What Causes a Hangover?

Hangovers suck. Millions of people out there probably woke up this morning with one, overdoing it slightly last night. I was luckily spared and have only a slight headache this morning. I've realized how much alcohol I can drink without feeling like utter crap the next day, cause let's face it, is it really worth it? Anyways, this gives me an opportunity to describe what biochemical processes actually lead to the development of a hangover, because I believe there is a mass misconception out there that hangovers are caused by dehydration, when that is only a small part of the whole process. Yes, alcohol is a diuretic, but do you really pee that much more when you drink? Read on.
A hangover is a complex process, but if you took biochemistry and learned the basic metabolic pathways that are involved in glucose metabolism, you can easily see why they occur. Let's explain a few basics.
First, you must go back to high-school chemistry and re-visit the concept of redox reactions. Redox is short for reduction-oxidation. It is slightly more complex than stated here, but you can think of reduction as the addition of electrons to an atom or molecule, and oxidation as the removal of electrons from an atom or molecule. These reactions occur together such that there is a net balance of reduction and oxidation in terms of addition-subtraction of electrons. I will explain this concept shortly. Particularly in biochemistry, there exist reduction and oxidation substances which donate and accept electrons in organic (carbon-containing) molecules in basic metabolism of food substances (carbohydrates, proteins, fats, and alcohols). These substances can oxidize or reduce intermediates in metabolic pathways to facilitate movement and further metabolism of the organic substance for energy storage and utilization. When these agents oxidize an organic molecule, they are in turn reduced themselves by accepting electrons from that molecule (hence the balance is preserved). Conversely, when these agents reduce an organic molecule by donating electrons, they are in turn oxidized themselves.
There are 2 main redox agents in the human body, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). They are somewhat related to nucleotides chemically (DNA and RNA), and are synthesized from niacin, also known as nicotinic acid or Vitamin B3.
We will be dealing with NAD, since it is mainly involved in carbohydrate and alcohol metabolism (NADP is mainly involved in nucleotide and fat metabolism). When NAD is oxidized, we notate this as NAD+ (note that oxidation also refers to an increase in oxidation state of the molecule, the + sign indicating an oxidation state of +1). When NAD is reduced, we notate this as NADH. Therefore, NADH can donate electrons to an organic molecule, thereby reducing that molecule, and the NADH itself is thus oxidized to NAD+. The converse is also true.
Alcohol as contained within alcoholic beverages is ethanol (yes, the same exact substance which destroys so many lives is the same exact substance which may save the planet's energy crisis! As an organic molecule, it contains energy just like other foodstuffs!). The -ol denotes an alcohol group (-OH), and the ethan- just denotes the presence of a 2-carbon chain (i.e. methanol aka wood alcohol is an alcohol with a 1-carbon chain). The chemical structure of ethanol is as follows:

CH3CH2-OH

When you take in ethanol, it is metabolized in the liver as follows:

An enzyme known as alcohol dehydrogenase, in the presence of NAD+, oxidizes ethanol to a substance known as acet-aldehyde (aka ethanal) by removing the hydrogen (hence the enzyme is a de-hydrogen-ase) and converting the alcohol -OH group to a double-bonded aldehyde =O group. An aldehyde is a molecule which has a double-bounded oxygen on the carbon at the end of a chain (as opposed to a ketone which has a double-bonded oxygen somewhere in the middle of a chain).
NAD+, in turn, is reduced to NADH by accepting the hydrogen (and electrons) from ethanol, completing the redox reaction. This reaction can be notated simply as follows:

CH3CH2-OH + NAD+ + alcohol dehydrogenase <-> CH3CH2=O + NADH + alcohol dehydrogenase

Note that as an enzyme (i.e. a catalyst), alcohol dehydrogenase is not changed or consumed in any way, simply facilitating the reaction to occur much more quickly than it would occur spontaneously.

Acetaldehyde is toxic to the body, so the metabolization of ethanol continues in the liver. Acetaldehyde is further oxidized in the presence of NAD+ and another enzyme known as acetaldehyde dehydrogenase to form acetic acid (aka vinegar!), converting the aldehyde =O group to a carboxy acid group. Although I won't attempt to draw this reaction, it is analagous to the reaction above except the aldehyde is further oxidized to a carboxy acid.
Acetic acid can then easily be metabolized for energy in cells similar to other organic molecules such as carbohydrates, with the end result being CO2 (carbon dioxide), eliminated via respiration.
As you can see, the end result of the metabolization of ethanol in the liver is the harmless substance acetic acid, vinegar. However, as noted in the reactions above, the net result is also the reduction of TWO molecules of NAD+ to TWO molecules of NADH for every ONE molecule of ethanol that is metabolized. Continued metabolization of many ethanol molecules thus results in "tipping" the balance of NAD+ <-> NADH towards the reduced form as NADH. Thus, metabolization of an excessive amount of ethanol lead to an excess of NADH molecules within the body.
NAD+ <-> NADH is a delicate balance in the human body, since I previously stated that it is utilized in redox reactions involving metabolization of glucose, the main energy containing molecule in the body, and the preferred molecule to be metabolized by the brain.
Glucose is mainly metabolized an-aerobically through a process known as glycolysis (a word that simply means breakdown, or lysis of glucose). Glucose and subsequent products are successively oxidized repeatedly through various steps, resulting in a net generation NADH. This process generates some energy, but the end product of glycolysis, pyruvate, in the presence of a sufficient amount of oxygen, can further be metabolized aerobically in mitochondria via the Krebs' cycle to generate much more energy. Thus, glycolysis is an anaerobic process, no oxygen is utilized in this metabolic pathway.
This is partly why cells must switch from aerobic to anaerobic metabolism if you overwork yourself too much and you can't deliver enough oxygen to tissues to sustain the aerobic metabolism of glucose and other carbohydrates, and thus metabolism stops at the end of glycolysis in such cases.
The end product of glycolysis is a substance known as pyruvate. The chemical structure is as follows:












