VOLUNTARY MADNESS - THE PHYSIOLOGICAL EFFECTS OF WINE

The American television show "Drunk History" features comedians trying to describe a historical event after drinking an immoderate amount of alcohol. Jen Kirkman was the first comic to appear on the series. After imbibing two bottles of wine, Kirkman, eyes rolling, face flushed, words garbled, gives a lecture on Frederick Douglass, employing such descriptions of Civil War luminaries as “Lincoln wasn’t a douchebag.” At one point she suddenly has to lie down to overcome a bout of dizziness, but then she continues, a new glass of wine in hand. In a slurred voice, she confuses Richard Dreyfus with Frederick Douglass, and President Lincoln with President Clinton. At the point in which she is describing Lincoln’s assassination, Kirkman turns to the camera and asks, “I didn’t take my pants off did I?” Apparently she has started to feel a chill in her extremities. She ends her recital with “Now my head is shutting to sleep” and “I have a mental illness.”

Jen Kirkman’s performance on "Drunk History" is a perfect representation of someone in the throes of what the Roman philosopher Seneca, two thousand years ago, delicately called voluntary madness. She shows the classic effects of alcohol on the brain: dilated pupils, slurred words, dizziness, loss of memory, altered physiology, drowsiness, and, above all, the shedding of inhibitions. How we get drunk has been the subject of much research, and scientific understanding of voluntary madness has increased. The recent attention to drunkenness is not purely because dependence on ethanol can be a social scourge. It is also because, as we hope to show, it is a complex physiological phenomenon. The human body has evolved to tolerate many chemicals and compounds that come into it as a result of breathing, eating, or drinking. The challenges alcohol makes to our bodies are ones that we as a species have faced for a long time. Evolutionary history tells us that our remote ancestors had to cope with alcohol, too, as evidenced by the existence of genes for alcohol tolerance in insects, worms, and other vertebrates. So it is not alcohol itself that is the problem: a little of it can actually be good for you. But overindulgence can be harmful, even deadly.

What happens when a person drinks too much alcohol? To help understand the phenomenon of drunkenness, let’s follow a wine-derived ethanol molecule as it passes through the body to the brain, and examine how this simple little drug impacts the physiological systems along the way. While following this path, many ethanol molecules will fall by the wayside, but the particular molecule we are concerned with will be one of the billions that will eventually make the subject drunk as they hit the brain.

As a glass of good wine nears the mouth, it will give off a bouquet and an aroma (most of us equate the two, but to a professional wine taster, aroma refers to the scents that come from the grapes themselves and bouquet to the scents that arise as a result of the process of aging) as some of the wine dissipates into the air as a weak vapor. Along with the molecules that give wine its wonderful bouquet and aroma, this vapor contains ethanol molecules and their byproducts. As we’ve seen, any of the molecules for which humans have receptors will register in the brain as a particular smell. Humans do not have an ethanol receptor in their olfactory system, but they do have receptors for a byproduct of ethanol called acetaldehyde—so purely by association, the acetaldehyde scent will elicit thoughts of ethanol.

The sensation continues as the wine passes the lips. Ethanol can bind both to a sweet-taste receptor on the tongue called T1r3, and to a bitter-taste receptor called hTAS2R16. Some ethanol molecules will be sucked up by these taste receptors and interact with them to tell the brain that something both sweet and bitter has been ingested. Mutated versions of the genes for both these receptors cause a tolerance for the taste of ethanol in mice (for T1r3) and in humans (hTAS2R16), and some hTAS2R16 variants in human populations are associated with an increased risk for alcoholism. Conversely, because some versions of hTAS2R16 taste bitterness more intensely because their proteins better bind ethanol, the signal these receptors send to the brain is stronger, often causing aversion. This bitter-taste receptor is an excellent example of how a tiny change in a receptor molecule can radically change behavior with respect to ethanol. But first impressions are not everything, and there are other reasons for drinking wine that involve deeper levels of pleasure than how it tastes.

