Hangovers – how to reduce the effects of a heavy night’s drinking

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Debaucherous evening last night? You’re probably dealing with veisalgia right now.

More commonly known as a hangover, this unpleasant phenomenon has been dogging humanity since our ancestors first happened upon fermentation.

Those nasty vertigo-inducing, cold sweat-promoting and vomit-producing sensations after a raucous night out are all part of your body’s attempt to protect itself from injury after you overindulge in alcoholic beverages.

Your liver is working to break down the alcohol you consumed so your kidneys can clear it out ASAP.

But in the process, your body’s inflammatory and metabolic reactions are going to lay you low with a hangover.

As long as people have suffered from hangovers, they’ve searched in vain for a cure. Revelers have access to a variety of compounds, products and devices that purport to ease the pain.

But there’s a lot of purporting and not a lot of proof. Most have not been backed up well by science in terms of usefulness for hangover treatment, and often their effects don’t seem like they’d match up with what scientists know about the biology of the hangover.

Working overtime to clear out the booze

Hangovers are virtually guaranteed when you drink too much. That amount varies from person to person based on genetic factors as well as whether there are other compounds that formed along with ethanol in the fermentation process.

Over the course of a night of heavy drinking, your blood alcohol level continues to rise.

Your body labors to break down the alcohol – consumed as ethanol in beer, wine or spirits – forming damaging oxygen free radicals and acetaldehyde, itself a harmful compound.

The longer ethanol and acetaldehyde stick around, the more damage they can do to your cellular membranes, proteins and DNA, so your body’s enzymes work quickly to metabolize acetaldehyde to a less toxic compound, acetate.

Over time, your ethanol levels drop through this natural metabolic process. Depending on how much you consumed, you’re likely to experience a hangover as the level of ethanol in your blood slowly returns to zero.

Your body is withdrawing from high levels of circulating alcohol, while at the same time trying to protect itself from the effects of alcohol.

Scientists have limited knowledge of the leading causes of the hangover. But they do know that the body’s responses include changes in hormone levels to reduce dehydration and cellular stress.

Alcohol consumption also affects a variety of neurotransmitter systems in the brain, including glutamate, dopamine and serotonin.

 Inflammation increases in the body’s tissues, and the healthy gut bacteria in your digestive system take a hit too, promoting leaky gut.

Altogether, the combination of all these reactions and protective mechanisms activated by your system gives rise to the experience of a hangover, which can last up to 48 hours.

Your misery likely has company

Drinking and socializing are cultural acts, and most hangovers do not happen in isolation. Human beings are social creatures, and there’s a high likelihood that at least one other individual feels the same as you the morning after the night before.

Each society has different rules regarding alcohol use, which can affect how people view alcohol consumption within those cultures.

Drinking is often valued for its relaxing effect and for promoting sociability. So it’s common to see alcohol provided at celebratory events, social gatherings and holiday parties.

In the United States, drinking alcohol is largely embraced by mainstream culture, which may even promote behaviors involving excessive drinking.

It should be no surprise that overindulgence goes hand in hand with these celebratory social events – and leads to hangover regrets a few hours later.

Your body’s reactions to high alcohol intake and the sobering-up period can influence mood, too. The combination of fatigue that you experience from sleep deprivation and hormonal stress reactions, in turn, affect your neurobiological responses and behavior.

As your body is attempting to repair itself, you’re more likely to be easily irritated, exhausted and want nothing more than to be left alone. Of course, your work productivity takes a dramatic hit the day after an evening of heavy drinking.

When all is said and done, you’re the cause of your own hangover pain, and you’re the one who must pay for all the fun of the night before. But in short order, you’ll forget how excruciating your last hangover was. And you may very soon talk yourself into doing the things you swore you’d never do again.

Speeding up recovery

While pharmacologists like us understand a bit about how hangovers work, we still lack a true remedy.

