Alcohol — Health Benefit or Hazard?

by Ben Best




Alcohol — specifically ethanol (ethyl alcohol, EtOH, CH3CH2OH) — is the most socially-accepted addictive drug which can have life-threatening health hazards. Its pleasures are very widely acknowledged and form a bond of community for the majority of adults in Western countries. References to those pleasures form a kind of "standing joke" — physical & mental discoordination/disorientation are viewed with bemused affection. Alcoholic beverages are a standard "lubricant" (anxiety-reliever) at social gatherings, and those who refuse to consume ethanol run the risk of being social outcasts.

Yet some people, myself included, feel concern about consuming a substance which causes physical & mental discoordination/disorientation. Although the effects appear to be temporary, one could easily wonder about the physiological changes being wrought on the brain. And one could wonder whether the temporary effects are really desireable — even if pleasurable — and whether the brain really escapes permanent harm. Because ethanol enters tissues in proportion to water content it is far more prevalent in the brain than in muscle or fat. For those who highly value their brains/minds this should be a matter of great concern.

In the United States alcohol is responsible for about one-third of fatal car crashes, one-third of hospital admissions, one-third of all suicides, and half of all homicides  [NATURE; 468:475 (2010)].

People who are genetically disposed to experience alcohol as tasting bitter are the least likely to drink alcohol. As well, alcohol taste becomes increasingly unpleasant with age, which correlates with age-related decrease in the consumption of alcoholic beverages [ALCOHOLISM, CLINICAL AND EXPERIMENTAL RESEARCH; Duffy,VB; 28(11):1629-1637 (2004)].

Health benefits are frequently claimed for alcohol — when consumed in moderation. Most of the claimed benefits are associated with reducing cardiovascular disease. The incentives for wishful thinking are very high and study designs are often poor — conditions which can make for bad science. Between 16% and 33% of people in Europe and North America are estimated to abstain from drinking beverage alcohol, many of whom are former alcoholics. Ex-drinkers have high rates of ischemic heart disease, hypertension, ulcers, diabetes, gall bladder disease and bronchitis [INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 17(2):307-316 (1988)]. Life-long abstainers are more often non-conformists and are less frequently married (unmarried people have a higher mortality rate). People often abstain from alcohol due to interaction with prescription drugs or other health-related reasons. The poor health of many abstainers should not be taken as proof of the beneficial effects of ethanol — but usually are.

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Epidemiology is widely used to establish health benefits & hazards of various substances, including ethanol. And few substances demonstrate the perils of poor study design, confounding proxy variables (hidden variables which are more significant in producing the outcome than the reputed causative variables of the study) and bad judgement to the extent of ethanol in the hands of epidemiologists. A controlled clinical trial of ethanol would be randomized (individuals randomly assigned to be nondrinkers, light drinkers and heavy drinkers with no differences between subject groups other than the variables under study), double-blind (neither the subjects nor the experimenters know which individuals are receiving alcohol or a placebo), longitudinal (same individuals over time) and long-term (individuals designated nondrinkers, light drinkers or heavy drinkers are not to change drinking patterns for many years). Blinded studies of alcohol consumption are probably not feasible.

(Although cross-sectional studies can be called "controlled", they record a cross-section of characteristics within a short time-frame — in contrast to longitudinal studies which follow the same cohort of subjects over a long time period. A cross-sectional study in a Miami Hospital found that most people are born Cuban and die Jewish. More seriously, it has been observed that smokers have fewer beta-amyloid plaques upon autopsy than non-smokers, but smokers die at an earlier age and the autopsy results cannot be taken as proof that smoking reduces the risk of Alzheimer's Disease.)

In reality, studies of ethanol are usually based on self-reported descriptions of current alcohol consumption. Like a village idiot chasing a wallet on a string, epidemiologists typically take self-reporting at face value and fail to distinguish between ex-drinkers and lifetime teetotalers — calling both "abstainers". Not surprisingly, the abstainers (including the former alcoholics) are deemed to be less healthy than light drinkers.

A study of nearly 4,500 former University of North Carolina students (intended to be a somewhat uniform socio-economic group) [AMERICAN JOURNAL OF CLINICAL NUTRITION; Barefoot,JC; 76:466-472 (2002)]] sought to discover the possible confounding lifestyle variables (masked by "proxy variables"). Drinkers were distinguished from nondrinkers and drinkers were divided into those who prefer wine, beer, spirits or have no preference among types of alcoholic beverages. A tabulation of health behaviors by sex and beverage preference included the following:

Health (hazard) practices by gender and beverage preference







Female Smokers (%) 7.0 6.6 12.8 15.8 8.2
Male Smokers (%) 9.8 6.1 9.6 22.0 9.8
Female Exercisers (%) 31.3 43.4 39.5 34.9 42.6
Male Exercisers (%) 39.8 54.0 53.3 47.3 54.1

Wine drinkers would clearly be the healthiest subset insofar as they smoke less and engage in more aerobic exercise. But why would non-drinkers smoke more than wine-drinkers and exercise less than any of the other groups? Upon further investigation, only 27% of the nondrinkers said they had never been drinkers and 27% provided no information about their past drinking or non-drinking habits. The vast majority of alcoholics are smokers — who very often continue to smoke while abstaining from alcohol. This would also be true of non-alcoholic ex-drinkers who stopped drinking because of health problems. It would be no surprise to find higher rates of cardiovascular disease among nondrinkers who smoke more than light drinkers — an effect not due to the difference in drinking behavior. Not surprisingly, the investigators discovered that the lifelong teetotalers among the nondrinkers had lower rates of smoking. Additionally, even among the nondrinkers who did not have a previous history of drinking there may have been those who did not drink because of concern about interaction with prescription drugs.

Further investigation of the wine-drinkers revealed that they consumed more fruit & vegetables and had higher fiber intakes than the other groups. All these confounding influences show how highly irrelevant epidemiological data indicating the so-called health benefits of light drinking are to the life-extensionist who does not drink ethanol, does not smoke, exercises regularly and eats lots of fruits, vegetables & fiber — while restricting calories.

