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Alcohol “hangover” or veisalgia (from the Norwegian kveis, "uneasiness following debauchery", and the Greek algia, "pain") seems to be the way our body bears to remind us about the harms of excessive alcohol consumption. Hangover is always associated to acute alcohol intoxication; it typically begins within 6 to 8 hours after alcohol consumption (approximately when the blood alcohol concentration decreases and returns to zero) and may last for up to 24 h. It is characterized by physical and mental effects with a variety of symptoms. The most common symptoms include: headache, nausea, attention problems, dry mouth, dizziness, gastrointestinal discomfort, fatigue, tremors, loss of appetite, sweating, drowsiness, anxiety, and irritability. However, the symptoms experienced and their intensity may vary from person to person and from occasion to occasion, which makes it impossible to exactly define hangover1.2.
There are several hypotheses to explain the onset and severity of a hangover. In addition to the amount of alcohol consumed, other factors related to the consumption itself (duration of consumption or type of beverage) can influence hangover onset. Psychological factors as well as vulnerability to alcohol dependence (such as genetic predisposition) also seem to be involved. For example, children of alcoholic parents (who are more vulnerable to alcoholism) showed more severe hangovers than children of non-alcoholics, in comparable conditions of frequency and amount of alcohol consumed3. The presence of some personality traits in individuals with a family history of alcoholism has also been related to hangover severity4. This situation could favor alcohol consumption, because in addition to their genetic vulnerability, these individuals could consume alcohol even more, in order to alleviate hangover symptoms. However, further studies are still necessary to establish the associations among genetic and psychosocial factors, alcohol effects and hangover.
The prevalence of hangovers in the general population is assumed to be very high. Studies show that 75% of the subjects who had consumed intoxicating doses of alcohol experienced hangover at least once in a lifetime. While 50% of frequent drinkers (one or two drinks per day5) experienced hangover in the previous year, 90% of students who were heavy episodic drinkers (defined by the study as the consumption of 5 or more doses on a single occasion) had suffered from hangover5. Overall, research suggests that hangover is a very prevalent phenomenon, but there are few epidemiologic studies to determine more accurately and, specifically, the actual prevalence of hangover in different populations.
THE ECONOMIC COSTS OF HANGOVER
Hangover is relatively a very frequent experience among people who consume alcohol, and it has been associated with a high economic cost. In this economic context; however, it is difficult to separate the hangover effects from the general alcohol effects. In workplace and academic areas, great economic loss is associated with the negative consequences of alcohol, such as absenteeism (absence from work), lower productivity or performance, increased work-related accidents and interpersonal conflicts.
A survey with 2,805 US employed adults showed that alcohol use at workplace and its consequencesdirectly affect 15% of the workforce. More specifically, this study estimated that, among workers, 9.23% work with a hangover, 1.68% work under the influence of alcohol, 1.83% drink before work, and 7.06% drink during the workday. Thus, the costs derived from workers that perform their activity while suffering from hangover would be greater than the costs derived from workers who drink during the workday, those working under the influence of alcohol, or those who drink before work6.
THE PHYSIOLOGY OF HANGOVER (Figure 1)
The physiology of hangover is intriguing because its symptoms manifest only after (almost) complete elimination of alcohol and its metabolites from the body, usually in the day after excessive alcohol consumption. There is a popular belief (not scientifically proven) that dehydration is the main cause of hangover symptoms. It is suggested that the hangover and dehydration are two independent processes that occur concurrently, through different mechanisms.
During hangover, there are significant physiological changes in endocrine parameters (increased vasopressin, aldosterone and renin concentrations), and metabolic acidosis (decreased pH due to increased blood lactate, ketone bodies and free fatty acids). These effects are also related to dehydration and may cause symptoms such as dry mouth and thirst. Since alcohol itself also induces dehydration, it is essential to rehydrate as much as possible during hangover (or during/after the non-excessive consumption of alcohol). The consumption of 50 g of alcohol in 250 ml of water (approximately 4 drinks) is estimated to induce the elimination of 600 to 1000 ml of water over several hours7: alcohol is diuretic (because it decreases the concentration of vasopressin, or antidiuretic hormone), and some of its effects, such as sweating, vomiting and diarrhea (common during hangover), promote even more water loss in the body.
There are many hypotheses that attempt to explain the physiology of hangover. However, they only partially explain some of the symptoms of hangover, or they explain how various factors influence hangover appearance and severity. The theories most widely accepted or discussed at present, according to Verster (2008)1, Stephens and colleagues (2008)8 and Pratt and colleagues (2009)2, are described below.
a) The hangover as a result of the direct effects of alcohol in different physiological systems
Several symptoms of hangover can be attributed to direct effects of alcohol on different physiological systems. However, the overlap between the physiological processes and the various symptoms of hangover difficult the elucidation of the mechanisms involved. For example, headache, which is one of the most common symptoms during hangover, can be explained by alcohol effects on vasodilatation, or on the increase of prostaglandins and cytokines. The alcohol effects, that are related to hangover and have been recently studied, rely on the increase of cytokines, changes in sleep and hypoglycemia.
