individuals with alcohol use disorder often use alcohol as a source of calories to the exclusion of other food sources, which may also lead to a nutrient deficiency and malnutrition. In the late stage of the disease, patients may develop anorexia or severe loss of appetite, and refuse to eat. Persons with alcohol use disorder account for a significant proportion of patients hospitalized for malnutrition [130].

Direct toxic effects of alcohol on the small bowel causes a decrease in the absorption of water-soluble vitamins (e.g., thiamine, folate, B6). Studies have suggested that alcoholism is the most common cause of vitamin and trace-element deficiency in adults in the United States. Alcohol's effects are dose dependent and the result of malnutrition, malabsorption, and ethanol toxicity [135]. Vitamins A, C, D, E, K, and the B vitamins are deficient in some individuals with alcohol use disorder. All of these vitamins are involved in wound healing and cell maintenance. Because vitamin K is necessary for blood clotting, deficiencies can cause delayed clotting and result in excess bleeding. Vitamin A deficiency can be associated with night blindness, and vitamin D deficiency is associated with softening of the bones. Deficiencies of other vitamins involved in brain function can cause severe neurologic damage (e.g., deficiencies of folic acid, pyridoxine, thiamine, iron, zinc).

Thiamine deficiency from chronic heavy alcohol consumption can lead to devastating neurologic complications, including Wernicke-Korsakoff syndrome, cerebellar degeneration, dementia, and peripheral neuropathy [136]. Thiamine deficiency in patients with alcohol use disorder who are suffering from Wernicke-Korsakoff syndrome leads to lesions and increased microhemorrhages in the mammillary bodies, thalamus, and brainstem. This syndrome can also be associated with diseases of the gastrointestinal tract when there is inadequate thiamine absorption. All patients with alcohol use disorders should receive supplemental thiamine whenever entered into hospitalization or treatment to reduce this possibility.

Alcohol abuse is a major risk factor for many infectious diseases, especially pulmonary infections [137]. Studies have shown that alcohol abuse increases the risk for acute respiratory distress syndrome and chronic obstructive pulmonary disease [138,139,140,141]. Pneumonia, tuberculosis, and other pulmonary infections are frequent causes of illness and death among patients with alcohol use disorder [142]. Other infectious diseases that are over-represented among individuals with alcohol use disorder are bacterial meningitis, peritonitis, and ascending cholangitis. Less serious infections are chronic sinusitis, pharyngitis, and other minor infections.

Acute and chronic alcohol abuse also increase the risk for aspiration pneumonia. Alcohol use disorders are associated with increased risk of aspiration of gastric acid and/or oropharyngeal flora, decreased mucus-facilitated clearance of bacterial pathogens from the upper airway, and impaired pulmonary host defenses [143]. In addition, pathogenic colonization of the oropharynx is more common in patients with alcohol use disorder.

The consumption of alcohol alters T-lymphocyte functions, immunoglobulin production by B cells, NK cell function, and neutrophil and macrophage activities making patients with alcohol use disorder more susceptible to septic infection [144,145,146]. Studies have shown that animals given ethanol are unable to suppress infections that can ultimately result in progressive organ damage and death [147,148,149].

Alcohol affects most neurochemical systems including NMDA, GABA, serotonin, dopamine (DA), and opioid systems.

Although the literature on gender differences in addiction can appear at times to be inconsistent, as a whole men are more substance dependent than women for all substances except benzodiazepines and analgesics, on which women are equally or more frequently dependent [166]. However, on average, women show the effects of alcohol more immediately, more intensely, and for longer periods of time than men. They achieve higher concentrations of alcohol in the blood after drinking the same amounts of alcohol [167]. Women also produce a lower level of the enzymes required to break down alcohol. In addition, female hormones make women's bodies more susceptible to alcohol at certain times of the menstrual cycle. Women also tend to be shorter and weigh less than men. Because women generally have a higher percentage of body fat, they reserve alcohol in the body for longer periods of time. This is important because when a person drinks a large amount of alcohol, it is deposited in fatty tissues. Neurophysiology is more compromised in women with alcohol use disorder than men [168].

