Alcohol (ethyl alcohol) is consumed in large amounts throughout the world, and excessive use produces many adverse medical and social consequences. Excessive use of alcohol is termed alcoholism, and in common and historic usage, alcoholism refers to any condition that results in the continued consumption of alcoholic beverages despite the health problems and negative social consequences it causes. Epidemiology: Alcohol has been is use for at least 7,000–8,000 years. It is widely used in all countries and cultures although there is considerable variation depending on culture and religion (France has 22 times the per capita consumption than Saudi Arabia). In the USA, 2/3 of the adult population are regular drinkers and 5% are heavy drinkers. Excessive alcohol use causes 4% of all deaths (compared to 18% for tobacco and 2% for motor vehicle accidents) and there is an increased rate of mortality for women who drink more than 2 drinks per day and men 3 drinks per day. About 1/2 of all alcohol use is either illegal or excessive and the yearly expenditure for alcohol (118 billion) is over 20 times the budget for the National Cancer Institute. Pharmacology: At the clinical level, alcohol intake is usually measured by the number of drinks. One drink is defined as 14 ml of pure alcohol, which is equivalent to 12 oz of beer, 5 oz of wine, or 1.5 oz of distilled beverage. Alcohol is rapidly absorbed in the stomach and small intestine and peak blood alcohol levels (BAL) are reached within 30 to 60 minutes. BAL is commonly expressed as mg% (mg/100 ml) where the legal limit for driving in the USA is 80 mg/100 ml or 80 mg%. BAL levels under 80 mg% produce mild euphoria, decreased anxiety, decreased inhibition, and increased talkativeness, sociability and assertiveness. This is accompanied by decreased alertness, concentration and memory. With increasing BAL levels over 80 mg% there is disinhibition, with impaired reasoning, judgment depth perception and motor function. As BAL levels increase up toward 150 mg% behavior is overly expressive, boisterous and disinhibited with a staggering, slurred speech and impaired reaction time. BAL levels over 250 mg% produce stupor and impaired sensation that can lead to loss of consciousness–blackout. Lethal effects can occur with BAL levels over 400 mg%. Metabolism: Ethyl alcohol is metabolized to acetaldehyde by alcohol dehydrogenase, which is present in gastric fluid where it is 60% more active in men than women, which contributes to the increased BAL per drink in women compared to men. Acetaldehyde is metabolized to acetic acid in the liver by acetaldehyde dehydrogenase. Increased levels of acetaldehyde produce symptoms of flushing, nausea, headache, and tachycardia. Individuals with a genetic deficiency of acetaldehyde dehydrogenase have higher levels of acetaldehyde following alcohol and the resulting symptoms are protective against the development of alcoholism. Methyl alcohol and isopropyl alcohol are also metabolized by alcohol dehydrogenase to formaldehyde (which is toxic) and acetone respectively. Ethyl alcohol, by competing with alcohol dehydrogenase, can be used to treat methyl alcohol poisoning by reducing the formation of toxic metabolites. In contrast ethyl alcohol is contraindicated in isopropyl alcohol poisoning because it slows the metabolism of isopropyl alcohol and it is the isopropyl alcohol that is toxic. Clinical Effects: Because of tolerance, the BAL does not accurately reflect the behavioral effects of alcohol. As BAL increases, there is a good correspondence between BAL and motor impairment, but motor impairment improves much more rapidly than BAL levels drop so there can be little motor impairment while BAL levels are still significantly elevated. Subjective elation increases more rapidly than the BAL, but it rapidly decreases even though BAL is near peak levels. In contrast, accuracy of performance is impaired in both rising and falling BAL, it can be impaired even when the BAL is zero and it can persist at least 14 hours later. There is considerable tolerance to the motor impairing effects of alcohol with chronic use. Neurobiology: The most prominent effects of alcohol involve stimulation of the gamma amino butyric acid (GABA) neurotransmitter system, which accounts for many of the sedative and other effects. As with other drugs of abuse, there is release of dopamine in the nucleus accumbens that relates to the rewarding effects of alcohol. Alcohol also activates aspects of the opioidergic system and it affects the hypothalamic pituitary adrenal system (HPA) and other neuropeptide systems. Alcohol acts to inhibit glutamatergic function. During chronic alcohol exposure there is down regulation of the GABA system and up regulation of the glutamatergic system and so that during alcohol withdrawal there is impaired inhibition and excessive excitation, which can account for the observed alcohol withdrawal symptoms. Stress increases voluntary alcohol intake and corticotrophin-releasing hormone (CRH) antagonists reduce alcohol intake following stress and during alcohol withdrawal. Genetics: Genetic factors play a role in alcohol dependence with a heritability of over 50%, but since alcoholism is a multifactorial disease, overall, there is no clear pattern of mendelian inheritance. Family studies indicate that both genetic and environmental factors play a role in alcohol dependence. Individuals with genetic variants in alcohol metabolizing enzymes that result in increased acetaldehyde levels following alcohol have a dysphoric response to alcohol ingestion and are protected from developing alcoholism. In some instances genetic variation in the neurobiologic pathways involved in alcohol pathophysiology have been found to relate to some alcohol effects and the development of alcohol dependence and its response to treatment. Variations in genes that result in decreased availability of dopamine D2 receptors increase the risk of alcohol and substance use and relate to some treatment effects. Genetic variations in the GABA A receptor alpha 2 sub unit are associated with alcoholism, reduce subjective effects of alcohol and relate to treatment. Genetic variations in the opioid u receptor gene alter alcohol induced “high” in heavy drinkers and the treatment response of alcohol dependent individuals to naltrexone. Stress increases alcohol drinking and genetic variations that increase activity in the CRF system