The February 1998 issue of the journal ADDICTION contains a research report which greatly advanced the study of the relationship between alcohol consumption and mortality. It was probably also larger than previous studies because it pooled the results of the best available previous studies [ADDICTION; Fillmore,KM; 93(2):183-229 (1998)].

Unlike many previous studies which have a single category for non-drinkers, this study carefully distinguished between former drinkers and long-term abstainers. Using this distinction, the reputed reduced mortality risk for light drinkers over long-term abstainers was disproven for both men and women. However, a large meta-analysis of epidemiological studies that attempted to adjust for lifetime abstainers within the category of non-drinkers concluded that minimum risk of coronary artery disease occurred for 1-2 drinks per day [BMJ; Ronksley,PE; 342:d671 (2011)], although there was no adjustment for health conditions that could reduce alcohol consumption.

In the case of males, the confounding effect of grouping former drinkers with long-term abstainers was particularly illuminating. Six statistically significant differences were seen between the two groups. Compared to long-term abstainers, former male drinkers were more likely to be: (1) heavy smokers (2) marijuana users (3) unemployed (4) depressed (5) less well educated and (6) have better educated fathers. The last result is somewhat puzzling. It might be a marker for "downward mobility" — people who are depressed & unemployed because they failed to achieve the standards of their parents.

There have been fewer alcohol studies on women than on men, so there is less data available, and the results are less definitive — except to rule-out a definite conclusion that light drinkers have less mortality than long-term abstainers OR former drinkers. Evidence was found for demographic factors which might account for the mortality results of some studies on women. These factors are unrelated to the physical effects of alcohol. Both "long-term abstainers and former drinkers were more likely to have low income, had less education, were less likely to be employed and were less likely to be European American than light drinkers ..." Among the females, there were 5 statistically significant differences between former drinkers and long-term abstainers. Former drinkers tended to be: (1) heavy smokers (2) in poorer health (3) unmarried (4) less religious (5) better educated. A demographic study in Australia indicated that abstainers had a higher incidence of asthma, diabetes, arthritis, thyroid abnormalities, religiosity, lower education, and lower cognitive scores [ADDICTION; Anstey,KJ; 100(9); 1291-1301 (2005)]. No adjustment was made to account for former alcoholics being abstainers, nor was it established whether abstension is a cause or consequence of health problems.

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An epidemiological phenomenon often cited in favor of alcoholic beverages is the fact that France has the highest per capita alcohol consumption among 21 developed countries and the second-lowest (after Japan) rate of coronary heart disease mortality [LANCET 344:1719-1723 (1994)]. But there are many proxy variables, only a few of which can be isolated and quantified. Among those 21 countries, France has the highest per capita wine consumption, high vegetable consumption and moderate consumption of animal fat. (The so-called "French Paradox" of high dietary fat and low rate of cardiovascular disease is mistaken with regard to the animal fat — the French eat a great deal of fish.) Japan has very low animal fat consumption and less than half the per capita ethanol consumption of France. The highest rates of coronary heart disease mortality are in Ireland & Finland, where per capita ethanol consumption is about the same as in Japan. Ireland has the lowest per capita fruit consumption and wine consumption of the 21 countries. Drinking patterns in Finland are very different from those in France. Wine is often consumed with meals in France, which may reduce alcohol absorption. By contrast, moderate daily imbibing is rare in Finland where the principle aim of drinking is rapid intoxication once every week or two [INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 12(2):151-155 (1983)].

An ardent defense of the benefits of red wine was written by a group in Montpellier, France [JOURNAL OF NUTRITION 132:1207-1213 (2002)]. Using hamsters, the group demonstrated that red wine extract significantly reduces atherosclerotic fatty streaks in the aorta and that this effect is even greater when combined with ethanol. In contrast to studies that have usually shown increased plasma triglycerides due to ethanol in humans, this study showed reduced triglycerides. Most of the benefits of red wine extract were attributed to polyphenols (compounds with multiple hydroxylated benzene rings), also known to be very effective in preventing cancer. [For a good summary of grape phenolics see ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 957:21-36 (2002)]. A phenol is a benzene ring with an alcohol (-OH) group that can act as an anti-oxidant by donating a hydrogen atom to a hydroxyl radical. A polyphenol is a molecule with many phenols and better antioxidant properties. However, all phenolic antioxidants (including Vitamin E) neutralize hydroxyl radicals by becoming weaker pro-oxidants — in contrast to an antioxidant like melatonin which donates electrons to hydroxyl radicals [JOURNAL OF PINEAL RESEARCH 32:135-142 (2002)].

Resveratrol (trans-3,4',5-trihydroxystilbene), present in purple grape juice, peanuts and red wine, is known to be a modulator of lipid and lipoprotein synthesis. Resveratrol is also an antioxidant which can cross the blood-brain barrier to protect against brain ischemic injury [BRAIN RESEARCH 958:439-447 (2002)] (melatonin also crosses the blood-brain barrier). Andrew Waterhouse (a professor of hydroxyl chemistry — author of the grape phenolics paper cited above) has described resveratrol as "trendy and famous", adding "it is no better an antioxidant than the hundred or so other phenolic compounds in red wine". But Waterhouse himself adds to the pro-alcohol hype by referring to red wine rather than grapes or grape juice, as if children & teetotallers are excluded from the benefits. During fermentation, alcohol draws phenolics from grape seed & skin, resulting in a drink with 50% greater concentration of antioxidants. But there are plenty of fruits with more antioxidant capacity than red grapes, like blueberries, strawberries or raspberries — see THE COLOR CODE by Joseph, Nadeau & Underwood. Concerning red wine as a source of antioxidants, THE COLOR CODE quotes cancer expert Dr. John D. Potter: "Drink grape juice".

