Critical Issues in Alcohol and Drugs of Abuse Testing

Kingdom

Preface

Amitava Dasgupta, Houston, TX, United States

The first edition of Critical Issues in Alcohol and Drugs of Abuse Testing was published in 2009 and since then significant changes in the field of alcohol and drugs of abuse testing have occurred. These changes are reflected in the significant expansion of the second edition, adding 13 new chapters covering topics such as bath salts (synthetic cathinone) and synthetic cannabinoids (spices, K2 etc). These were just emerging when the first edition was prepared, but today many cathinone derivatives and over synthetic cannabinoids are described in medical literature. In addition, there also reports of abuse of many other novel psychoactive substances that are covered in new chapters. Chapter 20, Novel Psychoactive Substances: An Overview, provides an overview of novel psychoactive substances while baths salts on illicit drug market are discussed in Chapter 21, Review of Bath Salts on Illicit Drug Market. In Chapter 22, Review of Synthetic Cannabinoids on the Illicit Drug Market, synthetic cannabinoids are reviewed. Drug assisted sexual assaults are a critical problem and are discussed in detail in Chapter 18, Drug-Assisted Sexual Assaults: Toxicology, Fatality, and Analytical Challenge, addressing toxicity, fatality, and analytical challenges associated with date rape drugs.

Gas chromatography/mass spectrometry (GC/Ms) was originally used for confirmation of drugs of abuse in urine and other biological matrix. This method is still useful today and is widely used (Chapter 15: Confirmation Methods for SAMHSA Drugs and Other Commonly Abused Drugs). Later, liquid chromatography combined with mass spectrometry or tandem mass spectrometry emerged as a useful analytical technique for confirmation of drugs of abuse. This method is superior to GC/Ms because no derivatization is needed (Chapter 13: Overview of Analytical Methods in Drugs of Abuse Analysis: Gas Chromatography/Mass Spectrometry, Liquid Chromatography Combined With Tandem Mass Spectrometry and Related Methods). More recently, liquid chromatography combined with high resolution mass spectrometry emerged as a power method for confirmation of drugs of abuse in urine and body fluids. In Chapter 14, High Resolution Mass Spectometry: An Emerging Analytical Method for Drug Testing, technical aspects of high resolution mass spectrometry are discussed while in Chapter 23, Application of Liquid Chromatography Combined with High Resolution Mass Spectrometry for Urine Drug Testing, application of high resolution mass spectrometry in urine drug analysis is addressed.

Drug testing using point of care devices is becoming more common because such tests can be conducted bedside or in a physician’s office. Therefore, a new chapter (Chapter 11: Point of Care Devices for Drugs of Abuse Testing: Limitations and Pitfalls) discusses usefulness and pitfalls of point of care devices in screening for drugs of abuse in urine. Chapter 25, Drug Testing in Pain Management, addresses drug testing in pain management with a chapter on drug testing in death investigation. As expected, all chapters from the 1st edition are included with significant updates by the respective authors. All chapters also include a long list of references so that readers can look into source materials.

I would like to thank my wife, Alice, for her support during long evenings and weekend hours while I devoted time editing this revision. I hope, like the 1st edition, readers will find this 2nd edition valuable as it contains more extensive coverage on this topic.

Respectfully submitted

Chapter 1

Alcohol

Pharmacokinetics, Health Benefits With Moderate Consumption and Toxicity

Amitava Dasgupta,    Department of Pathology and Laboratory Medicine, University of Texas McGovern Medical School at Houston, Houston, TX, United States

Abstract

Alcohol containing beverages are popular worldwide and are consumed on a regular basis. Current guidelines for drinking in moderation are up to 1 drink per day for woman and up to 2 drinks per day for man. If consumed in moderation, alcohol has many health benefits including protection from cardiovascular diseases, stroke, Type 2 diabetes, and many others, but if consumed in excess all these benefits disappear. Alcohol is a poison if consumed in excess. Major problem of drinking in excess is alcoholic liver diseases with most severe form being cirrhosis of liver. Moreover, drinking in excess increases risk of cardiovascular diseases, stroke and cancer as well as may significantly reduce longevity. Currently, legal limit of driving in all states is 0.08% whole blood alcohol (80 mg/dL).

Keywords

Alcohol; moderate drinking; heavy alcohol use; binge drinking; benefits of drinking in moderation

Introduction

Ethyl alcohol (also known as ethanol) is commonly referred as alcohol. Alcohol use by human can be traced back to prehistoric time. Professor Robert Dudley, University of California, Berkeley, proposed an interesting hypothesis known as Drunken Monkey Hypothesis, which speculates that the human attraction to alcohol may have a genetic basis because primate ancestors of Homo sapiens consumed large amounts of fruits. Alcohol produced by yeast from fructose diffused out of the fruit, and alcoholic smell could help a primate to identify fruits as ripe and ready to be consumed. As a result natural selection favored monkeys with a keen appreciation for the smell and taste of alcohol. By the time humans evolved from apes approximately 1–2 million years ago, fruits were mostly replaced by roots, tubers, and meat as diet. However, it is still possible that human taste for alcohol arose during our long-shared ancestry with primates. Anecdotally, humans often consume alcohol with food, suggesting that drinking alcohol along with food is a natural instinct [1].

The first historical evidence of alcoholic beverages came from the archeological discovery of Stone Age beer jugs, approximately 10,000 years ago. Egyptians probably consumed wine approximately 6000 years ago. Egyptians used alcoholic beverages (both beer and wine) for pleasure, rituals, medical, and nutritional purposes. Some myths suggest that Egyptian bakers noticed the formation of bubbles when wet grains sat for extended periods before being used to make bread. The earliest evidence of alcohol use in China dated back to 5000 BC, when alcohol was mainly produced from rice, honey, and fruits. In ancient India, alcohol beverages were known as sura. Use of such drinks was known in 3000–2000 BC and ancient ayurvedic texts concluded that alcohol is a medicine if consumed in moderation, but a poison if consumed in excess. Beer was known to Babylonians as early as 2700 BC. In ancient Greece, wine-making was common in 1700 BC. Hippocrates identified numerous medicinal properties of wine, but was critical of drunkenness. In ancient civilization, alcohol was used primarily to quench thirst because water was unsafe for drinking due to bacterial contamination. Hippocrates specifically cited that water only from springs, deep wells, and rainfall were safe for human consumption. Beer was a drink for common people, while wine was the preferred drink for elites. In ancient Eastern civilization, drinking alcoholic beverages for thirst-quenching was less common than Western civilization because drinking tea was very popular in Asian countries. Tea is a safe drink because during preparation, boiling kills pathogens [2].