As we follow the ethanol molecule, we need to bear in mind that it is one of billions in a bottle of wine, and how any one of these molecules impacts on the body depends entirely on where it finds a receptor—a matter entirely of chance. But as more ethanol is drunk, more of it will find its way to the organ systems it affects, and the effect of a bottle of wine far exceeds the effect of a glass. Another important variable is the blood volume of the drinker, because the ethanol from wine eventually crosses the membranes of the digestive tract and enters the blood. Indeed, blood-alcohol content has become the standard by which society measures—and judges—the amount of ethanol someone has in his or her body at any given time.

The math of blood-alcohol content is straightforward. A blood-alcohol content of 0.1 percent means that one-tenth of one percent of blood volume, or one part per thousand, is ethanol. This blood-alcohol content would mean that the person was pretty drunk. The blood alcohol sweet spot, the point at which a person becomes pleasantly tipsy, has been estimated at between 0.030 and 0.059 percent—a bit under the legal driving limit of 0.080 percent in the United States, and under or at the legal limit in most European countries. The amount of ethanol needed to reach a particular blood-alcohol content depends on body weight: heavier people have more blood. The time over which the ethanol is consumed is also important, because blood-ethanol concentration decreases as the ethanol is absorbed, released via the urinary tract, and broken down in the liver. For instance, bulky males would have to drink two glasses of wine in a half hour to exceed the U.S. legal limit, whereas a petite female would need to drink less than one glass of wine over the same time period. And, of course, the higher the blood-alcohol content, the more severe will be the impact of ethanol on the body.

Once past the palate, the ethanol molecule next hits a part of the throat called the pharynx, before sliding into the esophagus. Both these regions are lined with mucus that is packed with proteins and enzymes that normally begin the digestive process. But since ethanol is a molecule with which the machinery of digestion cannot deal, it remains unaffected by the digestive enzymes and passes by—though not without consequences, because it is actually toxic to some of the enzymes in the mucous layer of the esophagus. Besides altering the esophageal mucus, ethanol may also seep into the glands that produce saliva, occasionally in concentrations high enough to damage them.

The molecule has now reached the bottom of the esophagus, where it encounters the esophageal sphincter, the gateway to the stomach. If working properly, the sphincter will let food and drink into the stomach but not back out. Large amounts of ethanol, however, may cause the lower esophageal sphincter to become lazy, resulting in a backwash of some of the stomach contents into the esophagus. This is what is experienced as acid reflux, or heartburn. If it avoids setting off the backwash, the ethanol molecule will slide into the stomach, where it encounters a new set of cells, enzymes, and challenges.

Once in the stomach, the molecule finds itself in contact with digestive enzymes, especially the one known as pepsin. It also encounters the small molecule known as hydrochloric acid, which the stomach produces in abundance after the ingestion of food. As a small molecule, ethanol is relatively impervious to the digestive enzymes that target the larger proteins. But it can damage the stomach by overstimulating the production of digestive enzymes in low doses, and by shutting down their production in high ones. Any amount of ethanol, however, will disrupt normal functioning. Food in the stomach will help by sopping up ethanol molecules and keeping them from doing too much damage, and it will also absorb the ethanol and prevent it from entering the bloodstream.

After the ethanol passes through the stomach, it finds itself in the intestinal tract. From the small intestine, the molecules pass across the intestinal lining and are absorbed into the bloodstream. But in both the small and large intestines, the ethanol in wine can continue to make mischief by causing the muscles of the intestinal walls to weaken and under-perform, allowing food to pass through more rapidly than usual. This accounts for the diarrhea sometimes encountered after a drinking binge. At the risk of appearing indelicate, we might also mention that occasionally people report having green excreta after an evening spent drinking red wine. This apparent paradox is caused by the rapid passage through the weakened intestine of the green digestive enzyme known as bile.

