#56564: Alcohol and Alcohol Use Disorder

Alcohol is defined as a substance of abuse by self-administration in lab animals and man. All drugs of abuse affect the brain's reward pathways. The effects of alcohol appear to be related to complex multiple interactions with the dopamine, gamma-aminobutyric acid (GABA), serotonin, opioid, and N-methyl-D aspartate (NMDA) neurotransmitter systems [3,4]. Studies suggest that the reinforcing effect of alcohol is partially mediated through nicotinic receptors in the ventral tegmental area, which when combined with nicotine may be a factor in the high incidence of smoking among those with alcohol use disorder [5,6,7]. Alcohol, food, and other drugs of abuse have similar effects on dopamine receptors. The development of addiction, including to alcohol, is affected by genetic predisposition and influenced by alterations in the rewarding chemicals released per dose.

Substances of abuse are often put into categories based on their effects. Alcohol has effects similar to other depressants. Characteristics include:

The established criteria for the diagnosis of alcohol abuse and dependence will be discussed in detail later in this course.

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 [16].

Nearly three-fourths (72%) of the costs of alcohol abuse are related to lost workplace productivity ($179 billion); 11% are related to healthcare expenses for treating problems caused by excessive drinking ($28 billion); 10% are law enforcement and other criminal justice expenses ($25 billion); and 5% are losses from motor vehicle crashes related to excessive alcohol use ($13 billion) [16]. Binge drinking is responsible for the majority of the cost at $191 billion [16]. Alcohol use disorder generally reduces the lifespan by 15 years [11]. Approximately $99.6 billion of the total costs of alcohol abuse is paid by federal, state, and local governments [16]. When both direct and indirect costs are included, the estimated annual cost of alcohol-related problems alone may be much greater [16].

Tolerance: Either (1) a need for markedly increased amounts of the substance to achieve intoxication or desired effect; or (2) a markedly diminished effect with continued use of the same amount of the substance [17].

A Standard Drink: 1.5 ounces of 80-proof distilled spirits, 5 ounces of table wine, or 12 ounces of standard beer [18,19].

Alcohol Intoxication: Clinically significant problematic behavioral or psychological changes (e.g., inappropriate sexual or aggressive behavior, mood lability, impaired judgment) that developed during, or shortly after, alcohol ingestion [17]. Changes include slurred speech, loss of coordination, unsteady walking or running, impairment of attention or memory, nystagmus, stupor, or coma.

Alcohol Withdrawal: The presence of certain symptoms after stopping or reducing heavy and prolonged alcohol use [17]. The symptoms of alcohol withdrawal may develop within a few hours to a few days after stopping or reducing use and symptoms cause significant physical and emotional distress in social, occupational, or other important areas of functioning. Symptoms include increased hand tremor, sweating, increased pulse rate, nausea, vomiting, insomnia, temporary hallucinations or illusions, anxiety, psychomotor agitation, and generalized tonic-clonic seizures. Fewer than 5% of persons who develop alcohol withdrawal experience severe symptoms such as seizures and death [20].

Blood Alcohol Concentration (BAC): The percentage of alcohol present in the bloodstream. The BAC is usually what is measured by police officers to determine legal intoxication. It can be measured directly from a blood sample or a breath sample collected by a "Breathalyzer." The national legal limit for intoxication is a BAC of 0.08.

Moderate Drinking: No more than one drink per day for women and no more than two drinks per day for men [19].

Current Use: At least one drink in the past 30 days [16].

Binge Drinking: Consuming five or more drinks on the same occasion in the past 30 days [16,19].

Heavy Drinking: Five or more drinks on the same occasion on each of 5 or more days in the past 30 days [16].

Fetal Alcohol Syndrome (FAS): A severe fetal alcohol spectrum disorder (FASD), FAS is a lifelong syndrome in children with confirmed prenatal exposure to alcohol. Signs include growth deficiencies, facial abnormalities, and neurocognitive deficits that may lead to problems with vision, hearing, attention, learning, memory, or any combination thereof [21]. There is no safe recommended level of alcohol use in pregnancy.

Although alcohol appears to have some moderate health benefits, physicians need not alter the drinking habits of those who consume low-to-moderate amounts of alcohol. It is problematic to advise a patient who is abstinent or who drinks infrequently to begin or increase alcohol consumption. In addition, social and religious factors may already dictate the patient's drinking habits.

Vulnerability to alcohol use disorders, depression, and alcohol-related pathologies varies greatly among individuals and cannot always be predicted before a patient begins or escalates drinking. Some individuals may be genetically predisposed to acquiring problems with alcohol use disorder. Similarly, excessive consumption often escapes detection before the onset of related health consequences. The balance of risk to benefit appears to favor encouraging some patients in midlife who are very infrequent drinkers to increase slightly the frequency of drinking. Again, this is debatable and will vary with the individual patient. Consuming alcohol is not the only means to reduce the risk of cardiovascular disease. Exercising, not smoking, lowering fat intake and lipids, and other health-related lifestyle issues should also be addressed.

For those who already have heart disease, it is clear that heavy drinkers should reduce their consumption or abstain and that everyone should avoid heavy and binge drinking. Data does not support advising abstainers with a history of myocardial infarction or decreased left ventricular function to start drinking for their health [44]. In general, moderate drinkers with these conditions should be able to continue to drink alcohol in moderation [44].

Alcohol is not without risks. Alcohol abuse worsens the course of psychiatric disorders. In countries with high alcohol consumption, the suicide rate is also high. One should ask whether the promotion of moderate alcohol consumption, justified on the basis of a biomedical effect (e.g., a reduction in all-cause mortality), might change a patient's quality of life or cause them to take offense. However, existing public educational efforts that target reductions in hazardous and harmful drinking and at the same time encourage drinkers to consume alcohol at responsible levels are appropriate and ethical.

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 [45,46]. 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 [46]. 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 [47].

As mentioned previously, genetic factors are thought to account for 40% to 60% of the risk of developing alcohol use disorder [25,46]. Animal studies have shown that genetic factors may be responsible for enhanced brain reward produced by alcohol, decreased initial impairment, or even altered metabolism of alcohol [48,49,50,51,52,53,54].