As stated, this substance usually enters the Krebs' cycle for aerobic metabolism, but if sufficient oxygen is not available (i.e. anaerobic exercise, sprinting, etc.), then it is further diverted to other substances, which we will see shortly!! The anaerobic metabolism of pyruvate to these other substances are different in different organisms. Where is this leading?
Well, the process comes FULL CIRCLE in yeast and various other organisms (yeast only extract energy through anaerobic glycolysis and have NO Krebs' cycle to metabolize glucose aerobically). Organisms such as yeast use glycolysis to metabolize glucose and other sugars to the end product of pyruvate too, but they have an "extra" step to extract the tiniest bit of more energy, a process known as FERMENTATION. They subsequently metabolize pyruvate into acetaldehyde and then into ethanol utilizing the same enzymes which our liver uses to reverse the process (ethanol -> acetaldehyde)! Yes, that is how your favorite alcoholic beverage is produced.....
Other organisms (such as animals and various bacteria) also have an "extra" step to further metabolize pyruvate anaerobically if sufficient oxygen is not available for pyruvate to enter the Krebs' cycle. Luckily, we don't act like yeast and convert pyruvate into ethanol (otherwise I would get smashed every time I ran the 100 meter dash LOL). Instead, in anaerobic conditions, we convert pyruvate into a substance known as lactic acid, the structure as follows:













Compare the structure of lactic acid to pyruvate above. Notice anything? The ketone =O group on pyruvate is reduced to an alcohol -OH group, forming lactic acid. HOW is this done? By our helpful redox agent, NAD. NADH reduces pyruvate to lactic acid, generating NAD+, in the presence of the enzyme lactate dehydrogenase (LDH).
What is the purpose of converting pyruvate to lactate or ethanol? Well, we are getting to the point, finally! Since pyruvate is reduced to lactic acid in humans, it helps to regenerate NAD+. If glycolysis simply stopped at pyruvate, NADH would build up quickly. Since there is a fine balance between red-ox agents (NADH <-> NAD+), if NADH builds up, NAD+ is depleted, and anaerobic glycolysis can't continue. NAD+ needs to be regenerated so that glycolysis can be continued in an anaerobic environment.
Lactate is subsequently shuttled from anaerobic environments such as skeletal muscle to the liver for metabolism back into glucose via a process known as gluconeogenesis. The gluconeogenetic pathway is not the exact reverse of glycolysis, however, the 1ST STEP involves oxidation of lactic acid back to pyruvate, which is the substrate the liver uses to begin gluconeogenesis. Just as the anaerobic fermentation process uses NADH to reduce pyruvate to lactic acid, the reverse happens in the liver, as NAD+ must be utilized to oxidize lactic acid back into pyruvate for entry into the gluconeogenetic pathway. This can't occur if there is an excess of NADH equivalents, and NAD+ is deplete. Therefore, an excess of NADH tends to favor conversion of pyruvate to lactate, whereas the liver needs to do the reverse in order to initiate gluconeogenesis. Thus, in summary, an excess of NADH impairs gluconeogenesis, and glucose can't be made by the liver.
And so we come back to ethanol metabolism, which we had previously stated also generates an excess of NADH molecules. Therefore, if you imbibe too much ethanol, an excess of reducing agent is produced in the form of NADH, and gluconeogenesis is impaired. This is the main effect producing the symptoms of hangover. As well, as previously stated, the intermediary step in ethanol metabolism, acetaldehyde, is also toxic to the body, and thus is further metabolized to vinegar. However, if an excess of ethanol is taken in faster than it can be metabolized through these pathways, acetaldehyde can also build up, further contributing to the unpleasantness of hangover. This notion is exploited in a particular treatment for alcoholics, a medication known as disulfiram (Antabuse). Disulfiram inhibits the enzyme acetaldehyde dehydrogenase, and thus acetaldehyde levels build up quickly when an alcoholic tries to drink, and they get sick. Sadly, it doesn't work too well.
It is therefore the excess of reducing equivalents in the form of NADH which contribute the most to the development of a hangover, through its inhibitory effect on gluconeogenesis. The biochemical processes involved are very much linked to metabolism of food through the glycolytic pathway, as seen in the creation of ethanol by anaerobic organisms, and our breakdown of this substance. So next time somebody tells you that "dehydration" causes a hangover, tell them that is only part of the story, and refer them to this article!