Ethanol readily passes across the membranes of the small intestine and into the bloodstream, which transports it to other regions of the body. The molecule’s first stops around the bloodstream are in the organs that further break down ingested nutrients, notably the kidney and the liver. In the words of Murray Epstein, a specialist in kidneys and how they work: “A cell’s function depends not only on receiving a continuous supply of nutrients and eliminating metabolic waste products but also on the existence of stable physical and chemical conditions in the extracellular fluid bathing it.” And when ethanol is in the extracellular fluid that bathes the cells of the kidneys, some interesting things happen. The kidneys regulate the levels in the body of water and of several electrolytes such as sodium, potassium, calcium, and phosphate. Abnormal concentrations of these electrolytes can wreak havoc, and may eventually cause loss of kidney function and even death.

Ethanol is toxic to the release of the antidiuretic hormone vasopressin, and it also stimulates the kidneys to increase the amount of urine produced. When vasopressin is absent or inhibited, the intricate tubes in the kidney tend to release water, diluting the urine produced by the kidney. As a result, the electrolyte concentration in the bloodstream goes up, and the body senses dehydration. This is why it is a good idea to drink a lot of water when imbibing wine and other alcoholic beverages.

Now that the ethanol molecule has circumvented the actions of the kidney, it must pass through another major organ of the body. This is the liver, a massive organ (the largest in the body, weighing a little more than the brain) that filters the blood. The liver is a fibrous mass made up of sub-units called lobules, in which the filtering process occurs. There are more than fifty thousand lobules in a healthy liver, each of which has several veins running across it. Branching from these veins is a slew of smaller capillaries that form a canal-like system leading to a central vein through which the filtered blood exits. This system acts to increase the surface area of the lobule, and hence improves the chances for the blood to come into contact with the cells of the lobule. The canals are lined with cells of two kinds. The Kupfer cells are immune system cells that eliminate bacteria and other large toxic items, while the hepatocytes, the workhorses of the liver, do a broad array of jobs that include synthesizing cholesterol, storing vitamins and sugars, and processing fats.

The liver function of importance here, though, is the metabolism of ethanol arriving in the bloodstream. This process is dependent on an enzyme called alcohol dehydrogenase, or ADH, which converts ethanol into acetaldehyde through oxidation (basically the reverse of the process of fermentation). Acetaldehyde is extremely toxic to the body, so many organisms, including humans, have evolved the ability to rapidly break it down into useful acetate. The enzyme that undertakes this detoxification is called aldehyde dehydrogenase, or ALDH, and it is specified by two kinds of genes: ALDH1 and ALDH2. Acetate is valuable fuel for the body, so once the liver breaks down the ethanol-derived acetal-dehyde, it is transported to other organs for further processing.

ADH and ALDH did not evolve initially to aid in detoxifying the body of ethanol. Over evolutionary time, our ancestors were probably not ingesting much of this chemical. Instead, these two enzymes were originally important in the metabolism of vitamin A (also known as retinol), and seem to have been pirated away for their function in ethanol metabolism. Their new dual function results because retinol and ethanol molecules have similar shapes, and it is the shape of the molecule that ALDH enzymes recognize.

Liver cells metabolize ethanol in another way, using an enzyme called cytochrome P4502E1 (CYP2E1), which also oxidizes ethanol to acetaldehyde. The liver does not usually have many CYP2E1 enzymes, but when it is chronically bombarded with ethanol it tends to produce more of them. Excessive CYP2E1 has been associated with cirrhosis, the scourge of the liver, a condition that occurs when normal metabolic processes of proteins, carbohydrates, and so forth are disrupted by alcohol. Eventually the tissue of the liver begins to atrophy, and the hepatocytes start to die. This leaves the liver riddled with Mallory bodies (damaged filaments inside liver cells), one of the telltale signs of cirrhosis, a disease for which there is no cure.

