Hangover - Causes

Causes

Ethanol has a dehydrating effect by causing increased urine production (diuresis), which causes headaches, dry mouth, and lethargy. Dehydration also causes fluids in the brain to be less plentiful. This can be mitigated by drinking water before, during and after consumption of alcohol. Alcohol's effect on the stomach lining can account for nausea.

Another contributing factor is the presence of products from the breakdown of ethanol by liver enzymes. Ethanol is converted to acetaldehyde by the enzyme alcohol dehydrogenase, and then from acetaldehyde to acetic acid by the enzyme acetaldehyde dehydrogenase. Acetaldehyde (ethanal) is between 10 and 30 times more toxic than alcohol itself.

These two reactions also require the conversion of NAD+ to NADH. With an excess of NADH, three enzymes of the Citric Acid Cycle are inhibited (citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase) essentially shutting it down. Pyruvate (the end product of glycolysis) starts to accumulate, and the excess NADH drives lactate dehydrogenase to produce lactate from pyruvate in order to regenerate NAD+ and sustain life. This diverts pyruvate from other pathways such as gluconeogenesis, thereby impairing the ability of the liver to compensate for a drop in blood glucose levels, especially for the brain. Because glucose is the primary energy source of the brain, this lack of glucose (hypoglycemia) contributes to symptoms such as fatigue, weakness, mood disturbances, and decreased attention and concentration.

Alcohol consumption can result in depletion of the liver's supply of glutathione and other reductive detoxification agents, reducing its ability to effectively remove acetaldehyde and other toxins from the bloodstream. Additionally, alcohol induces the CYP2E1 enzyme, which itself can produce additional toxins and free radicals.

In addition, it is thought that the presence of other alcohols (fusel oils) and other by-products of alcoholic fermentation (also called congeners), exaggerate many of the symptoms; this probably accounts for the mitigation of the effects when distilled alcohol, particularly vodka, is consumed instead. A 2009 study provided evidence that darker-coloured liquors, such as bourbon, cause worse hangovers than lighter-coloured liquors, such as vodka. The higher amount of congeners found in darker liquors compared to lighter ones was indicated as the cause. Studies that attempt to compare hangover producing potential and hangover severity of different alcoholic drinks suggest the following ordering (starting with the least hangover-inducing): distilled ethanol diluted in fruit juice; beer; vodka; gin; white wine; whisky; rum; red wine; brandy. In a 2006 study, an average of 14 standard drinks (330 ml bottles) of beer was needed to produce a hangover, compared with only 7 to 8 drinks of wine or liquor. One potent congener is methanol. It is naturally formed in small quantities during fermentation and it can be accidentally concentrated by improper distillation techniques. Metabolism of methanol produces an extremely toxic compound, formaldehyde; however, its metabolism is suppressed when ethanol is present in the bloodstream. This is thought to provide a mechanism for hangover that starts when blood alcohol content approaches zero and can be "cured" by alcohol.

Most people of East Asian descent have a mutation in their alcohol dehydrogenase gene that makes this enzyme unusually effective at converting ethanol to acetaldehyde, and about half of such people also have a form of acetaldehyde dehydrogenase that is less effective at converting acetaldehyde to acetic acid. This combination causes them to suffer from alcohol flush reaction, in which acetaldehyde accumulates after drinking, leading to immediate and severe hangover symptoms. These people are therefore less likely to become alcoholics.

It is often said that hangovers grow worse as one ages; this is thought to be caused by declining supplies of alcohol dehydrogenase, the enzyme involved in metabolizing alcohol.

However, in a model of migraine, it was demonstrated that acetate is the primary metabolite of alcohol responsible for alcohol induced periorbital hypersensitivity. Furthermore, in the same model they recapitulated the effectiveness of caffeine, ketorolac for ameliorating this hypersensitivity. This model raises questions about the status quo hypothesis of hangover headache.