The greatest benefits of resveratrol may not be due to its antioxidant effects. Mice fed a high-calorie diet who were supplemented with resveratrol (equivalent to 2,000 milligrams per day in a 200 pound human — more than 300 times the amount found in a glass of red wine) showed physiology similar to mice fed a standard diet. Unlike mice fed a high-calorie diet who did not receive resveratrol, the resveratrol-supplemented mice showed insulin sensitivity, IGF−1 levels, motor function, mitochondrial number and survival comparable to mice fed a standard diet [NATURE; Baur,JA; 444(7117):337-342 (2006)]. Because of these results and because resveratrol enhances SIRT1 activity it is suggested that resveratrol mimics the effects of Calorie Restriction with Adequate Nutrition — although a better suggestion might be opposing some of the health effects of the metabolic syndrome.

Modest doses of ethanol beneficially increases plasma HDL cholesterol and reduces blood pressure while harmfully raising plasma triglycerides, decreasing heart muscle contractility and increasing heart rate. Heavier drinking increases blood pressure. A six-year study of nearly three thousand men showed nearly four times greater incidence of ischemic heart disease in abstainers as in heavy drinkers and nearly twice the incidence in moderate drinkers over heavy drinkers for the fifth with the highest LDL cholesterol levels. For those in the lowest fifth no association was seen, and only a non-significant association was seen for the middle three-fifths [BRITISH MEDICAL JOURNAL; Hein,HO; 312(7033):736-741 (1996)]. This might indicate that alcohol is only of benefit for those with high LDL cholesterol (the French have high LDL cholesterol and drink heavily, hence the "French Paradox"), but it is worth noting that the abstainers in the study were taking more medications and were more likely to be suffering from non-insulin dependent diabetes. For diabetics, ethanol may produce atherosclerosis at all doses in a direct dose-dependent fashion [DIABETES CARE 25:1425-1431 (2002)], although not all studies agree on this. A meta-analysis of intervention studies concerning effects of ethanol on plasma risk factors of heart disease concluded that alcohol significantly increases HDL cholesterol, apolipoprotein A1, and adiponectin while significantly decreasing fibrinogen [BMJ; Brian,SE; 342:d636 (2011)].

Reduced clotting is another benefit of light ethanol consumption — an effect ethanol shares with aspirin. And as with aspirin, with less clotting there is less chance of coronary artery disease, but a greater danger of hemorrhagic stroke. Reduced levels of thromboxane A2 due to ethanol reduce blood vessel constriction and platelet aggregation [BRITISH MEDICAL JOURNAL 293:715-718 (1986)]. The Honolulu Heart Study found a direct correlation between incidence of hemorrhagic stroke and all levels of alcohol consumption — in contrast to the Framingham Study which did not show this association [STROKE 33:230-237 (2002)]. In contrast to chronic alcohol consumption, drinking to intoxication significantly increases the risk of brain infarction within 24 hours [STROKE 26:40-45 (1995)].

Many studies of cardiovascular disease, have given mixed results: "Use of ethanol has been associated with higher risk of mortality from hypertension, hemorrhagic stroke and cardiomyopathy, but with lower risk from CAD, occlusive stoke and nonspecific cardiovascular disease." Cardiomyopathy is damaged heart muscle cells unrelated to coronary artery disease. Ethanol reacts with fatty acids to produce fatty acid ethyl esters [general molecular formula CH3(CH2)nCOOCH2CH3] which are toxic to mitochondria — leading to heart muscle cell damage.

Ethanol impairment of protein synthesis affects both skeletal and heart muscle. In isolated heart cells ethanol reduces the number & uniformity of fibrils (minute fibers). Heart muscle in alcoholics shows a loss of contractile elements and/or fragmentation & disarrangement of those elements [THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 33:457-473 (2001)].

In seeing claims of the benefits of light alcohol consumption to prevent cardiovascular disease, one should always consider the possible role of proxy variables, as cited above. A good investigation that did not grouped ex-drinkers with long-term abstainers under the rubric "non-drinkers" was a very large study of over 100,000 people done in 1990 [AMERICAN JOURNAL OF CARDIOLOGY 66:1237-1242]. This study established that light drinkers have no less risk of mortality for non-cardiovascular disease than lifetime abstainers, but do have lower coronary artery disease (CAD) mortality.

A person practicing CRAN (Caloric Restriction with Adequate Nutrition) and/or who exercises would probably have an excellent HDL/LDL profile anyway, and would probably be better off without extra calories from alcohol — or the metabolic disturbances it creates. Epidemiological studies of Chinese have shown that for people who are lean and active, HDL cholesterol is not lowered with ethanol. Clotting can as easily be reduced by aspirin as by ethanol — or even better by the use of a higher ratio of omega-3 to omega-6 fatty acids in the diet.

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Ethanol Metabolism
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Most ethanol (CH3CH2OH) is metabolized in the cell cytosol of the liver (and to a lesser extent kidney, lungs and other tissues) by the enzyme alcohol dehydrogenase to produce acetaldehyde (CH3CHO), with NAD as the hydrogen acceptor.

About 50% of drugs (including alcohols) are metabolized by a family of liver endoplasmic reticulum (microsome) enzymes known as CYtochrome P450s, (CYP, so-called because when the reduced form is exposed to carbon monoxide it exhibits a spectrum Peak of 450nm). An enzyme in the E subfamily of the second family of P450s (CYP2E1) normally accounts for under 10% of ethanol metabolism, also using NAD as a co-factor. Ethanol can increase liver concentrations of CYP2E1 up to tenfold. Induction of CYP2E1 by ethanol may be a significant contributer to alcohol-induced liver disease [BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 205(2):1064-1071 (1994)]. CYP2E1 generates many different free-radicals, while depeting glutathione (GSH). CYP2E1 can covert many xenobiotics — such as industrial solvents, anesthetics, isoniazid, phenylbutazone, cocaine and acetaminophen — into highly toxic metabolites.

As a third route of ethanol metabolism, catalase in the peroxisomes of liver and in other cells metabolizes a small amount of ethanol when sufficient hydrogen peroxide (H2O2) is available — without requiring NAD as a cofactor. All three of these means of metabolizing ethanol result in acetaldehyde.