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 [55]. 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 [55,56].

Genetic differences in metabolic or other biologic processes may play a role in the development of alcohol use disorder in specific individuals. Studies using a self-rated scale have shown consistent results in sons of alcoholic fathers scoring themselves lower than sons of nonalcoholic fathers on feelings of drunkenness, dizziness, drug effect, and sleepiness following alcohol consumption [57]. This suggests that sons of alcoholic fathers have a less intense reaction to alcohol than sons of nonalcoholic fathers. Low reaction to alcohol suggests tolerance and impaired ability to recognize even modest levels of alcohol intoxication, indicators of tendency towards dependence [58,59]. High alcohol sensitivity in men is associated with substantially decreased risk of alcohol use disorder. Understanding reactions to alcohol could establish a better understanding of future risk of developing alcohol use disorder in these men.

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 [60]. 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 [61]. 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 [62]. 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 [62].

Native Americans and Alaskan Natives have a lower level of response and an increased risk of alcohol use disorder [46]. 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 [46].

An estimated 178,000 people (approximately 120,000 men and 59,000 women) die from alcohol-related causes annually. According to NIAAA, alcohol is a significant cause of death, disease, and disability, currently ranked as one of the leading preventable causes of death in the United States [63]. According to a 2022 SAMSHA survey reported by NSDUH, 29.5 million Americans 12 years of age and older (10.5% of this age group) have alcohol use disorder [63]. Almost 1 in 4 adults have had a heavy drinking event in the past year (defined as five or more drinks for men and four or more drinks for women). The NIH and the CDC report increasing alcohol problems, deaths, and alcohol use disorders. An analysis of death certificates from 2019 and 2020 showed that deaths involving alcohol rose from approximately 79,000 to more than 99,000, a 25.5% increase [64]. Increases in alcohol-related deaths are consistent with reports of increased alcohol sales, consumption, alcohol-involved emergency department visits, and hospitalizations. The most recent alcohol data provide more evidence of increasing heavy alcohol use and associated consequences during the COVID-19 pandemic [65]. A 2023 study demonstrated that only individuals with prepandemic history of alcohol use disorder reported greater increases in drunkenness frequency during the COVID-19 pandemic [66]. Increased alcohol use may also worsen medical and mental health problems. Among people who die by suicide, alcohol use disorder is the second most common mental disorder and involved in an estimated one in four deaths by suicide [64].

Researchers who study risk factors have developed models of how known risk factors may interact to create pathways in children that lead to alcohol use disorders.

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 [11,84]:

Childhood abuse is a significant risk factor for later alcohol and substance abuse [85]. Women who were physically abused are 1.5 to 2 times more likely to abuse alcohol than non-abused adults. Children from crowded, noisy, and disorderly homes without rules or religion are more likely to abuse alcohol as teens. Children who are quick to anger, who perceive themselves to be highly stressed, who are resentful of parents' absences, or who have repeated conflicts at home are more likely to abuse alcohol as teens.

An exciting area of research is focused on protective factors and poses the question, "What protects children from taking one of the risk pathways to alcohol use disorder?"

In 1997, some good news came from the National Longitudinal Study on Adolescent Health, a survey in which nearly 12,000 students in grades 7 through 12 were given lengthy interviews timed one year apart. The researchers were trying to determine what kept children, over the course of that year, from taking health risks in four areas: substance abuse (cigarettes, alcohol, and marijuana), sexuality, violence, and emotional health [86]. The researchers found two factors that protected these children in all four areas. They named the factors: parent-family connectedness and school connectedness.

Children identified as having parent-family connectedness said they felt close to their mother or father, felt that their mother or father cared about them, felt satisfied with their relationship with their mother or father, and felt loved by family members [86]. School connectedness was experienced as a feeling of being part of one's school and a belief that students were treated fairly by the teachers.

There is broad evidence of the protective role of parenting on adolescent health risks. Another well-established protective factor is adolescents' perceived disapproval of alcohol use by their parents [87,88,89,90,91]. In 2022, the National Survey on Drug Use and Health asked children 12 to 17 years of age about their perceptions of the level of parental disapproval of substance use initiation, including alcohol [12]. Most adolescents (88.9%) reported that their parents would strongly disapprove of them having one or two alcoholic drinks nearly every day. This percentage was similar to percentages in most years since 2002, with rates ranging from 88.5% to 91.2% [12]. The number of past-year initiates 12 years of age or older for alcohol also remained stable between 2002 and 2022 [12].

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."

Long-term heavy drinking and genetic predisposition can result in the development of tolerance, which is the body's adaptation to the presence of alcohol. As tolerance develops, the drinker requires increasing amounts of alcohol to feel the same effect. For this reason, the usual reported effects for various BAC levels do not apply to individuals with tolerance. In our society, people are often admired for their ability to "hold their drinks." But the fact is, tolerance may be an early warning sign that a physical dependence on alcohol is developing. During the late stages of alcohol use disorder, reverse-tolerance occurs, meaning the individual becomes intoxicated more quickly and with less alcohol.

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.

Individuals with alcohol use disorder may have a preoccupation with alcohol, defined as a noticeable shift in priorities, with a focus on obtaining and consuming an adequate supply of alcohol. Drinking alcohol becomes a central focus in their lives. Over time, the energies of individuals with alcohol use disorder are diverted from people, places, and things that were once important to them.

Another highly noticeable feature of the preoccupation with alcohol may be the large amount of time that drinking consumes. Thinking about alcohol, obtaining alcohol, drinking alcohol, and recovering from the effects of alcohol take more and more of the individual's time. Hobbies and other activities once enjoyed are abandoned one by one, and the only pleasure seems to come from drinking.

Continued drinking despite adverse consequences is characterized by the inability of individuals with alcohol use disorder to stop drinking even when they recognize that their family, interpersonal, spiritual, occupational, legal, and financial problems are the result of their drinking. Furthermore, alcohol may be causing serious health and psychological problems (e.g., anemia, gastritis, liver disease, neurologic disorders, depression) and still the dependent individual cannot stop.