Currently, few chemicals such as ethyl alcohol (alcohol) are widely found or generate the degree of debate and controversy. Not only is alcohol readily available in the form of alcoholic beverages, also its chemical properties make it an ideal solvent for flavoring and other compounds used in food industries. Furthermore, it is a product of decomposition by bacteria, giving rise to small, but measurable, amounts in some nonpreserved foods [3,4]. Additional sources of alcohol exposure include mouthwashes, cough and cold preparations, hand cleaners, aftershaves, window cleaners, and many other personal and household products.

Alcohol Content of Various Beverages

Alcohol content of various alcoholic beverages varies widely, for example, beer contains approximately 4%–7% alcohol while average alcohol content of vodka is 40%–50%. However, due to wide differences between serving size of various alcoholic beverages, one drink (often called one standard drink) contains approximately 0.6 ounces of alcohol, which is equivalent to 14 g of alcohol in each drink. In the United States, a standard drink is defined as a bottle of beer (12 ounces) containing 5% alcohol, 8.5 ounces of malt liquor containing 7% alcohol, a 5-ounce glass of wine containing 12% alcohol, 3.5 ounces of fortified wine containing about 17% alcohol, or one shot of a distilled spirits such as gin, rum, vodka, or whiskey (1.5 ounces) containing 40% alcohol. In general, the average bottle of beer contains an average of 0.56 ounce of alcohol, but a standard wine drink may contain 0.66 ounce of alcohol while distilled spirits may contain up to 0.89 ounce of alcohol [5]. Alcohol content of various popular beverages is given in Table 1.1.

Table 1.1

Historically, the alcoholic content of various drinks was expressed as proof, a term originated in the 18th century when British sailors were paid with money as well as rum. In order to ensure that the rum was not diluted with water, it was proofed by dousing gunpowder with it and setting it on fire. If the gunpowder failed to ignite, it indicated that rum was diluted with excess water. In the United States, proof to alcohol by volume is defined as a ratio of 1:2. Therefore a beer which has 4% alcohol by volume is defined as 8 proof. In the United Kingdom, alcohol by volume to proof is a ratio of 4:7. Therefore multiplying alcohol by volume content with a factor of 1.75 would provide the proof of the drink.

Currently, in the United States, the alcohol content of a drink is measured as the percentage of alcohol by the volume. The Code of Federal Regulations requires that the label of alcoholic beverages must state the alcohol content by volume. The regulation does not require the proof of the drink to be printed. Alcoholic drinks primarily consist of water, alcohol, and variable amounts of sugars and carbohydrates (residual sugar and starch left after fermentation) but negligible amounts of other nutrients such as proteins, vitamins, or minerals. However, distilled liquors such as cognac, vodka, whiskey, and rum contain no sugars. Red wine and dry white wines contain 2–10 g of sugar per liter while sweet wines and port wines may contain up to 120 g of sugar per liter of wine. Beer and dry sherry contain 30 g of sugar per liter [6].

Pharmacokinetics of Alcohol

Alcohol is a weakly polar, aliphatic hydrocarbon soluble in both water and lipid, a characteristic that greatly influences the pharmacokinetics once in the body. Alcohol pharmacokinetics in humans are complex and depend on factors such as the amount and type of alcohol ingested, gender, age, body water, and metabolism. After ingestion, alcohol readily diffuses across cellular membranes and is rapidly absorbed within 30–60 min in the duodenum. Coingestion of food, some drugs, and medical conditions that inhibit gastric emptying delay absorption. In one study, 10 healthy men consumed a moderate dosage of alcohol (0.80 g of alcohol per kg of body weight) in the morning after an overnight fast or immediately after breakfast (two cheese sandwiches, one boiled egg, orange juice, and fruit yogurt). The blood alcohol analysis revealed that the average peak blood alcohol in subjects who consumed alcohol on an empty stomach was 104 mg/dL. In contrast, the average peak blood alcohol in subjects who consumed alcohol after eating breakfast was 67 mg/dL. The time required to metabolize total amount of alcohol was on average 2 h shorter in subjects who consumed alcohol after eating breakfast compared to subjects who consumed alcohol on an empty stomach. The authors concluded that food in the stomach before drinking not only reduces the peak blood alcohol concentration but also increases elimination of alcohol from the body [7]. However, the nature of food such as high fat versus high protein or high carbohydrate has lesser effect of peak alcohol consumption although peak concentration was reached in 30–60 min in volunteers who consumed alcohol in empty stomach versus 30–90 min in volunteers who consumed alcohol after eating a meal rich in fat or rich in carbohydrate [8].

Similar to many other drugs, alcohol absorbed by the stomach and intestines is transported via the mesenteric and portal vein to the liver, where a portion undergoes first-pass metabolism before distribution to the rest of the body. On reaching the circulation, alcohol is widely distributed throughout the body. It penetrates the blood–brain barrier and exerts effects on most organ systems. Because of its chemical nature, alcohol distributes in tissues and fluids according to water content. This is why serum alcohol concentrations are 1.2 times higher than whole blood concentrations. The volume of distribution for alcohol is considered equal to the body water. Total body water content varies with age, gender, and weight, and is greater for males than females (representing ~50%–60% of the total body weight for males compared to 45%–55% for females). Generally, when a male and female of similar age and weight ingest the same amount of alcohol, the female will achieve a higher peak concentration compared to male simply due to the female’s lower body water content.