Assume that our hardy ethanol molecule has avoided breakdown into acetaldehyde in the liver, and is still in the blood system. Eventually it will arrive at the brain, where it makes its major immediate impact on behavior. Ethanol traverses cell membranes fairly easily because it is relatively small, an attribute that helps it cross the “blood-brain barrier.” Once it gets to the brain, its main action is to interfere with the molecules, embedded in the membranes of neural cells, that are known as NMDA (N-methyl-D-aspartate) and GABA (gamma-aminobutyric acid) receptors.

The NMDA receptors are important in regions of the brain responsible for thinking, pleasure-seeking, and memory; like the sensory receptors for smell and taste, they bind to molecules that cause chain reactions in cells and thereby influence the transmission of information in the nervous system. The proper functioning of NMDA receptors is ensured by molecules known as glutamate receptor proteins, which interact with two kinds of small molecules: glutamate and glycine. Once these are bound to the right places in the NMDA receptor system, an ion channel opens. Proper brain activity depends on normal glutamate and glycine action.

In "The Astonishing Hypothesis", the distinguished biochemist Francis Crick remarked, “A person’s mental activities are entirely due to the behavior of nerve cells, glial cells, and the atoms, ions, and molecules that make them up and influence them.” Crick was saying, in essence, that glutamates and glycines are the currency of how humans think and behave. Those neurotransmitters are crucial to our nervous system, accepting and rejecting small molecules based on the needs of each neural cell. But various small molecules that are toxic to the nervous system have developed several ways to circumvent the neurotransmitters. One way is that of the “competitive antagonists,” which resemble the receptor proteins. But by far the most common method is that of the small molecules known as noncompetitive antagonists. These bind to other sites in the NMDA receptor proteins, changing their conformation so that the neurotransmitters don’t work. And uncompetitive antagonists, as small molecules that clog up the channels, confuse neural communication as well.

Ethanol is considered a noncompetitive antagonist, along with other molecules such as ibogaine (a controlled substance); methoxetamine, a so-called designer drug that currently is not controlled; and gases such as nitrous oxide (laughing gas) and xenon. But ethanol does not affect the brain simply as a noncompetitive antagonist. It additionally acts on the GABA receptors. When these are hyperstimulated by heightened ethanol levels in the brain, the ion channels they guard stay open, allowing chlorine ions to collect on one side of the cell. This disrupts normal ion distribution in the brain, and the neural cells stop communicating with one another. Whichever the mechanism, the end product of increased ethanol concentration is malfunctioning receptors and abnormal communication among the brain cells.

If the ethanol molecule is persistent enough, it might be transported to one of three particularly important areas of the brain where the NMDA receptors are in high concentration. These are the cortex (where much of our thinking occurs); the hippocampus (responsible for mediating memory); and the nucleus accumbens (from which reward-seeking behavior emanates). If the ethanol molecule binds to an NMDA receptor in any one of these regions of the brain, even though it is not near the glutamate or glycine binding sites, it will nonetheless change the shape of the protein, causing an alteration in the way glutamate binds that leaves the ion channel controlled by he receptor wide open. The open channel then stimulates that part of the brain, and a pleasurable sensation is felt.

The pleasurable feelings will continue even when the alcohol intake is excessive, but other side effects will develop. The high ethanol concentrations that reach the brain will desensitize the NMDA receptors, making them unresponsive to normal stimuli. Because the areas of the brain impacted in this way include both the thinking areas in the cortex and the pleasure areas in the nucleus accumbens, the higher functions will start to dwindle as more alcohol gets to the brain. Meanwhile, the ethanol molecules will also be affecting the other parts of the brain where GABA receptors reside. This happens as GABA receptors (and also some NMDA receptors) start to shut down in the hippocampus, a critical region for memory. After drinking two bottles of wine, Jen Kirkman’s brain was in no condition to formulate a coherent narrative about Frederick Douglass.