Countless articles describe a variety of foods, caffeine, ion replenishment, energy drinksherbal supplements including thyme and ginger, vitamins and the “hair of the dog” as ways to prevent and treat hangovers.

But the evidence isn’t really there that any of these work effectively. They’re just not scientifically validated or well reproduced.

For example, Kudzu root (Pueraria lobata), a popular choice for hangover remedies, has primarily been investigated for its effects in reducing alcohol-mediated stress and hangover.

But at the same time, Kudzu root appears to inhibit the enzymes that break down acetaldehyde – not good news since you want to clear that acetaldehyde from your system quickly.

To fill this knowledge gap, our lab is working with colleagues to see if we can find scientific evidence for or against potential hangover remedies. We’ve focused on the benefits of dihydromyricetin, a Chinese herbal medicine that is currently available and formulated as a dietary supplement for hangover reduction or prevention.

Dihydromyricetin appears to work its magic by enhancing alcohol metabolism and reducing its toxic byproduct, acetaldehyde.

From our findings in mice models, we are collecting data that support the usefulness of dihydromyricetin in increasing the expression and activity of enzymes responsible for ethanol and acetaldehyde metabolism in the liver, where ethanol is primarily broken down.

These findings explain one of the several ways dihydromyricetin protects the body against alcohol stress and hangover symptoms.

We are also studying how this enhancement of alcohol metabolism results in changes in alcohol drinking behaviors. Previously, dihydromyricetin was found to counteract the relaxation affect of drinking alcohol by interfering with particular neuroreceptors in the brain; rodents didn’t become as intoxicated and consequently reduced their ethanol intake.

Through this combination of mechanisms, we hope to illustrate how DHM might reduce the downsides of excessive drinking beyond the temporary hangover, and potentially reduce drinking behavior and damage associated with heavy alcohol consumption.

Of course, limiting alcohol intake and substituting water for many of those drinks during an evening out is probably the best method to avoid a painful hangover.

However, for those times when one alcoholic beverage leads to more than a few more, be sure to stay hydrated and catch up on rest. Your best bet for a smoother recovery is probably some combination of nonsteroidal anti-inflammatory drug like ibuprofen, Netflix and a little downtime.

Funding: Dr. Davies received a Donation from 82 Labs two years ago to conduct basic research on DHM that is mentioned in the article.

Joshua Silva and Terry David Church do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.


The alcohol hangover refers to the combination of mental and physical symptoms, experienced the day after a single episode of heavy drinking, starting when blood alcohol concentration (BAC) approaches zero [1].

The pathology underlying alcohol hangover is not well understood [2,3], and increasingly the subject of scientific investigation. In parallel, research has also been directed at the development of alcohol hangover treatments.

This has led to the study of compounds that can influence the immune response to heavy alcohol consumption (which is assumed to contribute to alcohol hangover). Several hangover treatments have been reported to attenuate the rise in blood cytokines concentrations seen after heavy drinking, as well as reducing selective next day hangover symptoms.

For example, Kim et al. [4] showed that Hovenia dulcis Thunb fruit extract (containing dihydromyricetin and heteropolysaccharides) significantly reduced blood cytokine concentrations that were increased due to heavy drinking.

This was accompanied by a significant reduction in overall hangover severity. Interestingly, Hovenia dulcis Thunb fruit extract had no effect on alcohol metabolism (i.e., blood ethanol and acetaldehyde concentrations were not different from the alcohol only condition).

A different approach is to develop compounds that accelerate alcohol metabolism. The rationale for this approach is that more rapid elimination of ethanol and acetaldehyde could reduce the presence and severity of alcohol hangover symptoms.

This hypothesis is supported by recent research showing that urine ethanol concentration was significantly lower in drinkers claiming to have no hangover after heavy alcohol consumption compared to drinkers who reported a hangover [5].