After ingestion, 85%–95% of alcohol undergoes metabolism within the hepatic and gastric mucosal cells, with only a small amount, 3%–10%, excreted unchanged by kidneys, lungs, and skin. The concentration of alcohol plays a role with the kinetics observed with alcohol metabolism, that is, it follows Michaelis–Menton kinetics in which metabolism changes from first-order to zero-order. At very low (<20 mg/dL) or high (>300 mg/dL) concentrations, alcohol elimination follows first-order kinetics (nonlinear); however, for the concentrations between, metabolism is independent of the dose due to the enzyme saturation and follows zero-order kinetics.

Several enzyme systems are involved in metabolism of alcohol, namely alcohol dehydrogenase (ADH), microsomal alcohol oxidizing system (MEOS), and catalase [9]. The first and most important of these, ADH, is a cytosolic enzyme family found primarily in hepatocytes:

At least five classes of ADH are found in humans. For several classes, multiple isoenzymes can be distinguished by kinetic and structural properties. Lung, stomach, and gastric mucosa also express ADH, but its role in these tissues with respect to alcohol metabolism is unclear. The enzyme is nonspecific and oxidizes several other alcohols and nonalcohols, as well, including methyl alcohol, propyl alcohol, butanediol, and ethylene glycol. The nonspecific nature of ADH has been capitalized based on the clinical treatment of poisonings resulting from the exposure of methyl alcohol, butanediol, and ethylene glycol which are metabolized by ADH to toxic metabolites [10]. When alcohol is administered intravenously it competes with any of these compounds if present in circulation for metabolism. Since the affinity of ADH is greater for alcohol than the other compounds, the production of their toxic products is minimized, thus significantly reducing formations of toxic metabolites after ingestion of methyl alcohol, butanediol, and ethylene glycol. A second therapeutic intervention was the development of the orphan-drug, Fomepizole (4-methylpyrazole, Antizol, United States) [10]. This chemical has long been used in alcohol research because of its ability to inhibit, or block, the action of ADH. In the patient intoxicated with methyl alcohol or ethylene glycol, the effect is similar to the prevention of the production of toxic metabolites.

ADH activity is greatly influenced by the frequency of alcohol consumption. Adults who consume 2–3 alcoholic beverages per week metabolize alcohol at a rate of ~100–125 mg/kg/h, whereas those considered to be an alcoholic, metabolize the compound at a rate up to 175 mg/k/h. For medium-sized adults, the blood alcohol level declines at an average rate of 15–20 mg/dL/h or a clearance rate of ~3 ounces of alcohol/h.

The MEOS, located within the smooth endoplasmic reticulum of hepatocytes, includes the cytochrome P-450 isoenzymes CYP2E1, CYP1A2, and CYP3A4. For nonalcoholics, this metabolic pathway is considered a minor, secondary route; but it becomes much more important in alcoholics for whom heavy use of alcohol induces CYP2E1. With induction of the MEOS enzymes, clearance of alcohol from the blood may increase to >30 mg/dL/h. CYP2E1 is also expressed in the brain, where ADH activity is low. Its action leads to the formation of reactive oxygen species such as superoxide, hydroxyl radicals, and hydroxyethyl, which increase the risk of tissue injury.

The role of peroxisomal catalase is thought to be quite small under most conditions, contributing to <2% of the oxidation of alcohol:

The acetaldehyde produced should be subsequently converted to acetate as the result of the action of mitochondrial aldehyde dehydrogenase most commonly by aldehyde dehydrogenase 2 (ALDH2).

But under conditions of excessive or chronic ingestion, the production of acetaldehyde may exceed the body’s ability to further metabolize it. Because acetaldehyde is a highly reactive molecule, its prolonged presence permits it to bind to numerous enzymes and proteins blocking their normal functions. For example, in the brain, acetaldehyde forms adducts with dopamine giving rise to salsolinol, a compound thought to be involved in alcohol addiction [11]. In other tissues, acetaldehyde readily forms DNA-adducts which may be carcinogenic. Some of the acetaldehyde–protein adducts impair the liver’s capacity to synthesize proteins and may contribute to the hepatomegaly encountered in later stages of disease [12]. Pharmacokinetic parameters of alcohol are listed in Table 1.2.

Table 1.2

Several nonoxidative pathways also contribute to the metabolism of alcohol and give rise to products that under investigation as potential markers of alcohol abuse. In one such pathway, esterases in liver, pancreas, adipose tissue, brain, and heart catalyze the reaction of alcohol with free fatty acids to form fatty acid ethyl esters (FAEEs) [13]. Esterase also catalyzes the production of cocaethylene when alcohol and cocaine are coingested. Another pathway leads to the formation of phosphatidyl alcohol via the enzyme phospholipase D. Poorly metabolized, phosphatidyl alcohol accumulates to detectable levels with chronic alcohol ingestion. The role of this product in alcohol toxicity is unclear, but its formation inhibits the activity of phospholipase D which, in turn, disrupts the formation of phosphatidic acid is inhibited. Without sufficient phosphatidic acid, cell signaling is disrupted [14]. Less than 0.1% of alcohol undergoes conjugation with glucuronic acid or sulfate to form ethyl glucuronide and ethyl sulfate, respectively. The first reaction is mediated by uridine diphosphate-glucuronyl transferases, while the second is mediated by sulfotransferases.