It may be because of these factors that women develop alcohol problems more quickly than men, and their progression to severe complications, such as liver disease, is more rapid. The death rate among women with alcohol use disorder is 50% to 100% greater than that of men because of their increased risk for suicide, alcohol-related accidents, cirrhosis, and hepatitis [169]. It is important to note, however, that women are more likely than men to obtain help, participate in treatment, and have long-term involvement in AA, and therefore are more likely to have better life outcomes [170].

The dangers of drinking while pregnant are well-documented. Pregnant women who drink risk the chance of their child developing FASD. Prenatal alcohol exposure is known to be toxic to the developing fetus and is one of the leading known preventable causes of mental retardation. Excess fetal mortality secondary to drinking is most prevalent during the first trimester of pregnancy. Even drinking as little as one beer a day has been associated with decreased birth weights and spontaneous abortions. Although FASD has received a great deal of publicity, the majority of people may not understand it correctly. For example, one large study of adults 18 to 44 years of age found that the majority of respondents incorrectly assumed that FAS referred to babies born with an addiction to alcohol.

There are a variety of conditions that are considered FASDs. Alcohol-related neurodevelopmental disorder (ARND) is associated with intellectual difficulties and problems with behavior and learning. Patients with ARND may do poorly in school, with particular issues with math, memory, attention, judgment, and impulse control [172]. Offspring of mothers who consumed alcohol, during pregnancy may also develop alcohol-related birth defects, including congenital malformations of the heart, kidneys, and/or bones or hearing problems.

The most commonly studied FASD is FAS. FAS is defined by the existence of certain physical characteristics of children whose mothers drank during pregnancy. These characteristics include [172]:

Living with a non-recovering family member with alcohol use disorder can contribute to stress for all members of the family. Children raised in these families have different life experiences than children raised in nonalcoholic families. For example, children living with a non-recovering alcoholic score lower on measures of family cohesion, intellectual cultural orientation, active recreational orientation, and independence. They also experience higher levels of conflict within the family. Many children of alcoholics experience other family members as distant and noncommunicative and may be hampered by their inability to grow in developmentally healthy ways. The level of dysfunction or resiliency of the nonalcoholic spouse is a key factor in the effects of problems impacting the children. Support groups, such as Children of Alcoholics, are available to help people deal with these issues.

Among some individuals and subgroups, excess alcohol consumption is associated with the risk of violent behavior. Alcohol may encourage aggression or violence by disrupting normal brain function, especially in levels of serotonin [188]. There is considerable overlap among nerve cell pathways in the brain that regulate aspects of aggression, sexual behavior, and alcohol consumption. Alcohol may weaken brain mechanisms that normally restrain impulsive behaviors, including inappropriate aggression.

Alcohol is both a stimulant and a depressant, depending on the levels and time after drinking. Patients with alcohol use disorder are often misdiagnosed with depression because of the many symptoms that mimic depression. Insomnia, reduced appetite, and decreased energy are just a few of the symptoms that can occur in both diseases. Alcohol can cause temporary depressive symptoms, even in persons who have no history of depression. In fact, as many as 80% of men and women with alcohol use disorder complain of depressive symptoms, and at least one-third meet the criteria for a major depressive disorder (excluding, of course, criterion D) [209]. Depression is often a comorbid disorder but can also be solely or partially due to alcohol. This carries important implications in the way depressive symptoms are evaluated and treated in patients with alcohol use disorders. Alcohol intoxication, especially binge drinking, can also cause mood swings that mimic the "highs" of people with manic depression/bipolar disorder. Thirty to fifty percent of persons with alcohol use disorder suffer from major depression at the same time [209,210].

How alcohol use disorder is related to depression is not clear. Some studies have suggested that both conditions may share common risk factors. For example, both problems may run in families. Co-occurrence is very common, but likely has independent though inter-related etiology.

Treatment professionals have found that after two to three weeks of abstinence from alcohol and with good nutrition, the temporary depressive effects of alcohol dissipate. However, there are subgroups of individuals with alcohol use disorder who have a co-occurring depression or manic depression, and it is critically important to diagnose and treat these illnesses during alcohol treatment. If true co-occurring depression is left untreated, many patients will drop out of treatment and relapse to drinking. Alcohol use disorders and depression are important risk factors for suicidal thinking or actions. Because alcohol can increase impulsivity and make depression worse, even intolerable, alcohol is often a factor in suicides.