Although overall hangover severity was positively associated with the amount of ethanol found in urine of those who reported having a hangover, the partial correlation controlling for eBAC was not statistically significant. Nevertheless, this finding suggests that drinkers with slower alcohol metabolism, i.e., those with more ethanol in their urine, report significantly more frequent, and more severe hangovers. In other words, speeding up alcohol metabolism may have a beneficial effect on reducing hangover severity.

Another approach to the development of hangover treatments is to examine whether dietary nutrient intake has an effect on hangover severity. Two review papers have addressed this [6,7].

Firstly, Min et al. [6] argued that various minerals, including selenium, zinc, copper, vanadium, iron, and magnesium, may have a direct effect on either alcohol metabolism, on glutamatergic activity, or may influence the presence and severity of alcohol hangover via their antioxidant and/or anti-inflammatory properties.

Secondly, Wang et al. [7] described the proposed mechanism of action of a number of natural products that might alleviate alcohol hangover symptoms. Both authors stressed that their hypotheses were based on limited animal research, and that research in humans is necessary to investigate the actual efficacy of minerals and herbal supplements in reducing or preventing alcohol hangover symptoms.

The scientific literature indicates that food intake can indeed have a significant effect on alcohol metabolism, both quantitatively and qualitatively. For example, relative to fasting, the consumption of foods before or together with alcohol reduces peak blood alcohol concentration (BAC), decreases absorption and slows metabolism [8,9,10].

In particular, ‘high-energy’ meals may slow down alcohol metabolism and reduce subjective intoxication [11,12,13]. Specific food products or nutrients have also been investigated. However, mixed results have been reported in relation to alcohol metabolism. For example, Kim et al. [14] found that consuming a mixed fruit and vegetable juice (Angelica keiskei/green grape/pear juice) significantly reduced peak BAC.

In another study, Hong [15] examined the effect of a purported hangover treatment (DTS20, a mixture that consists of Viscum album L.Lycium chinense L.Inonotus obliquus, and Acanthopanax senticosus H.). The proposed active ingredients of DTS20 are sugar, uronic acid, and polyphenols. Relative to placebo, DTS20 significantly reduced BAC at 2 h after drinking alcohol in the form of Soju. The reduction in blood acetaldehyde levels, however, did not reach statistical significance. Taken together, there is limited evidence to date to support the notion that acute intake of specific nutrients can alter alcohol metabolism.

Thus, further research into nutrients that can accelerate alcohol metabolism is warranted. Research on the possible impact of regular nutrient intake on hangover susceptibility to hangovers or relating nutrient intake to hangover symptom severity is currently lacking.

Alcohol is metabolized primarily in the liver via a two-step reaction (see Figure 1) [16,17]. First, ethanol is oxidized into acetaldehyde, which is highly toxic. Although the first step in alcohol metabolism is reversible, acetaldehyde is usually metabolized rapidly.

In this second step, acetaldehyde enters the mitochondria where it is oxidized into acetate and water. This process is facilitated by mitochondrial aldehyde dehydrogenase (ALDH). For both steps, nicotinamide adenine dinucleotide (NAD+) is essential to provide the necessary energy for the conversion, which becomes available when NAD+ is converted into NADH + H+.

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Figure 1
Pathways involved in alcohol metabolism. In the major metabolic pathway (A) ethanol is oxidized into acetaldehyde. This oxidative process is facilitated by alcohol dehydrogenase (ADH), which is present in high concentration in the cytosol of hepatocytes. In this second step, acetaldehyde enters the mitochondria where it is oxidized into acetate and water. This process is facilitated by mitochondrial aldehyde dehydrogenase (ALDH). For both steps, nicotinamide adenine dinucleotide (NAD+) is essential to provide the necessary energy for the conversion, which becomes available when NAD+ is converted into NADH + H+. A second major pathway for alcohol breakdown, especially active in subjects who chronically drink alcohol, is the microsomal ethanol oxidizing system (MEOS, see (B)). The reaction is catalyzed by CYP2E1 and requires nicotinamide adenine dinucleotide phosphate (NADP+) instead of NAD+ to convert ethanol into acetaldehyde.

