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Thursday, 17 March 2016

What causes hangovers?

What causes the dreaded hangover? The answer is simple, right? It’s alcohol. But how does alcohol cause hangovers? The answer is less straightforward.

Photograph of badge with writing Hangover On Board and the London Underground logo
Evidence of alcohol dates as far back as 10,000BC. We suspect hangovers do, too.
Image credit: Annie Mole, via Flickr (CC BY 2.0)

Some will say it’s dehydration, others will blame your electrolyte balance, or blood sugar levels, whilst insisting you ingest copious volumes of orange juice. But whilst orange juice might ease hangover symptoms, it doesn’t cure it. In fact, we don’t know of any reliable hangover cure at all - probably because even though the hangover predates the Egyptian pyramids[1], how it comes about remains a mystery.

A major reason for this massive void in our understanding is the fact that almost nobody seems to be researching it. It’s like we don’t care. Whilst the glut of folk remedies tells a different tale (we do care - we don’t want hangovers), some argue that hangovers are better left not understood so that we can’t cure them. Hangovers are an incentive to drink less, a natural mechanism that, if removed, could lead to widespread drunken barbarity with no comeuppance for the perpetrators. On the other hand, it’s important to point out that not all hangovers are equal. Some people don’t even get hangovers (23% - either because they never drink to excess or they’re just very lucky). We don’t know why this is either, but it does challenge the idea that removing hangovers would lead to epidemic alcoholism, or that experiencing a hangover is somehow “fair”.

And this isn’t all we don’t know about alcohol. We don’t know how alcohol causes mood swings, lowers inhibitions and reaction times, or makes us clumsy and bad at driving. We don’t know whether curing a hangover could lessen the damage caused by alcohol - combining making it easier to drink with making it safer - it’s certainly possible, but we can’t know until we know more about hangovers.

What DO we know about hangovers?


Hangovers differ from person to person, from time to time, and from drink to drink.

Symptoms also vary, but are unvaryingly nasty. Headaches, nausea and physiological symptoms like high blood pressure and rapid heart rate are typical. Like vampires, hangover victims are often thirsty, light-sensitive, and their muscles might feel like they have just crawled out of a crypt. They can also look pale but red about the eyes, shake or sweat all over, and wear the blank, confused expression of the recently undead.

Shockingly, this iconic group of horrible symptoms has only been recently recognised and scientifically named “veisalgia”.

Photograph of woman lying on a couch with a hangover
Headaches, nausea and light sensitivity are just some of the symptoms of hangovers, or veisalgia.
Photograph © Kristina Boneva via Flickr (CC BY-ND 2.0)

Whilst we are assured you can’t become a vampire by drinking too much, hangover victims do start feeling bad after they stop drinking - which is where the idea of hair of the dog comes from: hangovers go away if you drink again soon enough and never let your blood alcohol level start dropping off. It’s during this plummet that the nastiness typically begins, and researchers report that it starts 6-8 hours after a binge, or whenever blood alcohol concentration reaches zero, lasting for up to 24 hours after the fateful act[2].

Of the many symptoms brought about by boozing, nausea is definitely the easiest to isolate and explain. It isn’t even irreparably linked to hangovers - often, individuals start feeling sick from alcohol long before starting to feel hungover. And here’s why: alcohol irritates your stomach. This causes discomfort (gastritis) and sickness, and slows down the digestive system, leaving you something in there to throw back up.

What MIGHT Cause Hangovers?


Dehydration

Alcohol messes with your hormones, and one hormone you’ll notice in particular: the one that controls how often you wee. It’s well known that if you start on the beer, once you pop you can’t stop. This is because your vasopressin hormone has been suppressed, and you just don’t know how to hold it any more. Scientists calculate that if you drink 250ml of alcoholic beverages (half a pint) at 20% abv (this is roughly equivalent to a quarter pint of Vodka with an equal measure of non-alcoholic mixer, which we do not recommend), you’ll lose 600-1000 ml fluid over the next few hours[3].

Photograph of a green beer
We're not entirely sure what some pubs do to make beer green on St Patrick's day, but we're fairly certain it won't stop you getting a hangover. Image credit: SpaceAgeSage via Flickr (CC BY 2.0)

During the horrors of a hangover, sweating, vomiting and diarrhoea can cause further fluid loss and even put you at risk of hypovolemic shock - but a hangover is not hypovolemic shock. If it were, drinking lots of water would fix it. Hangover researcher Joris Vester even determines no link between extent of dehydration and hangovers[4].