Polymorphism of Aldehyde Dehydrogenase Gene and Alcohol Metabolism

Polymorphisms of ALDH2 gene that encodes aldehyde dehydrogenase-2 enzyme (responsible for the conversion of acetaldehyde to acetate) play an important role in alcohol metabolism. Currently, there is a strong evidence that variant allele ALDH2*2 (rs671 G>A) resulting from a single nucleotide exchange causing substitution of lysine for glutamate at position 487 of the mature ALDH2 enzyme protects an individual from alcohol abuse because the enzyme encoded by this defective gene has poor enzymatic activity. As a result, acetaldehyde produced from alcohol by the action of ADH is not effectively removed from blood. This acetaldehyde buildup in blood produces adverse reactions (rapid heartbeat, sweating, etc.) in these individuals thus deterring them from drinking. ALDH2*2 is a common variant among 45% of East Asians including Han Chinese, Japanese, and Koreans, but rare in other ethnic groups and it has been estimated that 540 million people worldwide (8% of world population) carry this allele. ALDH2*2 homozygotes (ALDH2*2/*2) exhibit essentially no ALDH2 enzymatic activity but heterozygotes (ALDH2*1/*2) may show partial ALDH2 activity. Genetic and epidemiological studies have shown that ALDH2*2 homozygous individuals are almost fully protected from alcohol use disorder, but heterozygous individuals have partial protection (approximately 60%) [15]. Moreover, certain genetic polymorphisms of genes encoding ADH enzyme produce super active enzyme which also results in acetaldehyde buildup in blood thus also deterring these individuals from drinking. Combination of super active ADH and inactive aldehyde dehydrogenase enzyme in an individual provide total protection from drinking.

Guidelines for Alcohol Use

United States Department of Agriculture (USDA) and Department of Health and Human Services jointly publish Dietary Guidelines for Americans every 5 years, suggesting Americans what constitutes a balanced diet. These guidelines also include suggestions for drinking in moderation. However, alcohol is not a component in USDA food pattern. If alcohol is consumed, the calories from alcohol must be accounted when other foods are consumed so that daily calorie intake does not exceed the recommended limit (1600–2400 calories per day for women and 2000–3000 calories per day for men). The latest Dietary Guidelines for Americans 2015–2000, eighth edition, suggest that if alcohol is consumed it should be consumed in moderation following these guidelines:

• Up to 1 drink per day for women and up to 2 drinks per day for men and only by adults of legal drinking age (21 years or older).

One drink is defined by the guidelines as containing 14 g (0.6 fluid ounces) of pure alcohol.

Federal Food and Drug Administration has determined that mixing alcohol and caffeine is not a safe practice and recommended four manufacturers of alcoholic beverages containing caffeine to discontinue use of caffeine in these alcoholic drinks. People who mix alcohol and caffeine may drink more alcohol and become more intoxicated than they realize, increasing the risk of alcohol-related adverse events. Energy drinks are gaining popularity among young adults as well as underage drinkers. Energy drinks may contain caffeine which increases craving for alcohol. Studies have indicated that energy drinks may increase the craving for alcohol and binge drinking. Moreover, pleasurable experience of drinking alcohol is also enhanced by consuming energy drinks at the same time [16].

National Institute of Alcohol Abuse and Alcoholism(NIAAA) considers high-risk drinking as consuming 4 or more drinks in any day or 8 or more drinks per week for women and 5 or more drinks in any day or 15 or more drinks per week for men. Binge drinking is defined by NIAAA as the consumption of 5 drinks in 2 h for men and 4 drinks in the same time period for women. However, another government agency Substance Abuse and Mental Health Services Administration (SAMHSA) defines binge drinking as consuming 5 or more alcoholic beverages on the same occasion for the past 30 days. SAMHSA also defines heavy drinking as consuming 5 or more drinks on the same occasion on each of 5 or more days for the past 30 days. Guidelines and various pattern of drinking are listed in Table 1.3.

Table 1.3

NIAAA: National Institute on Alcohol Abuse and Alcoholism; SAMHSA: Substance abuse and Mental Health Services Administration.

Benefits of Consuming Alcohol in Moderation

Consuming alcohol in moderation has many health benefits including increased longevity. These health benefits are summarized in Table 1.4. Some of these benefits are attributable to alcohol while many other benefits are due to the combined effect of both alcohol and many beneficial phytochemicals present in beer and wine which are excellent antioxidants. More than 400 different phytochemicals are present in beer; some of these compounds originate from raw materials while others are generated during the fermentation process. Melatonin is generated during the brewing process. Beers with higher alcoholic content usually have higher amounts of melatonin [17]. More than 1600 phytochemicals are present in wine prepared from grapes [18].

Table 1.4

Cardiovascular diseases including myocardial infarction are the number one killer in the United States and other industrialized countries, but drinking in moderation reduces the risk of cardiovascular diseases including myocardial infarction.

Reduced Risk of Cardiovascular Diseases

Probably the most notable benefit of drinking in moderation is the reduced risk of cardiovascular diseases. The relationship between alcohol consumption and coronary heart disease was examined in the original Framingham Heart Study which showed a U-shape curve with reduced risk of cardiovascular diseases with moderate drinking but higher risk with heavy drinking. Smoking is a risk factor for coronary heart disease but moderate alcohol consumption may also provide some protection even among smokers [19]. Interestingly, women may get the beneficial effect of alcohol by consuming lower amounts as well as consuming alcohol less frequently than men. [20]. Moderate alcohol consumption can also provide protective effects against heart failure [21]. Gemes et al. based on a study of 58,827 individuals and an 11.6-year follow-up observed that light to moderate consumption of alcohol was associated with lower risk of myocardial infarction [22].

O’Keefe et al. reviewed effect of alcohol on health of the human heart and commented that habitual light to moderate drink lowers the rate from death due to coronary artery disease, diabetes mellitus, congestive heart failure, and stroke. However, excessive alcohol consumption is the third leading cause of premature death in United States. In general, men older than age 50 get more favorable effects of consuming alcohol in moderation than younger men, but women of any age benefit from drinking in moderation. Unfortunately, cardioprotective effect of alcohol has not been documented in epidemiological studies of population from India and China. Interestingly, authors advise individuals who are teetotalers not to initiate light to moderate alcohol consumption for health benefits [23].

There are several hypotheses on how moderate drinking can reduce the risk of heart disease. Many studies have demonstrated increased high-density lipoprotein cholesterol (HDL cholesterol) levels in drinkers compared to nondrinkers and such increased HDL cholesterol is mostly attributable to the alcohol content of the drink. However, level of increased HDL cholesterol in blood may explain approximately 50% of protective effect of alcohol beverages while another 50% may be related to inhibition of platelet aggregation and antioxidant effect of various polyphenolic compounds present in beers and wines. The polyphenolic antioxidant compounds found in abundant in red wine can further reduce platelet activity via other mechanisms [24].

