Let’s assume that you are going to celebrate the slow thaw of this incessant winter by drinking. Saint Patrick’s Day is imminent and if you, like me, have become a lightweight in your old age, then odds are you’ll wake up on March 18th with a crushing headache, waves of nausea, and the desire to keep the lights low and avoid all human contact. Despite the prevalence of hangovers in the general population (as many as 75% of individuals who have consumed intoxicating quantities of alcohol have experienced hangover symptoms), the science behind hangovers is still incompletely understood (1, 2). This stems from difficulty in establishing objective measures that define hangovers rather than relying on self-reported symptoms. As such, it is difficult to correlate the incidence of hangover with precise etiologies. Even more challenging is identifying a factor or factors that explain the severity of an individual hangover.
Popular knowledge attributes hangover symptoms to dehydration and low blood sugar; however, scientific research indicates these variables alone do not explain the presence and severity of hangovers. Alcohol does promote urine production and subsequent transient dehydration because most of us don’t drink extra water as we drink alcohol. Dehydration may then cause hangover headaches either due to hormonal changes (specifically in the anti-diuretic hormone, vasopressin) or due to electrolyte imbalance. Very early studies show that vasopressin, while decreased during alcohol intake, is actually increased during the hangover phase, indicating that alcohol intake is followed by a period of rehydration (3). However, suppressed vasopressin during alcohol intake does not significantly correlate with severity of hangover, suggesting this hormone is not solely responsible for hangovers. In regard to electrolyte imbalance, concentrations of serum and urine electrolytes such as sodium, calcium, chloride, and potassium during hangover have been examined in several studies (4, 5, 6). However, none found a significant correlation between change in serum electrolyte concentration and incidence or severity of hangover. It’s worth noting that these studies were only performed with male subjects and, in one case, the subjects were allowed to drink water freely while they consumed alcohol (4). Therefore, better-controlled studies including female subjects should be performed to confidently conclude that hangover is not due to dehydration-mediated electrolyte imbalance.
Alcohol also induces transient hypoglycemia, or low blood sugar, because in order for the liver to metabolize alcohol, it co-opts an essential substrate from the gluconeogenesis pathway (i.e. the pathway that generates glucose from fatty acids). However, this hypoglycemia is rarely significant in individuals with normal glycogen stores because the breakdown of glycogen can replenish low blood sugar (7). Therefore, while Buzzfeed may recommend water, sports drinks, and a balanced brunch of carbs and protein as hangover remedies, these may not target the source of the problem.
Instead, current scientific studies demonstrate that buildup of acetaldehyde/acetate and immune factors are significantly related to the presence and severity of hangovers (reviewed in 8). To elaborate, as the body metabolizes alcohol, the enzymes alcohol dehydrogenase (ADH), cytochrome P451 (CYP2E1), and catalase convert the alcohol into acetaldehyde. Acetaldehyde is then further metabolized by aldehyde dehydrogenase (ALDH) to acetate (9, 10). Acetaldehyde is highly reactive and can cause tissue damage, which can ultimately lead to symptoms like nausea, sweating and headache (11). In support of acetaldehyde's being the harbinger of hangover, individuals with inactive ALDH suffered from hangovers after fewer drinks (12). However, serum and urine acetaldehyde levels are low and change little after alcohol intake, while acetate increases dramatically in the circulation, even after minimal alcohol intake (13). Additionally, acetate alone at these concentrations can provoke headaches (14). Moreover, rats treated with acetate directly suffer from headache-like symptoms. In contrast, rats treated with ethanol and ALDH inhibitor, which prevents the buildup of acetate, demonstrate reduced headache symptoms (15). Therefore, both acetate and acetaldehyde buildup may significantly explain hangover symptoms.
Symptoms of headache and nausea also mimic symptoms of immune response, particularly those mediated by cytokines. In fact, treatment with a prostaglandin inhibitor can alleviate hangover symptoms, suggesting a role for the immune system in hangover occurrence (16). As concrete evidence, immune cells isolated from individuals during the hangover state produce more IL-12 and IFN-gamma, two inflammatory cytokines, than those isolated from non-drinking patients (17). Additionally, c-reactive protein, which is a marker of inflammation, increases by 50% during hangover but does not increase in patients with hangover who are treated with an anti-inflammatory (18). Notably, patients who were hung-over in this study were not dehydrated, supporting that dehydration is not a significant explanation for hangovers. Instead, hangovers are associated with inflammation after alcohol consumption.
So what can you do to relieve your probable hangover on March 18th? Everyone seems to have a hangover cure that they swear by, and mention of hangover remedies can be found as far back as Galen the Greek...who recommends you wrap your head in cabbage leaves (19).
The long and short of it is: there’s not much you can do, especially not the morning after. Research indicates that increased congeners, which are trace chemicals resultant from the distillation and fermentation process, contribute to hangovers. High-congener, darker liquors like bourbon and whiskey lead to more severe hangovers than do clear alcohols, like vodka, which lack congeners (20). So if you are going to drink and want to avoid a hangover, head for the vodka. In fact, if you really want to avoid a hangover, don’t drink at all. However, if you find yourself in bed the morning after drinking, reviling that seventh green beer, your best bet is to reach for the ibuprofen or aspirin. These NSAIDs will relieve headaches and inflammation associated with a hangover. Avoid Tylenol, however, whose acetaminophen can be toxic to the liver with repeated use. If a greasy breakfast of bacon and eggs appeals to you as well, then by all means, indulge. Scientific data just might not support your decision.
References
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