Acetaldehyde is then further metabolized in mitochondria by the enzyme acetaldehyde dehydrogenase to acetic acid (CH3COOH) — which can be metabolized into carbon dioxide and water with a release of energy. Daily drinking can increase liver metabolism of ethanol by as much as a third. But acetaldehyde is not always rapidly metabolized. High doses of acetaldehyde are so unpleasant that alcoholics have been given an acetaldehyde dehydrogenase blocking agent (disulfiram). The alcoholics find the flushing, headache, nausea, vomiting and other side effects to be a strong disincentive for further ethanol ingestion.

Large quantities NADH resulting from heavy drinking can lead to triglyceride accumulation — fatty liver. High alcohol & fat consumption along with low protein & carbohydrate consumption helps turn fatty liver into alcoholic liver cirrhosis — a cause of death for some alcoholics. Protein deficiency increases liver damage due to ethanol. Fat accumulation in the liver is worsened by reduced lipoprotein biosynthesis & secretion and impaired fatty acid oxidation. Ethanol potentiates the capacity of Vitamin A to cause liver damage. Ethanol also increases the release of arachidonic acid from cell membranes, increasing oxidative stress. Liver cells degenerate & die, replaced by connective tissue, lymphocytes and leucocytes as inflammation proceeds. Only 10-15% of alcoholics develop liver cirrhosis, however.

Ethanol influence on mitochondrial free-radical production
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High levels of NADH in mitochondria can cause an increase in the number of superoxide (O2.-) free radicals leaked from oxidative phosphorylation — leading to the formation of hydroxyl radicals (.OH), lipid peroxidation and damage to mitochondrial DNA [GASTROENTEROLOGY 122:2049-2063 (2002)]. (For more on these subjects see "The Free Radical Theory of Aging" and "Mitochondria and Aging".)

Acetaldehyde which escapes immediate conversion to acetic acid can bind to cysteine, a constituent of the anti-oxidant peptide glutathione (GSH) — further compromising liver mitochondrial function with oxidative damage. Acetaldehyde released into the bloodstream can drift to other organs — notably the brain — where it can damage proteins & DNA as well as cause lipid peroxidation in membranes.

In ethanol-damaged livers there is a decrease in activity of S-AdenosylMethionine (SAMe) synthetase, the enzyme that synthesizes SAMe from methionine. SAMe is the principal methylating agent in the human body — important for the synthesis of proteins & nucleic acids. Deficiency of SAMe results in membrane damage, which further worsens liver damage [ANNUAL REVIEW OF NUTRITION 20:395-430 (2000)]. SAMe provides a source of cysteine for GSH production. Ethanol also inhibits methionine synthase, blocking the methionine cycle thereby inhibiting the capacity for methylation.

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It is a common assumption that light drinking can stimulate thinking and that heavier drinking has only temporary harmful effects on brain function. Brain damage to alcoholics is attributed to malnutrition rather than to neurotoxicity of ethanol. These assumptions should be questioned.

Even a low dose (blood alcohol concentration 0.4%) of alcohol reduces response-time and increases performance error-rate. And moderate doses of ethanol induce "a significant deterioration of capacity to detect the activation of erroneous responses." [ScienceExpress Reports (1076929), 7-Nov-2002,]. Even blood alcohol levels of 0.1% markedly impair visuospatial skills (for driving, flying or operating machinery) associated with the right parietal region of the brain [AVIATION, SPACE AND ENVIRONMENTAL MEDICINE 65:7-15 (1994)].

A review of MRI studies indicated brain shrinkage and decreases in grey matter volume for any amount of drinking [HUMAN PSYCHOPHARMACOLOGY; Verbaten,MN; 24(3):199-205 (2009)]. The studies were likely cross-sectional rather than longitudinal, and gave no indication of not counting former alcoholics as abstainers, or of adjusting for health conditions that limit alcohol use — which makes this study all the more persuasive (although longitudinal studies and better adjustments would be preferred).

Prefrontal neuron activity in rats is decreased in a dose-dependent fashion by ethanol [JOURNAL OF NEUROSCIENCE; Tu,Y; 27(17):4765-4775 (2007)]. Tissue slices of neurons show reduced duration, amplitude, and spike activity with increasing ethanol concentration [JOURNAL OF NEUROSCIENCE; Tu,Y; 27(17):4765-4775 (2007)]. Ethanol is a vasodilator which has been shown to increase brain blood flow [AMERICAN JOURNAL OF PSYCHIATRY; Tiihonen,J; 151(10):1505-1508 (1994)], but ethanol impairs memory encoding [EXPERIMENTAL CLINICAL PSYCHOPHARMACOLOGY; Saults,JS; 15(6):576-587 (2007) and [NEUROIMAGE; Soderlund,H; 35(2):928-939 (2007)]. Chronic ethanol administration to rats induces lipofuscin deposition in neurons of the hippocampus comparable to changes seen in aging [NEUROBIOLOGY OF AGING; Borges,MM; 7(5):347-355 (1986)].

Animal experiments have demonstrated that bouts of binge drinking can produce necrotic neurodegeneration in the areas of the brain most closely associated with the hippocampus [ALCOHOLISM: CLINICAL & EXPERIMENTAL RESEARCH 26(4):547-557 (2002)]. A small study of young, non-alcoholic social drinkers indicated cognitive & neurological impairment (reduced event-related brain potentials when sober) among the heavy drinkers [JOURNAL OF STUDIES ON ALCOHOL 57:125-135 (1996)]. The fatty acid ethyl esters produced in the brain from ethanol are particularly damaging to the hippocampus [JOURNAL OF BIOLOGICAL CHEMISTRY 271(51):32519-32522 (1996)]. Even low to moderate consumption of alcohol was associated with brain atrophy in a study of middle-aged men [STROKE 35(1):16-21 (2004)].