Significant research to understand epidemiological phenomenon known as French paradox (low incidence of cardiovascular diseases in French population despite consuming fatty foods) indicates superiority of wine especially red wine in reducing risk of cardiovascular diseases compared to other alcoholic beverages [25]. However, other authors disputed this finding. In an interesting study, Barefoot et al. concluded that the apparent health benefits of wine compared to other alcoholic beverages, as reported by some investigators, may be a result of dietary habits and other lifestyle factors. The authors observed that subjects who preferred wine had healthier diets than those who preferred beer or spirits or had no preference. Wine drinkers also reported eating more servings of fruits and vegetables and fewer servings of red or fried meat. In addition, wine drinkers were less likely to smoke [26]. Light to moderate consumption of alcohol also increases the chance of survival after the first heart attack [27].

Other Physical Health Benefits of Moderate Drinking

Another beneficial effect of consuming alcohol in moderation is reduction in the risk of stroke among both men and women regardless of age or ethnicity. The Copenhagen City Heart Study with 13,329 eligible men and women aged between 45 and 84 years with 16 years of follow-up indicated a U-shaped relation between intake of alcohol and risk of stroke. People who consumed low to moderate alcohol experienced protective effect of alcohol against stroke, but heavy consumers of alcohol were at higher risk of suffering from a stroke compared to moderate drinkers or nondrinkers [28].

Moderate consumption of alcohol reduces the risk of Type 2 diabetes by reducing oxidative stress and increasing insulin sensitivity. Based on the 15 studies conducted in the United States, Finland, Netherland, Germany, UK, and Japan with 369,862 men and women and an average follow-up of 12 years, light drinkers and moderate drinkers had a lower risk of Type 2 diabetes compared to nondrinkers. The risk reduction was approximately 30% in moderate drinkers compared to nondrinkers [29]. Baliunas et al., based on reviewing 20 studies, observed a U-shape relationship between alcohol consumption and risk of Type 2 diabetes, where moderate alcohol consumption decreased the risk of Type 2 diabetes but heavy alcohol consumption increased the risk [30]. Polsky and Akturk commented that light to moderate consumption of alcohol decreases the incidence of diabetes whereas heavy drinkers and binge drinkers are at an increased risk of diabetes. Among people with diabetes, light to moderate alcohol consumption reduces risk of cardiovascular diseases as well as all-cause mortality [31].

Moderate consumption of alcohol may reduce the risk of certain types of cancer because wine and beer contain anticarcinogenic compounds and antioxidants. In the California Men’s Health Study using 84,170 men aged between 45 and 69, the authors observed that consumption of one or more glasses of red wine per day was associated with approximately 60% reduced lung cancer risk ever in smokers [32]. Consumption of up to 1 drink per day reduced the risk of head and neck cancer in both men and women, but consuming more than three alcoholic beverages increased the risk of cancer. In an Italian study, the authors observed that moderate consumption of alcohol reduced the risk of renal cell carcinoma in both males and females [33]. However, the relation between moderate alcohol consumption and risk of breast cancer is controversial because there are conflicting reports in the medical literature. Pelucchi et al. concluded that consumption of less than 3 alcoholic drinks per week is not associated with increased risk of breast cancer in women, but consuming 3–6 drinks per week may be associated with a small increase in risk [34]. Beverage type is not associated with increased risk of breast cancer because alcohol acts as weak breast carcinogen. Acetaldehyde, a metabolite of alcohol is also a carcinogen. However, there are many other factors that may increase the risk of breast cancer including family history (BRCA1 and BRCA2 gene mutations are most common inherited factors), being older (only 10%–15% breast cancer diagnosis among women 45 years or younger), using hormone replacement therapy, previous or current use of birth control pills, not having a child, or having a dense breast.

Moderate alcohol consumption reduces the risk of rheumatoid arthritis [35]. Nissen et al. reported based on a study using 2908 patients suffering from rheumatoid arthritis that occasional or daily consumption of alcohol reduced the progression of the disease based on radiological studies (X-ray). Best results were observed in male patients [36]. Drinking all types of alcohol (beer wine and liquor) was associated with reduced risk of rheumatoid arthritis [37].

Moderate drinking (5–7 drinks per week) but not light drinking (1–2 drinks per week) may reduce the risk of gallstone disease. All alcoholic beverages types are associated with decreased risk [38]. The relation between moderate alcohol consumption and reduced incidence of common cold has been studied. In a large study using 4272 faculties and staff of five Spanish Universities as subjects, the investigators observed that total alcohol intake from drinking beer and spirits had no protective effect against common cold whereas moderate wine consumption was associated with some protection against common cold [39].

Because moderate consumption of alcohol can prevent many diseases, it is expected that moderate drinkers may live longer than lifetime abstainer. In Physician’s Health Study involving 22,071 male physicians in the United States between age 40 and 84 with no history of myocardial infarction, stroke, or cancer, and then 10 years of follow-up, the authors observed that men who consumed 2–6 drinks per week had the most favorable results (20%–28% lower mortality rate) than people who consumed 1 drink per week. In contrast, people who consumed more than 2 drinks per day had approximately 50% chance of higher mortality than people who consumed just 1 drink per week [40]. Interestingly, wine may be superior to beer or spirit in increasing longevity. In a study of 13,064 men and 11,459 women, Gronbaek et al. observed that compared to nondrinkers, light drinkers who avoided wine had a 10% lower chance of mortality but light wine drinkers had 34% lower chance of mortality [41]. In another study, the authors concluded that light drinkers of any kind of wine had lower mortality risk than beer or liquor drinkers [42]. Interestingly only drinking wine in moderation is associated with perception of good health [43].