If the ethanol molecule has been unable to bind to a receptor in the cortex, it might travel on to the occipital lobe of the brain. This region processes visual stimuli from the outside world. Ethanol has a toxic effect on the metabolism of glucose, a sugar that is an important source of energy for cells. If ethanol hits the occipital lobe in high concentrations, it will slow down the processing of glucose by some 30 percent. This means there will not be enough energy available to process accurately the images coming in from the eyes. The cells will cease to communicate properly, and visual problems will begin. Although double vision is perhaps the most famous visual impairment that results from too much alcohol, it is only one of them.

People frequenting the Internet chat room called “I’m Drunk and the Room Is Spinning” often complain of precisely the effect its title describes. This phenomenon has a medical name: positional alcohol nystagmus. And it is a disconcerting effect of ethanol that occurs in the head, but not entirely in the brain. Movement in many parts of the body can be impaired by ethanol, and dizziness starts out in the inner ear, where the sixth sense, or balance system, resides. Acting rather like a gyroscope, the organs of the inner ear sense the position of the body through tiny structures called the semicircular canals, tiny fluid-filled tubes oriented in each of the three axes of space. Associated with each canal is a conglomerate of cells called the cupula. This deflects as the head moves, and stimulates cells with small hairs on them that are connected to a nerve that leads to the brain, where the information supplied by the stimulated cells is interpreted as the body’s position in space.

Any ethanol molecules that reach the ear via the bloodstream will bathe the cupula and distort its cells, placing them in continuous contact with the hair cells. The resulting stream of impulses makes it seem to the brain that the body is rotating. It accordingly tries to keep balance by making the visual systems spin a little, hence the sensation of the spinning head. When the drinker finally goes to sleep or—more likely at this point—passes out, the effect of ethanol on the cupula will eventually wear off. But sometimes the room still seems to spin when the drinker wakes up. Why? Well, one feature of waking up after heavy drinking is that the brain remembers what was experienced before the drinker fell asleep, and thinks the head is still turning. So it tries to correct by spinning the visual system in the opposite direction.

We have yet to explore two of the most unpleasant aspects of excessive wine consumption: hangovers and alcoholism. The first is a short-lived and for the most part endurable hazard, while the second is a debilitating and often tragic disease. Ethanol in large amounts creates a physiological conundrum, and one of nature’s less endearing reactions is the hangover. If only hangovers had a single cause, researchers might have found a way to circumvent or alleviate them, but they result from multiple causes, making them much harder to manage.

We have already discussed one aspect of a hangover—the sensation that the room is spinning. But excess ethanol can affect many parts of the body. For a start, the ethanol sucks up water, dehydrating the bodily systems and leading to a number of uncomfortable, dangerous, and occasionally deadly physiological outcomes that most commonly include dry mouth, nausea, and headache. Those who have experienced a hangover might find it hard to believe that brain tissues and cells do not themselves have pain receptors, but that is nonetheless the case. Headaches are thus aptly named, because the brain is not what hurts. It is the pain receptors of the head and neck that are impacted, and they present a diverse set of pain phenomena—over two hundred different kinds of headaches have been described.

One important cause of headaches is the dilation of blood vessels in the brain. In addition to dehydration, ethanol lowers glucose metabolism levels, and this exacerbates dilation. Blood vessels in this condition cannot properly transport blood around the brain, and altered blood flow manifests itself in pain, as neural receptors called nociceptors are stimulated and send information to the brain. The pounding headaches that result from drinking too much wine are due to the abnormal pressure that occurs in the dilated vessels with every pump of the heart. An equally unwelcome side effect of stimulating the nociceptor cells is nausea. Less extreme is the excessive sensitivity to sound and light that is typical of the “morning after the night before” syndrome. This happens as the depressing effect of ethanol on the brain cells wears off, and physical stimuli such as light and sound become amplified enough to overwhelm normal levels of perception.