The next issue is determining which antidepressant to use. Lithium and tricyclics used to treat depression alone may not be effective or could have serious adverse effects when used in patients with comorbid depression and alcohol use disorder. Another class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), has been studied to treat depression after failing to treat alcohol use disorder. SSRIs generally cause less serious adverse effects than tricyclics, but some, like fluoxetine, work slowly and cause sexual performance side effects. SSRIs, such as fluoxetine, sertraline, and paroxetine, and herbal remedies such as St. John's wort have been tried in a variety of studies and are generally able to help alleviate depression, but do not appear to help with drinking outcomes. Venlafaxine and bupropion appear to be especially effective in treating patients with depression and alcohol use disorder. Venlafaxine is well suited to treat alcohol use disorder with depression and even depression with anxiety [219]. Venlafaxine is effective in mild and severe depression with anhedonia. Bupropion is effective as well, but it has seizure risks in this population [220]. Men with depression who are using alcohol appear very sensitive to the sexual side effects of the SSRIs and may discontinue their use and drop out of treatment. Patients with major depression and alcohol use disorder are generally treated with venlafaxine and, when necessary, are augmented with bupropion or mirtazapine. Transcranial magnetic stimulation is now available for refractory depression, and studies are in progress for its use in treating substance use disorder [221].

Alcohol withdrawal causes many of the signs and symptoms of anxiety and can even mimic panic attacks. Alcohol works much like a benzodiazepine; many people who abuse and are dependent on alcohol have learned to drink to temporarily relieve anxious feelings.

Both nicotine and alcohol consumption cause the release of dopamine in the nucleus accumbens. Neurobiology may make the combination of the two substances more rewarding than if either substance was taken alone. Certain enzymes in the liver (i.e., microsomal enzymes) convert some of the ingredients found in tar from cigarette smoke into chemicals that can cause cancer [230]. Long-term excessive alcohol consumption may activate these enzymes as well as decrease the body's ability to respond to infections or abnormal states. Smoking and excessive alcohol use are significant risk factors for cancer of the mouth, throat, and esophagus [229].

The three questions on the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) inquire about frequency of alcohol use, typical amount of alcohol use, and occasions of heavy use. The test takes one to two minutes to administer. Preliminary evidence suggests that the USAUDIT-C (based on U.S. standards) may be more valuable in identifying at-risk college drinkers [248]. In contrast, the SASQ inquires about past-year alcohol use and takes less than one minute to administer [246].

Ask current drinkers the CAGE questions:

Tests in this category look at the classic toxic markers that use of alcohol leaves on the body. They include [250]:

Miller and Sanchez proposed six elements, summarized by the acronym FRAMES, to describe the key elements of brief intervention: feedback, responsibility, advice, menu of strategies, empathy, and self-efficacy [271]. How these elements enhance effectiveness has been supported in other reviews [272,273]. Goal setting, follow-up, and timing are also important in brief intervention [274,275].

Motivational interviewing is a method of brief intervention that is used to help move individuals from the precontemplation, contemplation, or determination/preparation stage into the action stage of change related to their drinking. In addition to focusing on the patient's view of the problem and consequences of the behavior, the interview often includes a comprehensive assessment of drinking behaviors with personalized feedback. Motivational interviewing therapists emphasize personal responsibility and support their patients' feelings of self-efficacy for making a change in their drinking. This method has demonstrated empirical efficacy with problem drinkers [277].

To understand treatment and make the right treatment choices, it helps to have an overview. Treatment should be seen as having three phases.

Abrupt discontinuation or even cutting down on the amount of drinking by persons who are physiologically dependent on alcohol produces a characteristic withdrawal syndrome with sweating, rapid heartbeat, hypertension, tremors, anorexia, insomnia, agitation, anxiety, nausea, and vomiting [291]. In some ways, alcohol withdrawal resembles withdrawal from opioids, but unlike opioid withdrawal, which is rarely life-threatening in and of itself, alcohol withdrawal can be fatal. As many as 15% of persons with alcoholism progress from the autonomic hyperactivity and agitation common to withdrawal from other drugs to seizures and, for some, even death. In some cases, DT may occur within the first 48 to 72 hours and can include disorientation, confusion, auditory or visual hallucinations, and psychomotor hyperactivity [291].

The Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) is a symptom-triggered, 10-item scale that quantifies the risk and severity of alcohol withdrawal [291]. However, in order to be most useful, it requires patient input, which may not be feasible in patients undergoing severe DTs. If the patient is able, the assessment takes only minutes and aids in identification of patients who may need immediate pharmacologic treatment to prevent further complications. Very mild withdrawal usually corresponds with a score of 9 or less, mild withdrawal with a score between 10 and 15, modest withdrawal with a score between 16 and 20, and scores greater than 20 indicate severe withdrawal [292]. Patients scoring less than 9 may not require pharmacologic intervention. However, reassessment of symptoms should be performed every one to two hours until withdrawal is resolved.

Pharmacologic management of acute alcohol withdrawal generally involves the use of benzodiazepines, which reduce related anxiety, restlessness, insomnia, tremors, DT, and withdrawal seizures [291]. Benzodiazepines are the most widely used, and while they may have abuse liability in some patients, they have been safely used for years [293,294,295]. These medications may be administered either on a fixed interval or symptom-triggered schedule. However, both short-acting and long-acting benzodiazepines have their problems. The long-acting benzodiazepines can decrease rebound symptoms and work for long periods of time, but intramuscular absorption can be very erratic. Short-acting benzodiazepines have less risk of oversedation, no active metabolites, and considerable utility in patients with liver problems or disease. Yet, breakthrough symptoms can and do occur, and risk of seizure is imminent.

Research has shown that the longer people stay in treatment, remain sober, and are actively committed to sobriety, the more likely it is that they will maintain sobriety. Some treatment professionals think of the phase of active treatment as lasting from 6 to 12 months. During the first critical months of treatment, people often need a variety of supports, especially drug testing and AA or other self-help groups, to achieve and maintain lasting sobriety.

It is often difficult to pinpoint when the active treatment phase ends and a person enters the maintenance phase of recovery. In phase 2, people learn what they need to do to stay sober and they develop the many skills they will use to avoid relapse. A person could be said to enter this maintenance and growth stage when he or she is comfortable with these skills and has had a chance to rely on them to stay sober when life throws them the inevitable curveballs, either as a crisis or an everyday problem. Many people in recovery attribute their ongoing sobriety to participation in a support group such as AA or Women for Sobriety.

The grandfather of successful alcohol treatment is Alcoholics Anonymous, a self-help organization founded in 1935 that changed the way professionals thought about alcohol use disorder and treatment. AA developed a very successful 12-step program that combines self-help with a spiritual foundation and is based on the fellowship of recovering alcoholics. Although there is a spiritual foundation in AA, one is not required to be religious. The organization is run entirely by recovering alcoholics and reaches into virtually every community with a specific program as well as around-the-clock assistance. Membership is available to anyone wishing to join, and there are no financial dues. AA has probably done more to promote the self-help concept than any other organization.

For many people with alcohol use disorder, attending an AA meeting is like brushing their teeth. Prevention of relapse is an active daily process. AA provides fellowship that can be exceptionally positive and counterbalance the feelings of loss, grief, and shame often associated with alcohol use disorder.

AA and other 12-step programs are effective treatment programs that facilitate long-term abstinence after treatment, especially for patients with low psychiatric severity [300]. AA provides important peer-led support for individuals with alcohol use disorder. AA also helps individuals with relapse and relapse prevention by prescribing that people keep it simple, take it one day at a time, and avoid the people, places, and things associated with their use. They also help recovering alcoholics to develop positive lifestyles and find new ways to solve old problems. The feeling of fellowship, the support, and guidance to sobriety makes recovery more likely. Reduction of shame and guilt and acceptance of powerlessness over drinking may be reported by individuals with alcohol use disorder after attending meetings every day. An AA meeting may take one of several forms, but at any meeting you will find alcoholics talking about what drinking did to their lives and personalities, what actions they took to help themselves, and how they are living their lives today. The age distribution of AA members is illustrated in Figure 3.