Mental Health Benefits of Moderate Drinking

Alcohol if consumed in low to moderate amount is effective in reducing stress and increasing affective expression, happiness, euphoria, conviviality, and pleasant as well as carefree feelings. In addition, tension, depression, and self-consciousness have been reported to decrease with low to moderate alcohol consumption [44]. In general, alcohol has a euphoric effect at low to moderate blood alcohol (0.02%–0.05% whole blood alcohol levels; 20–50 mg/dL) concentrations and such effect starts 10–15 min after initiation of drinking. Alcohol is known to cause reduction in inhibition and such effect after drinking is more significant in women compared to men. In one study based on 184 degree-level and postgraduate students (94 females, 90 males), the authors concluded that alcohol at a level of approximately 50 mg/dL (0.05%) facilitated social interaction and communication [45]. Interestingly, moderate alcohol consumption increases happiness even in the unpleasant ambiance [46].

Subjective health may simply be an indicator of actual health status. Studies have shown that moderate consumption of alcohol may provide a rewarding sense of well-being in association with good physical health. Possible link between moderate drinking and success at work may be related to overall better physical health, better psychosocial adjustment as well as greater involvement in employment-related social experiences by moderate drinkers. Moreover, during stressful work environment, nondrinkers are more likely to be absent from work than moderate drinkers. Alcohol may have buffering effect between stress and sickness. In addition, nondrinkers are 27% more likely to be disabled compared to moderate drinkers. Incidentally, studies have shown that moderate drinkers may have higher income than teetotalers [47]. A Spanish study reported that moderate alcohol consumption, especially drinking wine was associated with more active lifestyle and better perception of health in elderly subjects [48]. Studies have shown that moderate alcohol consumption is associated with reduced depression in elderly subjects. However, heavy drinking is associated with higher rate of depression.

Age-related dementia and Alzheimer’s disease are neurodegenerative diseases associated with advanced age. Alzheimer’s disease is a devastating neurological disorder affecting 1 in 10 Americans over the age of 65 and almost half of all Americans over 85 years old. Moderate alcohol consumption can dramatically reduce the risk of age-related dementia and Alzheimer’s disease. The triggering agent for Alzheimer’s disease is β-amyloid peptide (Aβ-aggregates), which alters the synaptic activity and disrupts neurotransmission mediated by N-methyl-D-aspartate receptor in the brain. Alcohol in low dosage can prevent formation of Aβ-aggregates thus delaying or preventing onset of Alzheimer’s disease. Moreover, low to moderate consumption of alcohol is also associated with reduced risk of other neurodegenerative diseases as evidenced from data of several large clinical trials [49]. Dietary compounds (polyphenols) found in grapes have some protective effect against Alzheimer’s disease because these compounds interfere with generation and aggregation of β-amyloid peptide. Resveratrol, a compound found in abundance in red wine and also in grapes provides protection against Alzheimer’s disease [50].

Health Hazards of Heavy Drinking

All benefits of consuming alcohol in moderation disappear with heavy drinking. In addition, excess consumption of alcohol on a regular basis damages multiple organ systems including brain, heart, bone, immune system, and endocrine system. Major adverse effects of chronic alcohol consumption include decreased life span, increased risk of violent behavior, alcoholic liver diseases including cirrhosis of liver, mood disorders, and significantly increased risk of various cancers. Drinking during pregnancy may be associated with poor outcome in pregnancy including fetal alcohol syndrome. Major adverse effects of heavy drinking are summarized in Table 1.5.

Table 1.5

Alcohol Abuse and Liver Damage

In the United States, about 60% of the general population admits alcohol use with 8%–10% reported heavy drinking (more than 2 drinks per day). Alcohol abuse is a leading cause of global morbidity and mortality with majority of alcohol-related disease burden resulting from alcoholic liver diseases because alcohol is hepatotoxic if consumed in excess. The first sign of liver toxicity is fatty changes in the liver which may occur even after few days of heavy drinking, but such changes can be easily reversed by abstinence. However, drinking heavily for a longer period may cause more severe alcohol-related liver injuries such as alcoholic hepatitis. Individuals who continue to abuse alcohol may develop fibrosis and eventually cirrhosis of liver. Women are at greater risk of developing alcoholic liver diseases. Obesity as well as smoking may increase the risk of alcoholic liver diseases [51]. In the United States, alcoholic hepatitis occurs in 35%–40% of all alcohol abusers while approximately 20%–25% of all cases of liver cirrhosis are related to alcohol abuse [52]. Drinking daily increases the risk of alcohol-related liver disease including liver cirrhosis compared to people who drink 2–4 days per week (hazard ratio: 3.65). Moreover, alcohol abuse in recent periods is a better predictor of liver cirrhosis than alcohol abuse in past years. Men consuming 14–28 standard drinks per week also have higher risk than men who consuming less than 14 drinks per week. Interestingly compared to beer and liquor, drinking wine might be associated with lower risk of alcoholic cirrhosis [53]. Welsh and Alexander commented that above a threshold of 7–13 drinks per week for women and 14–27 drinks per week for men there is a risk of developing some alcohol-related liver problem. The greater sensitivity of women towards alcohol toxicity may be related to genetic predisposition of metabolism pattern of alcohol in women where more oxidative byproducts of alcohol are formed compared to men. Consumption of coffee may protect males against alcohol-induced liver damage, but no such data is currently available for females [54].

Risk of alcohol-related liver diseases is significantly higher in individuals infected with hepatitis B or C virus. In one study, the authors observed that even moderate alcohol consumption may adversely affect the progression of liver damage in individuals infected with hepatitis C virus [55]. Mechanism of alcohol-induced liver disease is complex. While in moderate drinkers alcohol is mostly metabolized by ADH in the liver, in alcoholics CYP2E1, a member of the cytochrome P-450 drug metabolizing family of enzymes in the liver becomes activated. In this process, reactive oxygen species are generated. Hydroxyethyl radicals are probably involved in the alkylation of proteins found in hepatocytes causing liver damage.