Denial is a common characteristic distortion in thinking that becomes profound in people with alcohol use disorder. For decades, those who have treated individuals with alcohol use disorder, and recovering alcoholics themselves, have puzzled over why these persons continue to drink when the link between alcohol and the losses they suffer is so clear. Denial is an integral part of the disease of alcohol use disorder and a major obstacle to recovery. Although the term denial is not specifically used in the wording of the diagnostic criteria, it underlies the primary criteria described as, "drinking despite adverse consequences."

Because alcohol use disorder is a chronic disease, another symptom that is increasingly being recognized and treated is relapse. Although alcohol use disorder is a treatable, chronic disease, as yet, no cure has been found. This means that even if individuals with alcohol use disorder have been sober for a long time and have regained their health and reclaimed other important aspects of their lives, they may experience a relapse that will require further treatment in order to return to remission.

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 [95].

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 [96,97]. 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 [97,98]. Women also have a higher incidence of alcoholic hepatitis and higher mortality rate from cirrhosis [99].

Alcohol use disorder is also a strong predictive factor for the development of hepatocellular cancer [100]. The presence of other hepatic risk factors, including hepatitis C, fatty liver disease, smoking, and obesity, further increases this risk.

Chronic heavy drinking appears to activate the enzyme CYP2E1, which may be responsible for transforming the over-the-counter pain reliever acetaminophen into toxic metabolites that can cause liver damage [103]. Even when acetaminophen is taken in standard therapeutic doses, liver damage has been reported in this population [104,105]. A review of studies of liver damage resulting from acetaminophen-alcohol interaction reported that, in individuals with alcohol use disorder, these effects may occur with as little as 2.6 grams of acetaminophen (four to five "extra-strength" pills) taken over the course of the day by persons consuming varying amounts of alcohol [106]. The damage caused by alcohol-acetaminophen interaction is more likely to occur when acetaminophen is taken after, rather than before, the alcohol has been metabolized [107]. Moderate drinkers should also be made aware of this potential for interaction. There is now a warning label on the bottle that states, "If you consume three or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers." Further, in 2014 the U.S. Food and Drug Administration (FDA) issued a statement that combination prescription pain relievers containing more than 325 mg acetaminophen per dosage unit should no longer be prescribed due to reported severe liver injury with acetaminophen in patients who took more than the prescribed dose in a 24-hour period; took more than one acetaminophen-containing product at the same time; or drank alcohol while taking acetaminophen products [108].

Alcohol can have a detrimental effect on the heart, including a decrease in myocardial contractility, hypertension, atrial and ventricular arrhythmias, and secondary nonischemic dilated cardiomyopathy [109]. A common complication in alcohol use disorder is elevated pulse and blood pressure, often in the hypertension range. Younger people with alcohol use disorder and those without existing hypertension are less likely to have an elevation than those who are older and predisposed to some hypertension. When drinking stops, the blood pressure often returns to normal over a period of a few days. One study found that people who had six or more drinks a day were twice as likely to suffer from hypertension than moderate drinkers (two or fewer drinks per day) or nondrinkers. Increased serum GGT levels may be an indicator of an individual's susceptibility to the hypertensive effect of alcohol [110].

Aside from hypertension, chronic heavy drinking can adversely affect the heart primarily through direct toxicity to striated muscle, leading to a form of cardiomyopathy [109,111]. Alcoholic cardiomyopathy is probably more common than is currently thought because of underdiagnosis of alcohol use disorder in general. The reported prevalence of alcoholic cardiomyopathy has varied widely from 4% to 40% or more, depending on the characteristics of the study population and the threshold of alcohol consumption used to identify the disorder [112].

The association between heavy alcohol consumption and rhythm disturbances, particularly supraventricular tachyarrhythmias in apparently healthy people, is called "holiday heart syndrome" [111,113]. The syndrome was first described in persons with heavy alcohol consumption, who typically presented on weekends or after holidays, but it may also occur in patients who usually drink little or no alcohol [111,114]. The most common rhythm disorder is atrial fibrillation, which usually converts to normal sinus rhythm within 24 hours. The incidence of holiday heart syndrome depends on the drinking habits of the studied population, but it continues to be a prevalent occurrence in emergency department settings, with alcohol serving as a precipitating factor for atrial fibrillation in 35% to 62% of cases, particularly 12 to 36 hours post-binge drinking [115]. Additionally, the observed trend for increased binge alcohol use in younger adults may be associated with an increased incidence of atrial fibrillation in this population [116]. Holiday heart syndrome should be considered as a diagnosis particularly in patients without overt heart disease presenting with new onset atrial fibrillation. Though recurrences occur, the clinical course is benign and specific antiarrhythmic therapy is usually not warranted [111,113,114].

Heavy drinking increases the risk of cancer of the upper gastrointestinal and respiratory tracts [121]. Almost 50% of cancers of the mouth, pharynx, and larynx and approximately 75% of esophageal cancers in the United States are associated with chronic, excessive alcohol consumption [122,123,124]. When alcohol consumption is combined with tobacco use, the risk of esophageal cancer increases markedly, as much as 130-fold in one study [125,126]. Alcohol increases production of estradiol, and increased levels of estradiol have been linked to an increased risk of breast cancer in women who drink [127].

Alcohol produces irritation and inflammation of the mucosal lining of the gastrointestinal tract and influences the motility in the esophagus, stomach, and small bowel [128]. Frank ulceration may occur with chronic excessive alcohol use. This well-known alcohol related "heartburn" is due to esophageal reflux with esophagitis that commonly occurs with irritation and inflammation of the gastroesophageal junction. Severe vomiting from alcohol gastritis may result in mucosal tears at the gastroesophageal junction, resulting in frank, usually transient pain in the upper gastrointestinal tract.

Short-term and long-term alcohol ingestion are associated with gastritis, erosive gastritis, gastric ulceration, atrophic gastritis, and gastric hemorrhage. Furthermore, duodenitis and duodenal ulcerations are a direct result of chronic excessive alcohol irritation and inflammation.

