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  1. 5-HT2A
    Good morning, sunshine! You are so screwed.

    The light coming in through the window is so … there. You’d kill for a glass of water but die if it came with food. Your guts are in full rebellion; whatever happens next is going to happen in the bathroom. You have at least a couple of the following symptoms: headache, malaise, diarrhea, loss of appetite, fatigue, nausea, the shakes. You might also be dehydrated and feel generally slow—a little stupider, a little less coordinated.

    You, my friend, have a hangover. And you can take heart in the fact that you’re not alone. Some 77 percent of all drinkers report suffering from them. (The scientific term for the other 23 percent is “jerks.”) But here’s the amazing part: The underlying cause of your suffering remains a mystery. “What causes a hangover? Nobody really knows,” says epidemiologist Jonathan Howland. “And what can you do about it? Nobody knows.”

    Alcohol has long been the only recreational drug for which scientists could not articulate a mechanism of action—which is to say, no one knew how it got you drunk, and no one knew how it got you hungover. And that’s weird. Because hangovers are a problem of vast proportions. By one estimate, hangovers cost $160 billion in lost revenue every year in the US alone. Yet for decades, even as scientists have written hundreds of thousands of articles about alcohol, only a tiny fraction of that attention—just a few hundred papers—have focused on the hangover. In fact, it wasn’t until the past decade or so that researchers even agreed to define hangover with a common group of symptoms.

    Now, though, that’s all beginning to change. In the past five or six years, a small group of researchers have dedicated themselves to the hangover, peering into both its causes and the truth behind all the purported cures. They’ve even made some progress on a few cures of their own. Thanks to science, the morning after is finally starting to look a little less bleak.

    In the mid-2000s, Howland, then a professor of community health services at the Boston University School of Public Health, partnered with Damaris Rohsenow, an alcohol and drug abuse researcher at Brown University, to look at how hangovers relate to the ability to perform a job. “We were interested not so much in hangover as a cluster of symptoms but in impairment the day after heavy drinking,” Howland says.

    It wasn’t until 2009, though, that a Dutch researcher named Joris Verster got the world’s hangover researchers together for an informal meeting. They dubbed themselves the Alcohol Hangover Research Group and adopted a whimsical logo: a red and white crest with a tipped-over wineglass in the foreground and a pint of beer in the background. (Look closely and you’ll see the beer glass is decorated with the AHRG logo in miniature—just the sort of infinite recursion that would, if you had a hangover, make you vomit.)

    Over the past five years, AHRG has put out research to reveal that pretty much everything anyone has ever told you about the causes of hangover is wrong—or at least unproven.

    Take dehydration. Sure, it makes sense: Alcohol suppresses the antidiuretic hormone vasopressin, which ordinarily keeps you from peeing too much. Plus, if you’re drinking booze, you’re probably not drinking water. But in dehydrated people with hangovers, levels of electrolytes don’t differ too much from baseline controls—and when they do, they don’t correlate with hangover severity.

    Over the past five years, researchers have revealed that pretty much everything anyone has ever told you about the causes of hangover is wrong.

    Some scientists have pointed to acetaldehyde, a demonstrably toxic byproduct of ethanol breakdown in the body. It’s a nice theory—but it turns out that hangover symptoms are at their worst when acetaldehyde levels are low.

    Low blood sugar is another common explanation, and it has some intuitive power behind it. Dehydration itself may not cause hangovers, but it does cause glucose levels to drop, and the body compensates by turning to other sources of energy, which can cause hangover-like symptoms. But if low blood sugar were the problem, administering glucose and fructose ought to be the solution. And it’s not—sugar doesn’t help the morning after. A more likely culprit is actually high blood sugar. Consuming ethanol with glucose turns out to elevate lactate levels, and one study shows that the presence of lactate makes hangovers worse. (So those warnings about sweet drinks might have something to them.)

    Despite the cloud of misinformation, the AHRG has been able to pin down some basics. Get your blood alcohol concentration above 0.10 percent and odds are you’ll be hungover the next day; symptoms will peak about 12 to 14 hours later, when your BAC is back at or near zero. There does also seem to be some truth to the notion that vodka delivers less of a hangover than red wine or whiskey. A comparison of people who drank enough bourbon or vodka to get to between 0.1 and 0.15 BAC—which is superdrunk, by the way—showed that all of them got hangovers, but the bourbon drinkers reported theirs as significantly worse.

    Best of all, AHRG’s researchers have begun to converge on a promising *theory about what really causes hangovers: namely, that they’re an inflammatory response, like what happens when we get an infection. A team in Korea noticed that hangovers are accompanied by elevated levels of molecules called cytokines, which are used as communication signals by the immune system. If you inject those into a healthy subject, that person will start to have all kinds of familiar-sounding symptoms, including nausea, gastrointestinal distress, headache, chills, and fatigue. Potentially even more interesting, higher-than-normal cytokine levels also interfere with memory formation—which might account for ethanol-*related lapses in recall as well.