We also have to remember that the effects of wines, most especially red wines, are not due only to the ethanol. Acetaldehyde, that problem byproduct of ethanol, is already present when the wine passes the lips, along with tannins and other chemicals in abundance from fermented seeds and stems. These too have an impact on headaches. In fact, some drinkers claim that hangovers are more severe from red wines than from whites precisely because of the extra chemical complexity of the wine, and particularly because of the impact the tannins have on human physiology.

So why do humans get drunk? In particular, why do they sometimes become addicted to alcohol? These questions have different answers, depending on whether they are considered as aspects of human physiology, mental states, free will, or, perhaps most important, genetics. As with any human behavioral disorder the genetic basis of alcoholism is complex, involving numerous genes and a strong environmental component. A person who is highly genetically predisposed to become dependent on ethanol might manage to avoid becoming an alcoholic because of social mores, behavioral modification, or some other cultural or social reason.

To understand why some succumb to alcoholism and others don’t, let us look at a few rather striking single genes that have been implicated in alcoholism. The human body does have some means of processing ethanol, especially within the liver. The two enzymes that are particularly important, ADH and ALDH, have been studied in depth, and it is clear that there is considerable variation among human populations in the genes that control them. People of Asian ancestry, for example, specifically those whose ancestors were already living in the Far East by tens of thousands of years ago, tend to have a particular variant of the ALDH2 gene called ALDH2.2. Close to 40 percent of Asians today have the variant, whereas it is rare in people with European or African ancestry. The ALDH2.2 gene produces a protein that is partly inactive, and fails to break down acetaldehyde. The toxic acetaldehyde thus collects in the tissues, an effect that is often initially visible in a flushing of the face but that later manifests itself in an array of uncomfortable physiological reactions. As a result, people with this ALDH variant tend to stay away from overindulgence in ethanol, and alcoholism has a generally lower prevalence among them.

But one group of people of ancient Asian ancestry is an exception to this finding. About seventeen thousand years ago, some intrepid people living in East Asia decided to travel east. They walked from Siberia to the Bering Strait, where a land bridge was exposed. Either walking or following the coast in boats, they crossed into the North American continent and moved down the Pacific coast, occupying most of North and South America within less than five thousand years. With them came their genes, and it might seem to be a safe bet that the ALDH2.2 gene would be found in high frequency among Native Americans. But studies have shown that the ALDH2.2 gene variant does not occur in these Native American populations.

A variant of the CYP2E1 enzyme has also been implicated in alcohol avoidance, and this enzyme is particularly active in the brain. People with the variant are much more susceptible to ethanol, become tipsy more easily, and tend to stop after fewer drinks. Hence they show a reduced tendency to alcoholism because they generally stop drinking before toxic ethanol levels are reached and before they become physically dependent. What is most intriguing here is the mechanism involved. Although CYP2E1 can work like ADH and ALDH by oxidizing acetaldehyde to acetate, it can also metabolize ethanol in a process that produces free radicals. Researchers who work with the CYP2E1 variant that enhances the impact of ethanol suggest that the free radicals are doing something in the brain that is very different from our classical understanding of what ADH and ALDH do.

The neurobiology of alcoholism—what is happening in the brain during addiction to ethanol—can help to explain the propensity to alcoholism that some people show. Key here is that human brains and those of other mammals and vertebrates have evolved in such a way that they seek pleasure. Pleasure reinforces some of the most basic things we do in life, such as eating, drinking, playing, performing good deeds, and having sex. If those activities were not pleasurable, we almost certainly wouldn’t do them as frequently as we do. Because pleasure is a crucial aspect of both individual survival and the success of the species, human bodies have evolved elaborate chemical methods to deliver stimuli for pleasure to the brain and to retain memories of that pleasure, so that people will seek more of it. Several parts of the brain and some complex neurochemistry are involved in those reward systems.