increase alcohol intake. Gene variants in the glutamate system relate to alcohol use. A genetic variant that decreases endocannabinoid metabolism is associated with problem drug and alcohol use, and variations of the nicotine receptor gene relate to decreased objective and subjective effects of alcohol and increased number of drinks to reach a desired effect. Adolescence: There is a large amount of alcohol use during adolescence. In college freshmen 20% have an alcohol use disorder and 40% report binge drinking. Early life adversity increases alcohol dependence and exposure to regular drinkers increases the risk for regular drinking. There is a graded increase in the probability of alcohol dependence the earlier the individual begins alcohol use. The adolescent brain is uniquely susceptible to the effects of alcohol. Adolescent rats voluntarily drink more alcohol and have less motor impairment but greater memory impairment than adults. Adolescent alcohol exposure in rats prevents the normal age-related development of increased sensitivity to motor impairment from alcohol and memory impairments produced by alcohol in adolescence last until adulthood. Alcohol exposure during adolescence produces greater inhibition of neurogenesis than adults and produces greater dopamine levels in adult hood. Adolescent alcohol use disorder is associated with a smaller prefrontal cortex. Adolescents have a unique sensitivity to alcohol that results in increased rates of impaired intellectual functioning and alcohol dependency in adulthood as a result of alcohol induced long-term changes in brain function. Medical Complications: There are many medical problems produced by excessive alcohol use including Wernicke's Encephalopathy, Korsakoff’s Syndrome, brain ventricular enlargement and cognitive dysfunction, peripheral neuropathy and myopathy. Alcohol is a major cause of morbidity from liver disease it produces inflammation of the esophagus and stomach and chronic pancreatitis. Alcohol abuse produces macrocytosis and thrombocytopenia and increases the risk of infection, and it increases the risk of hypertension, cardiomyopathy and supra ventricular arrhythmias. Excessive alcohol use is associated with a variety of negative behavioral events including: suicide, crime, violence and domestic abuse, motor vehicle and other accidents, trauma and burns, and it is a major co morbid factor complicating the management and treatment of patients with psychiatric illness. Alcohol withdrawal can range from low-level symptoms of irritability and nervousness to life threatening delirium tremens that requires robust medical intervention. The adaptive changes accounting for tolerance. (the decreasing effect of the same dose of a drug over time), when unopposed by alcohol are the neurobiologic causes of the increased nervous system excitability that produces the symptoms of the alcohol withdrawal syndrome. Benzodiazepines to augment GABA function, anticonvulsants to prevent seizures, and parentaral thiamine to prevent encephalopathy are the main treatment considerations for alcohol withdrawal. The fetal alcohol syndrome is the leading cause of mental retardation in the USA; it is diagnosed with 3 specific facial abnormalities, growth problems, and central nervous system problems. Drinking just 1 drink per week during pregnancy is associated with behavioral problems in the child, which is the basis for the recommendation of no drinking during pregnancy. Almost half of all traffic fatalities are related to alcohol, and they are more frequent at night. Risk of a crash increases with increasing BAL and decreasing and enforcement of the legal limit for driving to 50 mg% would reduce the yearly traffic fatalities by half. Diagnosis: The 4 questions in the CAGE questionnaire (Have you ever felt you needed to Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt Guilty about drinking? Have you ever felt you needed a drink first thing in the morning (Eye-opener) to steady your nerves or to get rid of a hangover?) has a 93% sensitivity in diagnosing alcoholism. The 10-item Alcohol Use Disorders Identification Test (AUDIT) has a sensitivity of 90% in identifying problematic drinking. The diagnosis of alcohol dependence is made when the patient meets 3 of 7 criteria and the diagnosis of alcohol abuse is made when 1 of 4 criteria are met. Hazardous alcohol use is a pattern of alcohol consumption that carries a potential risk of harmful consequences, and Harmful alcohol use is a pattern of drinking that has already caused damage to health. Physical signs of excessive alcohol use include: conjunctival injection, abnormal skin vascularization, hand and tongue tremor and hepatomegaly. Several laboratory tests are useful in the detection of alcohol misuse. Serum gamma-glutamyl transferase (GGT), carbohydrate deficient transferrin (CDT), mean corpuscular volume (MCV) of red blood cells and serum aspartate amino transferase (AST) are likely to provide, at relatively low cost, a possible indication of recent excessive alcohol consumption. Treatment: For treatment, brief interventions fill the gap between primary prevention efforts and more intensive treatments that include: individual and group therapy, cognitive-behavioral therapy (CBT), motivational interviewing (MI), motivational enhancement therapy (MET), brief intervention therapy, couples and family therapy. Self help groups including Alcoholics Anonymous, Al-Anon for family members and friends, Alateen for young people, utilize the 12 steps and self-help strategies. Medications shown to be effective in standard use include: naltrexone and injectable naltrexone-extended release which blocks opioid receptors resulting in reduced craving and reduced reward, acamprosate which alters glutamate and GABA neurotransmitter systems, disulfiram that inhibits aldehyde dehydrogenase resulting in a buildup of acetaldehyde and a reaction of blushing, sweating, nausea and tachycardia if the patient drinks alcohol. Medications shown to be effective in some studies include: topiramate thought to work by stimulating GABA neurotransmission and reducing glutamate transmission, bromocriptine, a dopamine agonist, ondansetron, a serotonin 3 receptor antagonist found to be more effective in early-onset alcoholics than late-onset alcoholics, varenicline, a nicotinic receptor partial agonist and memantine, a NMDA receptor antagonist that has been shown to reduce alcohol craving.