Alcohol Abuse and Brain Damage

Teenage drinking is a serious public health concern in the United States because alcohol has more damaging effects on the adolescent brain than the adult brain. Onset of drinking at an early age (13 or earlier) has devastating effects on the brain and such adverse effects may last lifetime. Early onset of drinking is also linked to greater risk of alcohol dependance in adult life. Although thiamine deficiency is one of the major factors involved in alcohol-related brain damage, both alcohol and its toxic metabolite acetaldehyde exert toxic effects on neurons. Underage drinkers are also susceptible to immediate ill effects of alcohol use such as blackouts, hangover, and alcohol poisoning and these individuals are also at higher risk of neurodegeneration, impairment of functional brain activity, and neurocognitive deficits. In general, adolescent drinking induces brain structure abnormalities and these changes lead to poor memory, impaired study habits, poor ability to learn, and poor academic performance. Moreover, female adolescent brain is more vulnerable to alcohol exposure than male adolescent brain [56].

Excessive drinking may also damage the adult brain. The two major alcohol-related brain damages are alcoholic Korsakoff’s syndrome and alcoholic dementia. Korsakoff’s syndrome is a brain disorder caused by deficiency of thiamine and major symptoms are severe memory loss, false memory, lack of insight, poor conversation skills, and apathy. Some heavy drinkers may also have a genetic predisposition to developing this syndrome. In Korsakoff’s syndrome, loss of neurons is a common feature including microbleeding in certain regions of gray matter [57]. When Wernicke’s encephalopathy accompanies Korsakoff’s syndrome in an alcoholic it is called Wernicke–Korsakoff syndrome. Wernicke’s encephalopathy and Korsakoff syndrome are the two related diseases, both caused by thiamine deficiency but clinical symptoms may be different. The Royal College of Physicians in London recommends that patients admitted to the hospital who show evidence of chronic misuse of alcohol and poor diet should be treated with B vitamins [58]. Binge drinkers, both males and females, are at higher risk of developing alcohol-related brain damage.

Alcohol Abuse Increases Risk of Cardiovascular Disease and Stroke

Although alcohol if consumed in moderation has cardioprotective effect, drinking more than three drinks a day (any type of beverage) may be harmful to the heart. Chronic alcohol abuse for several years may result in alcoholic cardiomyopathy and heart failure, systematic hypertension, heart rhythm disturbances, and hemorrhagic stroke [59]. Alcoholics who consume 90 g or more of alcohol a day (7–8 drinks) for 5 years are at high risk of alcoholic cardiomyopathy and if they continue drinking alcohol, cardiomyopathy may proceed to heart failure, a potentially fatal medical condition. Without complete abstinence, 50% of these patients will die within the next 4 years of developing heart failure [60]. Heavy drinking also increases the risk of stroke, particularly the risk of hemorrhagic stroke [61].

Fetal Alcohol Syndrome

Fetal alcohol syndrome and fetal alcohol spectrum disorders are due to devastating effect of alcohol on the fetus. A pregnant woman or a woman planning to get pregnant should avoid consuming any amount of alcohol to prevent such birth defects or miscarriage. Approximately 1–4.8 of every 1000 children born in the United States have fetal alcohol syndrome, while as many as 9.1 out of 1000 babies born have fetal alcohol spectrum disorder [62].

Other Adverse Effects of Alcohol Abuse

Alcohol abuse is associated with increased risk of bacterial and viral infection due to impairment of the immune system by excess alcohol in the blood. Exposure to alcohol can result in reduced cytokine production. Alcohol also reduces the viability of mast cells that contributes to the impaired immune system associated with alcohol abuse [63]. Alcohol also accelerates disease progression in patients with HIV infection because of immunosuppression. In one study using 231 patients with HIV infection who were undergoing antiretroviral therapy, the authors observed that even consumption of two or more drinks daily can cause a serious decline in CD4+ cell count (higher CD4+ counts indicates a good response to therapy) [64].

Alcohol abuse can have an adverse effect on the human endocrine system. Alcohol abuse may cause pseudo-Cushing’s syndrome which is indistinguishable from Cushing’s syndrome characterized by excess production of cortisol causing hypertension, muscle weakness, diabetes, obesity, and a variety of other physical disturbances. Diminished sexual function in alcoholic men has been described for many years. Administration of alcohol in healthy young male volunteers caused a diminished level of testosterone. Alcoholic women often experiences reproductive problems. However, these problems may resolve when a woman practices abstinence from alcohol. To form healthy bone calcium, phosphorus, and active form of Vitamin D is essential. Chronic consumption of alcohol may reduce bone mass through a complex process of inhibition of hormonal balance needed for bone growth including testosterone in men, which is diminished in alcoholics. Alcohol abuse may also interfere with pancreatic secretion of insulin causing diabetes [65].

Epidemiological research has demonstrated a dose-dependent relation between consumption of alcohol and certain types of cancers and the strongest link was found between alcohol abuse and cancer of the mouth, pharynx, larynx, and esophagus. Pancreatitis and gallstone are common among alcohol abusers. In alcoholics endotoxin may be released from gut bacteria by the action of excess alcohol and such process may trigger progression of acute pancreatitis into chronic pancreatitis. Chronic pancreatitis may lead to pancreatic cancer [66].

Although moderate drinking is associated with increased longevity, alcohol abuse is associated with all-cause decreased longevity compared to abstainers. Even occasional heavy drinking may be detrimental to health. Dawson reported an increased risk of mortality among individuals who usually drink more than 5 drinks per occasion but consumed alcohol less than once a month [67]. Binge drinking is a very dangerous practice. In one study, the authors using a population of 1641 men who consumed beer observed that relative risk (RR) of all-cause deaths was 3.10 and RR of fatal myocardial infarction was 6.50 in men who consumed 6 or more bottles of beer per session compared to men who consumed less than 3 bottles of beer per session [68].