Cognitive-behavioral therapies (CBTs) are among the most frequently evaluated approaches used to treat substance use disorders [302,303]. CBTs have been shown to be effective in several clinical trials of substance users [304]. Characteristics of CBTs include:

Basic principles of CBTs are that [305,306]:

Behavioral therapy techniques are often part of CBT. In this approach, substance use is believed to develop from changes in behavior and a reduction in opportunities for reinforcement of positive experience. The goal is to increase the person's engagement in positive or socially reinforcing activities. Techniques such as having patients complete a schedule of weekly activities, engaging in homework to learn new skills, role-playing, and behavior modification are used. Activity, exercise, and scheduling are major components of this approach based on the following:

Behavioral therapy techniques are often part of CBT. In this approach, substance use is believed to develop from changes in behavior and a reduction in opportunities for reinforcement of positive experience. The goal is to increase the person's engagement in positive or socially reinforcing activities. Techniques such as having patients complete a schedule of weekly activities, engaging in homework to learn new skills, role-playing, and behavior modification are used. Activity, exercise, and scheduling are major components of this approach based on the following:

Family therapy is a highly effective treatment for alcohol use disorder, especially in adolescents. While most treatments emphasize the individual as the target of intervention, the defining characteristic of family therapy is the transformation of family interactions. Repetitive patterns of family interactions are the focus of treatment. Changing these patterns results in diminished antisocial behavior including alcohol abuse. Family therapy can work with a broad range of family and social network populations. Family therapy approaches have developed specific interventions for engaging and keeping reluctant, unmotivated adolescents and family members in treatment.

Alcohol drinking is an immensely complex human behavior, but it has been modeled in laboratory animals. Two similar strains of alcoholic rats, the alcohol-preferring (P) rats and the high-alcohol-drinking (HAD) rats, have been successfully used to study alcohol use disorders. Like patients with DSM-5 qualifying alcohol use disorders, these rats self-administer alcohol, show tolerance, lose control over alcohol, and spend a lot of time. They also have cravings and physical stigmata of withdrawal, providing psychopharmacologic researchers with excellent face validity with animal models. Models have helped us develop anti-withdrawal, anti-craving, and harm-reducing treatments.

Naltrexone (ReVia) is an opioid antagonist that interferes with the rewarding or pleasurable effects of alcohol and reduces alcohol craving [314,315,316]. The exact mechanisms by which naltrexone induces the reduction in alcohol consumption observed in patients with alcohol use disorder is not entirely understood, but preclinical data suggest involvement of the endogenous opioid system [308]. Naltrexone has been shown to reduce alcohol relapses, decrease the likelihood that a slip becomes a relapse, and decrease the total amount of drinking [308]. The FDA approved the use of oral naltrexone in alcohol use disorder in December 1994 [308,316]. In 2006, the FDA approved an extended-release injectable formulation, which is indicated for use only in patients who can refrain from drinking for several days prior to beginning treatment [308]. In 2010, the FDA approved the injectable naltrexone for the prevention of relapse to opioid dependence following opioid detoxification [308]. Naltrexone, which has long been used to treat heroin addicts, was not known as a treatment that could reduce alcohol relapse until the 1980s. In 1980, researchers reported reductions in monkey ethanol self-administration when they were pretreated with naltrexone [317].

The most common side effects of naltrexone are light-headedness, diarrhea, dizziness, and nausea. Pain or tenderness at the injection site is a side effect unique to the extended-release injectable formulation [308]. Most side effects tend to disappear quickly in most patients. Naltrexone is not recommended for patients with acute hepatitis or liver failure, for adolescents, or for pregnant or breastfeeding women [308,325]. Weight loss and increased interest in sex have been reported by some patients. In general, patients maintained on opioid antagonists should be treated with nonopioid cough, antidiarrheal, headache, and pain medications. The patient's family or physician should call the treating physician if questions arise about opioid blockade or analgesia. It is important to realize that naltrexone is not disulfiram; drinking while maintained on naltrexone does not produce side effects or symptoms.

Even coerced or court-mandated treatment for alcohol use disorder can work. In a follow-up study (six months to one year) of Florida physicians with alcohol use disorder, 84% had positive outcomes, defined as positive counselor and physician assessment, negative alcohol testing, group attendance, and full return to work [86].