NADP+ can be formed from NAD+, and differs from NAD+ in the presence of an additional phosphate group [18]. The conversion of acetaldehyde into acetate and water is similar to that overserved in the major alcohol metabolism pathway and requires NAD+. A third minor pathway oxidizes ethanol into acetaldehyde via catalase (not shown in Figure 1) [17]. Together, the oxidative pathways account for over 90% of alcohol elimination [19]. Thus, ADH thus plays a vital role in alcohol metabolism.

Two nutrients are known to play an important role in alcohol metabolism, namely nicotinic acid and zinc [20,21]. Dietary intake of these micronutrients is necessary, as the body is unable to synthesize them itself [22,23]. Other nutrients do not seem to have an important direct influence on alcohol metabolism.

Zinc (Zn2+) is absorbed from the small intestine. Most zinc can be found in tissue, with only 0.1% of total bodily zinc present in blood, where most (~70%) is bound to serum albumin [24]. From here zinc is transported as needed to body tissues. Since zinc is essential in the conversion of ethanol into acetaldehyde [20,21], we hypothesize that drinkers who consume abundant amounts of dietary zinc metabolize alcohol faster than those who consume relatively lower levels.

Niacin and its equivalents are the main dietary source of NAD+. Tryptophan is also a source of NAD+, and its relative contribution is estimated as 60 mg of tryptophan equaling 1 mg of nicotinic acid and other niacin equivalents, although a 30% individual variability in the conversion from tryptophan into nicotinic acid has been observed [25]. For the MEOS alcohol metabolism pathway (see Figure 1), NADP+ is required. Nicotinic acid and its equivalents are the dietary sources of both NAD+ and NADP+, which together catalyze alcohol metabolism.

We hypothesize that when abundant amounts of nicotinic acid are present in the daily diet of a drinker, alcohol is metabolized faster than in drinkers who have lower levels of dietary nicotinic acid intake. To investigate the hypothesis that higher levels of dietary nicotinic acid and zinc may be protective against alcohol hangover of healthy social drinkers, dietary food intake was recorded during an experimental hangover study. Dietary nicotinic acid and zinc intake were computed and related to hangover severity.

Discussion

The current study demonstrated that dietary nicotinic acid and zinc intake were significantly and negatively associated with overall hangover severity. Both nutrients are essential in effective alcohol metabolism and, therefore, the current findings suggest that more rapid and efficient oxidation of ethanol into acetaldehyde, and acetaldehyde into acetate, may be associated with less severe hangovers. There was no similar association found for the other nutrients that were examined.

Sufficient dietary intake of zinc and nicotinic acid are important to maintain health. Examples of food rich in zinc are meat, shellfish (e.g., oysters), and legumes, such as lentils and beans. The recommended dietary allowance for zinc is 11 mg per day for men and 8 mg per day for women [39]. Deficiency of zinc can have serious health consequences and negatively impact immune defense [23]. Zinc deficiency is relatively more common among the elderly. For example, a US study found that only 42.5% of the elderly had an adequate level of dietary zinc intake [40].

Examples of food rich in nicotinic acid include those containing high levels of niacin or tryptophan such as meat, fish and poultry, avocado, peanuts, whole grains, and mushrooms. The recommended dietary allowance (RDA) for niacin and its equivalents is 16 mg per day for men and 14 mg per day for women [41,42].

Pellagra (pigmented skin rash) is a common consequence of severe niacin deficiency [43], and, although uncommon in the general population of Western countries, it is seen among chronic alcoholics [41]. In this context, niacin supplementation has been suggested as a treatment for alcoholism [44]. Our data suggest that this should be explored in more detail in different types of social drinkers, given the obvious relationship between frequent heavy drinking and hangover frequency.

