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Starting as an Internet craze, and now on Comedy Central, the Ameri- can television show Drunk History features comedians trying to describe a historical event after drinking an immoderate amount of alcohol. Jen Kirk- man 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 luminar- ies 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 representa- tion 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 de- pendence 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. Evolu- tionary history tells us that our remote ancestors had to cope with alco- hol, 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.

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What happens when a person drinks too much alcohol? To help under- stand the phenomenon of drunkenness, let’s follow a wine- derived etha- nol 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 way- side, 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 bou- quet 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 etha- nol 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 some- thing 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 vari- ants in human populations are associated with an increased risk for alco- holism. 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 im- pacts 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 vol- ume, 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 esti- mated 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 im- portant, 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 nor- mally 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 etha- nol 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 diges- tive 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 pro- teins. 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 func- tioning. 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 in- testinal 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 mis- chief by causing the muscles of the intestinal walls to weaken and under- perform, allowing food to pass through more rapidly than usual. This ac- counts 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 nutri- ents 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, potas- sium, calcium, and phosphate. Abnormal concentrations of these electro- lytes 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 bac- teria 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 en- zyme called alcohol dehydrogenase, or ADH, which converts ethanol into acetaldehyde through oxidation (basically the reverse of the process of fermentation described in Chapter 5). 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

The cellular organization of the liver (the stellate and endothelial cells play other roles in liver metabolism)

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.

As hinted in Chapter 2, 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 func- tion in ethanol metabolism. Their new dual function results because reti- nol 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 acetalde- hyde. 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 pro- teins, 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 behav- ior. 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 sys- tem. 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 be- havior of nerve cells, glial cells, and the atoms, ions, and molecules that make them up and influence them.” Crick was saying, in essence, that glu- tamates 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 vari- ous 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 recep- tor 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 chlo- rine ions to collect on one side of the cell. This disrupts normal ion dis- tribution 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 mem-

ory); 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 chan- nel controlled by the receptor wide open. The open channel then stimu-