By potentiation of GABA-mediated inhibition and blockage of glutamate release in the hippocampus, ethanol can significantly reduce spatial learning and memory by 30 minutes following administration, and the effect does not fully reverse until 24 hours in rats [BRAIN RESEARCH REVIEWS; Silvers,JM; 43:275-284 (2003)]. Ethanol also reversibly inhibits neurogenesis in the hippocampus in adults [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Herrera, DG; 100(13):7919-7924 (2003)], but may lead to permanent reduction of pyramidal hippocampal cells in a foetus subjected to binge-like alcohol bouts [HIPPOCAMPUS; Miki,T; 14:124-134 (2004)]. The hippocampus is also the area of the brain showing the greatest increase of lipofuscin deposition in neurons as a result of chronic alcohol consumption [NEUROBIOLOGY OF AGING; Borges, MM; 7:347-355 (1986)].

Light drinking increases social conversation and reduces inhibition among virtually all people who consume alcoholic beverages on social occasions. The effects are particularly dramatic for some people suffering from high anxiety. Light drinking can also increase violent aggression in some people. Yet the same doses of ethanol producing these seemingly stimulant effects usually reduce performance on complex tasks.

In the United States the legal definition of "intoxication" is based on Blood Alcohol Concentration (BAC) in grams of alcohol per deciliter of blood. Legal limits of BAC vary from state to state, typically between 0.08 and 0.10. A BAC of 0.10 usually results in slurred speech, 0.50 is associated with coma and 0.60 can lead to respiratory paralysis & death in adults. A BAC lower than 0.60 can kill children.

Ethanol exerts its primary effects through modulation of action of a number of brain neurotransmitters, notably subtypes of receptors for GABA & glutamate. Ethanol also alters the activity of the brain signaling chemicals serotonin, acetylcholine, dopamine, noradrenaline, endorphin, encephalin and neuropeptide Y. Ethanol also reversibly reduces sodium transport in neurotransmission [NATURE 200:476 (1963)].

As with caffeine, many of the effects of ethanol are through adenosine receptors. Ethanol may inhibit adenosine transport, interact directly with adenosine receptors and increase adenosine formation — the latter as a byproduct of ethanol metabolism [THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 259(1):403-408 (1991)]. Caffeine can offset the effects of alcohol when the levels of caffeine are high and the levels of alchohol are low. The reversal is best for the sleep-inducing effects of alcohol, but co-ordination & performance may not improve as much — leaving a "wide-awake drunk". Alcohol ingestion prior to bed reduces REM sleep — especially in the first half of the night — resulting in impaired memory for recently-learned procedural tasks [SLEEP; Smith,C; 26(2):185-191 (2003)].

GABA (Gamma-AminoButyric Acid) is the major inhibitory neurotransmitter in the brain. By increasing the inflow of chloride (Cl-) across neural membranes, GABA opposes the tendency of neurons to depolarize. Ethanol augments the influx of chlorine ions due to GABA, which has much to do with the sedative, tranquilizing and/or anaesthetic properties of beverage alcohol. Yet ethanol does not have this effect on all GABA receptors, only the GABA A subtypes (the GABA-benzodiazepine receptors) containing subunits that can be phosphorylated with Protein Kinase C (PKC) — an enzyme that normally provides negative feedback-inhibition for receptor stimulation. The motor incoordination due to ethanol is caused by potentiation of GABAA-associated adenosine A2A receptors in the striatum (caudate nucleus & putamen) [BRAIN RESEARCH 776:235-245 (1997)].

The second brain neurotransmitter receptor most strongly affected by ethanol is the NMDA (N-Methyl-D-Aspartate) receptor for glutamic acid (glutamate). Ethanol, especially in high doses associated with heavy drinking, is a potent inhibitor of the NMDA receptor. NMDA function in the hippocampus is associated with memory formation through a process known as LTP (Long-Term Potentiation). Ethanol produces a dose-dependent suppression of the magnitude of LTP [BRAIN RESEARCH 688:27-33 (1995)]. In high doses ethanol can block LTP almost entirely. LTP blockage is the likely explanation for the fact that after an evening of heavy drinking, 30-40% of males in their late teens or early twenties experience a blackout which eliminates all or part of their memory of what occurred while drinking.

Ethanol can increase release of arachidonic acid from cell membranes and (with increased cyclooxygenase activity) can cause oxidative stress in the brain. Hydroxyethyl free-radicals derived directly from ethanol are nearly as damaging as hydroxyl radicals and are more long-lived [FREE RADICAL BIOLOGY & MEDICINE 32(4):314-318 (2002)].

Serotonin induces slow-wave sleep, but serotonin activity is reduced during Rapid Eye Movement (REM) sleep. Ethanol potentiates serotonin activity, thereby suppressing REM sleep. Ethanol initially promotes sleep (even though suppressing REM sleep), but after several hours there will be more awakenings — an unsatisfying sleep experience.

Low doses of ethanol can enhance acetylcholine's muscarinic activation of the hippocampus (thereby opposing some of the NMDA blockage), but higher doses depress the acetylcholine effect. Ethanol increases dopamine release in the nucleus accumbens, a brain "pleasure center" similarly activated by cocaine. Ethanol also acts on voltage-gated calcium channels and adenosine receptors.

Pharmacological disruptions in brain signalling probably lead to erroneous thoughts & memories which accumulate and may be hard to remove — even if there is no permanent physiological damage. Such effects would be difficult to detect unless they were gross, in part because no individual person has a control subject.

Ethanol is known to produce both tolerance and dependence. Tolerance refers to the fact that an increasingly higher dose of the drug is required to produce the same effect. Dependence refers to the fact that withdrawal of the drug produces unpleasant physiological effects. Ethanol withdrawal symptoms include tremor, anxiety, aberrations in body temperature and potentially fatal convulsions.

Alcohol tolerance & dependence can be attributed to compensatory synaptic plasticity, particularly an adaptive increase in NMDA receptors. Hyperexcitablility of NMDA receptors is associated with the withdrawal convulsions and an increase in ischemic excitotoxicity [PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOR 59(4):981-991 (1998)]. There is evidence, however, that blockage of NMDA receptors by ethanol can reduce excitotoxic damage in head injury [JOURNAL OF NEUROSURGERY 86:876-882 (1997)].