The current finding may have implications for the development of effective hangover treatments. Although there is a buoyant market for so-called hangover treatment among social drinkers [45], currently they lack robust evidence of efficacy [46,47,48]. Several newly developed putative hangover treatments are comprised of natural ingredients, such as plant extracts, herbs, minerals and vitamins [48].

For example, studies were conducted to investigate the effects of, Korean pear juice [49] and red ginseng [50], which both showed some positive effects in reducing hangover severity. However, other products, such as artichoke extract [51], showed no beneficial effects on hangover. Kelly et al. [52] found that intravenous vitamin B complex and Vitamin C had no significant effect on alcohol metabolism. Kahn et al. [53] reported that pyritinol (1200 mg oral vitamin B6) significantly reduced the number of reported hangover symptoms, but unfortunately, no assessments were conducted with regard to the severity of hangover symptoms. Laas [54] conducted a double-blind placebo-controlled study to examine the efficacy of ‘Morning Fit’ (dried yeast, thiamine nitrate (Vitamin B1), pyridozine hydrochloride (Vitamin B6) and riboflavin (Vitamin B2) and found no significant differences in either blood alcohol or acetaldehyde concentrations between the Morning Fit and placebo condition.

Although significant improvements were reported for certain individual symptoms, namely ‘uncomfortable feelings’, ‘restlessness’, and ‘impatience’, no significant improvement was found on general wellbeing. A study conducted by Ylikahri et al. found no significant effect of sugars such as fructose and glucose on alcohol metabolism or hangover severity [55]. A more recent study by Bang et al. examined the effects on hangover of a polysaccharide-rich extract of Acanthopanax senticosus (PEA) [56].

While blood sample analysis revealed no significant effect on alcohol metabolism, PEA did, however, significantly reduce alcohol-induced next-day changes in glucose and c-reactive protein levels (i.e., it was effective in reducing alcohol-induced hypoglycemia and inhibiting the inflammatory response, respectively). Overall hangover severity, and the individual hangover symptoms, such as tiredness, headache, dizziness, stomachache and nausea, significantly improved after administering PEA.

Taken together, there is mixed evidence on acute effects of dietary nutrients on the presence and severity of hangover symptoms. The current findings are also in contrast to anecdotal evidence that suggests that taking fiber-rich food, consuming water, or eating fat-rich meals may reduce the severity of alcohol hangovers.

In the current study, dietary zinc and nicotinic acid intake (or any other nutrient that was assessed) did not significantly differ between hangover-sensitive drinkers and hangover-resistant drinkers. Thus, it is unlikely that supplementing diet with high levels of nicotinic acid and zinc makes a hangover sensitive drinker immune to hangovers. However, the data of hangover-sensitive drinkers clearly show that higher dietary intake of both nutrients is associated with experiencing less severe hangovers.

The issue of drinkers claiming hangover resistance is a complex one. Data show that this claim heavily depends on how much alcohol drinkers consume, but even at higher eBAC levels a small proportion of drinkers claim not to have hangovers [27,28]. At the same time, other hangover research showed no significant differences between the two groups of drinkers on several biomarkers such as urine ethyl glucuronide (EtG) and ethyl sulfate (EtS) [57] or methanol [58], saliva cytokine levels [59], sensitivity to acute alcohol effects [60], demographics [31], or psychological characteristics such as mental resilience [61]. Additionally, the current study could not differentiate hangover-sensitive and hangover-resistant drinkers based on their dietary nutrient intake.

Thus, there must be different unknown biopsychosocial factors (e.g., alexithymia) that may explain why some drinkers claim to be hangover-resistant. Research did show that experiencing alcohol hangovers (compared to claiming to be resistant) was associated with significantly poorer self-reported immune function [62] and having higher urine ethanol concentrations during the hangover state [5]. Future research should further investigate the puzzling phenomenon of hangover-resistance.

The study has several limitations. Firstly, it had a small sample size. Future research should, therefore, aim to replicate the current findings in larger samples. The use of bootstrapping techniques in hypothesis testing is increasingly popular [36] and was used in the current analysis to mitigate the small sample size.