Patients who have undergone gastric bypass surgery for obesity have higher breath-alcohol levels after drinking the same amount as other people. Many bypass surgeries attach the jejunum directly to the stomach, allowing delivery of alcohol more rapidly to the jejunal site of primary absorption as well minimizing the effect of the stomach's alcohol dehydrogenase. Findings from a small study suggest that it takes much longer for their levels to return to zero [129].

Alcohol consumption is the leading cause of chronic pancreatitis, accounting for approximately 70% of cases in the United States; however, fewer than 10% of heavy alcohol drinkers develop the disease [130,131,132,133,134]. While there are many theories regarding the pathophysiology of chronic pancreatitis, the most prevalent for alcohol-induced chronic pancreatitis involves the effect of toxic metabolites on the pancreas. This theory suggests that inflammation and fibrotic changes in the pancreas are the direct result of premature activation of enzymes due to ethanol's effect on the Golgi complex [132,134,135]. Another theory suggests that pancreatic hypoxia results from decreased blood flow to the pancreas. Alcohol-induced acinar injury may reduce capillary flow and result in edema and capillary compression [132]. Individuals with alcohol use disorder may develop diabetes mellitus or hyperglycemia as a result of chronic pancreatitis, when the islet cells in the pancreas are eventually destroyed. Once alcohol-induced chronic pancreatitis has developed, ingestion of even small amounts can result in severe flare-up requiring hospitalization.

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 [136]. When chronic heavy drinkers substitute alcohol for food in their diets, they typically lose weight and weigh less than their nondrinking counterparts [137].

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 [138]. 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 [139]. 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 [139].

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 [140]. 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 [141]. 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 [137].

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 [142]. 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 [143]. 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 [144]. Studies have shown that alcohol abuse increases the risk for acute respiratory distress syndrome and chronic obstructive pulmonary disease [145,146,147,148]. Pneumonia, tuberculosis, and other pulmonary infections are frequent causes of illness and death among patients with alcohol use disorder [149]. 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 [150]. 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 [151,152,153]. Studies have shown that animals given ethanol are unable to suppress infections that can ultimately result in progressive organ damage and death [154,155,156].

Although some people believe that alcohol helps them sleep, chronic excessive drinking can induce sleep disorders by disrupting the sequence and duration of sleep states and by altering total sleep time, as well as the time required to fall asleep [157,158]. Specifically, drinking within an hour of bedtime appears to disrupt the second half of the sleep period [159]. The person may sleep poorly during the second half of sleep, awakening from dreams and returning to sleep with difficulty, resulting in daytime fatigue and sleepiness [157,160].

Individuals with alcohol use disorder may be at increased risk for sleep apnea, a disorder in which the upper air passage narrows or closes during sleep [161,162,163,164]. The combination of alcohol, obstructive sleep apnea, and snoring increases a person's risk for heart attack, arrhythmia, stroke, and sudden death [165]. Obstructive sleep apnea significantly increases the risk of stroke or death from any cause, independent of other risk factors, including hypertension [166,167].

The most common neurologic abnormality among patients with alcohol use disorder is dementia syndrome, which manifests primarily as impairment in recent memory, and more subtle fluctuations in abstractions, calculations, and other aspects of cognitive functions. As previously stated, one specific neurologic complication resulting from thiamine deficiency is Wernicke-Korsakoff syndrome, which involves delirium, clouded sensorium, confusion, ophthalmoplegia, nystagmus, and ataxia [168]. Immediate administration of thiamine is usually successful in treating the symptoms, but in some cases permanent memory loss occurs [168]. Once delirium and confusion resolve, there is sometimes a profound loss in recent memory (out of proportion to the other cognitive deficits) and alcoholic peripheral neuropathy, which results in diminished sensitivity to touch, pinprick, and vibration (objectively, and paraesthesias subjectively).

The acute effects of alcohol on the nervous system are signs people commonly think of when they envision an intoxicated person, such as slurred speech, loss of coordination, unsteady gait, impairment of attention or memory, nystagmus, stupor, or coma. The degree to which the central nervous system is impaired is directly proportional to the BAC and degree of tolerance.

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 [174]. 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 [175]. 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 [176].

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 [177]. 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 [178].

International studies of gender differences indicate that the greater the societal gender equality in a country, the smaller the gender differences in drinking behavior. The gender gap in alcohol drinking is one of the few universal gender differences in human social behavior [179].

Fetal Alcohol Spectrum Disorders

The World Health Organization recommends that healthcare providers should offer a brief intervention to all pregnant women using alcohol.

(https://www.who.int/publications/i/item/9789241548731 Last Accessed: May 20, 2024)

Strength of Recommendation/Level of Evidence: Strong/Low

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 intellectual disability. 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 infants born with an addiction to alcohol.

FASDs refer to the whole range of conditions that can affect the offspring of mothers who drank alcohol during pregnancy. These conditions can affect each person in different ways and can range from mild to severe. A person with an FASD might have [180]:

• Abnormal facial features, such as a smooth ridge between the nose and upper lip (the philtrum)

• Small head size

• Shorter-than-average height

• Low body weight

• Poor coordination

• Hyperactive behavior

• Difficulty with attention

• Poor memory

• Difficulty in school (especially with math)

• Learning disabilities

• Speech and language delays

• Intellectual disability or low IQ

• Poor reasoning and judgment skills

• Sleep and sucking problems as an infant

• Vision or hearing problems

• Problems with the heart, kidneys, or bones

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 [180]. 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 [180]:

• Intellectual disability

• Growth deficiencies

• Central nervous system dysfunction

• Decreased brain size

• Low birth weight

• Distorted facial features

• Behavioral maladjustments

• Abnormal joints and limbs

Other less visible symptoms of FAS include [181,182,183,184,185,186,187,188,189,190]:

• Verbal learning and memory problems

• Visual-spatial learning problems

• Attention deficits and hyperactivity

• Increased reaction time/slow information processing

• Executive function problems

• Structural and functional changes in the brain

Alcohol apoptotic neurodegeneration has been shown to appear in the forebrain when rats are injected with alcohol. Seven-day-old rats were divided into a group receiving saline solution and another group receiving alcohol solution. The brains were examined after 24 hours of ingesting alcohol or saline. The alcohol group showed a very dense, widely distributed area of deterioration (cell death). When alcohol is administered, various neurons in the forebrain show sensitivity. Also, the brain weight of the alcohol-treated rats was much lower than the saline group. Exposure of the developing rat brain to alcohol for a certain period of time during a specific developmental stage induces destruction of brain cells that deletes large numbers of neurons from several areas of the brain. This period of time in humans is the last three months of gestation [191].