Nutritional deficiency is certainly a factor in alcoholic brain damage. Alcohol amnesic disorder (Korsakoff's Disease) is usually associated to a deficiency of Vitamin B1 (Thiamine). Lesions are found in the thalamus and mammillary bodies as well as in the hippocampus.

But even without nutritional deficiency, chronic alcoholics show significant reduction of white matter and reduction of neuron density, particularly in the prefrontal cortex, the cerebellum and the amygdala [JOURNAL OF NEUROPATHY AND EXPERIMENTAL NEUROLOGY 57(2):101-110 (1998)]. Even without thiamine deficiency, nearly a fifth of the neurons in the frontal association cortex are lost in chronic alcohol consumption [NEUROSCIENCE 79(4):993-998 (1997)]. Reductions in cerebral blood flow & brain function (observed when not under the immediate influence of alcohol) have been demonstrated in heavy drinkers with no nutritional deficiencies and whose ethanol consumption was less than that typically seen in alcoholics [JOURNAL OF THE AMERICAN GERIATRIC SOCIETY 31:540-543 (1983)]. (The study corrected for the effects of age and smoking.)

Females are more sensitive to brain damage by ethanol than are males [ALCOHOL & ALCOHOLISM 25(5):445-448 (1990)]. Nonetheless, although 3-5% of males are alcoholics, no more than 1% of women are.

The unborn foetus is also highly sensitive to brain damage by ethanol — in the extreme cases leading to Fetal Alcohol Syndrome (FAS), a condition characterized by facial disfigurement, growth retardation and brain damage (particularly to the corpus callosum, basal ganglia and cerebellum). FAS infants show reduced overall brain size and reduced thickness of the cerebral cortex due to fewer cells [ALCOHOL HEALTH & RESEARCH WORLD 18(1):17-21 (1994)]. Although clinically obvious FAS only occurs in a small percentage of alcoholic mothers, pregnant women are well advised to abstain from drinking ethanol. Serotonin is a trophic factor for brain development — and serotonin is significantly decreased in a foetus exposed to ethanol [PHARMACOLOGICAL EFFECTS OF ETHANOL ON THE NERVOUS SYSTEM Deitrich & Erwin, Editors, 1996, page 351]. Experiments on neonatal rats indicate that the combination of aspirin & ethanol results in a greater reduction of brain weight than either aspirin or ethanol alone [NEUROTOXICOLOGY AND TERATOLOGY 11:135-143 (1989)]. (For photographs of the effects of FAS, see FAS and the BRAIN.)

Acetaldehyde in the brain & liver forms adducts (attachments) to DNA, thiamine (worstening Korsakoff's Disease), enzymes (inactivating them) and tubulin. By binding the lysine of tubulin protein, acetaldehyde prevents the polymerization necessary for microtubule formation. Microtubules in neurons are essential for transport of proteins, nutrients and organelles along the long axons [ALCOHOL & ALCOHOLISM 25(2/3):217-230 (1990)].

Binding of reduced glutathione (GSH) and/or cysteine by acetaldehyde causes inhibition of GSH synthesis and marked decreases in GSH after acute or chronic ethanol intoxication. But increases in free-radical production with ethanol is not simply due to reduction in GSH [ALCOHOL & ALCOHOLISM 20(2):161-173 (1985)]. Ethanol has been shown to increase lipid peroxidation by 21.8% in the brain, but higher increases are seen in the heart (28.8%), lung (35.9%) and testes (45.3%) [ALCOHOL & ALCOHOLISM 34(6):842-850 (1999)]. Isolated synaptosomes (presynaptic membrane-containing vesicles) subjected to ethanol show considerable oxidative damage [JOURNAL OF NEUROCHEMISTRY 63:1855-1862 (1994)].

Aside from arachidonic acid release due to ethanol, hydroxyethyl radicals derived directly from ethanol can be nearly as reactive as hydroxyl radicals — while having a longer half-life. Polyphenols in grapes oppose the oxidative stress due to ethanol [FREE RADICAL BIOLOGY & MEDICINE 32(4):314-318 (2002)] — a better justification for eating grapes than for drinking red wine.

The amino acid taurine can protect the brain from alcohol-induced oxidative damage, and can protect against alcohol impairment of DNA methylation.

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The cancer rate in alcoholics is ten times higher than that in the general population. Epidemiological studies find a much lower incidence of cancer among abstaining religious groups such as Mormons and Seventh-Day Adventists (though non-smoking and vegetarianism are certainly influences). (As stated above, a controlled randomized, double-blind, long-term longitudinal epidemiological study of ethanol will probably never be done.)

Every 10 grams (10 milliliters — just under "one drink") per day of ethanol consumption is associated with a 9% increase in breast cancer [EUROPEAN JOURNAL OF CANCER 36:1085-1088 (2000) and JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 279(7):535-540 (1998)] — up to 60 grams (ie, a 9% greater risk of breast cancer with 10 grams per day and a 54% greater risk with 60 grams per day). Users of post-menopausal hormones who drink more than 20 grams of alcohol per day have nearly twice the incidence of breast cancer as users who do not drink [ANNALS OF INTERNAL MEDICINE 137:798-804 (2002)]. An extremely large study of nearly 60,000 women found that both smokers and nonsmokers increased their risk of breast cancer by 7.1% for each additional 10 grams per day of ethanol, concluding that about 4% of breast cancer in developed countries can be attributed to alcohol [BRITISH JOURNAL OF CANCER 87(11):1234-1245 (2002)].

Four drinks (60 grams ethanol) per day is associated with a 21% increased risk of prostate cancer [EPIDEMIOLOGIC REVIEWS 23(1):110-114 (2001)]. Heavy drinking accounts for nearly 20% of all prostate cancers.