    If it’s correct that cytokines are the key to hangovers, then that would suggest a simple and profound approach to treatment. That is, if the mechanism of hangover is an inflammatory response—as to a wound or illness—then maybe anti-*inflammatories are the way to dispel it. (I myself now take a couple of ibuprofen before bed after a long night.)

    Nobody really knows how booze works in the brain, but Richard Olsen, a neuro*scientist at UCLA who studies alcohol use, is pretty far along in figuring that out. He studies the range of blood alcohol concentrations you get from zero to a couple of drinks. In that range, he says, the neural mechanisms that respond to alcohol are very specific and present very interesting targets for treatment—of both drunkenness and hangover.

    Olsen thinks the key is a neurotransmitter, a molecule that neurons use to talk to each other. Specifically, he’s looking at one called gamma aminobutyric acid, or GABA. In particular, Olsen is looking at a subtype of the receptors that GABA sticks to, one that is exquisitely sensitive to ethanol. It is, Olsen says, “a unique ethanol receptor that responds to low concentrations of ethanol, as produced by one glass of wine, in the brain.”

    Now, GABA is an inhibitory neurotransmitter—i.e., it slows things down—so ethanol, in sparking these same receptors, would have a similar effect. That’s why at lower doses it mellows you out. If Olsen’s right, this could be the chemical mechanism that has eluded scientists until now. And he has some evidence: A drug that blocks those specific GABA receptors also blocks the effects of ethanol in rats. (Unfortunately that drug is in a family called the benzodiazepines—cousins of Valium—and taking it knocks you on your ass as surely as a stiff drink.) Another piece of favorable evidence: After repeated exposure to ethanol, neurons start to make a different kind of receptor, one that’s more resistant to the stuff. (This has its own downside—the new receptors are also less sensitive to GABA, which means all those neurons are more difficult to inhibit generally. Parts of the brain become overexcitable, leading to tremors, almost a pre*seizure condition, and symptoms that look a lot like a hangover.)

    Knowing that she was looking for a drug that would bind to that specific receptor—and nothing else—one of Olsen’s postdoctoral students, a researcher named Jing Liang, started experimenting with herbs from her native China, beginning with the ones that traditional medicine claimed had an effect on alcohol. And she found one. “Hovenia,” she says. “It’s been used in Asia for 500 years. I found it in a grocery store.”

    The lab purified the plant until Olsen and his team had an ingredient that acted on the right receptor. It turned out to be a flavonoid, a common molecular family. It already had a name—ampelopsin—but they started talking about it according to the naming conventions of organic chemistry: dihydromyricetin.

    “Jing gave a talk at a meeting about our results, and we invited our friends to the bar afterward to try it out,” Olsen says. “Now, this is not publishable, and you can’t use it for evidence for the FDA, but it’s good for us to know what kind of dose we should be using in our clinical trial—and that it doesn’t hurt anybody and does something to us that we want.”

    The people who took the pill all reported feeling less intoxicated than they would ordinarily, he says. And they felt less hungover the next day. (Scientific research conferences are famous for active bar scenes, but I assume that the ones at alcohol research meetings rage the hardest and result in the most guilt afterward.) One of Liang and Olsen’s funders now sells dihydromyricetin over the counter as BluCetin. It joins an elite club of hard-to-find substances—a prickly pear extract called Opuntia ficus indica, a vitamin B6 analog called pyritinol, and a migraine drug called Clotam—that have been reliably shown to help the symptoms of a hangover.

    Olsen’s line of research also suggests a more radical approach to eliminating the hangover. What if our cocktails used something other than alcohol to get us tipsy? Given the seemingly analogous chemical effects of alcohol and some synthetic drugs, it’s hypothetically possible to find a chemical with almost the same effects as alcohol but that’s better understood and better controlled. Alcohol researchers have been looking for something like this for decades, and now a British psychiatrist named David Nutt claims to have figured it out.

    For a couple of years, Nutt—who was one of the British government’s top drug policy advisers until he pointed out, quite rationally, that it made no sense to regulate pot heavily and booze barely at all—has been reporting experiments on chemical analogs to ethanol that deliver the same glorious buzz but with a crucial difference: There are antidotes that instantly restore sobriety. In a paper in 2006, Nutt showed how his very Star Trek-ish synthohol would work on a particular subtype of receptors for GABA, one not entirely understood. Like the receptor that Olsen was studying, Nutt’s receptors also handle benzo*diazepines, so they clearly have an impact on alertness.

    Now, Nutt says, he has no less than five candidate chemicals ready to go. “After exploring one possible compound, I was quite relaxed and sleepily inebriated for an hour or so,” Nutt wrote in a commentary for the Guardian in late 2013. “Then, within minutes of taking the antidote, I was up giving a lecture with no impairment whatsoever.” All he needs, he says, is funding for more tests. If Nutt is right, his discovery would shed light not just on how ethanol affects the brain but how the brain works more broadly. And existence of antidotes means that all you’ll need is a pill or a swig to avoid a hangover entirely. Remember to take it the night before and there will never again be a morning after. Or so we can hope.

    by Adam Rogers

    May 20, 2014



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