Alcohol is especially neurotoxic to the developing fetus. Vulnerability is highest at six months' gestation to several years after birth. During this period, alcohol exposure can kill millions of neurons in the developing brain. This helps to explain reduced brain size and behavior disturbances associated with FAS. The most disabling effects are hyperactivity and learning disabilities, depression, and psychosis. Depending on the time of exposure to alcohol, different neurons are depleted, which shows evidence of alcohol being an agent that can contribute to many mental disabilities.

The Centers for Disease Control and Prevention (CDC) reported in 2022 that nearly 14% (or 1 in 7) pregnant women 18 to 44 years of age used alcohol and 5.0% (1 in 20) were binge drinkers [192]. According to the CDC, the cost to the United States for FAS alone is more than $4 billion annually [192]. Additionally, an estimated 6 to 9 out of 1,000 U.S. school children may have FASDs [180]. Binge drinking among pregnant women increased from 4.7% in 2021 to 5.3% in 2022[12]. FASD is 100% preventable when pregnant women abstain from drinking alcohol [180,193].

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.

Alcohol use disorder usually has strong negative effects on marital relationships. Separated and divorced men and women were three times as likely as married men and women to say they had been married to a person with alcohol use disorder or problem drinker. Almost two-thirds of separated and divorced women and almost one-half of separated or divorced men younger than 45 years of age have been exposed to alcohol use disorder in the family at some time. As of 2022, approximately 29.7 million Americans met the diagnostic criteria for alcohol use disorder; this number represents an increase from 18.1 million Americans in 2002 [12].

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 [196]. 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.

Drinking and violence may occur together by chance. Also, violent criminals who drink heavily are more likely to be caught and consequently are over-represented in samples of people arrested for violent behavior. Antisocial personality disorder (ASPD) and early-onset alcoholism are common traits in many criminals. A person who intends to engage in a violent act may drink to bolster his or her courage or in hopes of evading punishment or censure. The motive of drinking to avoid censure is encouraged by the popular view of intoxication as a "time-out," during which a person is not subject to the same rules of conduct as when sober. Such alcohol-violence interactions are not readily treated. However, ongoing research has identified medications that have the potential to reduce violent behavior in both alcoholic and nonalcoholic subjects.

Young men who exhibit violent and antisocial behaviors often "burn out" with age [197]. By the time they reach 40 years of age, serotonin concentrations are increasing and testosterone concentrations are decreasing, both of which help to restrain violent behavior [198].

Research suggests that increasing the unit price of alcohol by raising alcohol taxes is an effective strategy for reducing excessive alcohol consumption and related harms, including violent behavior [199]. An examination of the impact of the price of alcoholic beverages on violence and other delinquent behavior among college students found that an increase in the price of beer could reduce the overall number of students involved in some sort of violent behavior by 4% [200]. In a study that used data from the National Household Survey on Drug Abuse, higher taxes on beer led to significant reductions in crime (e.g., property damage, use of force), with the largest impact among individuals younger than 21 years of age [201]. Another study that examined the impact of tax increases and advertising bans on reducing the prevalence of underage drinking and subsequent alcohol-related harms found both interventions to be effective [202]. A literature review of studies of underage populations found that increased taxes were significantly associated with reduced consumption and alcohol-related harms [203]. Public policies that affect the price of alcohol appear to have significant effects on alcohol-related disease and injury rates. The results of one systematic review suggest that doubling the tax on alcoholic beverages could reduce alcohol-related violence by 2% and crime by 1.4% [204].

According to the National Council on Alcoholism and Drug Dependence, on college campuses each year an estimated 696,000 students 18 to 24 years of age are assaulted by another student who has been drinking, and 97,000 students report experiencing alcohol-related sexual assault or date rape [205]. Four out of every five juvenile and teen arrestees are under the influence of alcohol or drugs while committing their crimes, test positive for drugs, are arrested for committing an alcohol- or drug-related offense, admit having substance abuse problems, or share some combination of these characteristics [206].

In 2022, 10,317 people died in alcohol-related traffic fatalities, accounting for 32% of all traffic-related deaths in the United States [207]. Of the 1,090 traffic-related fatalities in 2020 among children 0 to 14 years of age, 229 (21%) involved an alcohol-impaired driver [208]. Of the estimated 127 million episodes of alcohol-impaired driving among U.S. adults, 1 million drivers were arrested for driving under the influence [208]. The CDC estimates that 32 people in the United States die in alcohol-related crashes every day [208]. In a study of persons who have been convicted of driving while impaired, 85% of women and 91% of men reported a lifetime alcohol use disorder [209]. Psychiatric comorbidity may be a key element distinguishing driving under the influence (DUI) offenders from others and in distinguishing repeat offenders from first-time offenders [210].

A study found that although marijuana's effects on driving performance were small or moderate when taken alone, the effects were severe when combined with even a low dose of alcohol. These findings are very serious considering the frequency with which these two substances are combined, especially in young inexperienced drivers [211,212,213,214,215]. One study conducted at seven trauma centers involving 4,243 drivers who were seriously injured in crashes found that 54% of these drivers tested positive for alcohol and/or drugs from September 2019 to July 2021. Of these, 22% of the drivers tested positive for alcohol, 25% tested positive for cannabis, 9% tested positive for opioids, 10% tested positive for stimulants, and 8% tested positive for sedatives [216].

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) [218]. 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 [218,219]. Studies have found that many cases initially diagnosed as substance-induced depression were later reclassified as independent depression (i.e., not substance-induced) because the condition persisted after a period of abstinence [220].

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.