Many investigators reported a close link between violent behavior, homicide, and alcohol intoxication. Studies conducted on convicted murders suggested that about half of them were under the heavy influence of alcohol at the time of murder [69]. Alcohol abuse by husband may be related to husband to wife marital violence. Studies have shown the link between alcohol abuse by the husband before marriage and husband to wife aggression in the first year of marriage. The most violence occurs when the husband was a heavy drinker and wife was not [70].

Acute Versus Chronic Alcohol Toxicity

Alcohol is present in a variety of beverage products in which the amount of alcohol varies considerably. Ingestion of one drink generally leads to an approximate blood alcohol concentration of 25 mg/dL. In general, alcohol blood levels between 20 and 50 mg/dL produce pleasurable effects, but even at 80 mg/dL, the legal limit of driving, minor impairments are possible in a person who drinks infrequently. However, significant impairment of motor skill and decreased cognitive abilities are observed at blood alcohol levels between 100 and 150 mg/dL. Symptoms and signs associated with mild acute intoxication, which may occur at a blood alcohol level of 150 mg/dL and higher, include slurred speech, poor coordination, unsteady gait, and uninhibited behavior. However, at blood alcohol level of 200–300 mg/dL, the mental status changes and physical effects become more pronounced and the individual may show signs of dehydration and hypotension which are signs of alcohol intoxication. Severe intoxication (blood alcohol levels over 300 mg/dL) requires aggressive care as respiratory depression, coma, and hypothermia are likely. In general, alcohol poisoning occurs at blood alcohol level of 0.35% but even at blood alcohol concentration over 0.25% (250 mg/dL) some patients may be at a higher risk of coma. However, alcoholics may tolerate higher blood alcohol levels than alcohol-naïve individuals [71]. Celik et al. reported that postmortem blood alcohol level ranged from 136 to 608 mg/dL in 39 individuals who died due to alcohol overdose. Most of these deceased were male [72]. The mechanism of death from alcohol poisoning is usually attributed to paralysis of respiratory and circulatory centers in the brain causing asphyxiation.

Laboratory Testing for Alcohol

Because of its wide distribution into the body water, alcohol is measured in most body fluids: whole blood, serum, breath, oral fluid, urine, sweat, and in vitreous. In the clinical laboratory, gas chromatographic and enzymatic methods are employed with the choice depending upon the laboratory and the setting. Gas chromatography offers the most specific method and there are procedures which allow for the simultaneous measurement of alcohol, methyl alcohol, isopropanol, acetone, and even ethylene glycol. The enzymatic methods are rapid and used by more than 95% of laboratories participating in College of American Pathologists’ (CAP) proficiency surveys. The most frequently encountered enzymatic method utilizes a yeast-derived ADH and NAD+ to convert alcohol to acetaldehyde and reduced NADH. The amount of NADH produced is (absorbs at 340 nm while NAD+ has no absorption at 340 nm) proportional to the alcohol concentration. Care must be taken to prepare the phlebotomy site correctly when using the enzymatic methods because of the potential for cross-reactivity with any other alcohol which may be present. Please see Chapter 2 (Alcohol Analysis in Various Matrixes: Clinical Versus Forensic Testing) for an in-depth discussion on this topic.

The use of breath as a sample is most commonly found in forensic settings but because blood collection from an intoxicated patient is difficult, the technique has piqued the interest of some emergency departments. The ready partitioning of alcohol from an aqueous solution (blood) into a vapor (inspired air within the lungs) permits the measurement of alcohol in expired air or breath. Techniques most commonly employed today in these devices include infrared spectroscopy, electrochemical sensors, and semiconductors.

Biomarkers of Alcohol Abuse

Given the difficulty of firmly identifying the person who is abusing alcohol, biomarkers of alcoholism have long been sought. The enzyme gamma-glutamyltransferase (GGT) and mean corpuscular volume (MCV) are two of the more popular older tests that have been used as indirect biomarkers of alcohol abuse. GGT activity increases in response to the hepatocellular toxicity of alcohol. However, GGT and MCV may also be elevated for many reasons other than alcohol abuse. Carbohydrate-deficient transferrin (CDT) is an isoform of transferrin deficient in sialic acid residues which can be used as a biomarker of alcohol abuse. However, normal transferrin levels as well as CDT levels are different in men and women. As a result, %CDT is usually used as a biomarker for alcohol abuse because it has the same reference range in both men and women.

Although GGT, MCV, %CDT, etc. are the indirect biomarkers of alcohol abuse, there are also direct alcohol biomarkers. Acetaldehyde–protein adducts, a direct marker of alcohol consumption, are formed due to the interaction of alcohol metabolite acetaldehyde and various proteins present in blood and such adducts persist for days following alcohol ingestion. Ethyl glucuronide and ethyl sulfate are the minor metabolites of alcohol which are detected in biological samples including blood, serum, cerebrospinal fluid, urine, hair, meconium, along with other various organ tissues. Other direct alcohol biomarkers are FAEEs, phosphatidylethonol (measured in whole blood) [73]. Armer et al. commented that although breath alcohol, urine alcohol, urine ethyl glucuronide, and urine sulfate can be measured to monitor patients enrolled in community alcohol treatment programs, urine ethyl glucuronide and ethyl sulfate demonstrated optimum diagnostics performance. The authors recommend routine use of ethyl glucuronide and ethyl sulfate in monitoring patients enrolled in alcohol treatment programs [74]. For an in-depth discussion of alcohol biomarkers please see Chapter 3 (Alcohol Biomarkers: Clinical Issues and Analytical Methods).

Conclusions

Studies on the impact of alcohol on the body continue to raise as many questions as answers. The compound has such diverse and wide-reaching uses as a solvent that it is virtually impossible to avoid contact. Fortunately, most of these exposures are of low doses and minimal consequences. Clearly, when alcohol is misused or abused as in alcoholism, toxicity is observed in every organ system and there are significant social consequences. However, there is an evidence that when ingested in moderation some alcoholic beverages convey cardioprotective benefits as well as many other benefits. Alcohol testing has expanded from the measurement of alcohol in various body fluids to now include the measurement of various biomarkers of alcohol use.

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