Electrolyte Imbalance

One side effect of dehydration, or at least lower water content in the blood, should be a disturbance in electrolyte concentration - salts in the body. These are not only essential signal messengers, but also monitor the amount of water in healthy cells, helping them function normally. Long-term dietary deficiency in the essential vitamins and minerals that provide these electrolytes led to deaths of Captain Scott and his men in the Antarctic in 1912.

But this does not seem to be what is happening with hangovers: once again, Joris Verster and the Alcohol Hangover Research Group report that electrolyte levels are pretty much the same in hungover people to those who haven’t had a drink at all[4], leaving the reason orange juice and bananas seem to help hangovers as a mystery.

Other scientists think more complex salt stuff is going on, such as conversion of the enzyme NAD+ into NADH. Whilst this conversion is normal in the body and goes backwards and forwards, using up one and building up the other interferes with metabolic processes. Evidence is still needed to support or contradict theories about specific processes.

Blood Sugar Level

When alcoholics binge and forget to eat, they sometimes end up with hypoglycemia rather than blood poisoning. Low blood sugar levels are a symptom of dehydration, and causes the brain to stop working properly. Symptoms of hypoglycemia are mysteriously similar to those of a hangover, but although this theory holds water on the face of it, sugar does not appear to be the remedy either…

High blood sugar levels are equally dangerous, and lots of alcohol contains sugar. Sugar can also boost lactate levels in the body - a possible lead on understanding hangovers; although Wired magazine reported that the presence of lactate makes hangovers worse (who volunteered for that study?), a study of 109 volunteers found that both fructose and glucose “do not affect the symptoms or signs of alcohol intoxication and hangover” [5]. Alcohol also stimulates the release of the hormone adrenocorticotropic, which stimulates the release of the hormone cortisol, which monitors and blood sugar level by counterbalancing insulin. Too much cortisol and excess sugar doesn’t get properly removed by the body. This could lead to hyperglycemia.

Circadian rhythm

As if that wasn’t enough, cortisol also stops a natural stimulant called glutamine from being produced, making you feel relaxed and sleepy - the depressant effect of alcohol. However, once you stop drinking and your blood alcohol concentration drops off, the body compensates by making masses and masses of glutamine stimulant, basically setting up a glutamine production line, throwing your circadian rhythm totally off wack, making you stressed, and keeping you up at night. The result is feeling jet-lagged[6]. This might mean that the bad effects of alcohol are a result of over-excitation: in essence, it’s all in your head. Neurotransmitters are being suppressed that shouldn’t be, or overstimulated. Researchers even found that alcohol decreases the seizure threshold in animals a few hours later - increasing the chance that they will fit[7].

If this is indeed how we get hangovers, the solution may lie in other drugs that affect neurons in the brain. Scientists such as Richard Olson from UCLA are investigating GABA blocking - one molecule that may be involved in signalling[8].

However, alcohol can disrupt your circadian rhythm in other ways as well, and this solution could be far from complete. You may have heard people talking about putting their “beer jackets” on - but what does beer actually do to your body temperature? Alcohol makes your body temperature crazy cold when you’re drinking and crazy hot when you’re hungover, and suppresses the release of growth hormone at night that makes proteins and keeps your bones healthy.

Personality

Alongside the neurological processes in your head, there are cognitive processes as well. Some scientists have observed that physiological symptoms of over drinking (bad hangovers) are highest amongst people who feel the most guilt about drinking, suffer from more anxiety or anger, or have personality traits that make them more likely as well as those with a family history of bad hangovers. If true, this could mean that hangovers could be genetic, or even psychogenic - brought on by emotional distress or our own expectations.

Acetaldehyde

One suspect metabolite of alcohol is acetaldehyde, which is produced by the liver. In the metabolism of alcohol, there are two steps: alcohol dehydrogenase metabolises it to acetaldehyde; then aldehyde dehydrogenase breaks that down to acetate. Most of the time, this second step is much faster than the first step, so acetaldehyde does not build up in the body - and good job too, because it’s toxic - 10-30 times more so than alcohol is - binding to biologically important molecules like proteins, and inhibiting their functions. Some people, particularly those of Asian descent, metabolise acetaldehyde more slowly, leading to the most distinctive side effect, a reddening in the face nicknamed the “Asian glow”. Accumulate more, and the drinker can find themselves sweating, shaking and vomiting. Unfortunately for the hangover theories, as acetaldehyde concentrations drop off away after drinking, symptoms deteriorate, rather than peak.