Three areas of the brain are particularly influenced by ethanol: the ventral tegmental area (VTA), the nucleus accumbens, and the frontal cortex. These also happen to be the three areas of the brain involved in the reward system. The technical name for the part of the reward system that is influenced by ethanol and other drugs is the mesolimbic dopamine system. This refers both to the group of brain structures that includes the VTA and the nucleus accumbens, and to the important neurotransmitter that is impacted by some drugs. Pleasure starts out as an impulse to the VTA, where dopamine is released. The dopamine then acts as a chemical messenger to activate the nucleus accumbens, which is implicated in motivation and reward-seeking. If there is a single “sweet spot” in the brain for pleasure, this is it. The more dopamine the nucleus accumbens receives, the more intense the pleasure will seem, and the more powerful the reward-seeking response will be.

Researchers have shown that neurons with GABA receptors extend into the reward pathway (the VTA and the nucleus accumbens). When ethanol bathes GABA receptors and causes them to malfunction, the impacted neurons in turn release dopamine and another neurotransmitter, endorphin. This latter is involved both in analgesia and in feelings of well-being; when lots of endorphins are present, the pain receptors become numbed. As the saying goes, we “feel no pain.”

Ethanol’s impact on the reward system differs a bit from that of other drugs. Cocaine and amphetamines make a good contrast. These compounds also affect the reward system via dopamine. But unlike ethanol, they alter the dopamine receptors directly: they are more direct in their intensity of addiction, and harder to break through. Equally devastating, every dopamine receptor in the brain is impacted by these drugs. Comparing the effects of different addictions is tough, but cocaine and amphetamine addictions are particularly nasty because the focus of these drugs on dopamine results in more intense addiction. Alcoholism, while also debilitating, falls into a different category because ethanol’s effects are not focused on a single receptor. Instead, while ethanol’s impact on dopamine receptors is localized to the nucleus accumbens and the reward system, it also impacts other receptors, such as GABA and NMDA, which are widely distributed throughout the brain. This is a significant difference, and one that makes alcoholism difficult to classify as equivalent to other addictions.

The genetics of alcoholism has been studied for decades, with procedures ranging from studies of twins to the more recently developed Genome Wide Association Studies (GWAS). Studies of twins use behavioral data from monozygotic (identical) and dizygotic (fraternal) twins to determine the degree to which a trait is heritable, while GWAS uses whole-genome sequence data to associate regions of the genome with a disorder. Because alcoholism is so complex, the results must often be interpreted with caution. But at this point it appears that genes are responsible for some 50 to 60 percent of the risk of developing alcoholism, which means that the environment has an almost equal impact. Furthermore, although several single gene variants are known to increase the risk of alcoholism, this is not the only thing that these genes control. Geneticists, genomicists, and behaviorists are in general agreement that alcoholism is a heterogeneous disease controlled by many genes, and that there is no one single kind of alcoholism. The alcoholism a researcher observes in an individual from Chicago might only slightly overlap in its genetic basis with the alcoholism seen in an individual from Detroit, or even from next door. Individual behaviors that might be involved in alcoholism include such things as impulsive and externalizing behaviors, relaxed inhibition, risk-seeking, and sensation-seeking, all of them also with complex genetic bases. The precise genetic basis for alcoholism remains largely a mystery.

Looking over what we have just written, we found it just as difficult to banish fleeting thoughts of taking the Pledge as to resist pouring a hasty glass of wine. Humans, as we’ve already remarked, tend to take good ideas to extremes, and as in all other realms of human experience, there is a calculation to be made. It is a good idea to moderate the intake of any alcoholic beverage, including wine, not only to avoid the short-term repercussions of over-imbibing, but also to avoid long-term addiction to alcohol. Yet, as we celebrate throughout this book, wine has since the earliest times played a special role in human life, both as an emblem of civilization and as an enhancement of our experience of the world. There is, quite simply, nothing to replace it. We can offer no alternative to the standard exhortation: drink, responsibly.

By Ian Tattersall & Rob Desalle in "A Natural History of Wine", Yale University Press, USA,2015, excerpts pp. 364-397. Adapted and illustrated to be posted by Leopoldo Costa.