A 2000 study analyzed the substance/alcohol abuse patterns of 89 patients with a confirmed diagnosis of bipolar disorder (71 with bipolar I and 18 with bipolar II) [238]. The diagnosis was confirmed by a structured clinical interview for DSM-IV Axis I, an attending psychiatrist, a medical records review, and family members. The age of the patients ranged from 18 to 65 years. Among those with bipolar disorder I, 41 patients (57.8%) abused or were dependent on one or more substances (including alcohol), 28.2% abused or were dependent on two substances, and 11.3% abused or were dependent on three or more substances. Among those with bipolar disorder II, 39% of patients abused or were dependent on one or more substances, 17% were dependent on two or more substances, and 11% were dependent on three or more substances. The risk for substance or alcohol abuse was higher among patients with bipolar I disorder than with bipolar disorder II. Patients with both bipolar disorders I and II abused alcohol more often than any other substances [238]. One study sought to identify the demographic and clinical differences between patients with bipolar disorder both with and without alcohol use disorder [239]. Data from 238 patients with bipolar disorder included alcohol use, social demographics, longitudinal course of bipolar disorder, clinical features of depressive episodes, comorbid physical diseases, anxiety disorder, and other substance use disorder. Of the 238 patients with bipolar disorder, 74 had alcohol use disorder, with the best predictors of alcohol use disorder being male sex, younger age, and comorbidity with other unclassified substance dependence [239].

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.

Special problems exist for people who drink to self-medicate the symptoms of a true generalized anxiety disorder, social phobia, or panic disorder. Alcohol may provide temporary relief, but it is not a good treatment for shyness or an anxiety disorder. The price a person may pay for self-medication are two diseases: anxiety and alcohol use disorder. Social anxiety can be a major impediment to active participation and even attendance to group therapy and 12-step meetings.

Pain is a subjective experience, and the perception of being in pain is an important factor of the alcohol use disorder. It is hypothesized, as well as established in some research, that individuals in pain will drink as a means to decrease their perception of pain or as a reaction to painful stimuli [240]. According to the National Institute on Alcohol Abuse and Alcoholism, an estimated one in four adults in chronic pain reports self-medicating with alcohol and 43% to 73% of people with alcohol use disorder report experiencing chronic pain [241].

All drugs of abuse, including alcohol, cause dopamine release in the mesolimbic system in the brain. This dopamine system, sometimes referred to as the neuroanatomy of pleasure or reinforcement, starts in the ventral tegmental area and projects to the nucleus accumbens. Alcohol- or drug-taking results in a dopamine reward that stimulates its taking. Pavlovian conditioning to environmental cues (e.g., sights, smells, and sounds of a bar) that precede use become associated with use of the drug. Notably, this sense of "reward," which confers evolutionary fitness, is more likely to be perceived as crucial than even that produced by natural, survival-oriented stimuli (e.g., food, sex). This conditioning is reflective of synaptic strengthening mediated by the glutamatergic system, with neuroplasticity changes in brain areas thought to mediate drug-taking behavior, including the amygdala (stress and anxiety), hippocampus (memory), and dorsal striatum (routine motor movements). Natural stimuli (e.g., food, sex, other previously pleasurable activities) become less enjoyable, resulting in a profound state of anhedonia. With time, alcohol use disorders become ingrained. Ultimately, this preference for alcohol compared to natural rewards is mediated through a process of "bad learning," or neuroplasticity changes in the extended amygdala, also referred to as the antireward system. The anti-reward system involves stress-response hormones, including corticotrophin-releasing hormone and dynorphin. Long- or short-term abstinence activates the antireward system, and with more abstinence, it becomes even more difficult to ignore with the attendant anxiety, dysphoria, craving, and anhedonia. Over time, with repeated administration, nucleus accumbens dopamine receptors desensitize, leading to a functional decrease in available dopamine, anhedonia, and decreased sense of pleasure. Real-world examples include an individual with alcohol dependence developing a sudden craving for a drink when watching a beer commercial, walking by a bar, or seeing a place where s/he drinks. This stage reveals one of the remarkable properties of addiction; the act of drug-taking transitions from being impulsive (i.e., pleasure-seeking without afterthought) to compulsive (i.e., undertaken to relieve stress, tension, or physical signs such as pain).

Alcohol use disorders are often associated with dependence on or abuse of other substances, such as marijuana, cocaine, opioids, amphetamines, anxiolytics, designer or "club drugs," and tobacco. Alcohol may be used to alleviate the unwanted effects of these other substances or to augment their effects or substitute for them when they are not available.

Alcohol use disorder and eating disorders are commonly comorbid conditions, with patterns of comorbidity differing by eating disorder subtype [258]. A community-based sample of women found that those with lifetime alcohol use disorder or nicotine dependence were at higher risk for eating disorders [259]. The process of alcohol detoxification and treatment is often accompanied by overeating with weight gain, and in some cases food becomes a replacement for alcohol [141,260].

As lotteries proliferate and states legalize casino gambling, pathologic or compulsive gambling is being recognized as a major public health problem. Alcohol use disorder is often a comorbid condition among compulsive gamblers. As with depression, each disorder can make the other more serious. Individuals with alcohol use disorder may bet more money and may be reluctant to quit chasing their losses. In one study, subjects received either three alcoholic drinks or an equal volume of a nonalcoholic beverage (placebo) [261]. The alcohol group persisted for twice as many gaming trials as the placebo group. One-half of the alcohol group lost their entire cash stake, compared with 15% of the placebo group [261].

Another study examined how alcohol affects judgment and decision-making during gambling, with a focus on sequential decision-making, including the gambler's fallacy (i.e., thinking that a certain event is more or less likely, given a previous series of events) [262]. Thirty-eight male participants completed a roulette-based gambling task 20 minutes after receiving either an alcoholic or placebo beverage. The task measured color choice decisions (red/black) and bet size, in response to varying lengths of color runs and winning/losing streaks. Color choice affected run length in line with the gambler's fallacy, which further varied by previous wins or losses. Bet size increased particularly for losing streaks. The alcohol group placed higher bets following losses than did the placebo group [262].

Alcohol metabolism alters the balance of reproductive hormones in men and women. In men, alcohol can impair the synthesis of testosterone and reduce sperm production. In women, chronic excessive alcohol use may cause a decreased interest in sex.