Photograph of 22-year-old ALDH2 heterozygote before and after drinking alcohol
Facial flushing in a 22-year-old ALDH2 heterozygote before (left) and after (right) drinking alcohol. Brooks PJ et al. (2009) The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption. PLoS Med 6(3): e1000050. doi:10.1371/journal.pmed.1000050  (CC BY 2.5) via Wikipedia

Congeners

During fermentation or ageing processes in the manufacture of alcoholic drinks, congeners are produced: chemical impurities that influence taste, smell and appearance. Some may be biologically active. Darker spirits, or drinks such as red wine that have lots of chemical constituents - and so lots of congeners. Scientists think that the correlation between hangover severity and drink type may be explained by the presence of harmful congeners (which would mean drinking the ethanol itself presented no hangover risk)[9]. Methanol is a particular nasty congener that is lethal at volumes of 100ml, causing blindness, comas and death. Lower quality drinks are more likely to contain small quantities of methanol. Although possible, this explanation does not get us closer to explaining the how? - it only changes the what?

Immune response

Some scientists think that hangovers could be caused not by alcohol, but by you. That is, by your immune system kicking in to fight off the trespassing alcohol molecules - treating them as a disease. This is supported by experiments that find large numbers of cytokine molecules, or "immune system messengers", in the blood of hangover victims[10]. In another one of those really pleasant and fun-sounding studies, healthy people were injected with cytokine, and became sick with hangover-like symptoms. Interestingly, they also struggled with memory formation - not an unknown side effect after heavy drinking!

Cytokine stimulates the release of molecules that normally appear when there’s an inflammation. Injecting just one, “interleukin-10”, produced flu-like symptoms, which suggests these molecules could be directly responsible. If so, anti-inflammatories like ibuprofen or immunosuppressants to prevent the release of cytokine could simply be the hangover cure.

It may sound far-fetched, but scientists do agree that “feeling ill” is brought about by your immune system - not the viruses or bacteria that have infected you. By making you feel rotten, your body is telling you to sleep and stay in, maximising your chance of defeating the disease. This is why so many different illnesses have similar “unwell” symptoms - they don’t come from the disease; they come from you yourself.

Alternatives to alcohol

So why not just cut out alcohol altogether?

If alcohol were discovered today, it would almost certainly be made instantly illegal, but now it’s here it’s not going away (as the Americans proved). Or that’s what you think. Neuropharmacologist David Nutt thinks differently: his work on curing hangovers has taken a totally different track: substituting alcohol for something with the same positive effects, but none of the negative ones. More than curing hangovers, if these kinds of substitutes were made legal, 2.5 million deaths could be prevented every year - now that is a reason to care.

References
why don't all references have links?

[1] Charles H, Patrick; Durham, NC (1952). Alcohol, Culture, and Society. Duke University Press (reprint edition by AMS Press, New York, 1970). pp. 26–27. ISBN 9780404049065
[2] Swift, Robert, and Dena Davidson. Alcohol hangover. Alcohol Health Res World 22 (1998): 54-60.
[3] Montastruc, P. "L’alcool exagere la soif.(Alcohol exaggerates thirst)." HCEIA Informations 4 (1986): 41-42.
[4] Penning, Renske, et al. "The pathology of alcohol hangover." Current drug abuse reviews 3.2 (2010): 68-75. DOI: 10.2174/1874473711003020068
[5] Ylikahri, R. H., et al. "Effects of Fructose and Glucose on Ethanol‐Induced Metabolic Changes and on the Intensity of Alcohol Intoxication and Hangover." European journal of clinical investigation 6.1 (1976): 93-102. DOI: 10.1111/j.1365-2362.1976.tb00498.x
[6] Gauvin, David V., et al. "Cross-generalization of an EtOH “hangover” cue to endogenously and exogenously induced stimuli." Pharmacology Biochemistry and Behavior 57.1 (1997): 199-206. DOI: 10.1016/S0091-3057(96)00310-3
[7] Begleiter, Henri, Bernice Porjesz, and Consolacion Yerre-Grubstein. "Excitability cycle of somatosensory evoked potentials during experimental alcoholization and withdrawal." Psychopharmacology 37.1 (1974): 15-21. DOI: 10.1007/BF00426678
[8] Hanchar, H. Jacob, et al. "Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity." Nature neuroscience 8.3 (2005): 339-345. DOI: 10.1016/j.pharmthera.2006.05.004
[9] Chapman, Loring F. "Experimental induction of hangover." Quarterly Journal of Studies on Alcohol. Supplement (1970).
[10] Kim, Dai-Jin, et al. "Effects of alcohol hangover on cytokine production in healthy subjects." Alcohol 31.3 (2003): 167-170. DOI: 10.1016/j.alcohol.2003.09.003

This article was written by TWDK's chemistry editor Rowena Fletcher-Wood, who has a PhD in environmental materials chemistry from the University of Birmingham. Rowena can be found on twitter as @RowenaFW.