Both acute & chronic ethanol consumption increases serum estrogen and decreases serum androgen in both men & women. Many alcoholic men have irreversible atrophy of their testicles. Because excess estrogen & androgen is associated with increased cancer risk, the effect of ethanol on sex hormones explains the increase in breast cancer, but the increase in prostate cancer with ethanol must be due to another mechanism. Ethanol may contribute to osteoporosis at least partially through testosterone reduction [THE AMERICAN JOURNAL OF MEDICINE 86:282-288 (1989)].

Animal experiments indicate that ethanol itself does not cause cancer, but that acetaldehyde (the first metabolic product of ethanol) is toxic, mutagenic and carcinogenic (cancer-causing). Acetaldehyde interferes with DNA repair by DNA-repair enzyme blockage and by binding to DNA and proteins [ALCOHOL & ALCOHOLISM; Poschl,G; 39(3):155-165 (2004)]. Alcohol induction of CYP2E1 enzyme in the liver leads to production of many carcinogens. Nearly half of all cancers in the oral cavity, pharynx, larynx and esophagus have been attributed to alcohol [same reference].

The combination of ethanol & cigarette smoking seems to have a powerful synergistic effect in oral & pharyngeal cancer. Daily consumption of 20-39 cigarettes (for a period of over 20 years) and 2-4 drinks (30-60 milligrams ethanol) results in a relative risk (increased probability compared to control, ie, compared to abstainers) of 7.2 for those cancers. The relative risk rises to nearly 38 times the probability of these cancers in those who consume more than 30 cigarettes and 4 drinks daily. 75% of all oral/pharyngeal cancer cases are attributed to the smoking/drinking combination. Both alcohol & tobacco have been shown to reduce epithelial thickness by cell shrinkage on human tongues [CANCER RESEARCH 52(suppl):2119s-2123s (1992)].

Ethanol is known to reduce T-cells (Thymus-derived lymphocytes) — suppression of the immune system that can increase cancer incidence and decrease resistance to infectious diseases [IMMUNOPHARMACOLOGY 15:85-94 (1988)]. Ethanol may also suppress DNA methylation of oncogenes (cancer-inducing genes) leading to dedifferentiation & proliferation [GUT 51:132-139 (2002)].

Other mechanisms suggested for increased incidence of cancer with ethanol include effects on liver carcinogen metabolism, generation of free-radicals, depression of DNA-repair, reduced nutrients due to reduced absorption and reduced consumption of food nutrients associated with obtaining calories from alcohol.

Polyphenols & resveratrol (a phytochemical synthesized by grapes in response to fungal infections) are anti-cancer compounds found in high quantities in red wine — and to a lesser extent in peanuts, grape juice and cranberry juice [JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 50:431-435 (2002)]. But there is no need to drink red wine to get polyphenols — the polyphenols in green tea may well be more potent. Tablets of concentrated resveratrol can be purchased at health food stores or online from the Life Extension Foundation (LEF, — catalog number 13356).

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Both acute and chronic alchohol consumption can suppress the immune system, leading to increased susceptibility to infections. Decreased antigen-presenting cell function appears to be the most important factor in reduced cell-mediated immunity. Acute ethanol increases apoptosis ("cell suicide") of both thymocytes & blood mononucleocytes. Although the acute effect of ethanol is transcient, it can create a window of opportunity for serious infection by AIDS, hepatitis or other pathogens. Alcoholics show increased blood levels of inflammatory cytokines, elevated immunoglobulins and decreased activity of NK (Natural Killer) cells [ALCOHOL AND ALCOHOLISM 34(4):830-841 (1999)] (Alcohol & Alcoholism Online).

Ethanol stimulates excess levels of plasma cortisol, which can have harmful immunosuppressant and anabolic consequences. Some alcoholics develop hypercortisolism (pseudo-Cushing's syndrome) [ENDOCRINOLOGY 124(1):518-526 (1989)].

A general review entitled "Alcohol and energy intake" can be found in THE AMERICAN JOURNAL OF CLINICAL NUTRITION 62(suppl):1101S-1106S (1995). Despite the fact that alcohol does not reduce average food intake (evidently being a stimulant to the appetite), alcohol does not always lead to weight gain. Part of the reason is that alcohol drinkers reduce their consumption of food as a result of the calories they get from alcohol. But there is also a suppression of oxidation of fat. Alcohol damages energy-generating systems of mitochondria, while at the same time increasing metabolism. "Liver mitochondria from ethanol-fed rats had 55% fewer active ribosomes and 46% less initiation of protein synthesis."

The INTERNATIONAL JOURNAL OF OBESITY [19(Supplement 5):S44-S50 (1995)] contains a review of the "paradox of alcohol" which ends by speculating about the dehydrating effects of alcohol perhaps affecting weight — or an effect on insulin. The paper concludes that further studies are required to determine the paradoxical nature of alcohol calories. There is evidently much individual variation to the effects of alcohol. Alcohol appears to have no trend of making lean individuals obese, but causes obese individuals to become more obese. Ethanol contains 7.1 Calories (kilocalories) per gram and it decreases total body fat metabolism by nearly 80%.

Ethanol stimulates acid-rich gastric secretions, making alcohol consumption inadvisable for patients with peptic ulcers. Ethanol ingestion is inadvisable for epileptics taking phenytoin (Dilantin) due to interference with metabolic clearance. Ethanol also interferes with the metabolism of oral hypoglycemics (such as tolbutamide) taken by some diabetics. Asthma is worsened by alcoholic beverages for nearly a third of asthmatics. For Caucasians, this effect is usually due to the non-alcohol components ("congeners"), being more serious for wine (30%) than beer (23%) or whisky (16%) [CLINICAL AND EXPERIMENTAL ALLERGY 32:186-191 (2002)].

Aspirin & ethanol are not a good combination. Taken together they significantly worsen bleeding time (hemorrhagic stroke), gastric irritation and foetal brain damage.