A variety of screening instruments are available to detect unhealthy alcohol use in adults. After conducting a systematic evidence review of trials published between 1985 and 2011 on screening and behavioral counseling interventions for unhealthy alcohol use in adults, the U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen all patients 18 years of age or older for alcohol abuse using one of the following tools [263,264]:

For patients in general medical and mental healthcare settings, Veterans Affairs recommends recommend screening for unhealthy alcohol use periodically using the three-item Alcohol Use Disorders Identification Test, Consumption (AUDIT-C) or Single Item Alcohol Screening Questionnaire (SASQ).

(https://www.healthquality.va.gov/guidelines/mh/sud Last Accessed: May 20, 2024)

Strength of Recommendation: Strong for

The USPSTF concludes that there is insufficient evidence to determine the benefits and harms of screening for unhealthy alcohol use in adolescents 12 to 17 years of age [263].

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 [265]. In contrast, the SASQ inquires about past-year alcohol use and takes less than one minute to administer [263].

The CAGE questionnaire is the best known and most often studied screening tool used to detect alcohol problems. In an office setting, the four CAGE questions are often used to detect alcohol problems [266]. The first question, "Have you ever felt the need to cut down on your drinking?" is an easy question to ask. It is not threatening and at the same time suggests to the patient that you understand their pathologic attachment to alcohol [266]. A positive answer to the first and second questions strongly suggests further evaluation and brief intervention [263]. However, by itself, the CAGE questionnaire is not an adequate screening for alcohol use problems; it should trigger more intensive screening if positive [266,267].

Communication with patients regarding history and current alcohol use patterns is a necessary step in determining if alcohol use has become a problem. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Frequently, this may be easier said than done, as there may be institutional and/or patient barriers.

If an interpreter is required, the practitioner should acknowledge that an interpreter is more than a body serving as a vehicle to transmit information verbatim from one party to another. Instead, the interpreter should be regarded as part of a collaborative team, bringing to the table a specific set of skills and expertise [277]. Several important guidelines should be adhered to in order to foster a beneficial working relationship and a positive atmosphere.

When interpreters are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. When providing care for patients for whom English is a second language, the consideration of the use of an interpreter and/or patient education materials in their native language may improve patient understanding and outcomes.

In addition, several organizations provide information and toolkits in languages other than English. The National Hispanic Medical Association offers an alcohol screening kit in Spanish, including patient education sheets [278]. The National Institute on Alcohol Abuse and Alcoholism also provides patient education brochures and pamphlets in English and Spanish [279].

The FDA has approved a test to detect alcohol use disorder and alcohol-related diseases. The test detects the level of carbohydrate-deficient transferrin (CDT) in the body, which is elevated in persons with alcohol use disorder and remains elevated even several weeks after drinking is stopped [280]. The advantages of the CDT test are reliability and the availability of automated test results within four hours [281,282]. The CDT is often used in combination with other screening tests, such as the gamma-glutamyl transferase (GGT) test. While both CDT and GGT are independently associated with alcohol abuse, combining tests may dramatically increase sensitivity [267,283]. CDT is less sensitive/specific in women than in men [267].

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 [289]. How these elements enhance effectiveness has been supported in other reviews [290,291]. Goal setting, follow-up, and timing are also important in brief intervention [292,293].

In addition to FRAMES, the following items are important:

Patients are more likely to change their behavior when they recognize they have a problem and when they are optimistic about prospects for change; therefore, evaluating readiness to change is an important part of brief intervention. Some patients are not ready to change at the start of brief intervention, but may be ready when they experience adverse consequences of alcohol use. One study found that 77% of patients who were very confident and motivated were able to reduce their alcohol consumption by using self-help instructions and drinking diaries [291]. Motivation techniques are more useful to the resistant patient than self-help instructions.

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 [294].

Many studies have documented that brief intervention can assist patients without clinical alcohol use disorder to reduce alcohol consumption [295,296,297,298,299]. Brief intervention can also help motivate the patient with alcohol use disorder to enter treatment. One study in an emergency care setting found that 65% of individuals with alcohol use disorder who received brief counseling kept a follow-up appointment for treatment, compared with only 5% percent of those who did not have counseling [295]. Some studies have found that brief intervention may be as effective as more specialized treatment for some patients with alcohol use disorder [296,300].

Researchers conducted a comprehensive meta-analysis of controlled studies of brief intervention in treatment and nontreatment settings [301]. In this meta-analysis, effect sizes were calculated for several outcome variables, including amount and timing of alcohol consumed, abstinence rates and duration, proportion and duration of non-problem drinking, frequency of intoxication, laboratory markers, ratings of drinking severity, ratings of improvements, dependence symptoms, and problems resulting from drinking [301]. Two types of investigations were examined. The first group of studies (N=34) compared brief intervention to control conditions in non-treatment-seeking patients and generally did not include persons with severe alcohol problems. The second group of investigations (N=20) included persons who had more severe alcohol problems in a treatment setting. The effect size for brief intervention on alcohol consumption was noted at between three to six months in studies that excluded more severe alcohol problems [301]. This meta-analysis provides further documentation of the effectiveness of brief intervention provided by healthcare professionals to patients with alcohol problems, especially during the first three to six months after intervention. Effectiveness may decrease over time, so progress should be monitored and referrals made if necessary. For those with more severe alcohol problems in a treatment setting, brief intervention may be appropriate as an initial treatment with nonresponders receiving more extensive/intensive treatment [301].

In summary, brief intervention can help patients without disordered alcohol consumption reduce or stop drinking, can help motivate patients with alcohol use disorder to enter treatment, and can be used to treat some patients with alcohol use disorder. One study reported that brief intervention is associated with decreased alcohol consumption and decreased healthcare utilization, motor vehicle events, and other related costs [302]. The study also reported that the cost-benefit analysis suggests that for every $10,000 invested in early intervention, there will be a $43,000 decrease in future healthcare costs [302]. A meta-analysis of brief alcohol interventions for adolescents and young adults found that the interventions yielded modest, but clinically significant positive effects on problematic alcohol use trajectories among youth [303].