Alcohol increases the concentrations of some pro-inflammatory cytokines, which would be responsible for the more "cognitive" effects in a hangover, such as memory loss and mood alterations8. Memory impairment in the hangover could be related to an activation of the immune system, which differentially communicates with the central nervous system (CNS). Cytokines effects are very similar to several hangover symptoms, such as headache, nausea, diarrhea and fatigue, suggesting that the underlying processes could be the same5. Other studies found a relationship between cytokines levels and memory disorders in humans9,10.
Alcohol-induced hypoglycemia can affect brain function, leading to weakness, fatigue and mood alteration, as observed during the hangover. However, it is important to mention that alcohol-induced hypoglycemia varies depending on the person's metabolism and also the circumstances in which alcohol is consumed (if someone eats before or during alcohol consumption, hypoglycemia induction is much lower)12.
Alcohol consumption can also cause sleep disturbances by interfering with both brain activity and levels of hormones that regulate sleep and the "biological rhythm”. Some of the hangover symptoms are significantly related to the duration and quality of sleep, and not only related to the amount of alcohol consumed. Some authors observed that shortly after the ingestion of high doses of alcohol, the latency of sleep onset decreases13. Nevertheless, as the blood alcohol concentration decreases - period when hangover symptoms appear, there are changes in the sleep pattern and loss in sleep quality. Thus, the alcohol effects on sleep could explain the fatigue and cognitive impairment observed during the hangover1,2.
b) The hangover as a consequence of the effects of congeners within alcoholic beverages
Alcoholic beverages contain several compounds chemically related to alcohol (congeners), which are produced during fermentation or added to the beverage during the production process, including methanol, amines, amides, ketones, polyphenols and other substances that confer flavor and color to the beverages. These congeners can exert different effects on the body, and their intoxicating effects potentially contribute to some of the hangover symptoms.
One of the most studied congeners is methanol, whose metabolism is correlated with the onset of hangover14, and it also causes various effects on the CNS. Alcoholic beverages with higher levels of methanol induce more toxic effects and hangover. In parallel, the consumption of alcoholic beverages with a high concentration of congeners (e.g., red wine, whisky, brandy and tequila) increases the frequency and intensity of hangover symptoms, compared to "clear" beverages, such as rum, gin and vodka, which usually contain few additives14.
c) The hangover as alcohol abstinence syndrome (alcohol withdrawal)
One theory is that hangover would be a first stage of alcohol withdrawal, based on the overlap of symptoms between alcohol hangover and withdrawal, such as headache, nausea, tremors and cognitive impairment. People usually drink more alcohol to relieve these symptoms, in both hangover and abstinence, but the use of alcohol as a “cure” for hangover does not permit the body to recover and alcohol continues to exert its effects.
Because the symptoms are similar, it was suggested that both processes may share a common biological pathway. However, several studies point out a number of differences between hangover and alcohol withdrawal: there are different hormonal and hemodynamical?? changes; the withdrawal usually occurs after multiple and continued consumption of large doses of alcohol for a long period of time, while hangover may occur after a single occasion of alcohol use; during hangover there is a decrease in brain activity, unlike the CNS hyper-excitability observed during alcohol withdrawal. Therefore, most researchers believe that hangover is a different phenomenon from the alcohol withdrawal.
d) The hangover as a result of acetaldehyde effects
Alcohol is metabolized by the enzyme alcohol dehydrogenase and transformed into acetaldehyde. At high concentrations, acetaldehyde can exert toxic effects (such as tachycardia, sweating, nausea and vomiting) and since these symptoms are also associated with hangover, some researchers have suggested that this metabolite may contribute to hangover. However, some studies show that acetaldehyde is not accumulated in such high concentrations in the body during hangover. Thus, the role of acetaldehyde in hangover is not well established yet.
Alcohol hangover is probably one of the most prevalent negative consequences of acute alcohol use that is experienced by the general population. Nonetheless, this phenomenon has not been fully elucidated, despite its high prevalence (especially among the young) and its derived economic costs. Scientific research is limited mainly by the lack of a validated instrument to measure hangover (due to the great variability and subjectivity of the symptoms involved). Furthermore, in humans, most of the studies reported so far have not been able to assess a representative sample; they have generally assessed less than 200 individuals. Other factors, such as the impact of gender, food and smoking, on hangover severity also deserve future attention. There are several aspects that need to be clarified in order to prevent and reduce the negative consequences of clinical, economic and social issues related to hangover.