The risk of spinal osteoporosis with vertebral fractures is significantly greater among men who drink alcoholic beverages than those who don't. The risk increases by a factor of 1.007 for each ounce per-day-for-a-year of cumulative ethanol exposure [THE AMERICAN JOURNAL OF MEDICINE 75:977-983 (1983)].

Small amounts of alcohol can increase (disinhibit?) the sex drive of men, while at the same time reducing their capacity to get an erection.

Ethanol has a reputation as an appetite stimulant. The claim is dubious, but if true this would count against it from the point of view of health & longevity (see Caloric Restriction with Adequate Nutrition).

One of the purported benefits of ethanol is for hypothermia — associated with the legend of a St. Bernard dog wearing a barrel of brandy on his neck coming to the rescue of a snow-stranded skier. But although ethanol causes a sensation of warmth through dilation of peripheral blood vessels, the loss of heat can be fatal. Large amounts of ethanol reduce body temperature by depressing the temperature-regulating mechanisms in the brain.

10-15% of alcoholics experience peripheral neuropathy, causing numbness & tingling.

Studies of all-cause mortality show a linear relationship between alcohol consumption and death below the age of 60 [ADDICTION 90(2):471-498 (1995)]. This relationship should not be surprising in light of the fact that accidents contribute to such a large proportion of deaths below the age of 60. Driving under the influence of alcohol is the most important cause of death in automobile accidents. In the United States between 1975-1995 33% of motor vehicle fatalities were due to intoxication (nearly half of the motor vehicle fatalities in the 25-29 age group were due to intoxication). For non-motor vehicle accidents, ethanol intoxication accounted for 32% of fatal falls, 42% of fatal fires/burns, 34% of fatal drownings and 29% of fatal poisonings. 32% of homicide victims and 23% of suicide victims were intoxicated [ANNALS OF EMERGENCY MEDICINE 33(6):659-701 (1999)].

Ethanol is implicated in up to half of all cases of marital violence.

Small doses of alcohol can reduce inhibition and allow personalities to become "expansive", while at the same time reducing manual dexterity and good judgement. A person under the influence of only one or two drinks may be less capable of dealing effectively with an unexpected life-threatening emergency situation.

Hangovers result from blockage of AntiDiuretic Hormone (ADH) by alcohol, which leads to high urination and subsequent dehydration. The most severe hangovers occur with alcoholic beverages which are high in methanol, such as brandy & red wine, whereas less severe hangovers occur for alcoholic beverages which are low in methanol, such as white wine, gin and vodka. The symptoms are throbbing head (due to reduced cranial blood pressure), dry mouth, lethargy, nausea and hypersensitivity to light & sound. Drinking large amounts of water before, during and after a binge can prevent & treat symptoms. Caffeine, aspirin and more alcohol can relieve hangover symptoms, although alcohol & caffeine worsen the dehydration because both are diuretics (increase urination). Aspirin before or during a binge can worsen matters because aspirin blocks alcohol dehydrogenase — elevating blood alcohol (while contributing to ulcers.

Medical authorities typically suggest total abstinence from ethanol for those who have uncontrolled high blood pressure, substantially elevated triglycerides, liver disease, gastrointestinal ulcers and alcoholic myopathy. Ethanol is also contraindicated for patients on many medications, including antihistamines such as diphenhydramine (Benadryl), tricyclic antidepressants such as amitriptyline (Elavil), and antianxiety drugs such as alprazolam (Xanax) and lorazepam (Ativan).

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Most of the so-called benefit of light alcohol consumption is inferred from the bogus lumping of ex-drinkers with lifetime teetotalers in epidemiological studies. Even for studies which are careful to separate ex-drinkers from other abstainers, it is questionable to attribute the reputed better health of light drinkers to alcohol because many abstainers have other health problems which preclude alcohol consumption — including asthma, epilepsy, gout, hypertension, ulcers and diabetes. Many people with health problems are disinclined to drink — or prohibited from drinking — alcoholic beverages.

When examining the multitude of studies showing that light drinkers are healthier than abstainers, ask how "abstainer" is defined (such as "patients who had allegedly abstained from all ethanol for a period of six months or more before the study" [THE AMERICAN JOURNAL OF MEDICINE 86:282-288 (1989)]). And even if ex-drinkers have been entirely excluded from the abstainers group, ask if other variables rather than ethanol might be critical. It is not hypocritical to learn from epidemiological studies that point to the harmful aspects of ethanol (such as the link between smoking & drinking and oral cancer) because the confounding proxy variables are not critical in such cases. But animal studies or studies of isolated cells, organs or even people subjected to ethanol under controlled conditions yield the most reliable information.

There is reason to believe that ethanol might have some benefit for coronary heart disease for those with low blood HDL cholesterol. But the benefit can usually be achieved more safely by other means of raising HDL cholesterol. Brain atrophy and damage to the hippocampus by ethanol in even the lowest doses should be alarming to rational persons. Ethanol (and/or acetaldehyde) is so damaging to so many body organs, organelles and molecules — most troublingly the brain — that grasping at one possible benefit while ignoring all of the harms sounds suspiciously like the rationalizations of an addict. Or the rationalizations of an entire addicted society. Whatever the reputed health benefits of ethanol, the health costs (known and unknown) are vastly greater. By my values, the possibility of brain damage makes any mild cardiovascular benefit pale by comparison — especially when there are so many other ways to improve cardiovascular health.

An editorial in the December 1997 issue of the JOURNAL OF THE ROYAL SOCIETY OF MEDICINE [JOURNAL OF THE ROYAL SOCIETY OF MEDICINE; Abdulla,S; 90:651 (1997)] concluded that because of the many obvious health hazards of alcohol (including temporary impairment of neurological function) and because of the availability of so many other cardiovascular drugs [ I would add niacin, DHA, weight loss and exercise ] and because "the benefits of alcohol are small and ill-understood" that the recommendation to be a light drinker is "not only meaningless but also irresponsible".

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IX. GENERAL BOOK REFERENCES (by publication date)
(references to scientific papers are incorporated in the text)