Readiness to Change was Dimension 4 of the third edition of the American Society of Addiction Medicine's (ASAM's) Six Dimensions of Multidimensional Assessment (also known as the ASAM Criteria) that is the standard for placement, continued stay, transfer, or discharge of patients with substance use disorder and co-occurring conditions [304]. Readiness to Change is now considered within each of the six dimensions in the fourth edition of the ASAM Criteria. The six dimensions of the fourth edition include: intoxication, withdrawal, and addiction medications; biomedical conditions; psychiatric and cognitive conditions; substance use-related risks; recovery environment interactions; and person-centered considerations (new). This new sixth dimension considers barriers to care, patient preferences, and need for motivational enhancement [304]. Several factors influence a person's readiness and ability to change behaviors. It is useful to help patients to weigh the risks of continued alcohol consumption and benefits of decreasing or eliminating alcohol consumption. Physicians can help motivate the patient to become ready for treatment if the patient appears ready to change.

Is the patient ready to change? The role of motivation is an important part of changing behavior. Table 2 summarizes the "pros" and "cons" of changing [305].

The Stages of Change Model is also useful in determining where a patient is in the process of change [306]. The stages of change include:

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

Drug testing frequently, randomly, and for-cause should be a mandatory component of all phases. Transition from one phase to the next should not be based on time but on individual symptoms and progress.

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 [316]. 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.

Patients can find the listing for a nearby AA group in the telephone book or online. Typically, a person in recovery will answer the telephone. Websites provide printable lists of all local meetings with time, location, types of meeting, and often directions. One of AA's principles is the value of performing services that will help other alcoholics. Answering the telephone at the local AA office is one of these services, reserved for those who have been in recovery long enough to answer questions in a knowledgeable manner and provide a nonjudgmental ear.

A Cochrane review found that AA, the premier mutual aid peer-recovery program definitely helps people get sober [317]. In addition, AA has significantly higher rates of continuous sobriety compared with evidence-based professional mental health therapy, such as cognitive-behavioral therapy, alone. AA was often was found to be markedly better than other interventions or quitting cold turkey. One study found the program 60% more effective than alternatives [317].

The study by Harvard and Stanford addiction researchers of 10,565 subjects determined that AA was nearly always found to be more effective than psychotherapy in achieving abstinence [317].This review concluded that AA participation improved the duration of abstinence and the amount they reduced their drinking (if they continued drinking). AA had harm reduction features as well, reducing the medical consequences of drinking and related healthcare costs. While not a random assignment treatment comparison study, in this analysis, AA was never found less effective than other treatments. As such, AA could be a helpful addition to any treatment for alcohol use disorder. For example, adding AA to naltrexone would be expected to be better than pharmacotherapy alone. Recent studies and the preponderance of evidence supports the effectiveness of 12-step program involvement in sustaining abstinence [10]. Stable and long-term abstinence was associated with living longer, better mental health, better marriages, being more responsible parents, and being successful employees.

A brain imaging study by Yale researchers showed that those diagnosed with alcohol use disorder showed disruptions of activity between the ventromedial prefrontal cortex and striatum, a brain network linked to decision making [318]. Time is necessary for re-learning how to be sober but also for brain recovery. The more recent the last drink, the more severe the disruption, and the more likely the individual will relapse to drinking. The Yale researchers also found that the severity of disruption between these brain regions recovers very slowly, day after day, gradually over time. They conclude the longer subjects with alcohol use disorder abstain from alcohol, the better. The number of days of alcohol abstinence at treatment initiation significantly affected functional disruption of the prefrontal-striatal responses to alcohol cues in patients with alcohol use disorder and brain imaging abnormalities [318].

Cognitive-behavioral therapies (CBTs) are among the most frequently evaluated approaches used to treat substance use disorders [319,320]. CBTs have been shown to be effective in several clinical trials of substance users [321]. Characteristics of CBTs include:

Basic principles of CBTs are that [322,323]:

Structured behavior therapy techniques can be effective components of alcohol use disorder treatment. Contingent incentive procedures are designed to enhance a patient's motivation to meet treatment goals by offering concrete rewards for specific performance outcomes.

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-TR 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.

Several medications are available to help treat alcohol use disorder [324,325]. Some are used for detoxification and others are used to prevent relapse. Research has shown that medications are most effective when used in conjunction with other therapies.

Benzodiazepines have been used for 30 years in the United States as the primary medical treatment for alcohol withdrawal syndrome. All benzodiazepines appear similarly effective in the treatment of alcohol withdrawal syndrome [370]. Although benzodiazepines are the drugs of choice, there are concerns about the side effects and, as stated, problems of abuse, especially for outpatient detoxification. Benzodiazepines are sedatives and cause deficiencies in psychomotor abilities that, when combined with alcohol, can cause accidents and affect the ability to think clearly. However, benzodiazepines are, and have been, effective in treating alcohol withdrawal symptoms and preventing most seizures. Other regimens for alcohol withdrawal syndrome include barbiturates, propofol, and ethanol [371,372,373].

A desirable alternative to benzodiazepines would be a nonsedative anticonvulsant that has less potential for abuse and dependence. Valproic acid has been used in Europe safely and successfully for many years for alcohol withdrawal syndrome, but is only approved by the FDA for the treatment of mania, seizures, and migraines. Valproic acid should be used as an adjunctive therapy, not as monotherapy [370]. According to clinical reports, valproic acid is an anticonvulsant with no potential for abuse and is better tolerated by patients. Valproic acid also has less cognitive impairment and causes fewer deficiencies of psychomotor abilities than benzodiazepines; however, benzodiazepines have allowed for safe detoxification for patients with alcohol use disorder since they were approved. While detoxification is not treatment, and detoxification problems have not been the most important problem area in successful treatment of the patient with alcohol use disorder, these are important findings.

Recognizing that relapse prevention and harm-reducing medications are safe and effective in alcohol use disorders, fewer than 10% of these patients are given medication-assisted treatment. In a 2018 meeting of the American Psychiatric Association, experts suggested [374]:

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 [375].