Secondly, the sample size was too small to reliably assess possible gender differences. Explorative analysis revealed that men had a higher intake of dietary nicotinic acid and zinc. Moreover, women reported non-significantly higher hangover severity than men, and eBAC levels did not differ significantly. These findings are in line with a recent analysis showing that the presence and severity of hangover symptoms experienced at the same eBAC levels show no relevant sex differences [63].

However, studies have shown sex differences in cognitive functioning and driving performance the morning following bedtime administration of other psychoactive drugs, such as hypnotics [64]. Therefore, future replication research with larger sample size is required to further investigate possible sex differences during the hangover state in these domains. Thirdly, eBAC assessments were based on subjective retrospective recall of the number of alcoholic drinks consumed.

These reports may to some extent be inaccurate. In naturalistic study designs, researchers are not present during the drinking occasion, to ensure the real-life ‘natural’ drinking setting, and retrospective assessments of alcohol consumption are common practice. However, very recently real-time objective BAC assessment devices have been developed that are capable of continuously recording transdermal BAC. It would be useful to use such devices in future naturalistic studies.

Fourthly, there were many statistical comparisons made in the analysis. Although the primary aim was to investigate the association between dietary nicotinic acid and zinc intake with overall hangover severity, we also collected data on 25 other nutrients and 23 individual hangover symptoms. A strict Bonferroni’s correction (p < 0.002) was applied to account for this, and therefore we are confident with the reported statistical significance thresholds.

Dietary nutrient intake was collected via 24-h dietary recall records. These were completed by the subjects the day after drinking, and thus recall bias may have resulted in underestimation or overestimation of food portions, omitting food items or erroneously adding others. On the other hand, there was good correspondence between the diary measures across the two collection periods.

Furthermore, the group average nutrient intake in the current study corresponds well to large scale studies that assessed nutrient intake via elaborate food frequency questionnaires [41,42]. This provides some confidence that recall bias played a minor role in the current study. Clearly, future research should utilize more elaborate food frequency questionnaires, or nutrient-specific dietary records for nicotinic acid or zinc. Additionally, assessments of nutrient status in blood or urine would provide an objective measure of nutrient status.

It is relevant to note that dietary nutrients can impact alcohol metabolism via the gut and oral microbiome. Dietary nutrient intake, as well as alcohol consumption, have an influence on the composition of the microbiome. Several studies have reported the effects of alcohol consumption and dietary intake on microbiota composition [65,66].

The effect of these on hangover is not well understood, but a high abundance of several microbiota, including RothiaNeisseria, and Streptococcus, is associated with accelerated alcohol metabolism by producing relatively higher amounts of acetaldehyde [67].

Future research should investigate the relationship between the microbiome, and the presence and severity of alcohol hangover. Moreover, there are several other factors that may influence alcohol metabolism that were not assessed in the current study.

These include, for example, various genetic and environmental factors, sex, age, race, biological rhythms (time of day), and medicinal and recreational drug use (e.g., compounds which inhibit ADH such as pyrazoles or isobutyramine), Antabuse (disulfiram, which inhibits the elimination of acetaldehyde), or other alcohols that compete with ethanol for ADH (e.g., methanol) [17]. These are also important topics for future research.

Finally, the oxidative pathways account for over 90% of alcohol elimination [19]. In addition, there are also nonoxidative pathways for alcohol metabolism, producing metabolites such as ethyl-glucuronide (EtG), ethyl-sulfate (EtS), phosphatidyl-ethanol (PEth) and fatty acid ethyl ester (FAEE) [19].

As these pathways usually only process a very limited amount of alcohol, and thus the overall impact of nutrients on alcohol metabolism via these pathways can be considered as marginal, they were not taken into account in the current paper.


Source:
The Conversation
Media Contacts:
Daryl Davies, Joshua Silva and Terry David Church – The Conversation

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